User login
Peripheral blood MRD correlates with treatment benefit in CLL
CHICAGO—Minimal residual disease (MRD) kinetics confirms the high, durable MRD-negativity with venetoclax plus rituximab in relapsed/refractory chronic lymphocytic leukemia (CLL), according to a further examination of the phase 3 MURANO study.
Undetectable MRD-negativity is associated with extended progression-free survival (PFS) and overall survival in patients receiving chemoimmunotherapy for CLL.
“Attainment of MRD-negativity in relapsed/refractory CLL is also a desired trial endpoint due to the subjectivity of complete response definition regarding pathologic lymph node size,” said Peter Hillmen, MD, of St James’s University Hospital, Leeds, United Kingdom, at the 2018 ASCO Annual Meeting.
Dr Hillmen reported new data on MRD response in cytogenetic and molecular risk groups, MRD sustainability and kinetics, and MRD conversion in the MURANO trial (abstract 7508).
MURANO trial (NCT02005471)
In the trial, venetoclax-rituximab showed superior PFS and peripheral blood and bone marrow MRD-negativity as compared to bendamustine plus rituximab (BR) in relapsed/refractory CLL patients.
Patients were randomized to venetoclax-rituximab for 6 months, followed by single-agent venetoclax for up to 1.5 years, or BR for 6 months. Peripheral blood samples were serially collected and bone marrow was collected at the end of combination treatment or at best response.
MRD findings
The new results show higher concordance in MRD-negativity between bone marrow and peripheral blood in venetoclax-rituximab (45 of 50 patients, 90%) vs BR (3 of 10 patients, 30%) in paired samples.
Focusing on peripheral blood MRD, Dr Hillmen said the best MRD-negativity rates were higher with venetoclax-rituximab (84%) than BR (23%). These results were independent of high-risk factors—such as del 17p, IGVH unmutated, and mutated TP53—only for venetoclax-rituximab treated patients.
“The superior peripheral blood MRD response with venetoclax-rituximab was consistent across subgroups at the end of completion of treatment,” Dr Hillmen said. “Most patients who achieved peripheral blood MRD-negativity on venetoclax-rituximab remained MRD-negative and were progression-free.”
Among 121 of 194 (62%) patients on venetoclax-rituximab who achieved MRD-negativity at the end of combination therapy, 100 (83%) patients maintained MRD-negativity and were progression-free at a median follow-up of 13.8 months. Two patients developed progressive disease and 2 patients died (unrelated to CLL).
Two patients developed Richter’s disease (with one MRD-positive directly before therapy) and 15 (12%) patients converted to confirmed MRD-positive at a median MRD-positive follow-up of 5.6 months.
“High peripheral blood MRD-negativity at the end of combination treatment and concordance with bone marrow MRD with venetoclax-rituximab,” Dr Hillmen said, “confirms the value of peripheral blood MRD for evaluation of treatment benefit in relapsed/refractory CLL patients. The high rate of peripheral blood MRD-negativity at end of combination treatment with venetoclax-rituximab was attained regardless of risk features.”
Some conversion to MRD-positivity occurred only in a small proportion of patients. Most cases were of intermediate level and remained progression-free, he said.
“MRD kinetics indicate that peripheral blood MRD-negativity with venetoclax-rituximab occurs early and is maintained over time with current follow-up,” Dr Hillmen added. The MRD data now provide a framework for designing response adaptive therapy.
The US Food and Drug Administration recently approved venetoclax-rituximab for CLL or small lymphocytic lymphoma for patients with or without del 17p.
Venetoclax is being developed by Genentech and Abbvie.
CHICAGO—Minimal residual disease (MRD) kinetics confirms the high, durable MRD-negativity with venetoclax plus rituximab in relapsed/refractory chronic lymphocytic leukemia (CLL), according to a further examination of the phase 3 MURANO study.
Undetectable MRD-negativity is associated with extended progression-free survival (PFS) and overall survival in patients receiving chemoimmunotherapy for CLL.
“Attainment of MRD-negativity in relapsed/refractory CLL is also a desired trial endpoint due to the subjectivity of complete response definition regarding pathologic lymph node size,” said Peter Hillmen, MD, of St James’s University Hospital, Leeds, United Kingdom, at the 2018 ASCO Annual Meeting.
Dr Hillmen reported new data on MRD response in cytogenetic and molecular risk groups, MRD sustainability and kinetics, and MRD conversion in the MURANO trial (abstract 7508).
