Jen Smith

Bristol-Myers Squibb

The U.S. Food and Drug Administration (FDA) has approved elotuzumab (Empliciti®) in combination with pomalidomide and dexamethasone.

The combination is now approved for use in adults with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is also FDA-approved in combination with lenalidomide and dexamethasone to treat adult MM patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from the phase 2 ELOQUENT-3 trial, which were presented at the 23rd Congress of the European Hematology Association in June.

ELOQUENT-3 enrolled MM patients who had refractory or relapsed and refractory MM and had received both lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n=60) or pomalidomide and dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P=0.0029). The rate of complete response or stringent complete response was 8.3% in the EPd arm and 1.8% in the Pd arm.

The median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (hazard ratio=0.54, P=0.0078).

Serious adverse events (AEs) occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious AEs (in the EPd and Pd arms, respectively) were pneumonia (13% and 11%) and respiratory tract infection (7% and 3.6%).

AEs occurring in at least 10% of patients in the EPd arm and at least 5% of those in the Pd arm (respectively) included:

• Constipation (22% and 11%)
• Hyperglycemia (20% and 15%)
• Pneumonia (18% and 13%)
• Diarrhea (18% and 9%)
• Respiratory tract infection (17% and 9%)
• Bone pain (15% and 9%)
• Dyspnea (15% and 7%)
• Muscle spasms (13% and 5%)
• Peripheral edema (13% and 7%)
• Lymphopenia (10% and 1.8%).

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available at www.empliciti.com.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Bristol-Myers Squibb

The U.S. Food and Drug Administration (FDA) has approved elotuzumab (Empliciti®) in combination with pomalidomide and dexamethasone.

The combination is now approved for use in adults with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is also FDA-approved in combination with lenalidomide and dexamethasone to treat adult MM patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from the phase 2 ELOQUENT-3 trial, which were presented at the 23rd Congress of the European Hematology Association in June.

ELOQUENT-3 enrolled MM patients who had refractory or relapsed and refractory MM and had received both lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n=60) or pomalidomide and dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P=0.0029). The rate of complete response or stringent complete response was 8.3% in the EPd arm and 1.8% in the Pd arm.

The median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (hazard ratio=0.54, P=0.0078).

Serious adverse events (AEs) occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious AEs (in the EPd and Pd arms, respectively) were pneumonia (13% and 11%) and respiratory tract infection (7% and 3.6%).

AEs occurring in at least 10% of patients in the EPd arm and at least 5% of those in the Pd arm (respectively) included:

• Constipation (22% and 11%)
• Hyperglycemia (20% and 15%)
• Pneumonia (18% and 13%)
• Diarrhea (18% and 9%)
• Respiratory tract infection (17% and 9%)
• Bone pain (15% and 9%)
• Dyspnea (15% and 7%)
• Muscle spasms (13% and 5%)
• Peripheral edema (13% and 7%)
• Lymphopenia (10% and 1.8%).

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available at www.empliciti.com.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Bristol-Myers Squibb

The U.S. Food and Drug Administration (FDA) has approved elotuzumab (Empliciti®) in combination with pomalidomide and dexamethasone.

The combination is now approved for use in adults with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is also FDA-approved in combination with lenalidomide and dexamethasone to treat adult MM patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from the phase 2 ELOQUENT-3 trial, which were presented at the 23rd Congress of the European Hematology Association in June.

ELOQUENT-3 enrolled MM patients who had refractory or relapsed and refractory MM and had received both lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n=60) or pomalidomide and dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P=0.0029). The rate of complete response or stringent complete response was 8.3% in the EPd arm and 1.8% in the Pd arm.

The median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (hazard ratio=0.54, P=0.0078).

Serious adverse events (AEs) occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious AEs (in the EPd and Pd arms, respectively) were pneumonia (13% and 11%) and respiratory tract infection (7% and 3.6%).

AEs occurring in at least 10% of patients in the EPd arm and at least 5% of those in the Pd arm (respectively) included:

• Constipation (22% and 11%)
• Hyperglycemia (20% and 15%)
• Pneumonia (18% and 13%)
• Diarrhea (18% and 9%)
• Respiratory tract infection (17% and 9%)
• Bone pain (15% and 9%)
• Dyspnea (15% and 7%)
• Muscle spasms (13% and 5%)
• Peripheral edema (13% and 7%)
• Lymphopenia (10% and 1.8%).

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available at www.empliciti.com.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Photo from Yale Cancer Center

Researchers have found evidence to suggest that phlebotomy and hydroxyurea (HU) provide real-world benefits for older patients with polycythemia vera (PV), but both treatments are underused.

In a study of more than 800 PV patients, phlebotomy and HU treatment were both associated with lower risks of death and thrombosis.

However, 39% of patients didn’t receive HU, and 36% didn’t undergo phlebotomy.

“Our study highlights the value of adhering to PV treatment guidelines,” said study author Nikolai A. Podoltsev, MD, PhD, of Yale Cancer Center in New Haven, Connecticut.

“Use of the two recommended treatments saves lives.”

Dr. Podoltsev and his colleagues described this survival benefit in Blood Advances.

The researchers studied data from the linked Surveillance, Epidemiology, and End Results–Medicare database. They collected information on 820 older adults diagnosed with PV from 2007 to 2013.

The patients’ median age was 77 (range, 71-83), 57% were female, 91.2% were white, 12.7% had a disability, and 13.2% had a prior thrombotic event.

Patients received the following PV treatments:

• Both phlebotomy and HU concurrently or sequentially (41.1%)
• Phlebotomy only (23.0%)
• HU only (19.6%)
• Neither phlebotomy nor HU (16.3%).

Survival

The median follow-up was 2.83 years. During that time, 37.2% of patients (n=305) died.

The median survival was 6.29 years for phlebotomy recipients and 4.50 years for non-recipients (P<0.01). The median survival was 6.02 years for HU recipients and 5.25 years for non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with decreased mortality. The hazard ratio (HR) for death was 0.65 (P<0.01) for phlebotomy recipients.

Increasing phlebotomy intensity (the number of phlebotomies per year) was also associated with decreased mortality, with an HR of 0.71 (P<0.01).

A higher proportion of days covered (PDC) by HU treatment was associated with decreased mortality as well.

The researchers said every 10% increase of HU PDC was associated with an 8% to 9% lower risk of death. The HR was 0.92 in a model where phlebotomy was a binary variable and 0.91 in a model that included the frequency of phlebotomy (P<0.01 for both).

Thrombosis

In all, 36.1% of patients (n=296) had a thrombotic event, which includes venous and arterial thrombosis.

The incidence of thrombosis was 29.3% (n=142) in phlebotomy recipients and 46.0% (n=154) in non-recipients (P<0.01). The incidence was 27.6% (n=118) in HU recipients and 45.4% (n=178) in non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with a decreased risk of thrombosis, with an HR of 0.52 (P<0.01).

Increasing phlebotomy intensity was associated with a decreased risk of thrombosis as well, with an HR of 0.46 (P<0.01).

And every 10% increase of HU PDC was associated with an 8% lower risk of thrombosis. The HR was 0.92 in both models (P<0.01 for both).

“All of the patients we studied were high-risk for clot development, and we now know from our findings that guideline-recommended treatments reduce the risk of both thrombosis and death,” Dr. Podoltsev said.

“We hope that our research will raise clinicians’ awareness of and adherence to the guidelines and improve the outcomes of PV patients in the future.”

This research was supported by the Frederick A. DeLuca Foundation. Study authors reported relationships with 24 pharmaceutical companies.

Photo from Yale Cancer Center

Researchers have found evidence to suggest that phlebotomy and hydroxyurea (HU) provide real-world benefits for older patients with polycythemia vera (PV), but both treatments are underused.

In a study of more than 800 PV patients, phlebotomy and HU treatment were both associated with lower risks of death and thrombosis.

However, 39% of patients didn’t receive HU, and 36% didn’t undergo phlebotomy.

“Our study highlights the value of adhering to PV treatment guidelines,” said study author Nikolai A. Podoltsev, MD, PhD, of Yale Cancer Center in New Haven, Connecticut.

“Use of the two recommended treatments saves lives.”

Dr. Podoltsev and his colleagues described this survival benefit in Blood Advances.

The researchers studied data from the linked Surveillance, Epidemiology, and End Results–Medicare database. They collected information on 820 older adults diagnosed with PV from 2007 to 2013.

The patients’ median age was 77 (range, 71-83), 57% were female, 91.2% were white, 12.7% had a disability, and 13.2% had a prior thrombotic event.

Patients received the following PV treatments:

• Both phlebotomy and HU concurrently or sequentially (41.1%)
• Phlebotomy only (23.0%)
• HU only (19.6%)
• Neither phlebotomy nor HU (16.3%).

