Jen Smith

Youn Kim, MD
Photo by Larry Young

SAN FRANCISCO—The phase 3 ALCANZA trial is the first to convincingly demonstrate that a new systemic agent can be more effective than standard of care (SOC) options for cutaneous T-cell lymphoma (CTCL), according to a speaker at the 9th Annual T-cell Lymphoma Forum.

The trial showed significant improvements in response, symptom burden, and progression-free survival (PFS) in patients with CD30-expressing CTCL who received brentuximab vedotin (BV), as compared to patients who received either bexarotene or methotrexate.

“[These are] compelling results that potentially may have practice-changing implications for the use of brentuximab in managing CD30-expressing CTCL patients who require systemic therapy,” said Youn H. Kim, MD, of Stanford University School of Medicine in California.

Dr Kim presented these results at this year’s T-cell Lymphoma Forum. The data were also presented at the recent ASH Annual Meeting (abstract 182).

The ALCANZA trial was sponsored by Millennium Pharmaceuticals, Inc. (now a part of Takeda Pharmaceutical Company Limited) and Seattle Genetics, Inc.

The study was designed to compare BV to the SOC options of methotrexate or bexarotene in patients with CD30-positive CTCL, including mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL).

There were 128 patients in the intent-to-treat and safety populations. Sixty-four patients (48 with MF and 16 with pcALCL) were randomized to receive BV at 1.8 mg/kg IV every 3 weeks for up to 48 weeks.

The other 64 patients (49 with MF and 15 with pcALCL) were randomized to receive methotrexate at 5 mg to 50 mg PO weekly or bexarotene at a target dose of 300 mg/m² PO daily for up to 48 weeks.

Patients received BV for a median of 36 weeks (12 cycles), bexarotene for a median of 17 weeks, and methotrexate for a median of 9 weeks. Three patients in the BV arm were still on treatment at the time of analysis.

Patient characteristics

The median age was 62 (range, 22-83) in the BV am and 59 (range, 22-83) in the SOC arm. More than half of patients in each arm were male—52% and 58%, respectively. And most patients in both arms had an ECOG performance status of 0-1—95% and 97%, respectively.

The median number of prior therapies was 4 (range, 0-13) in the BV arm and 3.5 (range, 1-15) in the SOC arm. The median number of systemic therapies was 2 in the BV arm (range, 0-11) and the SOC arm (range, 1-8).

“It was pretty well balanced in terms of baseline characteristics between the 2 arms,” Dr Kim said. “The brentuximab arm had more stage IV patients—in fact, 7 stage IVB in brentuximab and none in the standard of care. And more patients with ALCL [treated with BV] had extracutaneous disease.”

Among pcALCL patients, 44% in the BV arm had extracutaneous disease, compared to 27% in the SOC arm. Among MF patients, 67% in the BV arm had stage IIB-IVB disease, compared to 61% in the SOC arm.
 
Response

The study’s primary endpoint was the rate of objective response lasting at least 4 months (ORR4).

“[ORR4] was felt to be more meaningful than ORR because it includes not only the response rate but also a duration element in a single endpoint,” Dr Kim said.

ORR4 was significantly higher with BV than with SOC—56.3% and 12.5%, respectively (P<0.0001).

For patients with MF, the ORR4 was 50% with BV and 10% with SOC. For patients with pcALCL, the ORR4 was 75% with BV and 20% with SOC.

Overall, the complete response (CR) rates were 15.6% in the BV arm and 1.6% in the SOC arm (P=0.0046).

For patients with MF, the CR rate was 10% with BV and 0% with SOC. For patients with pcALCL, the CR rate was 31% with BV and 7% with SOC.

Symptoms

“In CTCL, there’s significant quality of life issues that are not captured adequately by objective response measures, and this patient outcome is very important,” Dr Kim said. “[Quality of life in this study] was captured by Skindex-29, which is an established quality of life measure in skin diseases.”

Patients in the BV arm had a significantly higher reduction in symptom burden according to Skindex-29 than patients receiving SOC. The mean maximum reduction in Skindex-29 symptom domain was -27.96 points in the BV arm and -8.62 points in the SOC arm (P<0.0001).

PFS

PFS was significantly longer in the BV arm than the SOC arm. The median PFS was 16.7 months and 3.5 months, respectively. The hazard ratio was 0.270 (P<0.0001).

For patients with MF, the median PFS was 15.9 months with BV and 3.5 months with SOC. For patients with pcALCL, the median PFS was 27.5 months with BV and 5.3 months with SOC.

Safety

The overall rate of adverse events (AEs) was 95% in the BV arm and 90% in the SOC arm.  The rate of grade 3 or higher AEs was 41% and 47%, respectively. And the rate of serious AEs was 29% in both arms.

AEs resulting in discontinuation occurred in 24% of patients in the BV arm and 8% in the SOC arm. In the BV arm, this included peripheral neuropathy (n=9), skin-related hypersensitivity (n=3), E coli infection (n=1), impetigo (n=1), pulmonary embolism (n=1), urticaria (n=1), and vertigo (n=1).

In the SOC arm, AEs leading to discontinuation included maculo-papular rash (n=1), asthenia (n=1), hematuria (n=1), hypernatremia (n=1), neutropenia (n=1), periorbital infection (n=1), and somnolence (n=1). One patient in each arm experienced more than 1 AE resulting in discontinuation.

The most common AEs of any grade (occurring in 15% or more of patients in the BV and SOC arms, respectively) were peripheral neuropathy (67% and 6%), nausea (36% and 13%), diarrhea (29% and 6%), fatigue (29% and 27%), vomiting (17% and 5%), alopecia (15% and 3%), pruritus (17% and 13%), pyrexia (17% and 18%), decreased appetite (15% and 5%), and hypertriglyceridemia (2% and 18%).

The majority of the peripheral neuropathy events in the BV arm were grade 1 or 2—26% and 32%, respectively. The rate of grade 3 peripheral neuropathy events was 9%, and there were no grade 4 events.

Eighty-two percent of patients reported resolution or improvement in peripheral neuropathy events in the BV arm at a median of 22.9 months of follow-up.

There were no on-study deaths (occurring within 30 days of the last dose) in the SOC arm, but there were 4 in the BV arm. Three of the BV deaths were considered unrelated to the drug.

The 1 BV-related death was a result of multiple organ dysfunction syndrome attributed to tumor necrosis at visceral disease sites in a patient with T3bN0M1 pcALCL. The other 3 deaths were due to lymphoma progression, pulmonary embolism, and sepsis.

Youn Kim, MD
Photo by Larry Young

SAN FRANCISCO—The phase 3 ALCANZA trial is the first to convincingly demonstrate that a new systemic agent can be more effective than standard of care (SOC) options for cutaneous T-cell lymphoma (CTCL), according to a speaker at the 9th Annual T-cell Lymphoma Forum.

The trial showed significant improvements in response, symptom burden, and progression-free survival (PFS) in patients with CD30-expressing CTCL who received brentuximab vedotin (BV), as compared to patients who received either bexarotene or methotrexate.

“[These are] compelling results that potentially may have practice-changing implications for the use of brentuximab in managing CD30-expressing CTCL patients who require systemic therapy,” said Youn H. Kim, MD, of Stanford University School of Medicine in California.

Dr Kim presented these results at this year’s T-cell Lymphoma Forum. The data were also presented at the recent ASH Annual Meeting (abstract 182).

The ALCANZA trial was sponsored by Millennium Pharmaceuticals, Inc. (now a part of Takeda Pharmaceutical Company Limited) and Seattle Genetics, Inc.

The study was designed to compare BV to the SOC options of methotrexate or bexarotene in patients with CD30-positive CTCL, including mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL).

There were 128 patients in the intent-to-treat and safety populations. Sixty-four patients (48 with MF and 16 with pcALCL) were randomized to receive BV at 1.8 mg/kg IV every 3 weeks for up to 48 weeks.

The other 64 patients (49 with MF and 15 with pcALCL) were randomized to receive methotrexate at 5 mg to 50 mg PO weekly or bexarotene at a target dose of 300 mg/m² PO daily for up to 48 weeks.

Patients received BV for a median of 36 weeks (12 cycles), bexarotene for a median of 17 weeks, and methotrexate for a median of 9 weeks. Three patients in the BV arm were still on treatment at the time of analysis.

Patient characteristics

The median age was 62 (range, 22-83) in the BV am and 59 (range, 22-83) in the SOC arm. More than half of patients in each arm were male—52% and 58%, respectively. And most patients in both arms had an ECOG performance status of 0-1—95% and 97%, respectively.

The median number of prior therapies was 4 (range, 0-13) in the BV arm and 3.5 (range, 1-15) in the SOC arm. The median number of systemic therapies was 2 in the BV arm (range, 0-11) and the SOC arm (range, 1-8).

“It was pretty well balanced in terms of baseline characteristics between the 2 arms,” Dr Kim said. “The brentuximab arm had more stage IV patients—in fact, 7 stage IVB in brentuximab and none in the standard of care. And more patients with ALCL [treated with BV] had extracutaneous disease.”

Among pcALCL patients, 44% in the BV arm had extracutaneous disease, compared to 27% in the SOC arm. Among MF patients, 67% in the BV arm had stage IIB-IVB disease, compared to 61% in the SOC arm.
 
Response

The study’s primary endpoint was the rate of objective response lasting at least 4 months (ORR4).

“[ORR4] was felt to be more meaningful than ORR because it includes not only the response rate but also a duration element in a single endpoint,” Dr Kim said.

ORR4 was significantly higher with BV than with SOC—56.3% and 12.5%, respectively (P<0.0001).

For patients with MF, the ORR4 was 50% with BV and 10% with SOC. For patients with pcALCL, the ORR4 was 75% with BV and 20% with SOC.

Overall, the complete response (CR) rates were 15.6% in the BV arm and 1.6% in the SOC arm (P=0.0046).

For patients with MF, the CR rate was 10% with BV and 0% with SOC. For patients with pcALCL, the CR rate was 31% with BV and 7% with SOC.

Symptoms

“In CTCL, there’s significant quality of life issues that are not captured adequately by objective response measures, and this patient outcome is very important,” Dr Kim said. “[Quality of life in this study] was captured by Skindex-29, which is an established quality of life measure in skin diseases.”

Patients in the BV arm had a significantly higher reduction in symptom burden according to Skindex-29 than patients receiving SOC. The mean maximum reduction in Skindex-29 symptom domain was -27.96 points in the BV arm and -8.62 points in the SOC arm (P<0.0001).

PFS

PFS was significantly longer in the BV arm than the SOC arm. The median PFS was 16.7 months and 3.5 months, respectively. The hazard ratio was 0.270 (P<0.0001).

For patients with MF, the median PFS was 15.9 months with BV and 3.5 months with SOC. For patients with pcALCL, the median PFS was 27.5 months with BV and 5.3 months with SOC.

Safety

The overall rate of adverse events (AEs) was 95% in the BV arm and 90% in the SOC arm.  The rate of grade 3 or higher AEs was 41% and 47%, respectively. And the rate of serious AEs was 29% in both arms.

AEs resulting in discontinuation occurred in 24% of patients in the BV arm and 8% in the SOC arm. In the BV arm, this included peripheral neuropathy (n=9), skin-related hypersensitivity (n=3), E coli infection (n=1), impetigo (n=1), pulmonary embolism (n=1), urticaria (n=1), and vertigo (n=1).

In the SOC arm, AEs leading to discontinuation included maculo-papular rash (n=1), asthenia (n=1), hematuria (n=1), hypernatremia (n=1), neutropenia (n=1), periorbital infection (n=1), and somnolence (n=1). One patient in each arm experienced more than 1 AE resulting in discontinuation.

The most common AEs of any grade (occurring in 15% or more of patients in the BV and SOC arms, respectively) were peripheral neuropathy (67% and 6%), nausea (36% and 13%), diarrhea (29% and 6%), fatigue (29% and 27%), vomiting (17% and 5%), alopecia (15% and 3%), pruritus (17% and 13%), pyrexia (17% and 18%), decreased appetite (15% and 5%), and hypertriglyceridemia (2% and 18%).

The majority of the peripheral neuropathy events in the BV arm were grade 1 or 2—26% and 32%, respectively. The rate of grade 3 peripheral neuropathy events was 9%, and there were no grade 4 events.

Eighty-two percent of patients reported resolution or improvement in peripheral neuropathy events in the BV arm at a median of 22.9 months of follow-up.

There were no on-study deaths (occurring within 30 days of the last dose) in the SOC arm, but there were 4 in the BV arm. Three of the BV deaths were considered unrelated to the drug.

The 1 BV-related death was a result of multiple organ dysfunction syndrome attributed to tumor necrosis at visceral disease sites in a patient with T3bN0M1 pcALCL. The other 3 deaths were due to lymphoma progression, pulmonary embolism, and sepsis.

Youn Kim, MD
Photo by Larry Young

SAN FRANCISCO—The phase 3 ALCANZA trial is the first to convincingly demonstrate that a new systemic agent can be more effective than standard of care (SOC) options for cutaneous T-cell lymphoma (CTCL), according to a speaker at the 9th Annual T-cell Lymphoma Forum.

The trial showed significant improvements in response, symptom burden, and progression-free survival (PFS) in patients with CD30-expressing CTCL who received brentuximab vedotin (BV), as compared to patients who received either bexarotene or methotrexate.

“[These are] compelling results that potentially may have practice-changing implications for the use of brentuximab in managing CD30-expressing CTCL patients who require systemic therapy,” said Youn H. Kim, MD, of Stanford University School of Medicine in California.

Dr Kim presented these results at this year’s T-cell Lymphoma Forum. The data were also presented at the recent ASH Annual Meeting (abstract 182).

The ALCANZA trial was sponsored by Millennium Pharmaceuticals, Inc. (now a part of Takeda Pharmaceutical Company Limited) and Seattle Genetics, Inc.

The study was designed to compare BV to the SOC options of methotrexate or bexarotene in patients with CD30-positive CTCL, including mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL).

There were 128 patients in the intent-to-treat and safety populations. Sixty-four patients (48 with MF and 16 with pcALCL) were randomized to receive BV at 1.8 mg/kg IV every 3 weeks for up to 48 weeks.

The other 64 patients (49 with MF and 15 with pcALCL) were randomized to receive methotrexate at 5 mg to 50 mg PO weekly or bexarotene at a target dose of 300 mg/m² PO daily for up to 48 weeks.

Patients received BV for a median of 36 weeks (12 cycles), bexarotene for a median of 17 weeks, and methotrexate for a median of 9 weeks. Three patients in the BV arm were still on treatment at the time of analysis.

Patient characteristics

The median age was 62 (range, 22-83) in the BV am and 59 (range, 22-83) in the SOC arm. More than half of patients in each arm were male—52% and 58%, respectively. And most patients in both arms had an ECOG performance status of 0-1—95% and 97%, respectively.

The median number of prior therapies was 4 (range, 0-13) in the BV arm and 3.5 (range, 1-15) in the SOC arm. The median number of systemic therapies was 2 in the BV arm (range, 0-11) and the SOC arm (range, 1-8).

“It was pretty well balanced in terms of baseline characteristics between the 2 arms,” Dr Kim said. “The brentuximab arm had more stage IV patients—in fact, 7 stage IVB in brentuximab and none in the standard of care. And more patients with ALCL [treated with BV] had extracutaneous disease.”

Among pcALCL patients, 44% in the BV arm had extracutaneous disease, compared to 27% in the SOC arm. Among MF patients, 67% in the BV arm had stage IIB-IVB disease, compared to 61% in the SOC arm.
 
Response

The study’s primary endpoint was the rate of objective response lasting at least 4 months (ORR4).

“[ORR4] was felt to be more meaningful than ORR because it includes not only the response rate but also a duration element in a single endpoint,” Dr Kim said.

ORR4 was significantly higher with BV than with SOC—56.3% and 12.5%, respectively (P<0.0001).

For patients with MF, the ORR4 was 50% with BV and 10% with SOC. For patients with pcALCL, the ORR4 was 75% with BV and 20% with SOC.

Overall, the complete response (CR) rates were 15.6% in the BV arm and 1.6% in the SOC arm (P=0.0046).

For patients with MF, the CR rate was 10% with BV and 0% with SOC. For patients with pcALCL, the CR rate was 31% with BV and 7% with SOC.