MURANO trial (NCT02005471)
In the trial, venetoclax-rituximab showed superior PFS and peripheral blood and bone marrow MRD-negativity as compared to bendamustine plus rituximab (BR) in relapsed/refractory CLL patients.
Patients were randomized to venetoclax-rituximab for 6 months, followed by single-agent venetoclax for up to 1.5 years, or BR for 6 months. Peripheral blood samples were serially collected and bone marrow was collected at the end of combination treatment or at best response.
MRD findings
The new results show higher concordance in MRD-negativity between bone marrow and peripheral blood in venetoclax-rituximab (45 of 50 patients, 90%) vs BR (3 of 10 patients, 30%) in paired samples.
Focusing on peripheral blood MRD, Dr Hillmen said the best MRD-negativity rates were higher with venetoclax-rituximab (84%) than BR (23%). These results were independent of high-risk factors—such as del 17p, IGVH unmutated, and mutated TP53—only for venetoclax-rituximab treated patients.
“The superior peripheral blood MRD response with venetoclax-rituximab was consistent across subgroups at the end of completion of treatment,” Dr Hillmen said. “Most patients who achieved peripheral blood MRD-negativity on venetoclax-rituximab remained MRD-negative and were progression-free.”
Among 121 of 194 (62%) patients on venetoclax-rituximab who achieved MRD-negativity at the end of combination therapy, 100 (83%) patients maintained MRD-negativity and were progression-free at a median follow-up of 13.8 months. Two patients developed progressive disease and 2 patients died (unrelated to CLL).
Two patients developed Richter’s disease (with one MRD-positive directly before therapy) and 15 (12%) patients converted to confirmed MRD-positive at a median MRD-positive follow-up of 5.6 months.
“High peripheral blood MRD-negativity at the end of combination treatment and concordance with bone marrow MRD with venetoclax-rituximab,” Dr Hillmen said, “confirms the value of peripheral blood MRD for evaluation of treatment benefit in relapsed/refractory CLL patients. The high rate of peripheral blood MRD-negativity at end of combination treatment with venetoclax-rituximab was attained regardless of risk features.”
Some conversion to MRD-positivity occurred only in a small proportion of patients. Most cases were of intermediate level and remained progression-free, he said.
“MRD kinetics indicate that peripheral blood MRD-negativity with venetoclax-rituximab occurs early and is maintained over time with current follow-up,” Dr Hillmen added. The MRD data now provide a framework for designing response adaptive therapy.
The US Food and Drug Administration recently approved venetoclax-rituximab for CLL or small lymphocytic lymphoma for patients with or without del 17p.
Venetoclax is being developed by Genentech and Abbvie.
CHICAGO—Minimal residual disease (MRD) kinetics confirms the high, durable MRD-negativity with venetoclax plus rituximab in relapsed/refractory chronic lymphocytic leukemia (CLL), according to a further examination of the phase 3 MURANO study.
Undetectable MRD-negativity is associated with extended progression-free survival (PFS) and overall survival in patients receiving chemoimmunotherapy for CLL.
“Attainment of MRD-negativity in relapsed/refractory CLL is also a desired trial endpoint due to the subjectivity of complete response definition regarding pathologic lymph node size,” said Peter Hillmen, MD, of St James’s University Hospital, Leeds, United Kingdom, at the 2018 ASCO Annual Meeting.
Dr Hillmen reported new data on MRD response in cytogenetic and molecular risk groups, MRD sustainability and kinetics, and MRD conversion in the MURANO trial (abstract 7508).
MURANO trial (NCT02005471)
In the trial, venetoclax-rituximab showed superior PFS and peripheral blood and bone marrow MRD-negativity as compared to bendamustine plus rituximab (BR) in relapsed/refractory CLL patients.
Patients were randomized to venetoclax-rituximab for 6 months, followed by single-agent venetoclax for up to 1.5 years, or BR for 6 months. Peripheral blood samples were serially collected and bone marrow was collected at the end of combination treatment or at best response.
MRD findings
The new results show higher concordance in MRD-negativity between bone marrow and peripheral blood in venetoclax-rituximab (45 of 50 patients, 90%) vs BR (3 of 10 patients, 30%) in paired samples.
Focusing on peripheral blood MRD, Dr Hillmen said the best MRD-negativity rates were higher with venetoclax-rituximab (84%) than BR (23%). These results were independent of high-risk factors—such as del 17p, IGVH unmutated, and mutated TP53—only for venetoclax-rituximab treated patients.