Survival

The median follow-up was 2.83 years. During that time, 37.2% of patients (n=305) died.

The median survival was 6.29 years for phlebotomy recipients and 4.50 years for non-recipients (P<0.01). The median survival was 6.02 years for HU recipients and 5.25 years for non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with decreased mortality. The hazard ratio (HR) for death was 0.65 (P<0.01) for phlebotomy recipients.

Increasing phlebotomy intensity (the number of phlebotomies per year) was also associated with decreased mortality, with an HR of 0.71 (P<0.01).

A higher proportion of days covered (PDC) by HU treatment was associated with decreased mortality as well.

The researchers said every 10% increase of HU PDC was associated with an 8% to 9% lower risk of death. The HR was 0.92 in a model where phlebotomy was a binary variable and 0.91 in a model that included the frequency of phlebotomy (P<0.01 for both).

Thrombosis

In all, 36.1% of patients (n=296) had a thrombotic event, which includes venous and arterial thrombosis.

The incidence of thrombosis was 29.3% (n=142) in phlebotomy recipients and 46.0% (n=154) in non-recipients (P<0.01). The incidence was 27.6% (n=118) in HU recipients and 45.4% (n=178) in non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with a decreased risk of thrombosis, with an HR of 0.52 (P<0.01).

Increasing phlebotomy intensity was associated with a decreased risk of thrombosis as well, with an HR of 0.46 (P<0.01).

And every 10% increase of HU PDC was associated with an 8% lower risk of thrombosis. The HR was 0.92 in both models (P<0.01 for both).

“All of the patients we studied were high-risk for clot development, and we now know from our findings that guideline-recommended treatments reduce the risk of both thrombosis and death,” Dr. Podoltsev said.

“We hope that our research will raise clinicians’ awareness of and adherence to the guidelines and improve the outcomes of PV patients in the future.”

This research was supported by the Frederick A. DeLuca Foundation. Study authors reported relationships with 24 pharmaceutical companies.

Photo from Yale Cancer Center

Researchers have found evidence to suggest that phlebotomy and hydroxyurea (HU) provide real-world benefits for older patients with polycythemia vera (PV), but both treatments are underused.

In a study of more than 800 PV patients, phlebotomy and HU treatment were both associated with lower risks of death and thrombosis.

However, 39% of patients didn’t receive HU, and 36% didn’t undergo phlebotomy.

“Our study highlights the value of adhering to PV treatment guidelines,” said study author Nikolai A. Podoltsev, MD, PhD, of Yale Cancer Center in New Haven, Connecticut.

“Use of the two recommended treatments saves lives.”

Dr. Podoltsev and his colleagues described this survival benefit in Blood Advances.

The researchers studied data from the linked Surveillance, Epidemiology, and End Results–Medicare database. They collected information on 820 older adults diagnosed with PV from 2007 to 2013.

The patients’ median age was 77 (range, 71-83), 57% were female, 91.2% were white, 12.7% had a disability, and 13.2% had a prior thrombotic event.

Patients received the following PV treatments:

• Both phlebotomy and HU concurrently or sequentially (41.1%)
• Phlebotomy only (23.0%)
• HU only (19.6%)
• Neither phlebotomy nor HU (16.3%).

Survival

The median follow-up was 2.83 years. During that time, 37.2% of patients (n=305) died.

The median survival was 6.29 years for phlebotomy recipients and 4.50 years for non-recipients (P<0.01). The median survival was 6.02 years for HU recipients and 5.25 years for non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with decreased mortality. The hazard ratio (HR) for death was 0.65 (P<0.01) for phlebotomy recipients.

Increasing phlebotomy intensity (the number of phlebotomies per year) was also associated with decreased mortality, with an HR of 0.71 (P<0.01).

A higher proportion of days covered (PDC) by HU treatment was associated with decreased mortality as well.

The researchers said every 10% increase of HU PDC was associated with an 8% to 9% lower risk of death. The HR was 0.92 in a model where phlebotomy was a binary variable and 0.91 in a model that included the frequency of phlebotomy (P<0.01 for both).

Thrombosis

In all, 36.1% of patients (n=296) had a thrombotic event, which includes venous and arterial thrombosis.

The incidence of thrombosis was 29.3% (n=142) in phlebotomy recipients and 46.0% (n=154) in non-recipients (P<0.01). The incidence was 27.6% (n=118) in HU recipients and 45.4% (n=178) in non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with a decreased risk of thrombosis, with an HR of 0.52 (P<0.01).

Increasing phlebotomy intensity was associated with a decreased risk of thrombosis as well, with an HR of 0.46 (P<0.01).

And every 10% increase of HU PDC was associated with an 8% lower risk of thrombosis. The HR was 0.92 in both models (P<0.01 for both).

“All of the patients we studied were high-risk for clot development, and we now know from our findings that guideline-recommended treatments reduce the risk of both thrombosis and death,” Dr. Podoltsev said.

“We hope that our research will raise clinicians’ awareness of and adherence to the guidelines and improve the outcomes of PV patients in the future.”

This research was supported by the Frederick A. DeLuca Foundation. Study authors reported relationships with 24 pharmaceutical companies.

Photo by Bill Branson

Denosumab can be effective against osteoporosis caused by transfusion-dependent thalassemia (TDT), according to research published in Blood Advances.

Researchers found that patients who received twice-yearly injections of denosumab experienced a significant increase in bone density and reduction in bone pain.

“Not only is denosumab associated with improved bone health and reduced pain, but its ease of administration may very well make this drug superior to bisphosphonates for the treatment of osteoporosis in patients with TDT and osteoporosis,” said study author Evangelos Terpos, MD, of the National and Kapodistrian University of Athens in Greece.

For this phase 2b study, Dr. Terpos and his colleagues evaluated 63 patients with TDT and osteoporosis.

They were randomized (in a double-blinded fashion) to receive 60 mg of denosumab (n=32) or placebo (n=31) on days 0 and 180 of a 12-month period. Patients in both arms also received daily supplements of calcium and vitamin D.

Baseline characteristics were largely similar between the treatment arms.

However, the mean value of bone-specific alkaline phosphatase (bALP) was significantly lower in the placebo arm than the denosumab arm—68.48 IU/L and 85.45 IU/L, respectively (P=0.013).

And the mean value of the tartrate-resistant acid phosphatase isoform-5b (TRACP-5b) marker was significantly higher in the denosumab arm than in the placebo arm—0.42 IU/L and 0.16 IU/L, respectively (P=0.026).

Results

The researchers measured bone mineral density in the L1-L4 lumbar spine, the wrist, and the femoral neck.

At 12 months, the mean increase in L1-L4 bone mineral density was 5.92% in the denosumab arm and 2.92% in the placebo arm (P=0.043).

The mean decrease in wrist bone mineral density was -0.26% and -3.92%, respectively (P=0.035).

And the mean increase in femoral neck bone mineral density was 4.08% and 1.96%, respectively (P=0.870).

Patients in the denosumab arm had a significant reduction in bone pain at 12 months, according to the McGill-Melzack scoring system and Huskisson’s visual analog scale (P<0.001 for both).

However, there was no significant change in pain for patients in the placebo arm (P=0.356 with Huskisson’s and P=0.768 with McGill-Melzack).

At 12 months, patients in the denosumab arm had experienced a significant reduction from baseline (P<0.001 for all) in several markers of bone remodeling, including:

• Soluble receptor activator of nuclear factor kappa-B ligand (sRANKL)
• Osteoprotegerin (OPG)
• sRANKL/OPG ratio
• C-terminal crosslinking telopeptide of type I collagen (CTX)
• TRACP-5b
• bALP.

There were no significant changes in dickkopf-1 (Dkk-1), sclerostin, or osteocalcin (OC) in the denosumab arm.

In the placebo arm, patients had a significant increase from baseline in several markers of bone remodeling, including sRANKL, OPG, Dkk-1, sclerostin, CTX, TRACP-5b, and bALP (P<0.001 for all). There was no significant change from baseline in the sRANKL/OPG ratio or OC.

In all, there were 17 adverse events (AEs) in 14 patients.

There were three grade 1 AEs in the placebo arm and 11 in the denosumab arm. Most grade 1 AEs in the denosumab arm were test abnormalities, although three were not—headache, diarrhea, and fever.

There were three serious AEs in the denosumab arm as well—pleural effusion (grade 3), atrial fibrillation (grade 3), and supraventricular tachycardia (grade 4). All three of these AEs were considered unrelated to denosumab.

This study was funded by Amgen, which markets denosumab as Xgeva. The authors said they had no competing financial interests.

Photo by Bill Branson

Denosumab can be effective against osteoporosis caused by transfusion-dependent thalassemia (TDT), according to research published in Blood Advances.