Symptoms

“In CTCL, there’s significant quality of life issues that are not captured adequately by objective response measures, and this patient outcome is very important,” Dr Kim said. “[Quality of life in this study] was captured by Skindex-29, which is an established quality of life measure in skin diseases.”

Patients in the BV arm had a significantly higher reduction in symptom burden according to Skindex-29 than patients receiving SOC. The mean maximum reduction in Skindex-29 symptom domain was -27.96 points in the BV arm and -8.62 points in the SOC arm (P<0.0001).

PFS

PFS was significantly longer in the BV arm than the SOC arm. The median PFS was 16.7 months and 3.5 months, respectively. The hazard ratio was 0.270 (P<0.0001).

For patients with MF, the median PFS was 15.9 months with BV and 3.5 months with SOC. For patients with pcALCL, the median PFS was 27.5 months with BV and 5.3 months with SOC.

Safety

The overall rate of adverse events (AEs) was 95% in the BV arm and 90% in the SOC arm.  The rate of grade 3 or higher AEs was 41% and 47%, respectively. And the rate of serious AEs was 29% in both arms.

AEs resulting in discontinuation occurred in 24% of patients in the BV arm and 8% in the SOC arm. In the BV arm, this included peripheral neuropathy (n=9), skin-related hypersensitivity (n=3), E coli infection (n=1), impetigo (n=1), pulmonary embolism (n=1), urticaria (n=1), and vertigo (n=1).

In the SOC arm, AEs leading to discontinuation included maculo-papular rash (n=1), asthenia (n=1), hematuria (n=1), hypernatremia (n=1), neutropenia (n=1), periorbital infection (n=1), and somnolence (n=1). One patient in each arm experienced more than 1 AE resulting in discontinuation.

The most common AEs of any grade (occurring in 15% or more of patients in the BV and SOC arms, respectively) were peripheral neuropathy (67% and 6%), nausea (36% and 13%), diarrhea (29% and 6%), fatigue (29% and 27%), vomiting (17% and 5%), alopecia (15% and 3%), pruritus (17% and 13%), pyrexia (17% and 18%), decreased appetite (15% and 5%), and hypertriglyceridemia (2% and 18%).

The majority of the peripheral neuropathy events in the BV arm were grade 1 or 2—26% and 32%, respectively. The rate of grade 3 peripheral neuropathy events was 9%, and there were no grade 4 events.

Eighty-two percent of patients reported resolution or improvement in peripheral neuropathy events in the BV arm at a median of 22.9 months of follow-up.

There were no on-study deaths (occurring within 30 days of the last dose) in the SOC arm, but there were 4 in the BV arm. Three of the BV deaths were considered unrelated to the drug.

The 1 BV-related death was a result of multiple organ dysfunction syndrome attributed to tumor necrosis at visceral disease sites in a patient with T3bN0M1 pcALCL. The other 3 deaths were due to lymphoma progression, pulmonary embolism, and sepsis.

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Prescription medications

Photo courtesy of CDC

SAN DIEGO—Results from the ARETA trial suggest patients with essential thrombocythemia (ET) can benefit from early treatment even if they are not considered high-risk.

In this phase 3 trial, non-high-risk patients were less likely to experience ET-related cardiovascular events or disease progression if they received extended-release anagrelide rather than placebo.

Patients who received extended-release anagrelide were also less likely to become high-risk over time.

And extended-release anagrelide had a safety profile consistent with conventional anagrelide formulations, according to investigator Heinz Gisslinger, MD, of the Medical University of Vienna in Austria.

Dr Gisslinger reported final results of the ARETA trial at the 2016 ASH Annual Meeting (abstract 476).

The trial was sponsored by AOP Orphan Pharmaceuticals AG, the company developing the extended-release formulation of anagrelide, known as anagrelide retard (AR).

Dr Gisslinger noted that the goals of developing AR are to achieve lower peak plasma concentration of anagrelide, reduce the frequency and intensity of peak concentration related to adverse events (AEs), allow for an easier dosing scheme (once daily vs 2 to 3 times daily), and improve patient compliance.

He also pointed out that results of the phase 3 TEAM-ET trial suggest AR is non-inferior to the standard formulation of anagrelide (Thromboreductin, also a product of AOP Orphan Pharmaceuticals).

So with the ARETA trial, Dr Gisslinger and his colleagues set out to determine if AR would be beneficial as an early intervention in patients with non-high-risk ET.

Patients

The trial enrolled 146 patients who had platelet counts below 1000 G/L and met at least 1 of the following criteria:

• Age 40 to 60 years
• ET duration of more than 3 years
• Any risk factor for thrombotic complications (JAK2 mutation, protein C and/or S deficiency, antithrombin III deficiency, factor V Leiden or prothrombin mutation, or cardiovascular risk factors).

Seventy-seven patients were randomized to AR, and 69 were randomized to placebo. In both treatment arms, 100% of patients were Caucasian, and about 74% were female.

The mean age was 40.9 (range, 20-60) in the AR arm and 45.2 (range, 19-59) in the placebo arm. The median disease duration was 75.0 days (range, 1-2502) and 78.0 days (range, 1-2195), respectively. The mean platelet count was 748.6 G/L and 745.3 G/L, respectively.

A majority of patients in both arms had JAK2 mutations (62.7% in the AR arm and 63.8% in the placebo arm). Fewer had CALR mutations (22.7% and 13.6%, respectively) and MPL mutations (16.7% and 12.5%).

Treatment

Patients were stratified by JAK2 status and randomized to receive AR at 2 to 8 mg/day or placebo.

The dosing of AR started at 1 tablet (2 mg) per day during week 1 and was titrated up according to platelet response to 2 tablets in week 2. Dosing was further increased or decreased according to platelet response in weeks 3 and 4.

The maximum dose was 4 tablets (8 mg) per day. After week 4, the maximum dose to achieve optimal platelet counts (<450 G/L) was maintained, and patients continued with weekly visits through week 6.

After that, patients had visits every 3 months in both the main phase of this study and the extension phase. The main phase lasted 1 year, and the extension phase lasted up to 3 years.

Sixty patients (77.9%) in the AR arm and 52 (75.4%) in the placebo arm completed the main phase of the study.

Fifty-seven patients in the AR arm entered the extension phase, and 44 (57.1%) completed it. Thirty-four patients in the placebo arm entered the extension phase, and 21 (30.4%) completed it.

Efficacy

The primary endpoint was time to ET-related cardiovascular events (as confirmed by a blinded expert panel) or disease progression/worsening (platelet increase >1000 G/L).

The 1-year event-free rate (patients who did not meet criteria for the primary endpoint) was 87% in the AR arm and 69% in the placebo arm (hazard ratio=0.356, P=0.0008).

According to the expert panel, there were 12 ET-related events in 11 patients in the AR arm, as well as 17 such events in 14 patients in the placebo arm. This included major and minor arterial, venous, and bleeding events.

In total, there were 13 patients who had ET-related events or met platelet criteria in the AR arm (13 events) and 26 patients who had ET-related events or met platelet criteria in the placebo arm (30 events).

Nine patients in the AR arm (11.7%) and 18 in the placebo arm (26.1%) changed to high-risk status at some point during the trial (odds ratio=2.67, P=0.033).

Safety

The overall incidence of AEs was 88.3% in the AR arm and 69.6% in the placebo arm. The incidence of treatment-related AEs was 76.6% and 27.5%, respectively.

The incidence of treatment-related serious AEs was 1.3% and 0%, respectively. And the incidence of treatment-related AEs leading to withdrawal was 9.1% and 7.2%, respectively.

Treatment-related AEs occurring in more than 10% of patients in either arm (the AR and placebo arms, respectively) included headache (41.6% and 15.9%), dizziness (35.1% and 14.5%), palpitations (28.6% and 1.4%), and tachycardia (10.4% and 1.4%).

In closing, Dr Gisslinger noted that the primary endpoint of this study was met, and AR allowed for platelet count normalization and delayed progression to high-risk status.

Furthermore, the safety profile of AR is consistent with conventional anagrelide formulations, but AR allows for a more convenient dosing schedule.

Dr Gisslinger concluded, “[T]hese data from the ARETA study support an early treatment concept for all ET patients where platelet count or symptom reduction is a goal and those patients who can be attributed as intermediate-risk patients.”

Prescription medications

Photo courtesy of CDC

SAN DIEGO—Results from the ARETA trial suggest patients with essential thrombocythemia (ET) can benefit from early treatment even if they are not considered high-risk.

In this phase 3 trial, non-high-risk patients were less likely to experience ET-related cardiovascular events or disease progression if they received extended-release anagrelide rather than placebo.

Patients who received extended-release anagrelide were also less likely to become high-risk over time.

And extended-release anagrelide had a safety profile consistent with conventional anagrelide formulations, according to investigator Heinz Gisslinger, MD, of the Medical University of Vienna in Austria.

Dr Gisslinger reported final results of the ARETA trial at the 2016 ASH Annual Meeting (abstract 476).

The trial was sponsored by AOP Orphan Pharmaceuticals AG, the company developing the extended-release formulation of anagrelide, known as anagrelide retard (AR).

Dr Gisslinger noted that the goals of developing AR are to achieve lower peak plasma concentration of anagrelide, reduce the frequency and intensity of peak concentration related to adverse events (AEs), allow for an easier dosing scheme (once daily vs 2 to 3 times daily), and improve patient compliance.

He also pointed out that results of the phase 3 TEAM-ET trial suggest AR is non-inferior to the standard formulation of anagrelide (Thromboreductin, also a product of AOP Orphan Pharmaceuticals).

So with the ARETA trial, Dr Gisslinger and his colleagues set out to determine if AR would be beneficial as an early intervention in patients with non-high-risk ET.

Patients

The trial enrolled 146 patients who had platelet counts below 1000 G/L and met at least 1 of the following criteria:

• Age 40 to 60 years
• ET duration of more than 3 years
• Any risk factor for thrombotic complications (JAK2 mutation, protein C and/or S deficiency, antithrombin III deficiency, factor V Leiden or prothrombin mutation, or cardiovascular risk factors).

Seventy-seven patients were randomized to AR, and 69 were randomized to placebo. In both treatment arms, 100% of patients were Caucasian, and about 74% were female.

The mean age was 40.9 (range, 20-60) in the AR arm and 45.2 (range, 19-59) in the placebo arm. The median disease duration was 75.0 days (range, 1-2502) and 78.0 days (range, 1-2195), respectively. The mean platelet count was 748.6 G/L and 745.3 G/L, respectively.

A majority of patients in both arms had JAK2 mutations (62.7% in the AR arm and 63.8% in the placebo arm). Fewer had CALR mutations (22.7% and 13.6%, respectively) and MPL mutations (16.7% and 12.5%).

Treatment

Patients were stratified by JAK2 status and randomized to receive AR at 2 to 8 mg/day or placebo.

The dosing of AR started at 1 tablet (2 mg) per day during week 1 and was titrated up according to platelet response to 2 tablets in week 2. Dosing was further increased or decreased according to platelet response in weeks 3 and 4.

The maximum dose was 4 tablets (8 mg) per day. After week 4, the maximum dose to achieve optimal platelet counts (<450 G/L) was maintained, and patients continued with weekly visits through week 6.

After that, patients had visits every 3 months in both the main phase of this study and the extension phase. The main phase lasted 1 year, and the extension phase lasted up to 3 years.

Sixty patients (77.9%) in the AR arm and 52 (75.4%) in the placebo arm completed the main phase of the study.

Fifty-seven patients in the AR arm entered the extension phase, and 44 (57.1%) completed it. Thirty-four patients in the placebo arm entered the extension phase, and 21 (30.4%) completed it.

Efficacy

The primary endpoint was time to ET-related cardiovascular events (as confirmed by a blinded expert panel) or disease progression/worsening (platelet increase >1000 G/L).

The 1-year event-free rate (patients who did not meet criteria for the primary endpoint) was 87% in the AR arm and 69% in the placebo arm (hazard ratio=0.356, P=0.0008).

According to the expert panel, there were 12 ET-related events in 11 patients in the AR arm, as well as 17 such events in 14 patients in the placebo arm. This included major and minor arterial, venous, and bleeding events.

In total, there were 13 patients who had ET-related events or met platelet criteria in the AR arm (13 events) and 26 patients who had ET-related events or met platelet criteria in the placebo arm (30 events).

Nine patients in the AR arm (11.7%) and 18 in the placebo arm (26.1%) changed to high-risk status at some point during the trial (odds ratio=2.67, P=0.033).

Safety

The overall incidence of AEs was 88.3% in the AR arm and 69.6% in the placebo arm. The incidence of treatment-related AEs was 76.6% and 27.5%, respectively.

The incidence of treatment-related serious AEs was 1.3% and 0%, respectively. And the incidence of treatment-related AEs leading to withdrawal was 9.1% and 7.2%, respectively.

Treatment-related AEs occurring in more than 10% of patients in either arm (the AR and placebo arms, respectively) included headache (41.6% and 15.9%), dizziness (35.1% and 14.5%), palpitations (28.6% and 1.4%), and tachycardia (10.4% and 1.4%).

In closing, Dr Gisslinger noted that the primary endpoint of this study was met, and AR allowed for platelet count normalization and delayed progression to high-risk status.

Furthermore, the safety profile of AR is consistent with conventional anagrelide formulations, but AR allows for a more convenient dosing schedule.

Dr Gisslinger concluded, “[T]hese data from the ARETA study support an early treatment concept for all ET patients where platelet count or symptom reduction is a goal and those patients who can be attributed as intermediate-risk patients.”

Prescription medications

Photo courtesy of CDC

SAN DIEGO—Results from the ARETA trial suggest patients with essential thrombocythemia (ET) can benefit from early treatment even if they are not considered high-risk.

In this phase 3 trial, non-high-risk patients were less likely to experience ET-related cardiovascular events or disease progression if they received extended-release anagrelide rather than placebo.

Patients who received extended-release anagrelide were also less likely to become high-risk over time.

And extended-release anagrelide had a safety profile consistent with conventional anagrelide formulations, according to investigator Heinz Gisslinger, MD, of the Medical University of Vienna in Austria.

Dr Gisslinger reported final results of the ARETA trial at the 2016 ASH Annual Meeting (abstract 476).

The trial was sponsored by AOP Orphan Pharmaceuticals AG, the company developing the extended-release formulation of anagrelide, known as anagrelide retard (AR).

Dr Gisslinger noted that the goals of developing AR are to achieve lower peak plasma concentration of anagrelide, reduce the frequency and intensity of peak concentration related to adverse events (AEs), allow for an easier dosing scheme (once daily vs 2 to 3 times daily), and improve patient compliance.

He also pointed out that results of the phase 3 TEAM-ET trial suggest AR is non-inferior to the standard formulation of anagrelide (Thromboreductin, also a product of AOP Orphan Pharmaceuticals).

So with the ARETA trial, Dr Gisslinger and his colleagues set out to determine if AR would be beneficial as an early intervention in patients with non-high-risk ET.

Patients

The trial enrolled 146 patients who had platelet counts below 1000 G/L and met at least 1 of the following criteria:

• Age 40 to 60 years
• ET duration of more than 3 years
• Any risk factor for thrombotic complications (JAK2 mutation, protein C and/or S deficiency, antithrombin III deficiency, factor V Leiden or prothrombin mutation, or cardiovascular risk factors).

Seventy-seven patients were randomized to AR, and 69 were randomized to placebo. In both treatment arms, 100% of patients were Caucasian, and about 74% were female.

The mean age was 40.9 (range, 20-60) in the AR arm and 45.2 (range, 19-59) in the placebo arm. The median disease duration was 75.0 days (range, 1-2502) and 78.0 days (range, 1-2195), respectively. The mean platelet count was 748.6 G/L and 745.3 G/L, respectively.

A majority of patients in both arms had JAK2 mutations (62.7% in the AR arm and 63.8% in the placebo arm). Fewer had CALR mutations (22.7% and 13.6%, respectively) and MPL mutations (16.7% and 12.5%).

Treatment

Patients were stratified by JAK2 status and randomized to receive AR at 2 to 8 mg/day or placebo.

The dosing of AR started at 1 tablet (2 mg) per day during week 1 and was titrated up according to platelet response to 2 tablets in week 2. Dosing was further increased or decreased according to platelet response in weeks 3 and 4.