“The superior peripheral blood MRD response with venetoclax-rituximab was consistent across subgroups at the end of completion of treatment,” Dr Hillmen said. “Most patients who achieved peripheral blood MRD-negativity on venetoclax-rituximab remained MRD-negative and were progression-free.”
Among 121 of 194 (62%) patients on venetoclax-rituximab who achieved MRD-negativity at the end of combination therapy, 100 (83%) patients maintained MRD-negativity and were progression-free at a median follow-up of 13.8 months. Two patients developed progressive disease and 2 patients died (unrelated to CLL).
Two patients developed Richter’s disease (with one MRD-positive directly before therapy) and 15 (12%) patients converted to confirmed MRD-positive at a median MRD-positive follow-up of 5.6 months.
“High peripheral blood MRD-negativity at the end of combination treatment and concordance with bone marrow MRD with venetoclax-rituximab,” Dr Hillmen said, “confirms the value of peripheral blood MRD for evaluation of treatment benefit in relapsed/refractory CLL patients. The high rate of peripheral blood MRD-negativity at end of combination treatment with venetoclax-rituximab was attained regardless of risk features.”
Some conversion to MRD-positivity occurred only in a small proportion of patients. Most cases were of intermediate level and remained progression-free, he said.
“MRD kinetics indicate that peripheral blood MRD-negativity with venetoclax-rituximab occurs early and is maintained over time with current follow-up,” Dr Hillmen added. The MRD data now provide a framework for designing response adaptive therapy.
The US Food and Drug Administration recently approved venetoclax-rituximab for CLL or small lymphocytic lymphoma for patients with or without del 17p.
Venetoclax is being developed by Genentech and Abbvie.
Interim PET scans identify HL patients with better outcomes
CHICAGO—Interim PET scans can identify a subset of Hodgkin lymphoma (HL) patients with a better outcome suitable for de-escalation treatment after upfront BEACOPP without impairing disease control, according to final results of the AHL2011-LYSA study.
BEACOPP, compared to ABVD, improves progression-free survival (PFS) but not overall survival (OS) and is associated with a higher risk of myelodysplasia, acute leukemia, and infertility.
Investigators evaluated whether some patients might be able to reduce treatment intensity without compromising the effectiveness of their therapy.
Olivier Casasnovas, MD, of CHU Le Bocage Service d'Hématologie Clinique, Dijon, France, presented the final analysis at the 2018 ASCO Annual Meeting (abstract 7503).
AHL2011-LYSA study (NCT01358747)
The randomized phase 3 study compared an early PET-driven treatment de-escalation to a non-PET-monitored strategy in patients with advanced-stage HL.
The study included 823 previously untreated patients, median age 30 years (range 16 – 60), with stage III, IV, or high-risk IIB HL.
The PET-driven strategy consisted of 2 BEACOPP* cycles (PET2), followed by 4 cycles of ABVD** for PET2-negative patients, and 4 cycles of BEACOPP for PET2-positive patients.
The experimental PET-driven strategy (410 patients) was randomly compared to a standard treatment delivering 6 cycles of BEACOPP (413 patients). PFS was the primary endpoint with a hypothesis of non-inferiority of the PET-driven arm compared to the standard arm.
Patients characteristics were well balanced between the arms, Dr Casasnovas said. PET2-positivity rate was similar in both arms (experimental 13%, standard 12%).
Based on PET2 results, 346 (84%) patients received 4 cycles of ABVD and 51 (12%) patients received 4 additional cycles of BEACOPP in the experimental arm.
Results
With a median follow-up of 50 months, the 5-year PFS was similar in the standard (86.2%) and the PET-driven arms (85.7%). The 5-year PFS for PET 2-negative/PET 4-negative patients was 90.9%, for PET 2-positive/PET4-negative patients was 75.4%, and for PET 4-positive patients was 46.5%.
The 5-year OS was similar in both arms (96.4% experimental, 95.2% standard).
The treatment toxicity was significantly higher in patients receiving 6 cycles of BEACOPP as compared to those who received 2 cycles of BEACOPP plus 4 cycles of ABVD.
Those who received more cycles of BEACOPP had more frequent grade 3 or higher adverse events than those with fewer cycles, including anemia (11% vs 2%), leukopenia (85% vs 74%), thrombocytopenia (44% vs 15%), and sepsis (7% vs 3%), as well as in serious adverse events (45% vs 28%).