Researchers found that patients who received twice-yearly injections of denosumab experienced a significant increase in bone density and reduction in bone pain.

“Not only is denosumab associated with improved bone health and reduced pain, but its ease of administration may very well make this drug superior to bisphosphonates for the treatment of osteoporosis in patients with TDT and osteoporosis,” said study author Evangelos Terpos, MD, of the National and Kapodistrian University of Athens in Greece.

For this phase 2b study, Dr. Terpos and his colleagues evaluated 63 patients with TDT and osteoporosis.

They were randomized (in a double-blinded fashion) to receive 60 mg of denosumab (n=32) or placebo (n=31) on days 0 and 180 of a 12-month period. Patients in both arms also received daily supplements of calcium and vitamin D.

Baseline characteristics were largely similar between the treatment arms.

However, the mean value of bone-specific alkaline phosphatase (bALP) was significantly lower in the placebo arm than the denosumab arm—68.48 IU/L and 85.45 IU/L, respectively (P=0.013).

And the mean value of the tartrate-resistant acid phosphatase isoform-5b (TRACP-5b) marker was significantly higher in the denosumab arm than in the placebo arm—0.42 IU/L and 0.16 IU/L, respectively (P=0.026).

Results

The researchers measured bone mineral density in the L1-L4 lumbar spine, the wrist, and the femoral neck.

At 12 months, the mean increase in L1-L4 bone mineral density was 5.92% in the denosumab arm and 2.92% in the placebo arm (P=0.043).

The mean decrease in wrist bone mineral density was -0.26% and -3.92%, respectively (P=0.035).

And the mean increase in femoral neck bone mineral density was 4.08% and 1.96%, respectively (P=0.870).

Patients in the denosumab arm had a significant reduction in bone pain at 12 months, according to the McGill-Melzack scoring system and Huskisson’s visual analog scale (P<0.001 for both).

However, there was no significant change in pain for patients in the placebo arm (P=0.356 with Huskisson’s and P=0.768 with McGill-Melzack).

At 12 months, patients in the denosumab arm had experienced a significant reduction from baseline (P<0.001 for all) in several markers of bone remodeling, including:

• Soluble receptor activator of nuclear factor kappa-B ligand (sRANKL)
• Osteoprotegerin (OPG)
• sRANKL/OPG ratio
• C-terminal crosslinking telopeptide of type I collagen (CTX)
• TRACP-5b
• bALP.

There were no significant changes in dickkopf-1 (Dkk-1), sclerostin, or osteocalcin (OC) in the denosumab arm.

In the placebo arm, patients had a significant increase from baseline in several markers of bone remodeling, including sRANKL, OPG, Dkk-1, sclerostin, CTX, TRACP-5b, and bALP (P<0.001 for all). There was no significant change from baseline in the sRANKL/OPG ratio or OC.

In all, there were 17 adverse events (AEs) in 14 patients.

There were three grade 1 AEs in the placebo arm and 11 in the denosumab arm. Most grade 1 AEs in the denosumab arm were test abnormalities, although three were not—headache, diarrhea, and fever.

There were three serious AEs in the denosumab arm as well—pleural effusion (grade 3), atrial fibrillation (grade 3), and supraventricular tachycardia (grade 4). All three of these AEs were considered unrelated to denosumab.

This study was funded by Amgen, which markets denosumab as Xgeva. The authors said they had no competing financial interests.

Photo by Bill Branson

Denosumab can be effective against osteoporosis caused by transfusion-dependent thalassemia (TDT), according to research published in Blood Advances.

Researchers found that patients who received twice-yearly injections of denosumab experienced a significant increase in bone density and reduction in bone pain.

“Not only is denosumab associated with improved bone health and reduced pain, but its ease of administration may very well make this drug superior to bisphosphonates for the treatment of osteoporosis in patients with TDT and osteoporosis,” said study author Evangelos Terpos, MD, of the National and Kapodistrian University of Athens in Greece.

For this phase 2b study, Dr. Terpos and his colleagues evaluated 63 patients with TDT and osteoporosis.

They were randomized (in a double-blinded fashion) to receive 60 mg of denosumab (n=32) or placebo (n=31) on days 0 and 180 of a 12-month period. Patients in both arms also received daily supplements of calcium and vitamin D.

Baseline characteristics were largely similar between the treatment arms.

However, the mean value of bone-specific alkaline phosphatase (bALP) was significantly lower in the placebo arm than the denosumab arm—68.48 IU/L and 85.45 IU/L, respectively (P=0.013).

And the mean value of the tartrate-resistant acid phosphatase isoform-5b (TRACP-5b) marker was significantly higher in the denosumab arm than in the placebo arm—0.42 IU/L and 0.16 IU/L, respectively (P=0.026).

Results

The researchers measured bone mineral density in the L1-L4 lumbar spine, the wrist, and the femoral neck.

At 12 months, the mean increase in L1-L4 bone mineral density was 5.92% in the denosumab arm and 2.92% in the placebo arm (P=0.043).

The mean decrease in wrist bone mineral density was -0.26% and -3.92%, respectively (P=0.035).

And the mean increase in femoral neck bone mineral density was 4.08% and 1.96%, respectively (P=0.870).

Patients in the denosumab arm had a significant reduction in bone pain at 12 months, according to the McGill-Melzack scoring system and Huskisson’s visual analog scale (P<0.001 for both).

However, there was no significant change in pain for patients in the placebo arm (P=0.356 with Huskisson’s and P=0.768 with McGill-Melzack).

At 12 months, patients in the denosumab arm had experienced a significant reduction from baseline (P<0.001 for all) in several markers of bone remodeling, including:

• Soluble receptor activator of nuclear factor kappa-B ligand (sRANKL)
• Osteoprotegerin (OPG)
• sRANKL/OPG ratio
• C-terminal crosslinking telopeptide of type I collagen (CTX)
• TRACP-5b
• bALP.

There were no significant changes in dickkopf-1 (Dkk-1), sclerostin, or osteocalcin (OC) in the denosumab arm.

In the placebo arm, patients had a significant increase from baseline in several markers of bone remodeling, including sRANKL, OPG, Dkk-1, sclerostin, CTX, TRACP-5b, and bALP (P<0.001 for all). There was no significant change from baseline in the sRANKL/OPG ratio or OC.

In all, there were 17 adverse events (AEs) in 14 patients.

There were three grade 1 AEs in the placebo arm and 11 in the denosumab arm. Most grade 1 AEs in the denosumab arm were test abnormalities, although three were not—headache, diarrhea, and fever.

There were three serious AEs in the denosumab arm as well—pleural effusion (grade 3), atrial fibrillation (grade 3), and supraventricular tachycardia (grade 4). All three of these AEs were considered unrelated to denosumab.

This study was funded by Amgen, which markets denosumab as Xgeva. The authors said they had no competing financial interests.

Photo by Rhoda Baer

A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia (FN) in patients with solid tumors and non-Hodgkin lymphoma (NHL).

Researchers found the timing and duration of corticosteroid use were both associated with FN.

The team also observed “marginal” associations between FN and certain dermatologic and mucosal conditions as well as the use of intravenous (IV) antibiotics before chemotherapy.

On the other hand, there was no association between oral antibiotic use and FN or between radiation therapy (RT) and FN.

Chun Rebecca Chao, PhD, of Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in JNCCN.

“Febrile neutropenia is life-threatening and often requires hospitalization,” Dr. Chao noted. “Furthermore, FN can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”

With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for FN by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.

Patients had been diagnosed with NHL (n=1,617) or breast (n=6,323), lung (n=3,584), colorectal (n=3,062), ovarian (n=924), or gastric (n=461) cancers.

In all, 4.3% of patients developed FN during their first cycle of chemotherapy.

Corticosteroid use

The researchers found corticosteroid use was associated with an increased risk of FN in a propensity score-adjusted (PSA) model (adjusted for age, sex, socioeconomic factors, comorbidities, etc.). The hazard ratio (HR) was 1.53 (95% CI, 1.17-1.98; P<0.01) for patients who received corticosteroids.

A longer duration of corticosteroid use was associated with a greater risk of FN. The adjusted HR (compared to no corticosteroid use) was:

• 1.78 for corticosteroid treatment lasting less than 15 days (P<0.01)
• 1.84 for treatment lasting 15 to 29 days (P<0.01)
• 2.27 for treatment lasting 30 to 44 days (P<0.01)
• 2.86 for treatment lasting 45 to 90 days (P<0.01).

More recent corticosteroid use was associated with a greater risk of FN as well. The adjusted HR was:

• 1.88 for corticosteroid treatment less than 15 days before chemotherapy (P<0.01)
• 1.13 for treatment 15 to 29 days before chemotherapy (P=0.72)
• 1.22 for treatment 30 to 44 days before chemotherapy (P=0.66)
• 1.41 for treatment 45 to 90 days before chemotherapy (P=0.32).