The maximum dose was 4 tablets (8 mg) per day. After week 4, the maximum dose to achieve optimal platelet counts (<450 G/L) was maintained, and patients continued with weekly visits through week 6.

After that, patients had visits every 3 months in both the main phase of this study and the extension phase. The main phase lasted 1 year, and the extension phase lasted up to 3 years.

Sixty patients (77.9%) in the AR arm and 52 (75.4%) in the placebo arm completed the main phase of the study.

Fifty-seven patients in the AR arm entered the extension phase, and 44 (57.1%) completed it. Thirty-four patients in the placebo arm entered the extension phase, and 21 (30.4%) completed it.

Efficacy

The primary endpoint was time to ET-related cardiovascular events (as confirmed by a blinded expert panel) or disease progression/worsening (platelet increase >1000 G/L).

The 1-year event-free rate (patients who did not meet criteria for the primary endpoint) was 87% in the AR arm and 69% in the placebo arm (hazard ratio=0.356, P=0.0008).

According to the expert panel, there were 12 ET-related events in 11 patients in the AR arm, as well as 17 such events in 14 patients in the placebo arm. This included major and minor arterial, venous, and bleeding events.

In total, there were 13 patients who had ET-related events or met platelet criteria in the AR arm (13 events) and 26 patients who had ET-related events or met platelet criteria in the placebo arm (30 events).

Nine patients in the AR arm (11.7%) and 18 in the placebo arm (26.1%) changed to high-risk status at some point during the trial (odds ratio=2.67, P=0.033).

Safety

The overall incidence of AEs was 88.3% in the AR arm and 69.6% in the placebo arm. The incidence of treatment-related AEs was 76.6% and 27.5%, respectively.

The incidence of treatment-related serious AEs was 1.3% and 0%, respectively. And the incidence of treatment-related AEs leading to withdrawal was 9.1% and 7.2%, respectively.

Treatment-related AEs occurring in more than 10% of patients in either arm (the AR and placebo arms, respectively) included headache (41.6% and 15.9%), dizziness (35.1% and 14.5%), palpitations (28.6% and 1.4%), and tachycardia (10.4% and 1.4%).

In closing, Dr Gisslinger noted that the primary endpoint of this study was met, and AR allowed for platelet count normalization and delayed progression to high-risk status.

Furthermore, the safety profile of AR is consistent with conventional anagrelide formulations, but AR allows for a more convenient dosing schedule.

Dr Gisslinger concluded, “[T]hese data from the ARETA study support an early treatment concept for all ET patients where platelet count or symptom reduction is a goal and those patients who can be attributed as intermediate-risk patients.”

 

 

HSCT preparation

Photo by Chad McNeeley

 

SAN DIEGO—Researchers believe they have identified patients with chronic myeloid leukemia (CML) who are likely to derive long-term benefit from allogeneic hematopoietic stem cell transplant (allo-HSCT).

The researchers found that CML patients have a low risk of long-term morbidity if they undergo HSCT before the age of 45, are conditioned with busulfan and cyclophosphamide (Bu/Cy), and receive a graft from a matched, related donor (MRD).

Jessica Wu, of the University of Alabama at Birmingham, presented these findings at the 2016 ASH Annual Meeting (abstract 823*).

Wu noted that allogeneic HSCT is potentially curative for CML, but this method of treatment has been on the decline since the introduction of tyrosine kinase inhibitors (TKIs). And today, few CML patients undergo allo-HSCT.

She said that although TKIs can induce remission in CML patients, the drugs also fail to eradicate leukemia, can produce side effects that impact patients’ quality of life, and come with a significant financial burden (estimated at $92,000 to $138,000 per patient per year).

With this in mind, Wu and her colleagues set out to determine if certain CML patients might benefit from allo-HSCT long-term. The team also wanted to quantify overall and cause-specific late mortality after allo-HSCT and the long-term burden of severe/life-threatening chronic health conditions after allo-HSCT.

Patient population

The researchers studied 637 CML patients treated with allo-HSCT between 1981 and 2010 at City of Hope in Duarte, California, or the University of Minnesota in Minneapolis/Saint Paul. The patients had to have survived at least 2 years post-transplant.

About 60% of patients were male, and 67% were non-Hispanic white. Their median age at HSCT was 36.4 years, and 65% received an MRD graft. Nineteen percent of patients were transplanted in 1980-1989, 52% were transplanted in 1990-1999, and 29% were transplanted in 2000-2010.

Fifty-eight percent of patients received Cy/total body irradiation (TBI), 18% received Bu/Cy, and 3% received reduced-intensity conditioning (RIC).

Sixty-one percent of patients had chronic graft-vs-host disease (cGVHD), and 32% had high-risk disease at the time of HSCT.

Survival

The patients were followed for a median of 16.7 years. Thirty percent (n=192) died after surviving at least 2 years post-HSCT.

The median time to death was 8.3 years (range, 2-29.5), and the median age at death was 49.2 (range, 7.8-69.8). At 20 years from HSCT, the overall survival was 68.6%.

HSCT recipients had a 4.4-fold increased risk of death compared with the age-, sex-, and race-matched general population.

“Non-relapse mortality was the major contributor to late mortality, with infection, second malignancies, and cGVHD being the most common causes of death,” Wu said.

Non-relapse mortality was 20%, and relapse-related mortality was 4%. Eight percent of patients died of infection, 6.3% died of cGVHD, and 3.7% died of second malignancies.

Health outcomes

Patients who were still alive at the time of the study were asked to complete the BMTSS-2 health questionnaire, which was used to examine the risk of grade 3/4 chronic health conditions.


A total of 288 patients completed the questionnaire, as did a sibling comparison group of 404 individuals.

Among the patients, the median age at allo-HSCT was 37.5 (range, 3.6-71.4), and the median duration of follow-up was 13.9 years (range, 2-34.6).

Sixty-two percent of patients received an MRD graft, and 38% had a matched, unrelated donor. Eighty-three percent of patients had TBI-based conditioning, 16% received Bu/Cy, and 2.7% received RIC.

The prevalence of grade 3/4 chronic health conditions was significantly higher among patients than among siblings—38% and 24%, respectively (P<0.0001).

The odds ratio (OR)—adjusted for age, sex, race, and socioeconomic status—was 2.7 (P<0.0001).

The cumulative incidence of any grade 3/4 condition at 20 years after HSCT was 47.2% among patients. Common conditions were diabetes (14.9%), second malignancies (12.6%), and coronary artery disease (10%).

The researchers found the risk of grade 3/4 morbidity was significantly higher for the following patient groups:

• Those age 45 and older (hazard ratio [HR]=3.3, P<0.0001)
• Patients with a matched, unrelated donor (HR=3.0, P<0.0001)
• Those who received peripheral blood or cord blood grafts as opposed to bone marrow (HR=2.7, P=0.006).

(This analysis was adjusted for race/ethnicity, sex, education, household income, insurance, cGVHD, and conditioning regimen).

Lower risk

To identify subpopulations with a reduced risk of long-term morbidity, the researchers calculated the risk in various CML patient groups compared to siblings.

The overall OR for CML patients compared with siblings was 2.7 (P<0.0001).

The OR for patients in first chronic phase who underwent HSCT before the age of 45 and had an MRD was 1.5 (P=0.1).

The OR for CML patients in first chronic phase who underwent HSCT before the age of 45, had an MRD, and received Bu/Cy conditioning was 0.8 (P=0.7).

“[W]e found that patients who received a matched, related donor transplant under the age of 45, with busulfan/cyclophosphamide, carried the same burden of morbidity as the sibling cohort,” Wu said. “These findings could help inform decisions regarding therapeutic options for the management of CML.”

Wu noted that the limited sample size in this study prevented the researchers from examining outcomes with RIC. And a lack of data at analysis prevented them from examining pre-HSCT and post-HSCT management of CML, the interval between diagnosis and HSCT, and the life-long economic burden of allo-HSCT.

However, she said data collection is ongoing, and the researchers hope to address some of these limitations.

*Information presented at the meeting differs from the abstract.

 

 

HSCT preparation

Photo by Chad McNeeley

 

SAN DIEGO—Researchers believe they have identified patients with chronic myeloid leukemia (CML) who are likely to derive long-term benefit from allogeneic hematopoietic stem cell transplant (allo-HSCT).

The researchers found that CML patients have a low risk of long-term morbidity if they undergo HSCT before the age of 45, are conditioned with busulfan and cyclophosphamide (Bu/Cy), and receive a graft from a matched, related donor (MRD).

Jessica Wu, of the University of Alabama at Birmingham, presented these findings at the 2016 ASH Annual Meeting (abstract 823*).

Wu noted that allogeneic HSCT is potentially curative for CML, but this method of treatment has been on the decline since the introduction of tyrosine kinase inhibitors (TKIs). And today, few CML patients undergo allo-HSCT.

She said that although TKIs can induce remission in CML patients, the drugs also fail to eradicate leukemia, can produce side effects that impact patients’ quality of life, and come with a significant financial burden (estimated at $92,000 to $138,000 per patient per year).

With this in mind, Wu and her colleagues set out to determine if certain CML patients might benefit from allo-HSCT long-term. The team also wanted to quantify overall and cause-specific late mortality after allo-HSCT and the long-term burden of severe/life-threatening chronic health conditions after allo-HSCT.

Patient population

The researchers studied 637 CML patients treated with allo-HSCT between 1981 and 2010 at City of Hope in Duarte, California, or the University of Minnesota in Minneapolis/Saint Paul. The patients had to have survived at least 2 years post-transplant.

About 60% of patients were male, and 67% were non-Hispanic white. Their median age at HSCT was 36.4 years, and 65% received an MRD graft. Nineteen percent of patients were transplanted in 1980-1989, 52% were transplanted in 1990-1999, and 29% were transplanted in 2000-2010.

Fifty-eight percent of patients received Cy/total body irradiation (TBI), 18% received Bu/Cy, and 3% received reduced-intensity conditioning (RIC).

Sixty-one percent of patients had chronic graft-vs-host disease (cGVHD), and 32% had high-risk disease at the time of HSCT.

Survival

The patients were followed for a median of 16.7 years. Thirty percent (n=192) died after surviving at least 2 years post-HSCT.

The median time to death was 8.3 years (range, 2-29.5), and the median age at death was 49.2 (range, 7.8-69.8). At 20 years from HSCT, the overall survival was 68.6%.

HSCT recipients had a 4.4-fold increased risk of death compared with the age-, sex-, and race-matched general population.

“Non-relapse mortality was the major contributor to late mortality, with infection, second malignancies, and cGVHD being the most common causes of death,” Wu said.

Non-relapse mortality was 20%, and relapse-related mortality was 4%. Eight percent of patients died of infection, 6.3% died of cGVHD, and 3.7% died of second malignancies.

Health outcomes

Patients who were still alive at the time of the study were asked to complete the BMTSS-2 health questionnaire, which was used to examine the risk of grade 3/4 chronic health conditions.


A total of 288 patients completed the questionnaire, as did a sibling comparison group of 404 individuals.

Among the patients, the median age at allo-HSCT was 37.5 (range, 3.6-71.4), and the median duration of follow-up was 13.9 years (range, 2-34.6).

Sixty-two percent of patients received an MRD graft, and 38% had a matched, unrelated donor. Eighty-three percent of patients had TBI-based conditioning, 16% received Bu/Cy, and 2.7% received RIC.

The prevalence of grade 3/4 chronic health conditions was significantly higher among patients than among siblings—38% and 24%, respectively (P<0.0001).

The odds ratio (OR)—adjusted for age, sex, race, and socioeconomic status—was 2.7 (P<0.0001).

The cumulative incidence of any grade 3/4 condition at 20 years after HSCT was 47.2% among patients. Common conditions were diabetes (14.9%), second malignancies (12.6%), and coronary artery disease (10%).

The researchers found the risk of grade 3/4 morbidity was significantly higher for the following patient groups:

• Those age 45 and older (hazard ratio [HR]=3.3, P<0.0001)
• Patients with a matched, unrelated donor (HR=3.0, P<0.0001)
• Those who received peripheral blood or cord blood grafts as opposed to bone marrow (HR=2.7, P=0.006).

(This analysis was adjusted for race/ethnicity, sex, education, household income, insurance, cGVHD, and conditioning regimen).

Lower risk

To identify subpopulations with a reduced risk of long-term morbidity, the researchers calculated the risk in various CML patient groups compared to siblings.

The overall OR for CML patients compared with siblings was 2.7 (P<0.0001).

The OR for patients in first chronic phase who underwent HSCT before the age of 45 and had an MRD was 1.5 (P=0.1).

The OR for CML patients in first chronic phase who underwent HSCT before the age of 45, had an MRD, and received Bu/Cy conditioning was 0.8 (P=0.7).

“[W]e found that patients who received a matched, related donor transplant under the age of 45, with busulfan/cyclophosphamide, carried the same burden of morbidity as the sibling cohort,” Wu said. “These findings could help inform decisions regarding therapeutic options for the management of CML.”

Wu noted that the limited sample size in this study prevented the researchers from examining outcomes with RIC. And a lack of data at analysis prevented them from examining pre-HSCT and post-HSCT management of CML, the interval between diagnosis and HSCT, and the life-long economic burden of allo-HSCT.

However, she said data collection is ongoing, and the researchers hope to address some of these limitations.

*Information presented at the meeting differs from the abstract.

 

 

HSCT preparation

Photo by Chad McNeeley

 

SAN DIEGO—Researchers believe they have identified patients with chronic myeloid leukemia (CML) who are likely to derive long-term benefit from allogeneic hematopoietic stem cell transplant (allo-HSCT).

The researchers found that CML patients have a low risk of long-term morbidity if they undergo HSCT before the age of 45, are conditioned with busulfan and cyclophosphamide (Bu/Cy), and receive a graft from a matched, related donor (MRD).

Jessica Wu, of the University of Alabama at Birmingham, presented these findings at the 2016 ASH Annual Meeting (abstract 823*).

Wu noted that allogeneic HSCT is potentially curative for CML, but this method of treatment has been on the decline since the introduction of tyrosine kinase inhibitors (TKIs). And today, few CML patients undergo allo-HSCT.

She said that although TKIs can induce remission in CML patients, the drugs also fail to eradicate leukemia, can produce side effects that impact patients’ quality of life, and come with a significant financial burden (estimated at $92,000 to $138,000 per patient per year).

With this in mind, Wu and her colleagues set out to determine if certain CML patients might benefit from allo-HSCT long-term. The team also wanted to quantify overall and cause-specific late mortality after allo-HSCT and the long-term burden of severe/life-threatening chronic health conditions after allo-HSCT.

Patient population

The researchers studied 637 CML patients treated with allo-HSCT between 1981 and 2010 at City of Hope in Duarte, California, or the University of Minnesota in Minneapolis/Saint Paul. The patients had to have survived at least 2 years post-transplant.

About 60% of patients were male, and 67% were non-Hispanic white. Their median age at HSCT was 36.4 years, and 65% received an MRD graft. Nineteen percent of patients were transplanted in 1980-1989, 52% were transplanted in 1990-1999, and 29% were transplanted in 2000-2010.

Fifty-eight percent of patients received Cy/total body irradiation (TBI), 18% received Bu/Cy, and 3% received reduced-intensity conditioning (RIC).

Sixty-one percent of patients had chronic graft-vs-host disease (cGVHD), and 32% had high-risk disease at the time of HSCT.

Survival

The patients were followed for a median of 16.7 years. Thirty percent (n=192) died after surviving at least 2 years post-HSCT.

The median time to death was 8.3 years (range, 2-29.5), and the median age at death was 49.2 (range, 7.8-69.8). At 20 years from HSCT, the overall survival was 68.6%.

HSCT recipients had a 4.4-fold increased risk of death compared with the age-, sex-, and race-matched general population.

“Non-relapse mortality was the major contributor to late mortality, with infection, second malignancies, and cGVHD being the most common causes of death,” Wu said.

Non-relapse mortality was 20%, and relapse-related mortality was 4%. Eight percent of patients died of infection, 6.3% died of cGVHD, and 3.7% died of second malignancies.

Health outcomes

Patients who were still alive at the time of the study were asked to complete the BMTSS-2 health questionnaire, which was used to examine the risk of grade 3/4 chronic health conditions.