“After 4 cycles of chemotherapy, it [PET positivity] identifies a subset of patients with a particularly poor outcome,” Dr Casasnovas said, “encouraging researchers to develop new treatment options in these patients.”
“PET performed after 2 cycles of BEACOPP escalation can be safely used to guide subsequent treatment,” he concluded.
“This approach allows clinicians to reduce the treatment-related immediate toxicity in most patients,” he added, “and provides similar patient outcomes compared to standard BEACOPP escalation treatment.”
* Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone
**Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine
CHICAGO—Interim PET scans can identify a subset of Hodgkin lymphoma (HL) patients with a better outcome suitable for de-escalation treatment after upfront BEACOPP without impairing disease control, according to final results of the AHL2011-LYSA study.
BEACOPP, compared to ABVD, improves progression-free survival (PFS) but not overall survival (OS) and is associated with a higher risk of myelodysplasia, acute leukemia, and infertility.
Investigators evaluated whether some patients might be able to reduce treatment intensity without compromising the effectiveness of their therapy.
Olivier Casasnovas, MD, of CHU Le Bocage Service d'Hématologie Clinique, Dijon, France, presented the final analysis at the 2018 ASCO Annual Meeting (abstract 7503).
AHL2011-LYSA study (NCT01358747)
The randomized phase 3 study compared an early PET-driven treatment de-escalation to a non-PET-monitored strategy in patients with advanced-stage HL.
The study included 823 previously untreated patients, median age 30 years (range 16 – 60), with stage III, IV, or high-risk IIB HL.
The PET-driven strategy consisted of 2 BEACOPP* cycles (PET2), followed by 4 cycles of ABVD** for PET2-negative patients, and 4 cycles of BEACOPP for PET2-positive patients.
The experimental PET-driven strategy (410 patients) was randomly compared to a standard treatment delivering 6 cycles of BEACOPP (413 patients). PFS was the primary endpoint with a hypothesis of non-inferiority of the PET-driven arm compared to the standard arm.
Patients characteristics were well balanced between the arms, Dr Casasnovas said. PET2-positivity rate was similar in both arms (experimental 13%, standard 12%).
Based on PET2 results, 346 (84%) patients received 4 cycles of ABVD and 51 (12%) patients received 4 additional cycles of BEACOPP in the experimental arm.
Results
With a median follow-up of 50 months, the 5-year PFS was similar in the standard (86.2%) and the PET-driven arms (85.7%). The 5-year PFS for PET 2-negative/PET 4-negative patients was 90.9%, for PET 2-positive/PET4-negative patients was 75.4%, and for PET 4-positive patients was 46.5%.
The 5-year OS was similar in both arms (96.4% experimental, 95.2% standard).
The treatment toxicity was significantly higher in patients receiving 6 cycles of BEACOPP as compared to those who received 2 cycles of BEACOPP plus 4 cycles of ABVD.
Those who received more cycles of BEACOPP had more frequent grade 3 or higher adverse events than those with fewer cycles, including anemia (11% vs 2%), leukopenia (85% vs 74%), thrombocytopenia (44% vs 15%), and sepsis (7% vs 3%), as well as in serious adverse events (45% vs 28%).
“After 4 cycles of chemotherapy, it [PET positivity] identifies a subset of patients with a particularly poor outcome,” Dr Casasnovas said, “encouraging researchers to develop new treatment options in these patients.”
“PET performed after 2 cycles of BEACOPP escalation can be safely used to guide subsequent treatment,” he concluded.
“This approach allows clinicians to reduce the treatment-related immediate toxicity in most patients,” he added, “and provides similar patient outcomes compared to standard BEACOPP escalation treatment.”
* Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone
**Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine
CHICAGO—Interim PET scans can identify a subset of Hodgkin lymphoma (HL) patients with a better outcome suitable for de-escalation treatment after upfront BEACOPP without impairing disease control, according to final results of the AHL2011-LYSA study.
BEACOPP, compared to ABVD, improves progression-free survival (PFS) but not overall survival (OS) and is associated with a higher risk of myelodysplasia, acute leukemia, and infertility.
Investigators evaluated whether some patients might be able to reduce treatment intensity without compromising the effectiveness of their therapy.