“One way to reduce the incidence rate for FN could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.

Other potential risk factors

The researchers found a “marginally” increased risk of FN in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus, etc.) and mucosal conditions (gastritis, stomatitis, mucositis, etc.).

In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P=0.05) for patients with these conditions.

IV antibiotic use was also found to be marginally associated with an increased risk of FN in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P=0.08).

On the other hand, there was no association between FN and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P=0.70) for patients who received oral antibiotics.

Dr. Chao and her colleagues said these results suggest IV antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received IV antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.

As with oral antibiotics, the researchers found no association between FN and the following factors (with the PSA model):

• Prior surgery (HR=0.89; 95% CI, 0.72-1.11; P=0.30)
• Prior RT (HR=0.91; 95% CI, 0.64-1.27; P=0.61)
• Concurrent RT (HR=1.32; 95% CI, 0.69-2.37; P=0.37).

The researchers noted that they did not account for radiation field or dose in this study, so additional evaluation of RT as a risk factor is needed.

In closing, Dr. Chao and her colleagues said these results suggest cor­ticosteroid use, IV antibiotics, and certain dermatologic and mucosal conditions should be tak­en into consideration when monitoring patients receiving myelosuppressive chemotherapy and when evaluating the need for prophylactic granulocyte colony-stimulating factor or chemotherapy dose reduction.

Dr. Chao and her colleagues received funding from Amgen, Inc., to perform this study.

Photo by Rhoda Baer

A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia (FN) in patients with solid tumors and non-Hodgkin lymphoma (NHL).

Researchers found the timing and duration of corticosteroid use were both associated with FN.

The team also observed “marginal” associations between FN and certain dermatologic and mucosal conditions as well as the use of intravenous (IV) antibiotics before chemotherapy.

On the other hand, there was no association between oral antibiotic use and FN or between radiation therapy (RT) and FN.

Chun Rebecca Chao, PhD, of Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in JNCCN.

“Febrile neutropenia is life-threatening and often requires hospitalization,” Dr. Chao noted. “Furthermore, FN can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”

With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for FN by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.

Patients had been diagnosed with NHL (n=1,617) or breast (n=6,323), lung (n=3,584), colorectal (n=3,062), ovarian (n=924), or gastric (n=461) cancers.

In all, 4.3% of patients developed FN during their first cycle of chemotherapy.

Corticosteroid use

The researchers found corticosteroid use was associated with an increased risk of FN in a propensity score-adjusted (PSA) model (adjusted for age, sex, socioeconomic factors, comorbidities, etc.). The hazard ratio (HR) was 1.53 (95% CI, 1.17-1.98; P<0.01) for patients who received corticosteroids.

A longer duration of corticosteroid use was associated with a greater risk of FN. The adjusted HR (compared to no corticosteroid use) was:

• 1.78 for corticosteroid treatment lasting less than 15 days (P<0.01)
• 1.84 for treatment lasting 15 to 29 days (P<0.01)
• 2.27 for treatment lasting 30 to 44 days (P<0.01)
• 2.86 for treatment lasting 45 to 90 days (P<0.01).

More recent corticosteroid use was associated with a greater risk of FN as well. The adjusted HR was:

• 1.88 for corticosteroid treatment less than 15 days before chemotherapy (P<0.01)
• 1.13 for treatment 15 to 29 days before chemotherapy (P=0.72)
• 1.22 for treatment 30 to 44 days before chemotherapy (P=0.66)
• 1.41 for treatment 45 to 90 days before chemotherapy (P=0.32).

“One way to reduce the incidence rate for FN could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.

Other potential risk factors

The researchers found a “marginally” increased risk of FN in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus, etc.) and mucosal conditions (gastritis, stomatitis, mucositis, etc.).

In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P=0.05) for patients with these conditions.

IV antibiotic use was also found to be marginally associated with an increased risk of FN in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P=0.08).

On the other hand, there was no association between FN and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P=0.70) for patients who received oral antibiotics.

Dr. Chao and her colleagues said these results suggest IV antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received IV antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.

As with oral antibiotics, the researchers found no association between FN and the following factors (with the PSA model):

• Prior surgery (HR=0.89; 95% CI, 0.72-1.11; P=0.30)
• Prior RT (HR=0.91; 95% CI, 0.64-1.27; P=0.61)
• Concurrent RT (HR=1.32; 95% CI, 0.69-2.37; P=0.37).

The researchers noted that they did not account for radiation field or dose in this study, so additional evaluation of RT as a risk factor is needed.

In closing, Dr. Chao and her colleagues said these results suggest cor­ticosteroid use, IV antibiotics, and certain dermatologic and mucosal conditions should be tak­en into consideration when monitoring patients receiving myelosuppressive chemotherapy and when evaluating the need for prophylactic granulocyte colony-stimulating factor or chemotherapy dose reduction.

Dr. Chao and her colleagues received funding from Amgen, Inc., to perform this study.

Photo by Rhoda Baer

A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia (FN) in patients with solid tumors and non-Hodgkin lymphoma (NHL).

Researchers found the timing and duration of corticosteroid use were both associated with FN.

The team also observed “marginal” associations between FN and certain dermatologic and mucosal conditions as well as the use of intravenous (IV) antibiotics before chemotherapy.

On the other hand, there was no association between oral antibiotic use and FN or between radiation therapy (RT) and FN.

Chun Rebecca Chao, PhD, of Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in JNCCN.

“Febrile neutropenia is life-threatening and often requires hospitalization,” Dr. Chao noted. “Furthermore, FN can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”

With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for FN by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.

Patients had been diagnosed with NHL (n=1,617) or breast (n=6,323), lung (n=3,584), colorectal (n=3,062), ovarian (n=924), or gastric (n=461) cancers.

In all, 4.3% of patients developed FN during their first cycle of chemotherapy.

Corticosteroid use

The researchers found corticosteroid use was associated with an increased risk of FN in a propensity score-adjusted (PSA) model (adjusted for age, sex, socioeconomic factors, comorbidities, etc.). The hazard ratio (HR) was 1.53 (95% CI, 1.17-1.98; P<0.01) for patients who received corticosteroids.

A longer duration of corticosteroid use was associated with a greater risk of FN. The adjusted HR (compared to no corticosteroid use) was:

• 1.78 for corticosteroid treatment lasting less than 15 days (P<0.01)
• 1.84 for treatment lasting 15 to 29 days (P<0.01)
• 2.27 for treatment lasting 30 to 44 days (P<0.01)
• 2.86 for treatment lasting 45 to 90 days (P<0.01).

More recent corticosteroid use was associated with a greater risk of FN as well. The adjusted HR was:

• 1.88 for corticosteroid treatment less than 15 days before chemotherapy (P<0.01)
• 1.13 for treatment 15 to 29 days before chemotherapy (P=0.72)
• 1.22 for treatment 30 to 44 days before chemotherapy (P=0.66)
• 1.41 for treatment 45 to 90 days before chemotherapy (P=0.32).

“One way to reduce the incidence rate for FN could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.

Other potential risk factors

The researchers found a “marginally” increased risk of FN in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus, etc.) and mucosal conditions (gastritis, stomatitis, mucositis, etc.).

In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P=0.05) for patients with these conditions.

IV antibiotic use was also found to be marginally associated with an increased risk of FN in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P=0.08).

On the other hand, there was no association between FN and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P=0.70) for patients who received oral antibiotics.

Dr. Chao and her colleagues said these results suggest IV antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received IV antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.

As with oral antibiotics, the researchers found no association between FN and the following factors (with the PSA model):

• Prior surgery (HR=0.89; 95% CI, 0.72-1.11; P=0.30)
• Prior RT (HR=0.91; 95% CI, 0.64-1.27; P=0.61)
• Concurrent RT (HR=1.32; 95% CI, 0.69-2.37; P=0.37).

The researchers noted that they did not account for radiation field or dose in this study, so additional evaluation of RT as a risk factor is needed.

In closing, Dr. Chao and her colleagues said these results suggest cor­ticosteroid use, IV antibiotics, and certain dermatologic and mucosal conditions should be tak­en into consideration when monitoring patients receiving myelosuppressive chemotherapy and when evaluating the need for prophylactic granulocyte colony-stimulating factor or chemotherapy dose reduction.

Dr. Chao and her colleagues received funding from Amgen, Inc., to perform this study.

Ali Bazarbachi, MD, PhD

DUBROVNIK, CROATIA—Hematopoietic stem cell transplant (HSCT) can be hit-or-miss in patients with peripheral T-cell lymphomas (PTCLs), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Ali Bazarbachi, MD, PhD, of the American University of Beirut in Lebanon, noted that the success of HSCT varies according to the subtype of PTCL and the type of transplant.