A total of 288 patients completed the questionnaire, as did a sibling comparison group of 404 individuals.

Among the patients, the median age at allo-HSCT was 37.5 (range, 3.6-71.4), and the median duration of follow-up was 13.9 years (range, 2-34.6).

Sixty-two percent of patients received an MRD graft, and 38% had a matched, unrelated donor. Eighty-three percent of patients had TBI-based conditioning, 16% received Bu/Cy, and 2.7% received RIC.

The prevalence of grade 3/4 chronic health conditions was significantly higher among patients than among siblings—38% and 24%, respectively (P<0.0001).

The odds ratio (OR)—adjusted for age, sex, race, and socioeconomic status—was 2.7 (P<0.0001).

The cumulative incidence of any grade 3/4 condition at 20 years after HSCT was 47.2% among patients. Common conditions were diabetes (14.9%), second malignancies (12.6%), and coronary artery disease (10%).

The researchers found the risk of grade 3/4 morbidity was significantly higher for the following patient groups:

• Those age 45 and older (hazard ratio [HR]=3.3, P<0.0001)
• Patients with a matched, unrelated donor (HR=3.0, P<0.0001)
• Those who received peripheral blood or cord blood grafts as opposed to bone marrow (HR=2.7, P=0.006).

(This analysis was adjusted for race/ethnicity, sex, education, household income, insurance, cGVHD, and conditioning regimen).

Lower risk

To identify subpopulations with a reduced risk of long-term morbidity, the researchers calculated the risk in various CML patient groups compared to siblings.

The overall OR for CML patients compared with siblings was 2.7 (P<0.0001).

The OR for patients in first chronic phase who underwent HSCT before the age of 45 and had an MRD was 1.5 (P=0.1).

The OR for CML patients in first chronic phase who underwent HSCT before the age of 45, had an MRD, and received Bu/Cy conditioning was 0.8 (P=0.7).

“[W]e found that patients who received a matched, related donor transplant under the age of 45, with busulfan/cyclophosphamide, carried the same burden of morbidity as the sibling cohort,” Wu said. “These findings could help inform decisions regarding therapeutic options for the management of CML.”

Wu noted that the limited sample size in this study prevented the researchers from examining outcomes with RIC. And a lack of data at analysis prevented them from examining pre-HSCT and post-HSCT management of CML, the interval between diagnosis and HSCT, and the life-long economic burden of allo-HSCT.

However, she said data collection is ongoing, and the researchers hope to address some of these limitations.

*Information presented at the meeting differs from the abstract.

Blood for transfusion

Photo from UAB Hospital

SAN DIEGO—Results of the phase 3 TRIST study support the use of a restrictive red blood cell (RBC) transfusion strategy in patients undergoing hematopoietic stem cell transplant (HSCT) to treat hematologic disorders.

The study suggests a restrictive strategy—in which patients receive 2 RBC units if their hemoglobin level is below 70 g/L—is non-inferior to a liberal strategy—in which patients receive 2 units if their hemoglobin level is below 90 g/L.

Clinical outcomes and health-related quality of life (HRQOL) were similar with both strategies.

Therefore, a restrictive strategy should be considered the standard of care in patients undergoing HSCT, according to study investigator Jason Tay, MD, of the University of Calgary/Tom Baker Cancer Center in Alberta, Canada.

Dr Tay presented results of the TRIST study at the 2016 ASH Annual Meeting (abstract 1032*).

He noted that recent AABB guidelines recommend using a restrictive RBC transfusion strategy in most circumstances. However, these recommendations do not apply to patients treated for hematologic or oncologic diseases who are at risk of bleeding, as there is a lack of randomized trials in such patients.

So Dr Tay and his colleagues decided to conduct a randomized, controlled trial comparing 2 RBC transfusion strategies in patients undergoing HSCT to treat hematologic disorders.

The study enrolled 300 patients who underwent HSCT between March 28, 2011, and February 3, 2016, at 4 Canadian centers.

The patients were randomized to 1 of 2 transfusion strategies from day 0 to day 100 post-HSCT:

• Restrictive strategy (n=149)—patients received 2 RBC units if their hemoglobin levels were below 70 g/L, to target a hemoglobin level of 70-90 g/L
• Liberal strategy (n=150)—patients received 2 RBC units if their hemoglobin levels were below 90 g/L, to target a hemoglobin level of 90-110 g/L.

The median age was 57.47 (range, 48.94-62.66) in the restrictive group and 56.04 (range, 48.27-62.24) in the liberal group. Most patients were male—65.10% and 62.67%, respectively.

Patients had acute leukemia (25.50% and 24.00%, respectively), chronic leukemia (6.71% and 6.00%), myeloproliferative disorders (2.68% and 2.00%), lymphoma (30.87% and 33.33%), myeloma (24.16% and 28.00%), and other disorders (10.07% and 6.67%, respectively).

About half of patients in each transfusion group received an autologous HSCT (49.66% and 50.00%, respectively), and about half received an allogeneic HSCT (50.34% and 50.00%, respectively).

Transfusion use

The total number of RBC units transfused was 407 in the restrictive group and 753 in the liberal group. The median number of RBC units transfused per patient was 2 (range, 0-2) and 4 (range, 2-6), respectively. The mean number was 2.73 and 5.02, respectively (P=0.0004).

The total number of RBC transfusion episodes was 234 in the restrictive group and 407 in the liberal group. The median number per patient was 1 (range, 0-2) and 2 (range, 1-3), respectively, and the mean was 1.57 and 2.70, respectively (P=0.002).

The median storage duration of the RBC units transfused was 17 days (range, 13-23) in the restrictive group and 20 days (range, 15-25) in the liberal group. The mean was 18.46 and 19.95, respectively (P=0.0003).

The between-group difference in the overall mean pre-transfusion hemoglobin per patient over the study period was 13.71 g/L.

The median number of platelet units transfused was 2 (range, 1-3) in the

restrictive group and 3 (range, 1-4) in the liberal group. The mean was 3.84 and 3.61, respectively (P=0.6930).

The median number of platelet transfusion episodes was 2 for both groups (range, 1-3 and

1-4, respectively). The mean was 3.84 in the restrictive group and 3.61 in the liberal group (P=0.77).

Adherence

In both groups, there were cases of non-adherence to the trigger hemoglobin value.

There were 49 non-adherent patients (32.89%) in the restrictive group—35 in whom an RBC transfusion occurred above the assigned trigger and 14 in whom a transfusion did not occur when the assigned trigger was reached.

There were 83 non-adherent patients (55.3%) in the liberal group—11 in whom an RBC transfusion occurred above the assigned trigger and 72 in whom a transfusion did not occur when the assigned trigger was reached.

Sixty-nine patients (46.31%) in the restrictive group and 21 (14%) in the liberal group never received an RBC transfusion.

Outcomes

The study’s primary endpoint was HRQOL, as measured by the FACT-BMT scale.

The total FACT-BMT score at day 100 was 116.3 (range, 98-129.2) in the restrictive group and 109.2 (range, 92.1-125.2) in the liberal group (P<0.0001 for non-inferiority).

Non-inferiority in HRQOL was shown for all other time points assessed as well—day 7 (P<0.001), day 14 (P<0.0001), day 28 (P<0.0001), and day 60 (P<0.0001). Total FACT-BMT scores at all time points were higher for patients in the restrictive group than the liberal one.

The study’s secondary endpoints included clinical outcomes and FACT-Anemia scores at several time points.

There was no significant difference in clinical outcomes between the restrictive and liberal transfusion groups.

There were 2 cases of transplant-related mortality in the restrictive group and 4 in the liberal group (P=0.42). And there were 4 cases of sinusoidal obstruction syndrome in both groups (P=0.98).

The median Bearman toxicity score at day 28 was 2 in both groups (range, 1-3 and 1-4, respectively). The mean was 2.5 in the restrictive group and 2.8 in the liberal group (P=0.33).

There was no significant between-group difference in WHO bleeding score at day 14 (P=0.13), day 28 (P=0.81), or day 100 (P=0.28).

There was no significant difference between the transfusion groups in the length of hospital stay for patients who received autologous HSCT (P=0.95) or allogeneic HSCT (P=0.23) or in the number of hospital readmissions for patients who received autologous HSCT (P=0.29) or allogeneic HSCT (P=0.81).

The total FACT-Anemia score was significantly higher in the restrictive transfusion group at day 7 (P=0.03) and day 60 (P=0.03) post-HSCT.

However, there was no significant between-group difference in FACT-Anemia score at 14 days (P=0.07), 28 days (P=0.51), or 100 days (P=0.14).

Dr Tay said these results suggest a restrictive RBC transfusion strategy is non-inferior to a liberal one in patients undergoing HSCT to treat a hematologic disorder.

“Moreover, a restrictive strategy is safe and results in less blood transfusions,” he said. “We’d like to suggest that a strategy of 70 g/L can be considered the standard of care in patients undergoing a stem cell transplantation.”

*Information presented at the meeting differs from the abstract.

Blood for transfusion

Photo from UAB Hospital

SAN DIEGO—Results of the phase 3 TRIST study support the use of a restrictive red blood cell (RBC) transfusion strategy in patients undergoing hematopoietic stem cell transplant (HSCT) to treat hematologic disorders.

The study suggests a restrictive strategy—in which patients receive 2 RBC units if their hemoglobin level is below 70 g/L—is non-inferior to a liberal strategy—in which patients receive 2 units if their hemoglobin level is below 90 g/L.

Clinical outcomes and health-related quality of life (HRQOL) were similar with both strategies.

Therefore, a restrictive strategy should be considered the standard of care in patients undergoing HSCT, according to study investigator Jason Tay, MD, of the University of Calgary/Tom Baker Cancer Center in Alberta, Canada.

Dr Tay presented results of the TRIST study at the 2016 ASH Annual Meeting (abstract 1032*).

He noted that recent AABB guidelines recommend using a restrictive RBC transfusion strategy in most circumstances. However, these recommendations do not apply to patients treated for hematologic or oncologic diseases who are at risk of bleeding, as there is a lack of randomized trials in such patients.

So Dr Tay and his colleagues decided to conduct a randomized, controlled trial comparing 2 RBC transfusion strategies in patients undergoing HSCT to treat hematologic disorders.

The study enrolled 300 patients who underwent HSCT between March 28, 2011, and February 3, 2016, at 4 Canadian centers.

The patients were randomized to 1 of 2 transfusion strategies from day 0 to day 100 post-HSCT:

• Restrictive strategy (n=149)—patients received 2 RBC units if their hemoglobin levels were below 70 g/L, to target a hemoglobin level of 70-90 g/L
• Liberal strategy (n=150)—patients received 2 RBC units if their hemoglobin levels were below 90 g/L, to target a hemoglobin level of 90-110 g/L.

The median age was 57.47 (range, 48.94-62.66) in the restrictive group and 56.04 (range, 48.27-62.24) in the liberal group. Most patients were male—65.10% and 62.67%, respectively.

Patients had acute leukemia (25.50% and 24.00%, respectively), chronic leukemia (6.71% and 6.00%), myeloproliferative disorders (2.68% and 2.00%), lymphoma (30.87% and 33.33%), myeloma (24.16% and 28.00%), and other disorders (10.07% and 6.67%, respectively).

About half of patients in each transfusion group received an autologous HSCT (49.66% and 50.00%, respectively), and about half received an allogeneic HSCT (50.34% and 50.00%, respectively).

Transfusion use

The total number of RBC units transfused was 407 in the restrictive group and 753 in the liberal group. The median number of RBC units transfused per patient was 2 (range, 0-2) and 4 (range, 2-6), respectively. The mean number was 2.73 and 5.02, respectively (P=0.0004).

The total number of RBC transfusion episodes was 234 in the restrictive group and 407 in the liberal group. The median number per patient was 1 (range, 0-2) and 2 (range, 1-3), respectively, and the mean was 1.57 and 2.70, respectively (P=0.002).

The median storage duration of the RBC units transfused was 17 days (range, 13-23) in the restrictive group and 20 days (range, 15-25) in the liberal group. The mean was 18.46 and 19.95, respectively (P=0.0003).

The between-group difference in the overall mean pre-transfusion hemoglobin per patient over the study period was 13.71 g/L.

The median number of platelet units transfused was 2 (range, 1-3) in the

restrictive group and 3 (range, 1-4) in the liberal group. The mean was 3.84 and 3.61, respectively (P=0.6930).

The median number of platelet transfusion episodes was 2 for both groups (range, 1-3 and

1-4, respectively). The mean was 3.84 in the restrictive group and 3.61 in the liberal group (P=0.77).

Adherence

In both groups, there were cases of non-adherence to the trigger hemoglobin value.

There were 49 non-adherent patients (32.89%) in the restrictive group—35 in whom an RBC transfusion occurred above the assigned trigger and 14 in whom a transfusion did not occur when the assigned trigger was reached.

There were 83 non-adherent patients (55.3%) in the liberal group—11 in whom an RBC transfusion occurred above the assigned trigger and 72 in whom a transfusion did not occur when the assigned trigger was reached.

Sixty-nine patients (46.31%) in the restrictive group and 21 (14%) in the liberal group never received an RBC transfusion.

Outcomes

The study’s primary endpoint was HRQOL, as measured by the FACT-BMT scale.

The total FACT-BMT score at day 100 was 116.3 (range, 98-129.2) in the restrictive group and 109.2 (range, 92.1-125.2) in the liberal group (P<0.0001 for non-inferiority).

Non-inferiority in HRQOL was shown for all other time points assessed as well—day 7 (P<0.001), day 14 (P<0.0001), day 28 (P<0.0001), and day 60 (P<0.0001). Total FACT-BMT scores at all time points were higher for patients in the restrictive group than the liberal one.

The study’s secondary endpoints included clinical outcomes and FACT-Anemia scores at several time points.

There was no significant difference in clinical outcomes between the restrictive and liberal transfusion groups.

There were 2 cases of transplant-related mortality in the restrictive group and 4 in the liberal group (P=0.42). And there were 4 cases of sinusoidal obstruction syndrome in both groups (P=0.98).

The median Bearman toxicity score at day 28 was 2 in both groups (range, 1-3 and 1-4, respectively). The mean was 2.5 in the restrictive group and 2.8 in the liberal group (P=0.33).

There was no significant between-group difference in WHO bleeding score at day 14 (P=0.13), day 28 (P=0.81), or day 100 (P=0.28).

There was no significant difference between the transfusion groups in the length of hospital stay for patients who received autologous HSCT (P=0.95) or allogeneic HSCT (P=0.23) or in the number of hospital readmissions for patients who received autologous HSCT (P=0.29) or allogeneic HSCT (P=0.81).

The total FACT-Anemia score was significantly higher in the restrictive transfusion group at day 7 (P=0.03) and day 60 (P=0.03) post-HSCT.

However, there was no significant between-group difference in FACT-Anemia score at 14 days (P=0.07), 28 days (P=0.51), or 100 days (P=0.14).

Dr Tay said these results suggest a restrictive RBC transfusion strategy is non-inferior to a liberal one in patients undergoing HSCT to treat a hematologic disorder.

“Moreover, a restrictive strategy is safe and results in less blood transfusions,” he said. “We’d like to suggest that a strategy of 70 g/L can be considered the standard of care in patients undergoing a stem cell transplantation.”

*Information presented at the meeting differs from the abstract.

Blood for transfusion

Photo from UAB Hospital

SAN DIEGO—Results of the phase 3 TRIST study support the use of a restrictive red blood cell (RBC) transfusion strategy in patients undergoing hematopoietic stem cell transplant (HSCT) to treat hematologic disorders.

The study suggests a restrictive strategy—in which patients receive 2 RBC units if their hemoglobin level is below 70 g/L—is non-inferior to a liberal strategy—in which patients receive 2 units if their hemoglobin level is below 90 g/L.

Clinical outcomes and health-related quality of life (HRQOL) were similar with both strategies.

Therefore, a restrictive strategy should be considered the standard of care in patients undergoing HSCT, according to study investigator Jason Tay, MD, of the University of Calgary/Tom Baker Cancer Center in Alberta, Canada.

Dr Tay presented results of the TRIST study at the 2016 ASH Annual Meeting (abstract 1032*).

He noted that recent AABB guidelines recommend using a restrictive RBC transfusion strategy in most circumstances. However, these recommendations do not apply to patients treated for hematologic or oncologic diseases who are at risk of bleeding, as there is a lack of randomized trials in such patients.