Olivier Casasnovas, MD, of CHU Le Bocage Service d'Hématologie Clinique, Dijon, France, presented the final analysis at the 2018 ASCO Annual Meeting (abstract 7503).
AHL2011-LYSA study (NCT01358747)
The randomized phase 3 study compared an early PET-driven treatment de-escalation to a non-PET-monitored strategy in patients with advanced-stage HL.
The study included 823 previously untreated patients, median age 30 years (range 16 – 60), with stage III, IV, or high-risk IIB HL.
The PET-driven strategy consisted of 2 BEACOPP* cycles (PET2), followed by 4 cycles of ABVD** for PET2-negative patients, and 4 cycles of BEACOPP for PET2-positive patients.
The experimental PET-driven strategy (410 patients) was randomly compared to a standard treatment delivering 6 cycles of BEACOPP (413 patients). PFS was the primary endpoint with a hypothesis of non-inferiority of the PET-driven arm compared to the standard arm.
Patients characteristics were well balanced between the arms, Dr Casasnovas said. PET2-positivity rate was similar in both arms (experimental 13%, standard 12%).
Based on PET2 results, 346 (84%) patients received 4 cycles of ABVD and 51 (12%) patients received 4 additional cycles of BEACOPP in the experimental arm.
Results
With a median follow-up of 50 months, the 5-year PFS was similar in the standard (86.2%) and the PET-driven arms (85.7%). The 5-year PFS for PET 2-negative/PET 4-negative patients was 90.9%, for PET 2-positive/PET4-negative patients was 75.4%, and for PET 4-positive patients was 46.5%.
The 5-year OS was similar in both arms (96.4% experimental, 95.2% standard).
The treatment toxicity was significantly higher in patients receiving 6 cycles of BEACOPP as compared to those who received 2 cycles of BEACOPP plus 4 cycles of ABVD.
Those who received more cycles of BEACOPP had more frequent grade 3 or higher adverse events than those with fewer cycles, including anemia (11% vs 2%), leukopenia (85% vs 74%), thrombocytopenia (44% vs 15%), and sepsis (7% vs 3%), as well as in serious adverse events (45% vs 28%).
“After 4 cycles of chemotherapy, it [PET positivity] identifies a subset of patients with a particularly poor outcome,” Dr Casasnovas said, “encouraging researchers to develop new treatment options in these patients.”
“PET performed after 2 cycles of BEACOPP escalation can be safely used to guide subsequent treatment,” he concluded.
“This approach allows clinicians to reduce the treatment-related immediate toxicity in most patients,” he added, “and provides similar patient outcomes compared to standard BEACOPP escalation treatment.”
* Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone
**Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine
Chemo-free combo provides potential first-line option for FL
CHICAGO—A chemotherapy-free combination of lenalidomide plus rituximab shows similar efficacy and a different safety profile to chemotherapy plus rituximab (R-chemo) followed by rituximab maintenance in patients with previously untreated follicular lymphoma (FL).
According to investigators, the multicenter, international phase 3 RELEVANCE trial is the first to evaluate the chemo-free combination against the standard of care, R-chemo with rituximab maintenance.
“These results show that lenalidomide plus rituximab, a novel immunomodulatory approach, is a potential first-line option for patients with FL requiring treatment,” said investigator Nathan H. Fowler, MD, of the University of Texas MD Anderson Cancer Center in Houston.
Dr Fowler presented the results of the study at the 2018 ASCO Annual Meeting (abstract 7500).
The current standard of care in previously untreated symptomatic FL is immunochemotherapy induction followed by rituximab maintenance.
The immunomodulatory agent lenalidomide has complementary mechanisms with rituximab. Phase 2 studies of combined immunotherapy with lenalidomide and rituximab demonstrated 3-year progression-free survival (PFS) of 79%-81% in previously untreated FL, Dr Fowler said.
Phase 3 RELEVANCE trial (NCT01650701)
Investigators evaluated 1030 previously untreated grade 1-3a FL patients who required therapy.
Patients in the lenalidomide-rituximab group (n=513) received lenalidomide doses of 20 mg per day on days 2 to 22 and 28 for 6 to 12 cycles. Responders continued on therapy at 10 mg per day for a total of 18 cycles.
The rituximab dose was 375 mg/m2 weekly in cycle 1 and day 1 in cycles 2 to 6 and continued in responders for 12 additional cycles.
Patients in the R-chemo arm (n=517) received the investigator’s choice of standard rituximab-CHOP, rituximab-bendamustine, or rituximab-CVP, followed by 12 cycles of rituximab.