For example, autologous (auto) HSCT given as frontline consolidation can be considered the standard of care for PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), and certain patients with anaplastic large-cell lymphoma (ALCL), according to Dr. Bazarbachi.

On the other hand, auto-HSCT should never be used in patients with adult T-cell leukemia/lymphoma (ATLL).

Both auto-HSCT and allogeneic (allo) HSCT are options for patients with non-localized, extranodal natural killer T-cell lymphoma (ENKTL), nasal type, but only at certain times.

State of PTCL treatment

Dr. Bazarbachi began his presentation by pointing out that patients with newly diagnosed PTCL are no longer treated like patients with B-cell lymphoma, but treatment outcomes in PTCL still leave a lot to be desired.

He noted that, with any of the chemotherapy regimens used, typically, about a third of patients are primary refractory, a third relapse, and a quarter are cured. Only two forms of PTCL are frequently curable—localized ENKTL and ALK-positive ALCL.

Current treatment strategies for PTCL do include HSCT, but recommendations vary. Dr. Bazarbachi made the following recommendations, supported by evidence from clinical trials.

HSCT in PTCL-NOS, AITL, and ALCL

For patients with PTCL-NOS, AITL, or ALK-negative, non-DUSP22 ALCL, auto-HSCT as frontline consolidation can be considered the standard of care in patients who responded to induction, Dr. Bazarbachi said.

In a study published in 2012¹, high-dose chemotherapy and auto-HSCT as consolidation improved 5-year overall survival—compared to previous results with CHOP²—in patients with ALK-negative ALCL, AITL, PTCL-NOS, and enteropathy-associated T-cell lymphoma.

Allo-HSCT may also be an option for frontline consolidation in patients with PTCL-NOS, AITL, or ALK-negative, non-DUSP22 ALCL, according to Dr. Bazarbachi.

“Allo-transplant is not dead in this indication,” he said. “But it should be either part of a clinical trial or [given] to some selected patients—those with persistent bone marrow involvement, very young patients, or patients with primary refractory disease.”

Results from the COMPLETE study³ showed improved survival in patients who received consolidation with auto- or allo-HSCT, as compared to patients who did not receive a transplant.

COMPLETE patients with AITL or PTCL-NOS had improvements in progression-free and overall survival with HSCT. The survival advantage was “less evident” in patients with ALCL, the researchers said, but this trial included both ALK-negative and ALK-positive patients.

Dr. Bazarbachi noted that allo- and auto-HSCT can be options after relapse in patients with PTCL-NOS, AITL, or ALK-negative, non-DUSP22 ALCL.

However, chemosensitive patients who have relapsed should only receive auto-HSCT if they did not receive it frontline. Patients who have already undergone auto-HSCT can receive allo-HSCT, Dr. Bazarbachi said.

He added that refractory patients should not undergo auto-HSCT and should receive allo-HSCT only within the context of a clinical trial.

HSCT in ATLL

Dr. Bazarbachi noted that ATLL has a dismal prognosis, but allo-HSCT as frontline consolidation is potentially curative.^4,5 It is most effective in patients who have achieved a complete or partial response to induction.

However, allo-HSCT should not be given as consolidation to ATLL patients who have received prior mogamulizumab. These patients have an increased risk of morbidity and mortality if they undergo allo-HSCT.

Allo-HSCT should not be given to refractory ATLL patients, although it may be an option for relapsed patients.

Dr. Bazarbachi stressed that ATLL patients should not receive auto-HSCT at any time—as frontline consolidation, after relapse, or if they have refractory disease.

Auto-HSCT “does not work in this disease,” he said. In a study published in 2014⁵, all four ATLL patients who underwent auto-HSCT “rapidly” died.

HSCT in ENKTL

Dr. Bazarbachi said frontline consolidation with auto-HSCT should be considered the standard of care for patients with non-localized ENKTL, nasal type.

Auto-HSCT has been shown to improve survival in these patients⁶, and it is most effective when patients have achieved a complete response to induction.

Allo-HSCT is also an option for frontline consolidation in patients with non-localized ENKTL, nasal type, Dr. Bazarbachi said.

He added that chemosensitive patients who have relapsed can receive allo-HSCT, but they should only receive auto-HSCT if they did not receive it in the frontline setting. Both types of transplant should take place when patients are in complete remission.

Patients with refractory, non-localized ENKTL, nasal type should not receive auto-HSCT, but allo-HSCT is an option, Dr. Bazarbachi said.

He did not declare any conflicts of interest.

1. d’Amore F et al. J Clin Oncol. 2012 Sep 1;30(25):3093-9. doi: 10.1200/JCO.2011.40.2719

2. AbouYabis AN et al. ISRN Hematol. 2011 Jun 16. doi:  10.5402/2011/623924

3. Park SI et al. Blood 2017 130:342

4. Ishida T et al. Blood 2012 Aug 23;120(8):1734-41. doi: 10.1182/blood-2012-03-414490

5. Bazarbachi A et al. Bone Marrow Transplant. 2014 Oct;49(10):1266-8. doi: 10.1038/bmt.2014.143

6. Lee J et al. Biol Blood Marrow Transplant. 2008 Dec;14(12):1356-64. doi: 10.1016/j.bbmt.2008.09.014

Ali Bazarbachi, MD, PhD

DUBROVNIK, CROATIA—Hematopoietic stem cell transplant (HSCT) can be hit-or-miss in patients with peripheral T-cell lymphomas (PTCLs), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Ali Bazarbachi, MD, PhD, of the American University of Beirut in Lebanon, noted that the success of HSCT varies according to the subtype of PTCL and the type of transplant.

For example, autologous (auto) HSCT given as frontline consolidation can be considered the standard of care for PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), and certain patients with anaplastic large-cell lymphoma (ALCL), according to Dr. Bazarbachi.

On the other hand, auto-HSCT should never be used in patients with adult T-cell leukemia/lymphoma (ATLL).

Both auto-HSCT and allogeneic (allo) HSCT are options for patients with non-localized, extranodal natural killer T-cell lymphoma (ENKTL), nasal type, but only at certain times.

State of PTCL treatment

Dr. Bazarbachi began his presentation by pointing out that patients with newly diagnosed PTCL are no longer treated like patients with B-cell lymphoma, but treatment outcomes in PTCL still leave a lot to be desired.

He noted that, with any of the chemotherapy regimens used, typically, about a third of patients are primary refractory, a third relapse, and a quarter are cured. Only two forms of PTCL are frequently curable—localized ENKTL and ALK-positive ALCL.

Current treatment strategies for PTCL do include HSCT, but recommendations vary. Dr. Bazarbachi made the following recommendations, supported by evidence from clinical trials.

HSCT in PTCL-NOS, AITL, and ALCL

For patients with PTCL-NOS, AITL, or ALK-negative, non-DUSP22 ALCL, auto-HSCT as frontline consolidation can be considered the standard of care in patients who responded to induction, Dr. Bazarbachi said.

In a study published in 2012¹, high-dose chemotherapy and auto-HSCT as consolidation improved 5-year overall survival—compared to previous results with CHOP²—in patients with ALK-negative ALCL, AITL, PTCL-NOS, and enteropathy-associated T-cell lymphoma.

Allo-HSCT may also be an option for frontline consolidation in patients with PTCL-NOS, AITL, or ALK-negative, non-DUSP22 ALCL, according to Dr. Bazarbachi.

“Allo-transplant is not dead in this indication,” he said. “But it should be either part of a clinical trial or [given] to some selected patients—those with persistent bone marrow involvement, very young patients, or patients with primary refractory disease.”

Results from the COMPLETE study³ showed improved survival in patients who received consolidation with auto- or allo-HSCT, as compared to patients who did not receive a transplant.

COMPLETE patients with AITL or PTCL-NOS had improvements in progression-free and overall survival with HSCT. The survival advantage was “less evident” in patients with ALCL, the researchers said, but this trial included both ALK-negative and ALK-positive patients.

Dr. Bazarbachi noted that allo- and auto-HSCT can be options after relapse in patients with PTCL-NOS, AITL, or ALK-negative, non-DUSP22 ALCL.

However, chemosensitive patients who have relapsed should only receive auto-HSCT if they did not receive it frontline. Patients who have already undergone auto-HSCT can receive allo-HSCT, Dr. Bazarbachi said.

He added that refractory patients should not undergo auto-HSCT and should receive allo-HSCT only within the context of a clinical trial.

HSCT in ATLL

Dr. Bazarbachi noted that ATLL has a dismal prognosis, but allo-HSCT as frontline consolidation is potentially curative.^4,5 It is most effective in patients who have achieved a complete or partial response to induction.