So Dr Tay and his colleagues decided to conduct a randomized, controlled trial comparing 2 RBC transfusion strategies in patients undergoing HSCT to treat hematologic disorders.

The study enrolled 300 patients who underwent HSCT between March 28, 2011, and February 3, 2016, at 4 Canadian centers.

The patients were randomized to 1 of 2 transfusion strategies from day 0 to day 100 post-HSCT:

• Restrictive strategy (n=149)—patients received 2 RBC units if their hemoglobin levels were below 70 g/L, to target a hemoglobin level of 70-90 g/L
• Liberal strategy (n=150)—patients received 2 RBC units if their hemoglobin levels were below 90 g/L, to target a hemoglobin level of 90-110 g/L.

The median age was 57.47 (range, 48.94-62.66) in the restrictive group and 56.04 (range, 48.27-62.24) in the liberal group. Most patients were male—65.10% and 62.67%, respectively.

Patients had acute leukemia (25.50% and 24.00%, respectively), chronic leukemia (6.71% and 6.00%), myeloproliferative disorders (2.68% and 2.00%), lymphoma (30.87% and 33.33%), myeloma (24.16% and 28.00%), and other disorders (10.07% and 6.67%, respectively).

About half of patients in each transfusion group received an autologous HSCT (49.66% and 50.00%, respectively), and about half received an allogeneic HSCT (50.34% and 50.00%, respectively).

Transfusion use

The total number of RBC units transfused was 407 in the restrictive group and 753 in the liberal group. The median number of RBC units transfused per patient was 2 (range, 0-2) and 4 (range, 2-6), respectively. The mean number was 2.73 and 5.02, respectively (P=0.0004).

The total number of RBC transfusion episodes was 234 in the restrictive group and 407 in the liberal group. The median number per patient was 1 (range, 0-2) and 2 (range, 1-3), respectively, and the mean was 1.57 and 2.70, respectively (P=0.002).

The median storage duration of the RBC units transfused was 17 days (range, 13-23) in the restrictive group and 20 days (range, 15-25) in the liberal group. The mean was 18.46 and 19.95, respectively (P=0.0003).

The between-group difference in the overall mean pre-transfusion hemoglobin per patient over the study period was 13.71 g/L.

The median number of platelet units transfused was 2 (range, 1-3) in the

restrictive group and 3 (range, 1-4) in the liberal group. The mean was 3.84 and 3.61, respectively (P=0.6930).

The median number of platelet transfusion episodes was 2 for both groups (range, 1-3 and

1-4, respectively). The mean was 3.84 in the restrictive group and 3.61 in the liberal group (P=0.77).

Adherence

In both groups, there were cases of non-adherence to the trigger hemoglobin value.

There were 49 non-adherent patients (32.89%) in the restrictive group—35 in whom an RBC transfusion occurred above the assigned trigger and 14 in whom a transfusion did not occur when the assigned trigger was reached.

There were 83 non-adherent patients (55.3%) in the liberal group—11 in whom an RBC transfusion occurred above the assigned trigger and 72 in whom a transfusion did not occur when the assigned trigger was reached.

Sixty-nine patients (46.31%) in the restrictive group and 21 (14%) in the liberal group never received an RBC transfusion.

Outcomes

The study’s primary endpoint was HRQOL, as measured by the FACT-BMT scale.

The total FACT-BMT score at day 100 was 116.3 (range, 98-129.2) in the restrictive group and 109.2 (range, 92.1-125.2) in the liberal group (P<0.0001 for non-inferiority).

Non-inferiority in HRQOL was shown for all other time points assessed as well—day 7 (P<0.001), day 14 (P<0.0001), day 28 (P<0.0001), and day 60 (P<0.0001). Total FACT-BMT scores at all time points were higher for patients in the restrictive group than the liberal one.

The study’s secondary endpoints included clinical outcomes and FACT-Anemia scores at several time points.

There was no significant difference in clinical outcomes between the restrictive and liberal transfusion groups.

There were 2 cases of transplant-related mortality in the restrictive group and 4 in the liberal group (P=0.42). And there were 4 cases of sinusoidal obstruction syndrome in both groups (P=0.98).

The median Bearman toxicity score at day 28 was 2 in both groups (range, 1-3 and 1-4, respectively). The mean was 2.5 in the restrictive group and 2.8 in the liberal group (P=0.33).

There was no significant between-group difference in WHO bleeding score at day 14 (P=0.13), day 28 (P=0.81), or day 100 (P=0.28).

There was no significant difference between the transfusion groups in the length of hospital stay for patients who received autologous HSCT (P=0.95) or allogeneic HSCT (P=0.23) or in the number of hospital readmissions for patients who received autologous HSCT (P=0.29) or allogeneic HSCT (P=0.81).

The total FACT-Anemia score was significantly higher in the restrictive transfusion group at day 7 (P=0.03) and day 60 (P=0.03) post-HSCT.

However, there was no significant between-group difference in FACT-Anemia score at 14 days (P=0.07), 28 days (P=0.51), or 100 days (P=0.14).

Dr Tay said these results suggest a restrictive RBC transfusion strategy is non-inferior to a liberal one in patients undergoing HSCT to treat a hematologic disorder.

“Moreover, a restrictive strategy is safe and results in less blood transfusions,” he said. “We’d like to suggest that a strategy of 70 g/L can be considered the standard of care in patients undergoing a stem cell transplantation.”

*Information presented at the meeting differs from the abstract.

 

Hydroxyurea

Photo by Zak Hubbard

 

SAN DIEGO—Results of the PROUD-PV trial suggest ropeginterferon alfa-2b is safer than hydroxyurea (HU) for patients with polycythemia vera (PV).

In this phase 3 trial, ropeginterferon alfa-2b demonstrated non-inferiority to HU with regard to complete hematologic response (CHR).

Ropeginterferon alfa-2b also had a significantly better overall safety profile.

Unlike the patients who received HU, none of the patients on ropeginterferon alfa-2b developed secondary malignancies.

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, presented these results at the 2016 ASH Annual Meeting (abstract 475). The PROUD-PV study was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Gisslinger noted that interferons have been successful in treating PV since the 1980s, although toxicities contribute to discontinuation rates of approximately 25%. Still, interferons are the only known drugs with the potential for disease modification by specific targeting of the malignant clone.

Ropeginterferon alfa-2b is a long-acting, mono-pegylated proline interferon with improved pharmacokinetic properties that allow for administration once every 2 weeks.

The goal of PROUD-PV was to determine how this drug stacks up against HU in both treatment-naive and HU-pretreated patients with PV.

“Our results from the first and largest, prospective, controlled trial of an interferon in polycythemia vera confirm previously reported efficacy,” Dr Gisslinger said.

“The observed safety and tolerability profile of ropeginterferon appears to be superior compared to previously reported data of interferon treatment. The unique disease-modification capability of interferon and its potential to improve progression-free survival hold promise for long-term benefit for patients.”

Patients and treatment

PROUD-PV enrolled 254 patients, and they were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127). In both arms, 100% of patients were Caucasian, slightly more than half were female, and the median age was 60 (overall range, 21-85).

The median disease duration was 1.9 months in the ropeginterferon alfa-2b arm and 3.6 months in the HU arm. Thirty-seven percent (n=47) of patients in each arm had previously received HU.

The mean hematocrit was about 50% in both arms, the median spleen length was about 13 cm, about 90% of patients had a normal/slightly enlarged spleen, and the mean JAK2V617F burden was slightly more than 40%.

The median plateau dose was 450 µg in the ropeginterferon alfa-2b arm and 1250 mg in the HU arm.

A quarter (25.2%) of patients had dose reductions due to adverse events (AEs) in the ropeginterferon alfa-2b arm, as did 51.2% of patients in the HU arm. The 12-month discontinuation rate was 16.5% in the ropeginterferon alfa-2b arm and 12.6% in the HU arm.

Response

The study’s primary objective was to demonstrate non-inferiority of ropeginterferon alfa-2b compared to HU. For this, the researchers used the 12-month CHR rate. CHR was defined as normalization of red blood cell, white blood cell, and platelet counts (without phlebotomy).

At 12 months, in the intent-to-treat population, the CHR rate was 43.1% in the ropeginterferon alfa-2b arm and 45.6% in the HU arm (P=0.0028). In the per-protocol population, the CHR rate was 44.3% and 46.5%, respectively (P=0.0036).

The researchers therefore concluded that non-inferiority was demonstrated.

The study’s pre-specified primary endpoint was actually a composite of CHR and spleen length normality. However, this was confounded by the fact that the patients’ median spleen length was almost normal at baseline and the observed change was not clinically relevant.

In the intent-to-treat-population, CHR with spleen normality occurred in 21.3% of patients in the ropeginterferon alfa-2b arm and 27.6% of patients in the HU arm (P=0.2233).

Safety

The incidence of AEs was 81.9% in the ropeginterferon alfa-2b arm and 87.4% in the HU arm. The incidence of grade 3 AEs was 16.5% and 20.5%, respectively. And the incidence of treatment-related AEs was 59.6% and 75.6%, respectively (P<0.05).

There was a significantly higher incidence (P<0.01) of the following AEs in the HU arm than the ropeginterferon alfa-2b arm: anemia (24.4% vs 6.3%), leukopenia (21.3% vs 8.7%), thrombocytopenia (28.3% vs 15.0%), and nausea (11.8% vs 2.4%).

There was no significant difference in the incidence of fatigue—13.4% in the HU arm and 12.6% in the ropeginterferon alfa-2b arm.

Patients in the ropeginterferon alfa-2b arm had a significantly higher incidence of gamma-glutamyl transferase increase—14.2% vs 0.8% in the HU arm (P<0.01).

Patients in the ropeginterferon alfa-2b arm also had a higher—but non-significant—incidence of endocrine disorders (3.1% vs 0.8%), psychiatric disorders (1.6% vs 0%), cardiac/vascular disorders (3.1% vs 1.6%), and tissue disorders (1.6% vs 0%).

None of the patients in the ropeginterferon alfa-2b arm developed secondary related malignancies. In the HU arm, however, there were 2 cases of acute leukemia, 2 cases of basal cell carcinoma, and 1 case of malignant melanoma. (This includes data from the ongoing follow-up trial CONTINUATION-PV.)

Drug development

AOP Orphan Pharmaceuticals AG said that, in the coming months, it will submit data from PROUD-PV and the ongoing follow-up trial, CONTINUATION-PV, to obtain European marketing authorization for ropeginterferon alfa-2b.

PharmaEssentia plans to submit the same data to the US Food and Drug Administration.

PharmaEssentia discovered ropeginterferon alfa-2b and has licensed the rights for development and commercialization of the drug in myeloproliferative neoplasms to AOP Orphan Pharmaceuticals AG in Europe, the Commonwealth of Independent States, and Middle Eastern markets.

*Information presented at the meeting differs from the abstract.

 

Hydroxyurea

Photo by Zak Hubbard

 

SAN DIEGO—Results of the PROUD-PV trial suggest ropeginterferon alfa-2b is safer than hydroxyurea (HU) for patients with polycythemia vera (PV).

In this phase 3 trial, ropeginterferon alfa-2b demonstrated non-inferiority to HU with regard to complete hematologic response (CHR).

Ropeginterferon alfa-2b also had a significantly better overall safety profile.

Unlike the patients who received HU, none of the patients on ropeginterferon alfa-2b developed secondary malignancies.

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, presented these results at the 2016 ASH Annual Meeting (abstract 475). The PROUD-PV study was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Gisslinger noted that interferons have been successful in treating PV since the 1980s, although toxicities contribute to discontinuation rates of approximately 25%. Still, interferons are the only known drugs with the potential for disease modification by specific targeting of the malignant clone.

Ropeginterferon alfa-2b is a long-acting, mono-pegylated proline interferon with improved pharmacokinetic properties that allow for administration once every 2 weeks.

The goal of PROUD-PV was to determine how this drug stacks up against HU in both treatment-naive and HU-pretreated patients with PV.

“Our results from the first and largest, prospective, controlled trial of an interferon in polycythemia vera confirm previously reported efficacy,” Dr Gisslinger said.

“The observed safety and tolerability profile of ropeginterferon appears to be superior compared to previously reported data of interferon treatment. The unique disease-modification capability of interferon and its potential to improve progression-free survival hold promise for long-term benefit for patients.”

Patients and treatment

PROUD-PV enrolled 254 patients, and they were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127). In both arms, 100% of patients were Caucasian, slightly more than half were female, and the median age was 60 (overall range, 21-85).

The median disease duration was 1.9 months in the ropeginterferon alfa-2b arm and 3.6 months in the HU arm. Thirty-seven percent (n=47) of patients in each arm had previously received HU.

The mean hematocrit was about 50% in both arms, the median spleen length was about 13 cm, about 90% of patients had a normal/slightly enlarged spleen, and the mean JAK2V617F burden was slightly more than 40%.

The median plateau dose was 450 µg in the ropeginterferon alfa-2b arm and 1250 mg in the HU arm.

A quarter (25.2%) of patients had dose reductions due to adverse events (AEs) in the ropeginterferon alfa-2b arm, as did 51.2% of patients in the HU arm. The 12-month discontinuation rate was 16.5% in the ropeginterferon alfa-2b arm and 12.6% in the HU arm.

Response

The study’s primary objective was to demonstrate non-inferiority of ropeginterferon alfa-2b compared to HU. For this, the researchers used the 12-month CHR rate. CHR was defined as normalization of red blood cell, white blood cell, and platelet counts (without phlebotomy).

At 12 months, in the intent-to-treat population, the CHR rate was 43.1% in the ropeginterferon alfa-2b arm and 45.6% in the HU arm (P=0.0028). In the per-protocol population, the CHR rate was 44.3% and 46.5%, respectively (P=0.0036).

The researchers therefore concluded that non-inferiority was demonstrated.

The study’s pre-specified primary endpoint was actually a composite of CHR and spleen length normality. However, this was confounded by the fact that the patients’ median spleen length was almost normal at baseline and the observed change was not clinically relevant.

In the intent-to-treat-population, CHR with spleen normality occurred in 21.3% of patients in the ropeginterferon alfa-2b arm and 27.6% of patients in the HU arm (P=0.2233).

Safety

The incidence of AEs was 81.9% in the ropeginterferon alfa-2b arm and 87.4% in the HU arm. The incidence of grade 3 AEs was 16.5% and 20.5%, respectively. And the incidence of treatment-related AEs was 59.6% and 75.6%, respectively (P<0.05).

There was a significantly higher incidence (P<0.01) of the following AEs in the HU arm than the ropeginterferon alfa-2b arm: anemia (24.4% vs 6.3%), leukopenia (21.3% vs 8.7%), thrombocytopenia (28.3% vs 15.0%), and nausea (11.8% vs 2.4%).

There was no significant difference in the incidence of fatigue—13.4% in the HU arm and 12.6% in the ropeginterferon alfa-2b arm.

Patients in the ropeginterferon alfa-2b arm had a significantly higher incidence of gamma-glutamyl transferase increase—14.2% vs 0.8% in the HU arm (P<0.01).

Patients in the ropeginterferon alfa-2b arm also had a higher—but non-significant—incidence of endocrine disorders (3.1% vs 0.8%), psychiatric disorders (1.6% vs 0%), cardiac/vascular disorders (3.1% vs 1.6%), and tissue disorders (1.6% vs 0%).

None of the patients in the ropeginterferon alfa-2b arm developed secondary related malignancies. In the HU arm, however, there were 2 cases of acute leukemia, 2 cases of basal cell carcinoma, and 1 case of malignant melanoma. (This includes data from the ongoing follow-up trial CONTINUATION-PV.)

Drug development

AOP Orphan Pharmaceuticals AG said that, in the coming months, it will submit data from PROUD-PV and the ongoing follow-up trial, CONTINUATION-PV, to obtain European marketing authorization for ropeginterferon alfa-2b.

PharmaEssentia plans to submit the same data to the US Food and Drug Administration.

PharmaEssentia discovered ropeginterferon alfa-2b and has licensed the rights for development and commercialization of the drug in myeloproliferative neoplasms to AOP Orphan Pharmaceuticals AG in Europe, the Commonwealth of Independent States, and Middle Eastern markets.