Most patients (72%) in the R-chemo arm received R-CHOP.
Baseline characteristics were similar in both groups, Dr Fowler said.
Co-primary endpoints were complete remission/complete remission unconfirmed (CR/Cru) at 120 weeks and PFS.
Results
At a median follow-up of 37.9 months, the superiority for lenalidomide and rituximab over rituximab-chemotherapy was not established.
For the lenalidomide-rituximab patients, the CR/Cru was 48% and 3-year PFS was 77% as compared to 53% and 78%, respectively, for rituximab-chemotherapy patients, as assessed by an independent review committee.
Overall survival was 94% in both groups.
Safety
“Important differences in safety profiles were observed between the arms,” Dr Fowler said.
Rituximab-chemotherapy patients had more frequent neutropenia, febrile neutropenia, growth factor usage, nausea, vomiting, neuropathy, and alopecia.
Lenalidomide and rituximab showed more cutaneous reactions, tumor flare, and diarrhea.
Toxicity profiles differed, with higher grade 4 neutropenia (31% vs 8%) and febrile neutropenia (7% vs 2%) with rituximab-chemotherapy compared with lenalidomide-rituximab, respectively.
More patients experienced grade 3/4 cutaneous events (7% vs 1%) with lenalidomide-rituximab.
Second primary malignancies were slightly higher with rituximab-chemotherapy (10%) than with lenalidomide-rituximab (7%). Grade 5 adverse events were 1% in both groups.
About 70% of patients completed treatment in both groups.
“Lenalidomide and rituximab was not superior to rituximab-chemotherapy based on mature CR/Cru at 120 weeks and interim PFS,” Dr Fowler said. “Both treatments showed similar efficacy results. Treatment effects on PFS were consistent across pre-specified subgroups.”
Dr Fowler presented data as of May 31, 2017. Continued follow-up on PFS and OS is ongoing.
The study is sponsored by Celgene Corporation and the Lymphoma Academic Research Organisation (LYSARC).
CHICAGO—A chemotherapy-free combination of lenalidomide plus rituximab shows similar efficacy and a different safety profile to chemotherapy plus rituximab (R-chemo) followed by rituximab maintenance in patients with previously untreated follicular lymphoma (FL).
According to investigators, the multicenter, international phase 3 RELEVANCE trial is the first to evaluate the chemo-free combination against the standard of care, R-chemo with rituximab maintenance.
“These results show that lenalidomide plus rituximab, a novel immunomodulatory approach, is a potential first-line option for patients with FL requiring treatment,” said investigator Nathan H. Fowler, MD, of the University of Texas MD Anderson Cancer Center in Houston.
Dr Fowler presented the results of the study at the 2018 ASCO Annual Meeting (abstract 7500).
The current standard of care in previously untreated symptomatic FL is immunochemotherapy induction followed by rituximab maintenance.
The immunomodulatory agent lenalidomide has complementary mechanisms with rituximab. Phase 2 studies of combined immunotherapy with lenalidomide and rituximab demonstrated 3-year progression-free survival (PFS) of 79%-81% in previously untreated FL, Dr Fowler said.
Phase 3 RELEVANCE trial (NCT01650701)
Investigators evaluated 1030 previously untreated grade 1-3a FL patients who required therapy.
Patients in the lenalidomide-rituximab group (n=513) received lenalidomide doses of 20 mg per day on days 2 to 22 and 28 for 6 to 12 cycles. Responders continued on therapy at 10 mg per day for a total of 18 cycles.
The rituximab dose was 375 mg/m2 weekly in cycle 1 and day 1 in cycles 2 to 6 and continued in responders for 12 additional cycles.
Patients in the R-chemo arm (n=517) received the investigator’s choice of standard rituximab-CHOP, rituximab-bendamustine, or rituximab-CVP, followed by 12 cycles of rituximab.
Most patients (72%) in the R-chemo arm received R-CHOP.
Baseline characteristics were similar in both groups, Dr Fowler said.
Co-primary endpoints were complete remission/complete remission unconfirmed (CR/Cru) at 120 weeks and PFS.
Results
At a median follow-up of 37.9 months, the superiority for lenalidomide and rituximab over rituximab-chemotherapy was not established.
For the lenalidomide-rituximab patients, the CR/Cru was 48% and 3-year PFS was 77% as compared to 53% and 78%, respectively, for rituximab-chemotherapy patients, as assessed by an independent review committee.