However, allo-HSCT should not be given as consolidation to ATLL patients who have received prior mogamulizumab. These patients have an increased risk of morbidity and mortality if they undergo allo-HSCT.

Allo-HSCT should not be given to refractory ATLL patients, although it may be an option for relapsed patients.

Dr. Bazarbachi stressed that ATLL patients should not receive auto-HSCT at any time—as frontline consolidation, after relapse, or if they have refractory disease.

Auto-HSCT “does not work in this disease,” he said. In a study published in 2014⁵, all four ATLL patients who underwent auto-HSCT “rapidly” died.

HSCT in ENKTL

Dr. Bazarbachi said frontline consolidation with auto-HSCT should be considered the standard of care for patients with non-localized ENKTL, nasal type.

Auto-HSCT has been shown to improve survival in these patients⁶, and it is most effective when patients have achieved a complete response to induction.

Allo-HSCT is also an option for frontline consolidation in patients with non-localized ENKTL, nasal type, Dr. Bazarbachi said.

He added that chemosensitive patients who have relapsed can receive allo-HSCT, but they should only receive auto-HSCT if they did not receive it in the frontline setting. Both types of transplant should take place when patients are in complete remission.

Patients with refractory, non-localized ENKTL, nasal type should not receive auto-HSCT, but allo-HSCT is an option, Dr. Bazarbachi said.

He did not declare any conflicts of interest.

1. d’Amore F et al. J Clin Oncol. 2012 Sep 1;30(25):3093-9. doi: 10.1200/JCO.2011.40.2719

2. AbouYabis AN et al. ISRN Hematol. 2011 Jun 16. doi:  10.5402/2011/623924

3. Park SI et al. Blood 2017 130:342

4. Ishida T et al. Blood 2012 Aug 23;120(8):1734-41. doi: 10.1182/blood-2012-03-414490

5. Bazarbachi A et al. Bone Marrow Transplant. 2014 Oct;49(10):1266-8. doi: 10.1038/bmt.2014.143

6. Lee J et al. Biol Blood Marrow Transplant. 2008 Dec;14(12):1356-64. doi: 10.1016/j.bbmt.2008.09.014

Ali Bazarbachi, MD, PhD

DUBROVNIK, CROATIA—Hematopoietic stem cell transplant (HSCT) can be hit-or-miss in patients with peripheral T-cell lymphomas (PTCLs), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Ali Bazarbachi, MD, PhD, of the American University of Beirut in Lebanon, noted that the success of HSCT varies according to the subtype of PTCL and the type of transplant.

For example, autologous (auto) HSCT given as frontline consolidation can be considered the standard of care for PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), and certain patients with anaplastic large-cell lymphoma (ALCL), according to Dr. Bazarbachi.

On the other hand, auto-HSCT should never be used in patients with adult T-cell leukemia/lymphoma (ATLL).

Both auto-HSCT and allogeneic (allo) HSCT are options for patients with non-localized, extranodal natural killer T-cell lymphoma (ENKTL), nasal type, but only at certain times.

State of PTCL treatment

Dr. Bazarbachi began his presentation by pointing out that patients with newly diagnosed PTCL are no longer treated like patients with B-cell lymphoma, but treatment outcomes in PTCL still leave a lot to be desired.

He noted that, with any of the chemotherapy regimens used, typically, about a third of patients are primary refractory, a third relapse, and a quarter are cured. Only two forms of PTCL are frequently curable—localized ENKTL and ALK-positive ALCL.

Current treatment strategies for PTCL do include HSCT, but recommendations vary. Dr. Bazarbachi made the following recommendations, supported by evidence from clinical trials.

HSCT in PTCL-NOS, AITL, and ALCL

For patients with PTCL-NOS, AITL, or ALK-negative, non-DUSP22 ALCL, auto-HSCT as frontline consolidation can be considered the standard of care in patients who responded to induction, Dr. Bazarbachi said.

In a study published in 2012¹, high-dose chemotherapy and auto-HSCT as consolidation improved 5-year overall survival—compared to previous results with CHOP²—in patients with ALK-negative ALCL, AITL, PTCL-NOS, and enteropathy-associated T-cell lymphoma.

Allo-HSCT may also be an option for frontline consolidation in patients with PTCL-NOS, AITL, or ALK-negative, non-DUSP22 ALCL, according to Dr. Bazarbachi.

“Allo-transplant is not dead in this indication,” he said. “But it should be either part of a clinical trial or [given] to some selected patients—those with persistent bone marrow involvement, very young patients, or patients with primary refractory disease.”

Results from the COMPLETE study³ showed improved survival in patients who received consolidation with auto- or allo-HSCT, as compared to patients who did not receive a transplant.

COMPLETE patients with AITL or PTCL-NOS had improvements in progression-free and overall survival with HSCT. The survival advantage was “less evident” in patients with ALCL, the researchers said, but this trial included both ALK-negative and ALK-positive patients.

Dr. Bazarbachi noted that allo- and auto-HSCT can be options after relapse in patients with PTCL-NOS, AITL, or ALK-negative, non-DUSP22 ALCL.

However, chemosensitive patients who have relapsed should only receive auto-HSCT if they did not receive it frontline. Patients who have already undergone auto-HSCT can receive allo-HSCT, Dr. Bazarbachi said.

He added that refractory patients should not undergo auto-HSCT and should receive allo-HSCT only within the context of a clinical trial.

HSCT in ATLL

Dr. Bazarbachi noted that ATLL has a dismal prognosis, but allo-HSCT as frontline consolidation is potentially curative.^4,5 It is most effective in patients who have achieved a complete or partial response to induction.

However, allo-HSCT should not be given as consolidation to ATLL patients who have received prior mogamulizumab. These patients have an increased risk of morbidity and mortality if they undergo allo-HSCT.

Allo-HSCT should not be given to refractory ATLL patients, although it may be an option for relapsed patients.

Dr. Bazarbachi stressed that ATLL patients should not receive auto-HSCT at any time—as frontline consolidation, after relapse, or if they have refractory disease.

Auto-HSCT “does not work in this disease,” he said. In a study published in 2014⁵, all four ATLL patients who underwent auto-HSCT “rapidly” died.

HSCT in ENKTL

Dr. Bazarbachi said frontline consolidation with auto-HSCT should be considered the standard of care for patients with non-localized ENKTL, nasal type.

Auto-HSCT has been shown to improve survival in these patients⁶, and it is most effective when patients have achieved a complete response to induction.

Allo-HSCT is also an option for frontline consolidation in patients with non-localized ENKTL, nasal type, Dr. Bazarbachi said.

He added that chemosensitive patients who have relapsed can receive allo-HSCT, but they should only receive auto-HSCT if they did not receive it in the frontline setting. Both types of transplant should take place when patients are in complete remission.

Patients with refractory, non-localized ENKTL, nasal type should not receive auto-HSCT, but allo-HSCT is an option, Dr. Bazarbachi said.

He did not declare any conflicts of interest.

1. d’Amore F et al. J Clin Oncol. 2012 Sep 1;30(25):3093-9. doi: 10.1200/JCO.2011.40.2719

2. AbouYabis AN et al. ISRN Hematol. 2011 Jun 16. doi:  10.5402/2011/623924

3. Park SI et al. Blood 2017 130:342

4. Ishida T et al. Blood 2012 Aug 23;120(8):1734-41. doi: 10.1182/blood-2012-03-414490

5. Bazarbachi A et al. Bone Marrow Transplant. 2014 Oct;49(10):1266-8. doi: 10.1038/bmt.2014.143

6. Lee J et al. Biol Blood Marrow Transplant. 2008 Dec;14(12):1356-64. doi: 10.1016/j.bbmt.2008.09.014

Photo by Darren Baker

The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.

The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.

“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.

The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.

The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.

How MRD can be used

The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.

MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:

1. The drug development tool qualification process
2. Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.

Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.

Disease specifics

The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:

• In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
• In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
• Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
• In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
• In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
• In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.

Types of technology

The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:

• Multiparametric flow cytometry
• Next-generation sequencing
• Quantitative reverse transcription polymerase chain reaction of specific gene fusions
• Allele-specific oligonucleotide polymerase chain reaction.

The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.

The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.

If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.

Photo by Darren Baker

The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.

The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.

“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.

The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.

The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.

How MRD can be used

The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.

MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:

1. The drug development tool qualification process
2. Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.

Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.

Disease specifics

The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:

• In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
• In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
• Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
• In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
• In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
• In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.

Types of technology

The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:

• Multiparametric flow cytometry
• Next-generation sequencing
• Quantitative reverse transcription polymerase chain reaction of specific gene fusions
• Allele-specific oligonucleotide polymerase chain reaction.

The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.

The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.

If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.

Photo by Darren Baker

The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.

The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.