*Information presented at the meeting differs from the abstract.

 

Hydroxyurea

Photo by Zak Hubbard

 

SAN DIEGO—Results of the PROUD-PV trial suggest ropeginterferon alfa-2b is safer than hydroxyurea (HU) for patients with polycythemia vera (PV).

In this phase 3 trial, ropeginterferon alfa-2b demonstrated non-inferiority to HU with regard to complete hematologic response (CHR).

Ropeginterferon alfa-2b also had a significantly better overall safety profile.

Unlike the patients who received HU, none of the patients on ropeginterferon alfa-2b developed secondary malignancies.

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, presented these results at the 2016 ASH Annual Meeting (abstract 475). The PROUD-PV study was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Gisslinger noted that interferons have been successful in treating PV since the 1980s, although toxicities contribute to discontinuation rates of approximately 25%. Still, interferons are the only known drugs with the potential for disease modification by specific targeting of the malignant clone.

Ropeginterferon alfa-2b is a long-acting, mono-pegylated proline interferon with improved pharmacokinetic properties that allow for administration once every 2 weeks.

The goal of PROUD-PV was to determine how this drug stacks up against HU in both treatment-naive and HU-pretreated patients with PV.

“Our results from the first and largest, prospective, controlled trial of an interferon in polycythemia vera confirm previously reported efficacy,” Dr Gisslinger said.

“The observed safety and tolerability profile of ropeginterferon appears to be superior compared to previously reported data of interferon treatment. The unique disease-modification capability of interferon and its potential to improve progression-free survival hold promise for long-term benefit for patients.”

Patients and treatment

PROUD-PV enrolled 254 patients, and they were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127). In both arms, 100% of patients were Caucasian, slightly more than half were female, and the median age was 60 (overall range, 21-85).

The median disease duration was 1.9 months in the ropeginterferon alfa-2b arm and 3.6 months in the HU arm. Thirty-seven percent (n=47) of patients in each arm had previously received HU.

The mean hematocrit was about 50% in both arms, the median spleen length was about 13 cm, about 90% of patients had a normal/slightly enlarged spleen, and the mean JAK2V617F burden was slightly more than 40%.

The median plateau dose was 450 µg in the ropeginterferon alfa-2b arm and 1250 mg in the HU arm.

A quarter (25.2%) of patients had dose reductions due to adverse events (AEs) in the ropeginterferon alfa-2b arm, as did 51.2% of patients in the HU arm. The 12-month discontinuation rate was 16.5% in the ropeginterferon alfa-2b arm and 12.6% in the HU arm.

Response

The study’s primary objective was to demonstrate non-inferiority of ropeginterferon alfa-2b compared to HU. For this, the researchers used the 12-month CHR rate. CHR was defined as normalization of red blood cell, white blood cell, and platelet counts (without phlebotomy).

At 12 months, in the intent-to-treat population, the CHR rate was 43.1% in the ropeginterferon alfa-2b arm and 45.6% in the HU arm (P=0.0028). In the per-protocol population, the CHR rate was 44.3% and 46.5%, respectively (P=0.0036).

The researchers therefore concluded that non-inferiority was demonstrated.

The study’s pre-specified primary endpoint was actually a composite of CHR and spleen length normality. However, this was confounded by the fact that the patients’ median spleen length was almost normal at baseline and the observed change was not clinically relevant.

In the intent-to-treat-population, CHR with spleen normality occurred in 21.3% of patients in the ropeginterferon alfa-2b arm and 27.6% of patients in the HU arm (P=0.2233).

Safety

The incidence of AEs was 81.9% in the ropeginterferon alfa-2b arm and 87.4% in the HU arm. The incidence of grade 3 AEs was 16.5% and 20.5%, respectively. And the incidence of treatment-related AEs was 59.6% and 75.6%, respectively (P<0.05).

There was a significantly higher incidence (P<0.01) of the following AEs in the HU arm than the ropeginterferon alfa-2b arm: anemia (24.4% vs 6.3%), leukopenia (21.3% vs 8.7%), thrombocytopenia (28.3% vs 15.0%), and nausea (11.8% vs 2.4%).

There was no significant difference in the incidence of fatigue—13.4% in the HU arm and 12.6% in the ropeginterferon alfa-2b arm.

Patients in the ropeginterferon alfa-2b arm had a significantly higher incidence of gamma-glutamyl transferase increase—14.2% vs 0.8% in the HU arm (P<0.01).

Patients in the ropeginterferon alfa-2b arm also had a higher—but non-significant—incidence of endocrine disorders (3.1% vs 0.8%), psychiatric disorders (1.6% vs 0%), cardiac/vascular disorders (3.1% vs 1.6%), and tissue disorders (1.6% vs 0%).

None of the patients in the ropeginterferon alfa-2b arm developed secondary related malignancies. In the HU arm, however, there were 2 cases of acute leukemia, 2 cases of basal cell carcinoma, and 1 case of malignant melanoma. (This includes data from the ongoing follow-up trial CONTINUATION-PV.)

Drug development

AOP Orphan Pharmaceuticals AG said that, in the coming months, it will submit data from PROUD-PV and the ongoing follow-up trial, CONTINUATION-PV, to obtain European marketing authorization for ropeginterferon alfa-2b.

PharmaEssentia plans to submit the same data to the US Food and Drug Administration.

PharmaEssentia discovered ropeginterferon alfa-2b and has licensed the rights for development and commercialization of the drug in myeloproliferative neoplasms to AOP Orphan Pharmaceuticals AG in Europe, the Commonwealth of Independent States, and Middle Eastern markets.

*Information presented at the meeting differs from the abstract.

Micrograph showing

acute myeloid leukemia

SAN DIEGO—A next-generation DNA hypomethylating agent has demonstrated clinical activity and an acceptable safety profile in relapsed/refractory acute myeloid leukemia (AML), according to researchers.

The agent, guadecitabine, produced a composite complete response (CRc) rate of 23% in a phase 2 study.

CRc was observed in all patient subgroups and was associated with longer survival, regardless of whether patients went on to receive a transplant.

Based on these results, researchers are initiating a phase 3 trial of the drug in relapsed/refractory AML.

Naval Daver, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented the phase 2 results at the 2016 ASH Annual Meeting (abstract 904). The study was sponsored by Astex Pharmaceuticals.

Guadecitabine (formerly SGI-110) is a hypomethylating dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase degradation. It is administered as a small volume subcutaneous injection, which results in extended decitabine exposure.

“Rapid metabolization, elimination shortens the in vivo exposure and may limit the efficacy of decitabine,” Dr Daver noted. “Guadecitabine was engineered to improve the in vivo levels . . . and the efficacy of decitabine by blocking the rapid elimination.”

In the phase 2 trial, Dr Daver and his colleagues investigated guadecitabine in 103 patients with relapsed/refractory AML. The patients’ median age was 60 (range, 22-82), and 60% were male. Eighty-six percent of patients had an ECOG performance status of 0-1, and 41% had poor-risk cytogenetics.

The median number of prior therapies was 2 (range, 1-7). All patients had received prior chemotherapy, 85% had received prior induction with 7+3 (a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days), and 18% had a prior hematopoietic stem cell transplant (HSCT).

Fifty-three percent of patients had a CR to first induction, and 47% were primary refractory.

Treatment

The researchers tested 2 different doses and schedules of guadecitabine. In the first cohort (5-day regimen), 50 patients were randomized (1:1) to either 60 mg/m²/day (n=24) or 90 mg/m²/day (n=26) on days 1-5.

In the second cohort (10-day regimen), 53 patients were assigned to treatment with 60 mg/m²/day on days 1-5 and days 8-12 for up to 4 cycles, followed by 60 mg/m²/day on days 1-5 in subsequent cycles.

Cycles were scheduled every 28 days for both regimens. Dose reductions and delays were allowed based on response and tolerability. And patients remained on treatment as long as they continued to benefit without unacceptable toxicity.

Response

The study’s primary endpoint was the CRc rate, which consisted of CR plus CR with incomplete platelet recovery (CRp) plus CR with incomplete neutrophil recovery (CRi).

The CRc rate was 16% in the 5-day cohort and 30% in the 10-day cohort. The CR rate was 6% and 19%, respectively. The CRp rate was 2% and 7%, respectively. And the CRi rate was 8% and 4%, respectively.

There was a trend toward a higher CR/CRc rate with the 10-day regimen (P=0.074 and 0.106, respectively).

There was no significant difference in CRc according to patient age (65 and older vs younger than 65), cytogenetics, prior HSCT, response to induction, or time from last therapy (less than 6 months vs 6 months or more).

However, the CRc rate was significantly lower for patients with an ECOG performance status of 2 than for those with a status of 0-1 (P<0.001).

Survival

For the entire study cohort, the median overall survival (OS) was 6.6 months, the 1-year OS was 28%, and the 2-year OS was 19%.

The median OS was 7.1 months with the 10-day regimen and 5.7 months with the 5-day regimen. This difference was not significant (P=0.51).

The median OS was not reached for patients who achieved a CR or for those who achieved a CRp plus a CRi. For patients who did not achieve a CRc, the median OS was 5.6 months (P<0.01).

The median OS was not reached for patients who had a CRc, whether or not they received a subsequent HSCT. There was no significant difference between patients who received an HSCT post-guadecitabine and those who did not (P=0.87).

Likewise, there was no significant difference in OS according to patient age, prior HSCT, or response to induction.

However, OS was significantly worse for patients with an ECOG performance status of 2 (P<0.001), those with poor-risk cytogenetics (P<0.001), and those for whom 6 months or more had elapsed since their last therapy (P=0.015).

Safety

Common grade 3 or higher adverse events (regardless of the relationship to therapy) were febrile neutropenia (60%), pneumonia (36%), thrombocytopenia (36%), anemia (31%), neutropenia (19%), and sepsis (16%).

The 30-day mortality rate was 3.9%, and the 60-day mortality rate was 11.7%.

Micrograph showing

acute myeloid leukemia

SAN DIEGO—A next-generation DNA hypomethylating agent has demonstrated clinical activity and an acceptable safety profile in relapsed/refractory acute myeloid leukemia (AML), according to researchers.

The agent, guadecitabine, produced a composite complete response (CRc) rate of 23% in a phase 2 study.

CRc was observed in all patient subgroups and was associated with longer survival, regardless of whether patients went on to receive a transplant.

Based on these results, researchers are initiating a phase 3 trial of the drug in relapsed/refractory AML.

Naval Daver, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented the phase 2 results at the 2016 ASH Annual Meeting (abstract 904). The study was sponsored by Astex Pharmaceuticals.

Guadecitabine (formerly SGI-110) is a hypomethylating dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase degradation. It is administered as a small volume subcutaneous injection, which results in extended decitabine exposure.

“Rapid metabolization, elimination shortens the in vivo exposure and may limit the efficacy of decitabine,” Dr Daver noted. “Guadecitabine was engineered to improve the in vivo levels . . . and the efficacy of decitabine by blocking the rapid elimination.”

In the phase 2 trial, Dr Daver and his colleagues investigated guadecitabine in 103 patients with relapsed/refractory AML. The patients’ median age was 60 (range, 22-82), and 60% were male. Eighty-six percent of patients had an ECOG performance status of 0-1, and 41% had poor-risk cytogenetics.

The median number of prior therapies was 2 (range, 1-7). All patients had received prior chemotherapy, 85% had received prior induction with 7+3 (a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days), and 18% had a prior hematopoietic stem cell transplant (HSCT).

Fifty-three percent of patients had a CR to first induction, and 47% were primary refractory.

Treatment

The researchers tested 2 different doses and schedules of guadecitabine. In the first cohort (5-day regimen), 50 patients were randomized (1:1) to either 60 mg/m²/day (n=24) or 90 mg/m²/day (n=26) on days 1-5.

In the second cohort (10-day regimen), 53 patients were assigned to treatment with 60 mg/m²/day on days 1-5 and days 8-12 for up to 4 cycles, followed by 60 mg/m²/day on days 1-5 in subsequent cycles.

Cycles were scheduled every 28 days for both regimens. Dose reductions and delays were allowed based on response and tolerability. And patients remained on treatment as long as they continued to benefit without unacceptable toxicity.

Response

The study’s primary endpoint was the CRc rate, which consisted of CR plus CR with incomplete platelet recovery (CRp) plus CR with incomplete neutrophil recovery (CRi).

The CRc rate was 16% in the 5-day cohort and 30% in the 10-day cohort. The CR rate was 6% and 19%, respectively. The CRp rate was 2% and 7%, respectively. And the CRi rate was 8% and 4%, respectively.

There was a trend toward a higher CR/CRc rate with the 10-day regimen (P=0.074 and 0.106, respectively).

There was no significant difference in CRc according to patient age (65 and older vs younger than 65), cytogenetics, prior HSCT, response to induction, or time from last therapy (less than 6 months vs 6 months or more).

However, the CRc rate was significantly lower for patients with an ECOG performance status of 2 than for those with a status of 0-1 (P<0.001).

Survival

For the entire study cohort, the median overall survival (OS) was 6.6 months, the 1-year OS was 28%, and the 2-year OS was 19%.

The median OS was 7.1 months with the 10-day regimen and 5.7 months with the 5-day regimen. This difference was not significant (P=0.51).

The median OS was not reached for patients who achieved a CR or for those who achieved a CRp plus a CRi. For patients who did not achieve a CRc, the median OS was 5.6 months (P<0.01).

The median OS was not reached for patients who had a CRc, whether or not they received a subsequent HSCT. There was no significant difference between patients who received an HSCT post-guadecitabine and those who did not (P=0.87).

Likewise, there was no significant difference in OS according to patient age, prior HSCT, or response to induction.

However, OS was significantly worse for patients with an ECOG performance status of 2 (P<0.001), those with poor-risk cytogenetics (P<0.001), and those for whom 6 months or more had elapsed since their last therapy (P=0.015).

Safety

Common grade 3 or higher adverse events (regardless of the relationship to therapy) were febrile neutropenia (60%), pneumonia (36%), thrombocytopenia (36%), anemia (31%), neutropenia (19%), and sepsis (16%).

The 30-day mortality rate was 3.9%, and the 60-day mortality rate was 11.7%.

Micrograph showing

acute myeloid leukemia

SAN DIEGO—A next-generation DNA hypomethylating agent has demonstrated clinical activity and an acceptable safety profile in relapsed/refractory acute myeloid leukemia (AML), according to researchers.

The agent, guadecitabine, produced a composite complete response (CRc) rate of 23% in a phase 2 study.

CRc was observed in all patient subgroups and was associated with longer survival, regardless of whether patients went on to receive a transplant.

Based on these results, researchers are initiating a phase 3 trial of the drug in relapsed/refractory AML.

Naval Daver, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented the phase 2 results at the 2016 ASH Annual Meeting (abstract 904). The study was sponsored by Astex Pharmaceuticals.

Guadecitabine (formerly SGI-110) is a hypomethylating dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase degradation. It is administered as a small volume subcutaneous injection, which results in extended decitabine exposure.

“Rapid metabolization, elimination shortens the in vivo exposure and may limit the efficacy of decitabine,” Dr Daver noted. “Guadecitabine was engineered to improve the in vivo levels . . . and the efficacy of decitabine by blocking the rapid elimination.”

In the phase 2 trial, Dr Daver and his colleagues investigated guadecitabine in 103 patients with relapsed/refractory AML. The patients’ median age was 60 (range, 22-82), and 60% were male. Eighty-six percent of patients had an ECOG performance status of 0-1, and 41% had poor-risk cytogenetics.

The median number of prior therapies was 2 (range, 1-7). All patients had received prior chemotherapy, 85% had received prior induction with 7+3 (a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days), and 18% had a prior hematopoietic stem cell transplant (HSCT).

Fifty-three percent of patients had a CR to first induction, and 47% were primary refractory.

Treatment

The researchers tested 2 different doses and schedules of guadecitabine. In the first cohort (5-day regimen), 50 patients were randomized (1:1) to either 60 mg/m²/day (n=24) or 90 mg/m²/day (n=26) on days 1-5.

In the second cohort (10-day regimen), 53 patients were assigned to treatment with 60 mg/m²/day on days 1-5 and days 8-12 for up to 4 cycles, followed by 60 mg/m²/day on days 1-5 in subsequent cycles.