Overall survival was 94% in both groups.
Safety
“Important differences in safety profiles were observed between the arms,” Dr Fowler said.
Rituximab-chemotherapy patients had more frequent neutropenia, febrile neutropenia, growth factor usage, nausea, vomiting, neuropathy, and alopecia.
Lenalidomide and rituximab showed more cutaneous reactions, tumor flare, and diarrhea.
Toxicity profiles differed, with higher grade 4 neutropenia (31% vs 8%) and febrile neutropenia (7% vs 2%) with rituximab-chemotherapy compared with lenalidomide-rituximab, respectively.
More patients experienced grade 3/4 cutaneous events (7% vs 1%) with lenalidomide-rituximab.
Second primary malignancies were slightly higher with rituximab-chemotherapy (10%) than with lenalidomide-rituximab (7%). Grade 5 adverse events were 1% in both groups.
About 70% of patients completed treatment in both groups.
“Lenalidomide and rituximab was not superior to rituximab-chemotherapy based on mature CR/Cru at 120 weeks and interim PFS,” Dr Fowler said. “Both treatments showed similar efficacy results. Treatment effects on PFS were consistent across pre-specified subgroups.”
Dr Fowler presented data as of May 31, 2017. Continued follow-up on PFS and OS is ongoing.
The study is sponsored by Celgene Corporation and the Lymphoma Academic Research Organisation (LYSARC).
CHICAGO—A chemotherapy-free combination of lenalidomide plus rituximab shows similar efficacy and a different safety profile to chemotherapy plus rituximab (R-chemo) followed by rituximab maintenance in patients with previously untreated follicular lymphoma (FL).
According to investigators, the multicenter, international phase 3 RELEVANCE trial is the first to evaluate the chemo-free combination against the standard of care, R-chemo with rituximab maintenance.
“These results show that lenalidomide plus rituximab, a novel immunomodulatory approach, is a potential first-line option for patients with FL requiring treatment,” said investigator Nathan H. Fowler, MD, of the University of Texas MD Anderson Cancer Center in Houston.
Dr Fowler presented the results of the study at the 2018 ASCO Annual Meeting (abstract 7500).
The current standard of care in previously untreated symptomatic FL is immunochemotherapy induction followed by rituximab maintenance.
The immunomodulatory agent lenalidomide has complementary mechanisms with rituximab. Phase 2 studies of combined immunotherapy with lenalidomide and rituximab demonstrated 3-year progression-free survival (PFS) of 79%-81% in previously untreated FL, Dr Fowler said.
Phase 3 RELEVANCE trial (NCT01650701)
Investigators evaluated 1030 previously untreated grade 1-3a FL patients who required therapy.
Patients in the lenalidomide-rituximab group (n=513) received lenalidomide doses of 20 mg per day on days 2 to 22 and 28 for 6 to 12 cycles. Responders continued on therapy at 10 mg per day for a total of 18 cycles.
The rituximab dose was 375 mg/m2 weekly in cycle 1 and day 1 in cycles 2 to 6 and continued in responders for 12 additional cycles.
Patients in the R-chemo arm (n=517) received the investigator’s choice of standard rituximab-CHOP, rituximab-bendamustine, or rituximab-CVP, followed by 12 cycles of rituximab.
Most patients (72%) in the R-chemo arm received R-CHOP.
Baseline characteristics were similar in both groups, Dr Fowler said.
Co-primary endpoints were complete remission/complete remission unconfirmed (CR/Cru) at 120 weeks and PFS.
Results
At a median follow-up of 37.9 months, the superiority for lenalidomide and rituximab over rituximab-chemotherapy was not established.
For the lenalidomide-rituximab patients, the CR/Cru was 48% and 3-year PFS was 77% as compared to 53% and 78%, respectively, for rituximab-chemotherapy patients, as assessed by an independent review committee.
Overall survival was 94% in both groups.
Safety
“Important differences in safety profiles were observed between the arms,” Dr Fowler said.
Rituximab-chemotherapy patients had more frequent neutropenia, febrile neutropenia, growth factor usage, nausea, vomiting, neuropathy, and alopecia.
Lenalidomide and rituximab showed more cutaneous reactions, tumor flare, and diarrhea.
Toxicity profiles differed, with higher grade 4 neutropenia (31% vs 8%) and febrile neutropenia (7% vs 2%) with rituximab-chemotherapy compared with lenalidomide-rituximab, respectively.