“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.

The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.

The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.

How MRD can be used

The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.

MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:

1. The drug development tool qualification process
2. Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.

Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.

Disease specifics

The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:

• In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
• In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
• Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
• In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
• In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
• In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.

Types of technology

The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:

• Multiparametric flow cytometry
• Next-generation sequencing
• Quantitative reverse transcription polymerase chain reaction of specific gene fusions
• Allele-specific oligonucleotide polymerase chain reaction.

The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.

The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.

If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.

Toni Valković, MD, PhD

DUBROVNIK, CROATIA—Clinical trials are needed to answer the many questions related to minimal residual disease (MRD) assessment in multiple myeloma (MM), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

MM patients are increasingly assessed for MRD, which is a strong prognostic factor and surrogate for overall survival, according to Toni Valković, MD, PhD, of University Hospital Center Rijeka in Croatia.

However, Dr. Valković said MRD assessment has not become a part of routine clinical practice, perhaps because we haven’t determined the best way to utilize MRD assessment in MM patients.

The optimal sensitivity threshold, technique, and timing of MRD assessment are not known, and it isn’t clear how MRD should be used to guide treatment.

What we know

Dr. Valković cited studies showing that MRD negativity is associated with superior survival in MM¹, and, when MRD negativity is achieved, high-risk cytogenetics, age, and previous treatment regimens appear to have no further impact on prognosis.²

Dr. Valković went on to explain the benefits and detriments of multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment.³

NGS requires a baseline patient sample, but MFC does not. More cells are required with MFC than with NGS (>5 million vs. <1 million).

With MFC, samples must be processed within 24 to 48 hours, whereas, with NGS, fresh or stored samples can be used. MFC can be done in a few hours, while NGS can take several days.

Despite these differences, both methods provide similar levels of sensitivity for detecting MRD (≥1 in 10⁵).

Dr. Valković also noted that MRD should be evaluated outside the bone marrow as well, which can be done with positron emission tomography-computed tomography (PET-CT).

Research has shown that patients who are MRD-negative according to both MFC and PET-CT have better outcomes than patients who are MRD-positive by MFC, PET-CT, or both.⁴

What we don’t know

Though he compared MFC and NGS, Dr. Valković said we don’t know the optimal technique for assessing MRD in the bone marrow.

Another uncertainty is the optimal sensitivity threshold. In the POLLUX study⁵, researchers found that a threshold of 10^-4 resulted in lots of patients with MRD negativity, but some of these were false-negatives.

So although 10^-4 proved inaccurate, it isn’t clear if the optimal threshold is 10^-5 or 10^-6, Dr. Valković said.

Likewise, it isn’t clear if PET-CT is the optimal method for evaluating MRD outside the bone marrow.

In a study published in 2017, PET produced false-negatives in MM patients.⁶ In 11% of patients (26/227), there was evidence of disease with diffusion-weighted magnetic resonance imaging with background signal suppression, but there was no apparent disease with PET. The researchers said low expression of hexokinase-2 was associated with a false-negative PET result.

Finally, Dr. Valković said we don’t know how best to use MRD to tailor therapy in MM patients. He posed the following questions:

• If patients don’t achieve MRD negativity, should they continue on the therapy?
• If MRD-negative patients become MRD-positive, should they begin therapy immediately, or should treatment be put off until a biochemical or clinical relapse?
• Should MRD status be used to determine the number of treatment cycles a patient receives, the timing of transplant, or when to begin and end maintenance therapy?

“There are a lot of issues and unanswered questions related to the optimal techniques for the evaluation of MRD and their sensitivity, the timing for MRD assessment during and after therapy, and its role in the treatment decisions, which should be answered in future clinical studies,” Dr. Valković concluded.

He did not declare any conflicts of interest.

1. Munshi NC et al. JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160

2. Paiva B et al. Blood. 2016 Jun 23;127(25):3165-74. doi: 10.1182/blood-2016-03-705319

3. Kumar S et al. Lancet Oncol. 2016; 17 (8):e328-46 doi: https://doi.org/10.1016/S1470-2045(16)30206-6

4. Fernandez RA et al. Blood. 2017; 130:3098

5. Dimopoulos MA et al. Haematologica. 2018 Sep 20. pii: haematol.2018.194282. doi: 10.3324/haematol.2018.194282

6. Rasche L et al. Blood. 2017 Jul 6;130(1):30-34. doi: 10.1182/blood-2017-03-774422

Toni Valković, MD, PhD

DUBROVNIK, CROATIA—Clinical trials are needed to answer the many questions related to minimal residual disease (MRD) assessment in multiple myeloma (MM), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

MM patients are increasingly assessed for MRD, which is a strong prognostic factor and surrogate for overall survival, according to Toni Valković, MD, PhD, of University Hospital Center Rijeka in Croatia.

However, Dr. Valković said MRD assessment has not become a part of routine clinical practice, perhaps because we haven’t determined the best way to utilize MRD assessment in MM patients.

The optimal sensitivity threshold, technique, and timing of MRD assessment are not known, and it isn’t clear how MRD should be used to guide treatment.

What we know

Dr. Valković cited studies showing that MRD negativity is associated with superior survival in MM¹, and, when MRD negativity is achieved, high-risk cytogenetics, age, and previous treatment regimens appear to have no further impact on prognosis.²

Dr. Valković went on to explain the benefits and detriments of multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment.³

NGS requires a baseline patient sample, but MFC does not. More cells are required with MFC than with NGS (>5 million vs. <1 million).

With MFC, samples must be processed within 24 to 48 hours, whereas, with NGS, fresh or stored samples can be used. MFC can be done in a few hours, while NGS can take several days.

Despite these differences, both methods provide similar levels of sensitivity for detecting MRD (≥1 in 10⁵).

Dr. Valković also noted that MRD should be evaluated outside the bone marrow as well, which can be done with positron emission tomography-computed tomography (PET-CT).

Research has shown that patients who are MRD-negative according to both MFC and PET-CT have better outcomes than patients who are MRD-positive by MFC, PET-CT, or both.⁴

What we don’t know

Though he compared MFC and NGS, Dr. Valković said we don’t know the optimal technique for assessing MRD in the bone marrow.

Another uncertainty is the optimal sensitivity threshold. In the POLLUX study⁵, researchers found that a threshold of 10^-4 resulted in lots of patients with MRD negativity, but some of these were false-negatives.

So although 10^-4 proved inaccurate, it isn’t clear if the optimal threshold is 10^-5 or 10^-6, Dr. Valković said.

Likewise, it isn’t clear if PET-CT is the optimal method for evaluating MRD outside the bone marrow.

In a study published in 2017, PET produced false-negatives in MM patients.⁶ In 11% of patients (26/227), there was evidence of disease with diffusion-weighted magnetic resonance imaging with background signal suppression, but there was no apparent disease with PET. The researchers said low expression of hexokinase-2 was associated with a false-negative PET result.

Finally, Dr. Valković said we don’t know how best to use MRD to tailor therapy in MM patients. He posed the following questions:

• If patients don’t achieve MRD negativity, should they continue on the therapy?
• If MRD-negative patients become MRD-positive, should they begin therapy immediately, or should treatment be put off until a biochemical or clinical relapse?
• Should MRD status be used to determine the number of treatment cycles a patient receives, the timing of transplant, or when to begin and end maintenance therapy?

“There are a lot of issues and unanswered questions related to the optimal techniques for the evaluation of MRD and their sensitivity, the timing for MRD assessment during and after therapy, and its role in the treatment decisions, which should be answered in future clinical studies,” Dr. Valković concluded.

He did not declare any conflicts of interest.

1. Munshi NC et al. JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160

2. Paiva B et al. Blood. 2016 Jun 23;127(25):3165-74. doi: 10.1182/blood-2016-03-705319

3. Kumar S et al. Lancet Oncol. 2016; 17 (8):e328-46 doi: https://doi.org/10.1016/S1470-2045(16)30206-6

4. Fernandez RA et al. Blood. 2017; 130:3098

5. Dimopoulos MA et al. Haematologica. 2018 Sep 20. pii: haematol.2018.194282. doi: 10.3324/haematol.2018.194282

6. Rasche L et al. Blood. 2017 Jul 6;130(1):30-34. doi: 10.1182/blood-2017-03-774422

Toni Valković, MD, PhD

DUBROVNIK, CROATIA—Clinical trials are needed to answer the many questions related to minimal residual disease (MRD) assessment in multiple myeloma (MM), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

MM patients are increasingly assessed for MRD, which is a strong prognostic factor and surrogate for overall survival, according to Toni Valković, MD, PhD, of University Hospital Center Rijeka in Croatia.

However, Dr. Valković said MRD assessment has not become a part of routine clinical practice, perhaps because we haven’t determined the best way to utilize MRD assessment in MM patients.