Cycles were scheduled every 28 days for both regimens. Dose reductions and delays were allowed based on response and tolerability. And patients remained on treatment as long as they continued to benefit without unacceptable toxicity.

Response

The study’s primary endpoint was the CRc rate, which consisted of CR plus CR with incomplete platelet recovery (CRp) plus CR with incomplete neutrophil recovery (CRi).

The CRc rate was 16% in the 5-day cohort and 30% in the 10-day cohort. The CR rate was 6% and 19%, respectively. The CRp rate was 2% and 7%, respectively. And the CRi rate was 8% and 4%, respectively.

There was a trend toward a higher CR/CRc rate with the 10-day regimen (P=0.074 and 0.106, respectively).

There was no significant difference in CRc according to patient age (65 and older vs younger than 65), cytogenetics, prior HSCT, response to induction, or time from last therapy (less than 6 months vs 6 months or more).

However, the CRc rate was significantly lower for patients with an ECOG performance status of 2 than for those with a status of 0-1 (P<0.001).

Survival

For the entire study cohort, the median overall survival (OS) was 6.6 months, the 1-year OS was 28%, and the 2-year OS was 19%.

The median OS was 7.1 months with the 10-day regimen and 5.7 months with the 5-day regimen. This difference was not significant (P=0.51).

The median OS was not reached for patients who achieved a CR or for those who achieved a CRp plus a CRi. For patients who did not achieve a CRc, the median OS was 5.6 months (P<0.01).

The median OS was not reached for patients who had a CRc, whether or not they received a subsequent HSCT. There was no significant difference between patients who received an HSCT post-guadecitabine and those who did not (P=0.87).

Likewise, there was no significant difference in OS according to patient age, prior HSCT, or response to induction.

However, OS was significantly worse for patients with an ECOG performance status of 2 (P<0.001), those with poor-risk cytogenetics (P<0.001), and those for whom 6 months or more had elapsed since their last therapy (P=0.015).

Safety

Common grade 3 or higher adverse events (regardless of the relationship to therapy) were febrile neutropenia (60%), pneumonia (36%), thrombocytopenia (36%), anemia (31%), neutropenia (19%), and sepsis (16%).

The 30-day mortality rate was 3.9%, and the 60-day mortality rate was 11.7%.

2016 ASH Annual Meeting

© Todd Buchanan 2016

SAN DIEGO—The oral BCL-2 inhibitor venetoclax can produce high objective response rates (ORRs) in chronic lymphocytic leukemia (CLL) patients who have failed treatment with at least one B-cell receptor inhibitor, according to investigators.

In a phase 2 study, venetoclax produced an ORR of 67% among all patients enrolled.

The drug produced a 70% ORR among patients who had failed treatment with ibrutinib and a 62% ORR among patients who had failed idelalisib.

“This represents the first prospective study in this patient population and does demonstrate high rates of durable responses, certainly making [venetoclax] a very viable option for a challenging group of patients to treat,” said study investigator Jeffrey Jones, MD, of The Ohio State University in Columbus.

Dr Jones presented results from this trial at the 2016 ASH Annual Meeting (abstract 637*). This study is sponsored by AbbVie in collaboration with Genentech/Roche.

The trial enrolled patients with CLL who relapsed after or were refractory to ibrutinib (arm A) or idelalisib (arm B). At the time of the data cut-off, 64 patients had been enrolled and treated with venetoclax, including 43 patients in arm A and 21 in arm B.

Patients received venetoclax via a recommended dose-titration schedule—20 mg once daily in week 1, 50 mg daily in week 2, 100 mg daily in week 3, 200 mg daily in week 4, and 400 mg daily from week 5 onward. Patients continued to receive the drug until disease progression or unacceptable toxicity.

To mitigate the risk of tumor lysis syndrome (TLS), patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before the first dose of venetoclax.

Patients with a high tumor burden were hospitalized for the first 20 mg dose and the first 50 mg dose, and they received intravenous hydration and rasburicase. Laboratory values were monitored at the first dose and all dose increases.

Patient characteristics: Arm A

Among patients who had failed ibrutinib, the median age was 66 (range, 48-80). Forty-nine percent of the patients had del(17p), and 35% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 4 (range, 1-12). All patients had received ibrutinib, but 9% had also received idelalisib. Ninety-one percent of patients were refractory to ibrutinib, and 5% were refractory to idelalisib.

The median time on ibrutinib was 17 months (range, 1-56), and the median time on idelalisib was 10 months (range, 2-31).

Patient characteristics: Arm B

Among patients who had failed idelalisib, the median age was 68 (range, 56-85). Ten percent of patients had del(17p), and 52% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 3 (range, 1-11). All patients had received idelalisib, but 24% had also received ibrutinib. Sixty-seven percent of patients were refractory to idelalisib, and 10% were refractory to ibrutinib.

The median time on idelalisib was 8 months (range, 1-27), and the median time on ibrutinib was 6 months (range, 2-11).

Results: Arm A

The median time on study in arm A was 13 months (range, 0.1-18). Eighteen patients in this arm discontinued the study—12 due to disease progression, 3 due to adverse events (AEs), 2 due to stem cell transplant, and 1 patient withdrew consent.

The ORR was 70% according to an independent review committee (IRC) and 67% according to investigators.

The rate of complete response (CR) was 0%, and the rate of CR with incomplete bone marrow recovery (CRi) was 2% according to the IRC. According to investigators, the CR rate was 5%, and the CRi rate was 2%.

Sixty-seven percent of patients had a partial response (PR) according to the IRC, and 56% had a PR according to investigators.

Results: Arm B

The median time on study in arm B was 9 months (range, 1.3-16). Four patients in this arm discontinued the study—3 related to disease progression and 1 for an “other” reason.

The ORR was 62% according to the IRC and 57% according to investigators.

The rate of CR/CRi was 0% according to the IRC. According to investigators, the CR rate was 10%, and the CRi rate was 5%.

Sixty-two percent of patients had a PR according to the IRC, and 43% had a PR according to investigators.

Results: Overall

The ORR was 67% according to the IRC and 64% according to investigators.

Forty-five percent of patient samples analyzed (14/31) demonstrated minimal residual disease (MRD) negativity in the peripheral blood between weeks 24 and 48. Five patients with sustained MRD negativity had bone marrow evaluations, and 1 was MRD negative.

At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival for all patients was 80%.

“Venetoclax has been well-tolerated,” Dr Jones noted. “The toxicity profile in this study is consistent with previous reports. Most of the toxicity has been cytopenias, which can be managed with dose adjustments or supportive care interventions, such as G-CSF.”

All 64 patients experienced an AE. Common AEs were neutropenia (58%), thrombocytopenia (44%), diarrhea (42%), nausea (41%), anemia (36%), fatigue (31%), decreased white blood cell count (22%), and hyperphosphatemia (22%).

Eighty-three percent of patients had grade 3/4 AEs, including neutropenia (45%), thrombocytopenia (28%), anemia (22%), decreased white blood cell count (13%), febrile neutropenia (11%), and pneumonia (11%).

Fifty-three percent of patients had serious AEs, including febrile neutropenia (9%), pneumonia (8%), multi-organ failure (3%), septic shock (3%), and increased potassium (3%).

There were no cases of clinical TLS. However, 1 patient with high tumor burden met Howard criteria for laboratory TLS.

*Information presented at the meeting differs from the abstract.

2016 ASH Annual Meeting

© Todd Buchanan 2016

SAN DIEGO—The oral BCL-2 inhibitor venetoclax can produce high objective response rates (ORRs) in chronic lymphocytic leukemia (CLL) patients who have failed treatment with at least one B-cell receptor inhibitor, according to investigators.

In a phase 2 study, venetoclax produced an ORR of 67% among all patients enrolled.

The drug produced a 70% ORR among patients who had failed treatment with ibrutinib and a 62% ORR among patients who had failed idelalisib.

“This represents the first prospective study in this patient population and does demonstrate high rates of durable responses, certainly making [venetoclax] a very viable option for a challenging group of patients to treat,” said study investigator Jeffrey Jones, MD, of The Ohio State University in Columbus.

Dr Jones presented results from this trial at the 2016 ASH Annual Meeting (abstract 637*). This study is sponsored by AbbVie in collaboration with Genentech/Roche.

The trial enrolled patients with CLL who relapsed after or were refractory to ibrutinib (arm A) or idelalisib (arm B). At the time of the data cut-off, 64 patients had been enrolled and treated with venetoclax, including 43 patients in arm A and 21 in arm B.

Patients received venetoclax via a recommended dose-titration schedule—20 mg once daily in week 1, 50 mg daily in week 2, 100 mg daily in week 3, 200 mg daily in week 4, and 400 mg daily from week 5 onward. Patients continued to receive the drug until disease progression or unacceptable toxicity.

To mitigate the risk of tumor lysis syndrome (TLS), patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before the first dose of venetoclax.

Patients with a high tumor burden were hospitalized for the first 20 mg dose and the first 50 mg dose, and they received intravenous hydration and rasburicase. Laboratory values were monitored at the first dose and all dose increases.

Patient characteristics: Arm A

Among patients who had failed ibrutinib, the median age was 66 (range, 48-80). Forty-nine percent of the patients had del(17p), and 35% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 4 (range, 1-12). All patients had received ibrutinib, but 9% had also received idelalisib. Ninety-one percent of patients were refractory to ibrutinib, and 5% were refractory to idelalisib.

The median time on ibrutinib was 17 months (range, 1-56), and the median time on idelalisib was 10 months (range, 2-31).

Patient characteristics: Arm B

Among patients who had failed idelalisib, the median age was 68 (range, 56-85). Ten percent of patients had del(17p), and 52% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 3 (range, 1-11). All patients had received idelalisib, but 24% had also received ibrutinib. Sixty-seven percent of patients were refractory to idelalisib, and 10% were refractory to ibrutinib.

The median time on idelalisib was 8 months (range, 1-27), and the median time on ibrutinib was 6 months (range, 2-11).

Results: Arm A

The median time on study in arm A was 13 months (range, 0.1-18). Eighteen patients in this arm discontinued the study—12 due to disease progression, 3 due to adverse events (AEs), 2 due to stem cell transplant, and 1 patient withdrew consent.

The ORR was 70% according to an independent review committee (IRC) and 67% according to investigators.

The rate of complete response (CR) was 0%, and the rate of CR with incomplete bone marrow recovery (CRi) was 2% according to the IRC. According to investigators, the CR rate was 5%, and the CRi rate was 2%.

Sixty-seven percent of patients had a partial response (PR) according to the IRC, and 56% had a PR according to investigators.

Results: Arm B

The median time on study in arm B was 9 months (range, 1.3-16). Four patients in this arm discontinued the study—3 related to disease progression and 1 for an “other” reason.

The ORR was 62% according to the IRC and 57% according to investigators.

The rate of CR/CRi was 0% according to the IRC. According to investigators, the CR rate was 10%, and the CRi rate was 5%.

Sixty-two percent of patients had a PR according to the IRC, and 43% had a PR according to investigators.

Results: Overall

The ORR was 67% according to the IRC and 64% according to investigators.

Forty-five percent of patient samples analyzed (14/31) demonstrated minimal residual disease (MRD) negativity in the peripheral blood between weeks 24 and 48. Five patients with sustained MRD negativity had bone marrow evaluations, and 1 was MRD negative.

At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival for all patients was 80%.

“Venetoclax has been well-tolerated,” Dr Jones noted. “The toxicity profile in this study is consistent with previous reports. Most of the toxicity has been cytopenias, which can be managed with dose adjustments or supportive care interventions, such as G-CSF.”

All 64 patients experienced an AE. Common AEs were neutropenia (58%), thrombocytopenia (44%), diarrhea (42%), nausea (41%), anemia (36%), fatigue (31%), decreased white blood cell count (22%), and hyperphosphatemia (22%).

Eighty-three percent of patients had grade 3/4 AEs, including neutropenia (45%), thrombocytopenia (28%), anemia (22%), decreased white blood cell count (13%), febrile neutropenia (11%), and pneumonia (11%).

Fifty-three percent of patients had serious AEs, including febrile neutropenia (9%), pneumonia (8%), multi-organ failure (3%), septic shock (3%), and increased potassium (3%).

There were no cases of clinical TLS. However, 1 patient with high tumor burden met Howard criteria for laboratory TLS.

*Information presented at the meeting differs from the abstract.

2016 ASH Annual Meeting

© Todd Buchanan 2016

SAN DIEGO—The oral BCL-2 inhibitor venetoclax can produce high objective response rates (ORRs) in chronic lymphocytic leukemia (CLL) patients who have failed treatment with at least one B-cell receptor inhibitor, according to investigators.

In a phase 2 study, venetoclax produced an ORR of 67% among all patients enrolled.

The drug produced a 70% ORR among patients who had failed treatment with ibrutinib and a 62% ORR among patients who had failed idelalisib.

“This represents the first prospective study in this patient population and does demonstrate high rates of durable responses, certainly making [venetoclax] a very viable option for a challenging group of patients to treat,” said study investigator Jeffrey Jones, MD, of The Ohio State University in Columbus.

Dr Jones presented results from this trial at the 2016 ASH Annual Meeting (abstract 637*). This study is sponsored by AbbVie in collaboration with Genentech/Roche.

The trial enrolled patients with CLL who relapsed after or were refractory to ibrutinib (arm A) or idelalisib (arm B). At the time of the data cut-off, 64 patients had been enrolled and treated with venetoclax, including 43 patients in arm A and 21 in arm B.

Patients received venetoclax via a recommended dose-titration schedule—20 mg once daily in week 1, 50 mg daily in week 2, 100 mg daily in week 3, 200 mg daily in week 4, and 400 mg daily from week 5 onward. Patients continued to receive the drug until disease progression or unacceptable toxicity.

To mitigate the risk of tumor lysis syndrome (TLS), patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before the first dose of venetoclax.

Patients with a high tumor burden were hospitalized for the first 20 mg dose and the first 50 mg dose, and they received intravenous hydration and rasburicase. Laboratory values were monitored at the first dose and all dose increases.

Patient characteristics: Arm A

Among patients who had failed ibrutinib, the median age was 66 (range, 48-80). Forty-nine percent of the patients had del(17p), and 35% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 4 (range, 1-12). All patients had received ibrutinib, but 9% had also received idelalisib. Ninety-one percent of patients were refractory to ibrutinib, and 5% were refractory to idelalisib.

The median time on ibrutinib was 17 months (range, 1-56), and the median time on idelalisib was 10 months (range, 2-31).

Patient characteristics: Arm B

Among patients who had failed idelalisib, the median age was 68 (range, 56-85). Ten percent of patients had del(17p), and 52% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 3 (range, 1-11). All patients had received idelalisib, but 24% had also received ibrutinib. Sixty-seven percent of patients were refractory to idelalisib, and 10% were refractory to ibrutinib.

The median time on idelalisib was 8 months (range, 1-27), and the median time on ibrutinib was 6 months (range, 2-11).

Results: Arm A

The median time on study in arm A was 13 months (range, 0.1-18). Eighteen patients in this arm discontinued the study—12 due to disease progression, 3 due to adverse events (AEs), 2 due to stem cell transplant, and 1 patient withdrew consent.

The ORR was 70% according to an independent review committee (IRC) and 67% according to investigators.

The rate of complete response (CR) was 0%, and the rate of CR with incomplete bone marrow recovery (CRi) was 2% according to the IRC. According to investigators, the CR rate was 5%, and the CRi rate was 2%.

Sixty-seven percent of patients had a partial response (PR) according to the IRC, and 56% had a PR according to investigators.

Results: Arm B

The median time on study in arm B was 9 months (range, 1.3-16). Four patients in this arm discontinued the study—3 related to disease progression and 1 for an “other” reason.

The ORR was 62% according to the IRC and 57% according to investigators.

The rate of CR/CRi was 0% according to the IRC. According to investigators, the CR rate was 10%, and the CRi rate was 5%.

Sixty-two percent of patients had a PR according to the IRC, and 43% had a PR according to investigators.

Results: Overall

The ORR was 67% according to the IRC and 64% according to investigators.

Forty-five percent of patient samples analyzed (14/31) demonstrated minimal residual disease (MRD) negativity in the peripheral blood between weeks 24 and 48. Five patients with sustained MRD negativity had bone marrow evaluations, and 1 was MRD negative.

At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival for all patients was 80%.

“Venetoclax has been well-tolerated,” Dr Jones noted. “The toxicity profile in this study is consistent with previous reports. Most of the toxicity has been cytopenias, which can be managed with dose adjustments or supportive care interventions, such as G-CSF.”

All 64 patients experienced an AE. Common AEs were neutropenia (58%), thrombocytopenia (44%), diarrhea (42%), nausea (41%), anemia (36%), fatigue (31%), decreased white blood cell count (22%), and hyperphosphatemia (22%).

Eighty-three percent of patients had grade 3/4 AEs, including neutropenia (45%), thrombocytopenia (28%), anemia (22%), decreased white blood cell count (13%), febrile neutropenia (11%), and pneumonia (11%).

Fifty-three percent of patients had serious AEs, including febrile neutropenia (9%), pneumonia (8%), multi-organ failure (3%), septic shock (3%), and increased potassium (3%).

There were no cases of clinical TLS. However, 1 patient with high tumor burden met Howard criteria for laboratory TLS.

*Information presented at the meeting differs from the abstract.

Jacqueline Mays, DDS, PhD

Photo courtesy of NIH

SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).

A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.

The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.

However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.

Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).

Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.

According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.

Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.

“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.

“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”

Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.

In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.

The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.

Patient population

The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.

The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.

The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.

Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.

Treatment

The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.

The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.

Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.

Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.

Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.

Safety

Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.

However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.

On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.

Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).

Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.

Efficacy

The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.

Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.

Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.

Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.

Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.

Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).

Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).

Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).

The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).

“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”

Jacqueline Mays, DDS, PhD

Photo courtesy of NIH

SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).

A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.

The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.

However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.

Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).

Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.

According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.

Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.

“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.

“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”

Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.

In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.

The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.

Patient population

The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.

The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.

The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.

Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.

Treatment

The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.

The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.

Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.

Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.

Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.

Safety

Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.

However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.

On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.

Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).

Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.

Efficacy

The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.

Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.

Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.

Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.

Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.

Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).

Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).

Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).

The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).

“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”

Jacqueline Mays, DDS, PhD

Photo courtesy of NIH

SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).

A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.

The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.

However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.

Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).

Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.

According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.

Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.

“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.

“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”

Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.

In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.

The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.

Patient population

The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.

The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.

The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.

Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.

Treatment

The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.

The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.

Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.

Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.

Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.

Safety

Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.

However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.

On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.

Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).

Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.

Efficacy

The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.

Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.

Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.

Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.

Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.

Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).

Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).

Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).

The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).

“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”

 

 

Attendees at the 2016

ASH Annual Meeting

 

SAN DIEGO—When patients with chronic lymphocytic leukemia (CLL) cannot tolerate one Bruton’s tyrosine kinase (BTK) inhibitor, they may do well on another, according to a presentation at the 2016 ASH Annual Meeting.

Researchers conducting a phase 1/2 study found that acalabrutinib was “well-tolerated” and demonstrated “promising activity” in patients intolerant to ibrutinib.

Seventy-nine percent of patients responded to acalabrutinib.

And although 36% of patients had a recurrence of an adverse event (AE) they experienced while on ibrutinib, none of the patients discontinued acalabrutinib due to AE recurrence.

Farrukh T. Awan, MD, of The Ohio State University in Columbus, Ohio, presented these results at the meeting as abstract 638.*

Dr Awan noted that integrating ibrutinib into standard CLL therapy has improved patient outcomes, but a lack of tolerability observed in some patients suggests that more selective BTK inhibition may be desirable.

“We know that around 10% to 20% of patients who are treated with ibrutinib would have to stop therapy because of an adverse event,” Dr Awan said. “Acalabrutinib is a highly selective, potent BTK inhibitor that has shown promising efficacy, and that [research] was published last year.”

In this ongoing, phase 1/2 study, Dr Awan and his colleagues are testing acalabrutinib in patients with CLL/small lymphocytic leukemia. The study has enrolled multiple cohorts of patients—relapsed/refractory, treatment-naïve, Richter’s transformation/prolymphocytic leukemia, and ibrutinib intolerant.

At this year’s ASH meeting, Dr Awan presented data on the 33 CLL patients who were ibrutinib intolerant. The patients’ median age was 64 (range, 50-82), 61% were male, 97% had an ECOG performance status of 0-1, 52% had Rai stage III-IV, and 31% had bulky disease.

The median number of prior therapies was 4 (range, 2-13), and 91% of patients had ibrutinib as their last therapy. The median duration of prior ibrutinib treatment was 11.5 months (range, 1-62), and the median time from ending ibrutinib to starting acalabrutinib was 47 days (range, 3-331 days).

Treatment and safety

Patients received acalabrutinib at 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The patients’ median time on therapy was 12.2 months (range, 0.2-23.6 months).

Nine patients discontinued treatment—3 due to disease progression, 3 due to AEs, 2 due to an increase in BTK C481S mutation frequency in the peripheral blood and central nervous system involvement, and 1 due to physician decision (because the patient had concurrent hemophilia).

The 3 AEs that led to treatment discontinuation were fatal hemorrhagic stroke, fatal fungal infection, and metastatic endometrial cancer. All 3 events were considered unrelated to acalabrutinib.

Serious AEs occurred in 11 patients (33%). A serious AE that occurred in more than 1 patient was pneumonia (n=2).

The most common AEs were diarrhea (52%, grade 1-2), headache (39%, grade 1-2), cough (24%, grade 1-2), increased weight (24%, grade 1-2), nausea (21%, grade 1-2), contusion (18%, grade 1-2), ecchymosis (18%, grade 1-2), fatigue (18%, grade 1-2), hypertension (18% overall, 6% ≥ grade 3), pyrexia (18% overall, 3% ≥ grade 3), vomiting (18%, grade 1-2), myalgia (15% overall, 3% ≥ grade 3), rash (15%, grade 1-2), stomatitis (15%, grade 1-2), upper respiratory tract infection (15%, grade 1-2), and urinary tract infection (15%, grade 1-2).

AE recurrence

Twelve patients (36%) had a recurrence of ibrutinib-related AEs—a total of 16 events. Fourteen of these events either decreased in severity or were unchanged with acalabrutinib treatment.

The events without a change in severity were atrial fibrillation (n=1), fatigue (n=1), muscle spasms (n=1), myalgia (n=1), peripheral edema (n=1), panniculitis (n=1), and rash (n=1).

The events that decreased in severity were diarrhea (n=2), arthralgia (n=1), ecchymosis (n=1), fatigue (n=1), panniculitis (n=1), and rash (n=1).

The events that increased in severity were contusion (n=1, grade 1 to 2) and fatigue (n=1, grade 1 to 2).

None of the patients discontinued acalabrutinib due to AE recurrence.

Efficacy

Twenty-nine patients were evaluable for efficacy.

The overall response rate was 79% (n=23). One patient had a complete response (3%), 15 had a partial response (52%), and 7 had a partial response with lymphocytosis (24%). Six patients had stable disease (21%).

The median time to response was 1.9 months. Eighty-one percent of responding patients have a response duration of 12 months or longer.

The median progression-free survival has not been reached.

The research is sponsored by Acerta Pharma.

*Information presented at the meeting differs from the abstract.

 

 

Attendees at the 2016

ASH Annual Meeting

 

SAN DIEGO—When patients with chronic lymphocytic leukemia (CLL) cannot tolerate one Bruton’s tyrosine kinase (BTK) inhibitor, they may do well on another, according to a presentation at the 2016 ASH Annual Meeting.

Researchers conducting a phase 1/2 study found that acalabrutinib was “well-tolerated” and demonstrated “promising activity” in patients intolerant to ibrutinib.

Seventy-nine percent of patients responded to acalabrutinib.

And although 36% of patients had a recurrence of an adverse event (AE) they experienced while on ibrutinib, none of the patients discontinued acalabrutinib due to AE recurrence.

Farrukh T. Awan, MD, of The Ohio State University in Columbus, Ohio, presented these results at the meeting as abstract 638.*

Dr Awan noted that integrating ibrutinib into standard CLL therapy has improved patient outcomes, but a lack of tolerability observed in some patients suggests that more selective BTK inhibition may be desirable.

“We know that around 10% to 20% of patients who are treated with ibrutinib would have to stop therapy because of an adverse event,” Dr Awan said. “Acalabrutinib is a highly selective, potent BTK inhibitor that has shown promising efficacy, and that [research] was published last year.”

In this ongoing, phase 1/2 study, Dr Awan and his colleagues are testing acalabrutinib in patients with CLL/small lymphocytic leukemia. The study has enrolled multiple cohorts of patients—relapsed/refractory, treatment-naïve, Richter’s transformation/prolymphocytic leukemia, and ibrutinib intolerant.

At this year’s ASH meeting, Dr Awan presented data on the 33 CLL patients who were ibrutinib intolerant. The patients’ median age was 64 (range, 50-82), 61% were male, 97% had an ECOG performance status of 0-1, 52% had Rai stage III-IV, and 31% had bulky disease.

The median number of prior therapies was 4 (range, 2-13), and 91% of patients had ibrutinib as their last therapy. The median duration of prior ibrutinib treatment was 11.5 months (range, 1-62), and the median time from ending ibrutinib to starting acalabrutinib was 47 days (range, 3-331 days).

Treatment and safety

Patients received acalabrutinib at 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The patients’ median time on therapy was 12.2 months (range, 0.2-23.6 months).

Nine patients discontinued treatment—3 due to disease progression, 3 due to AEs, 2 due to an increase in BTK C481S mutation frequency in the peripheral blood and central nervous system involvement, and 1 due to physician decision (because the patient had concurrent hemophilia).

The 3 AEs that led to treatment discontinuation were fatal hemorrhagic stroke, fatal fungal infection, and metastatic endometrial cancer. All 3 events were considered unrelated to acalabrutinib.

Serious AEs occurred in 11 patients (33%). A serious AE that occurred in more than 1 patient was pneumonia (n=2).

The most common AEs were diarrhea (52%, grade 1-2), headache (39%, grade 1-2), cough (24%, grade 1-2), increased weight (24%, grade 1-2), nausea (21%, grade 1-2), contusion (18%, grade 1-2), ecchymosis (18%, grade 1-2), fatigue (18%, grade 1-2), hypertension (18% overall, 6% ≥ grade 3), pyrexia (18% overall, 3% ≥ grade 3), vomiting (18%, grade 1-2), myalgia (15% overall, 3% ≥ grade 3), rash (15%, grade 1-2), stomatitis (15%, grade 1-2), upper respiratory tract infection (15%, grade 1-2), and urinary tract infection (15%, grade 1-2).

AE recurrence

Twelve patients (36%) had a recurrence of ibrutinib-related AEs—a total of 16 events. Fourteen of these events either decreased in severity or were unchanged with acalabrutinib treatment.

The events without a change in severity were atrial fibrillation (n=1), fatigue (n=1), muscle spasms (n=1), myalgia (n=1), peripheral edema (n=1), panniculitis (n=1), and rash (n=1).

The events that decreased in severity were diarrhea (n=2), arthralgia (n=1), ecchymosis (n=1), fatigue (n=1), panniculitis (n=1), and rash (n=1).

The events that increased in severity were contusion (n=1, grade 1 to 2) and fatigue (n=1, grade 1 to 2).

None of the patients discontinued acalabrutinib due to AE recurrence.

Efficacy

Twenty-nine patients were evaluable for efficacy.

The overall response rate was 79% (n=23). One patient had a complete response (3%), 15 had a partial response (52%), and 7 had a partial response with lymphocytosis (24%). Six patients had stable disease (21%).

The median time to response was 1.9 months. Eighty-one percent of responding patients have a response duration of 12 months or longer.

The median progression-free survival has not been reached.

The research is sponsored by Acerta Pharma.

*Information presented at the meeting differs from the abstract.

 

 

Attendees at the 2016

ASH Annual Meeting

 

SAN DIEGO—When patients with chronic lymphocytic leukemia (CLL) cannot tolerate one Bruton’s tyrosine kinase (BTK) inhibitor, they may do well on another, according to a presentation at the 2016 ASH Annual Meeting.

Researchers conducting a phase 1/2 study found that acalabrutinib was “well-tolerated” and demonstrated “promising activity” in patients intolerant to ibrutinib.

Seventy-nine percent of patients responded to acalabrutinib.

And although 36% of patients had a recurrence of an adverse event (AE) they experienced while on ibrutinib, none of the patients discontinued acalabrutinib due to AE recurrence.

Farrukh T. Awan, MD, of The Ohio State University in Columbus, Ohio, presented these results at the meeting as abstract 638.*

Dr Awan noted that integrating ibrutinib into standard CLL therapy has improved patient outcomes, but a lack of tolerability observed in some patients suggests that more selective BTK inhibition may be desirable.

“We know that around 10% to 20% of patients who are treated with ibrutinib would have to stop therapy because of an adverse event,” Dr Awan said. “Acalabrutinib is a highly selective, potent BTK inhibitor that has shown promising efficacy, and that [research] was published last year.”

In this ongoing, phase 1/2 study, Dr Awan and his colleagues are testing acalabrutinib in patients with CLL/small lymphocytic leukemia. The study has enrolled multiple cohorts of patients—relapsed/refractory, treatment-naïve, Richter’s transformation/prolymphocytic leukemia, and ibrutinib intolerant.

At this year’s ASH meeting, Dr Awan presented data on the 33 CLL patients who were ibrutinib intolerant. The patients’ median age was 64 (range, 50-82), 61% were male, 97% had an ECOG performance status of 0-1, 52% had Rai stage III-IV, and 31% had bulky disease.

The median number of prior therapies was 4 (range, 2-13), and 91% of patients had ibrutinib as their last therapy. The median duration of prior ibrutinib treatment was 11.5 months (range, 1-62), and the median time from ending ibrutinib to starting acalabrutinib was 47 days (range, 3-331 days).

Treatment and safety

Patients received acalabrutinib at 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The patients’ median time on therapy was 12.2 months (range, 0.2-23.6 months).

Nine patients discontinued treatment—3 due to disease progression, 3 due to AEs, 2 due to an increase in BTK C481S mutation frequency in the peripheral blood and central nervous system involvement, and 1 due to physician decision (because the patient had concurrent hemophilia).

The 3 AEs that led to treatment discontinuation were fatal hemorrhagic stroke, fatal fungal infection, and metastatic endometrial cancer. All 3 events were considered unrelated to acalabrutinib.

Serious AEs occurred in 11 patients (33%). A serious AE that occurred in more than 1 patient was pneumonia (n=2).

The most common AEs were diarrhea (52%, grade 1-2), headache (39%, grade 1-2), cough (24%, grade 1-2), increased weight (24%, grade 1-2), nausea (21%, grade 1-2), contusion (18%, grade 1-2), ecchymosis (18%, grade 1-2), fatigue (18%, grade 1-2), hypertension (18% overall, 6% ≥ grade 3), pyrexia (18% overall, 3% ≥ grade 3), vomiting (18%, grade 1-2), myalgia (15% overall, 3% ≥ grade 3), rash (15%, grade 1-2), stomatitis (15%, grade 1-2), upper respiratory tract infection (15%, grade 1-2), and urinary tract infection (15%, grade 1-2).

AE recurrence

Twelve patients (36%) had a recurrence of ibrutinib-related AEs—a total of 16 events. Fourteen of these events either decreased in severity or were unchanged with acalabrutinib treatment.

The events without a change in severity were atrial fibrillation (n=1), fatigue (n=1), muscle spasms (n=1), myalgia (n=1), peripheral edema (n=1), panniculitis (n=1), and rash (n=1).

The events that decreased in severity were diarrhea (n=2), arthralgia (n=1), ecchymosis (n=1), fatigue (n=1), panniculitis (n=1), and rash (n=1).

The events that increased in severity were contusion (n=1, grade 1 to 2) and fatigue (n=1, grade 1 to 2).

None of the patients discontinued acalabrutinib due to AE recurrence.

Efficacy

Twenty-nine patients were evaluable for efficacy.

The overall response rate was 79% (n=23). One patient had a complete response (3%), 15 had a partial response (52%), and 7 had a partial response with lymphocytosis (24%). Six patients had stable disease (21%).

The median time to response was 1.9 months. Eighty-one percent of responding patients have a response duration of 12 months or longer.

The median progression-free survival has not been reached.

The research is sponsored by Acerta Pharma.

*Information presented at the meeting differs from the abstract.