The optimal sensitivity threshold, technique, and timing of MRD assessment are not known, and it isn’t clear how MRD should be used to guide treatment.

What we know

Dr. Valković cited studies showing that MRD negativity is associated with superior survival in MM¹, and, when MRD negativity is achieved, high-risk cytogenetics, age, and previous treatment regimens appear to have no further impact on prognosis.²

Dr. Valković went on to explain the benefits and detriments of multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment.³

NGS requires a baseline patient sample, but MFC does not. More cells are required with MFC than with NGS (>5 million vs. <1 million).

With MFC, samples must be processed within 24 to 48 hours, whereas, with NGS, fresh or stored samples can be used. MFC can be done in a few hours, while NGS can take several days.

Despite these differences, both methods provide similar levels of sensitivity for detecting MRD (≥1 in 10⁵).

Dr. Valković also noted that MRD should be evaluated outside the bone marrow as well, which can be done with positron emission tomography-computed tomography (PET-CT).

Research has shown that patients who are MRD-negative according to both MFC and PET-CT have better outcomes than patients who are MRD-positive by MFC, PET-CT, or both.⁴

What we don’t know

Though he compared MFC and NGS, Dr. Valković said we don’t know the optimal technique for assessing MRD in the bone marrow.

Another uncertainty is the optimal sensitivity threshold. In the POLLUX study⁵, researchers found that a threshold of 10^-4 resulted in lots of patients with MRD negativity, but some of these were false-negatives.

So although 10^-4 proved inaccurate, it isn’t clear if the optimal threshold is 10^-5 or 10^-6, Dr. Valković said.

Likewise, it isn’t clear if PET-CT is the optimal method for evaluating MRD outside the bone marrow.

In a study published in 2017, PET produced false-negatives in MM patients.⁶ In 11% of patients (26/227), there was evidence of disease with diffusion-weighted magnetic resonance imaging with background signal suppression, but there was no apparent disease with PET. The researchers said low expression of hexokinase-2 was associated with a false-negative PET result.

Finally, Dr. Valković said we don’t know how best to use MRD to tailor therapy in MM patients. He posed the following questions:

• If patients don’t achieve MRD negativity, should they continue on the therapy?
• If MRD-negative patients become MRD-positive, should they begin therapy immediately, or should treatment be put off until a biochemical or clinical relapse?
• Should MRD status be used to determine the number of treatment cycles a patient receives, the timing of transplant, or when to begin and end maintenance therapy?

“There are a lot of issues and unanswered questions related to the optimal techniques for the evaluation of MRD and their sensitivity, the timing for MRD assessment during and after therapy, and its role in the treatment decisions, which should be answered in future clinical studies,” Dr. Valković concluded.

He did not declare any conflicts of interest.

1. Munshi NC et al. JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160

2. Paiva B et al. Blood. 2016 Jun 23;127(25):3165-74. doi: 10.1182/blood-2016-03-705319

3. Kumar S et al. Lancet Oncol. 2016; 17 (8):e328-46 doi: https://doi.org/10.1016/S1470-2045(16)30206-6

4. Fernandez RA et al. Blood. 2017; 130:3098

5. Dimopoulos MA et al. Haematologica. 2018 Sep 20. pii: haematol.2018.194282. doi: 10.3324/haematol.2018.194282

6. Rasche L et al. Blood. 2017 Jul 6;130(1):30-34. doi: 10.1182/blood-2017-03-774422

Image by Simon Caulton

DUBROVNIK, CROATIA—Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018, according to a presentation at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Duraković, MD, PhD, of the University Hospital Zagreb in Croatia.

However, Dr. Duraković said there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML).

Furthermore, studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

Dr. Duraković began her presentation with an overview of the 2016 WHO classification of CMML (Blood 2016 127:2391-2405).


According to the WHO, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L) with monocytes accounting for 10% of the white blood cell count
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement
• They have fewer than 20% blasts in the blood and bone marrow
• They have dysplasia in one or more myeloid lineages
• If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present.

Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Duraković said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions such as pregnancy.

However, Dr. Duraković pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“[T]here are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Duraković said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”

Distinguishing CMML from other conditions

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Duraković said. “There are dysplastic features that are present in CMML . . . but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Duraković noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She went on to explain that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Duraković also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Duraković said.

She also noted that it can be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Duraković explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Duraković noted.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Duraković said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Duraković said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes—SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood 2012 120:3080-3088).

However, Dr. Duraković noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML—monocyte subset distribution analysis (Blood 2015 125(23): 3618–3626).

For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻)
• Intermediate/MO2 (CD14^bright/CD16⁺)
• Non-classical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94.0%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis.

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML (Am J Clin Pathol 2018 150(4):293-302).

This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes.

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Duraković said.

She added that the technique can be implemented in clinical practice using the Hematoflow^TM solution (Cytometry B Clin Cytom 2018 94(5):658-661).

Dr. Duraković did not report any conflicts of interest.

Image by Simon Caulton

DUBROVNIK, CROATIA—Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018, according to a presentation at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Duraković, MD, PhD, of the University Hospital Zagreb in Croatia.

However, Dr. Duraković said there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML).

Furthermore, studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

Dr. Duraković began her presentation with an overview of the 2016 WHO classification of CMML (Blood 2016 127:2391-2405).


According to the WHO, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L) with monocytes accounting for 10% of the white blood cell count
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement
• They have fewer than 20% blasts in the blood and bone marrow
• They have dysplasia in one or more myeloid lineages
• If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present.

Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Duraković said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions such as pregnancy.

However, Dr. Duraković pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“[T]here are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Duraković said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”

Distinguishing CMML from other conditions

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Duraković said. “There are dysplastic features that are present in CMML . . . but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Duraković noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She went on to explain that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Duraković also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Duraković said.

She also noted that it can be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Duraković explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Duraković noted.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Duraković said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Duraković said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes—SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood 2012 120:3080-3088).

However, Dr. Duraković noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML—monocyte subset distribution analysis (Blood 2015 125(23): 3618–3626).

For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻)
• Intermediate/MO2 (CD14^bright/CD16⁺)
• Non-classical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94.0%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis.

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML (Am J Clin Pathol 2018 150(4):293-302).

This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes.

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Duraković said.

She added that the technique can be implemented in clinical practice using the Hematoflow^TM solution (Cytometry B Clin Cytom 2018 94(5):658-661).

Dr. Duraković did not report any conflicts of interest.

Image by Simon Caulton

DUBROVNIK, CROATIA—Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018, according to a presentation at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Duraković, MD, PhD, of the University Hospital Zagreb in Croatia.

However, Dr. Duraković said there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML).

Furthermore, studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

Dr. Duraković began her presentation with an overview of the 2016 WHO classification of CMML (Blood 2016 127:2391-2405).


According to the WHO, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L) with monocytes accounting for 10% of the white blood cell count
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement
• They have fewer than 20% blasts in the blood and bone marrow
• They have dysplasia in one or more myeloid lineages
• If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present.

Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Duraković said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions such as pregnancy.

However, Dr. Duraković pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“[T]here are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Duraković said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”

Distinguishing CMML from other conditions

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Duraković said. “There are dysplastic features that are present in CMML . . . but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Duraković noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She went on to explain that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Duraković also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Duraković said.

She also noted that it can be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Duraković explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Duraković noted.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Duraković said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Duraković said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes—SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood 2012 120:3080-3088).

However, Dr. Duraković noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML—monocyte subset distribution analysis (Blood 2015 125(23): 3618–3626).

For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻)
• Intermediate/MO2 (CD14^bright/CD16⁺)
• Non-classical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94.0%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis.

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML (Am J Clin Pathol 2018 150(4):293-302).

This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes.

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Duraković said.

She added that the technique can be implemented in clinical practice using the Hematoflow^TM solution (Cytometry B Clin Cytom 2018 94(5):658-661).

Dr. Duraković did not report any conflicts of interest.

Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.¹ In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.²

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal
• Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
• Are in chronic phase
• Achieved an optimal response to their first TKI
• Have been on TKI therapy for more than 8 years
• Achieved a complete molecular response (MR4.5)
• Have had a molecular response for more than 2 to 3 years
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.¹ In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.²

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal
• Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
• Are in chronic phase
• Achieved an optimal response to their first TKI
• Have been on TKI therapy for more than 8 years
• Achieved a complete molecular response (MR4.5)
• Have had a molecular response for more than 2 to 3 years
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.¹ In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.²

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal
• Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
• Are in chronic phase
• Achieved an optimal response to their first TKI
• Have been on TKI therapy for more than 8 years
• Achieved a complete molecular response (MR4.5)
• Have had a molecular response for more than 2 to 3 years
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.