More patients experienced grade 3/4 cutaneous events (7% vs 1%) with lenalidomide-rituximab.
Second primary malignancies were slightly higher with rituximab-chemotherapy (10%) than with lenalidomide-rituximab (7%). Grade 5 adverse events were 1% in both groups.
About 70% of patients completed treatment in both groups.
“Lenalidomide and rituximab was not superior to rituximab-chemotherapy based on mature CR/Cru at 120 weeks and interim PFS,” Dr Fowler said. “Both treatments showed similar efficacy results. Treatment effects on PFS were consistent across pre-specified subgroups.”
Dr Fowler presented data as of May 31, 2017. Continued follow-up on PFS and OS is ongoing.
The study is sponsored by Celgene Corporation and the Lymphoma Academic Research Organisation (LYSARC).
Pomalidomide triplet significantly extends PFS in R/R MM
CHICAGO—The addition of pomalidomide to bortezomib and low‐dose dexamethasone (PVd) significantly improves progression-free survival (PFS) in lenalidomide-exposed patients with relapsed or refractory (R/R) multiple myeloma (MM), a new study reveals.
Up until now, pomalidomide and dexamethasone (Pd) had been the only therapy investigated exclusively after lenalidomide therapy, according to Paul G. Richardson, MD.
Now, he said, “a triple combination of PVd demonstrated promising activity in early phase clinical trials of lenalidomide-refractory patients.”
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented the findings of the phase 3 OPTIMISMM trial (abstract 8001) at the 2018 ASCO Annual Meeting.
The oral immunomodulatory agent pomalidomide, a standard-of-care treatment in R/R MM, has demonstrated synergistic anti-myeloma activity with dexamethasone and proteasome inhibitors.
A combination of pomalidomide and dexamethasone is indicated for MM patients after 2 or more prior therapies, including lenalidomide and a proteasome inhibitor.
“Lenalidomide is an established therapy in newly diagnosed multiple myeloma,” Dr Richardson explained. “Therefore, patients for whom lenalidomide is no longer a treatment option represent a clinically relevant population with unmet need.”
Phase 3 OPTIMISMM trial (NCT01734928)
Dr Richardson reported the final PFS and safety data from the first phase 3 pomalidomide triplet trial comparing PVd against bortezomib and dexamethasone (Vd) in an entirely post-lenalidomide treated population.
The 559 patients had 1 to 3 prior lines of therapy and 2 or more cycles of prior lenalidomide. They were randomized to receive PVd (281 patients, median age 67 years) or Vd (278 patients, median age 68 years).
In 21-day cycles, patients received pomalidomide 4 mg per day on days 1-14 (PVd arm only); bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1-8 and on day 1 and 8 of cycles 9 and higher; and dexamethasone 20 mg per day (10 mg for those over age 75) on the days of and after bortezomib.
The primary endpoint was PFS.
Results
After a median follow-up of 16 months, “PVd reduced the risk of progression or death by 39% compared with Vd,” Dr Richardson said.
Median PFS was 11.2 months in the PVd group and 7.1 months in the Vd group. Overall survival data are not mature.
The overall response rate was significantly higher with PVd (82.2%) vs Vd (50%).
And the overall response rate was even higher in patients with only 1 prior line of therapy (90.1% vs 54.8%, respectively).
“PVd led to deeper responses with higher stringent complete response/complete response and more very good partial responses than Vd,” Dr Richardson noted.
“PFS was improved with PVd vs Vd across patient subgroups and regardless of lenalidomide refractoriness. The PFS benefit with PVd was maintained through the next line of therapy.”
He reported longer treatment duration and exposure with PVd compared with Vd.
Safety
The safety profile was consistent with known toxicities associated with pomalidomide and low-dose dexamethasone, he said.
Most common grade 3/4 treatment-emergent adverse events were higher with PVd than Vd, including neutropenia (42% vs 9%) and infections (31% vs 18%).
In conclusion, Dr Richardson said, “These results support the use of PVd in first relapse in patients with relapsed/refractory multiple myeloma and prior exposure to lenalidomide.”
Future analyses of the data will include correlatives, minimal residual disease, and quality of life, he said.
The trial was sponsored by Celgene.
CHICAGO—The addition of pomalidomide to bortezomib and low‐dose dexamethasone (PVd) significantly improves progression-free survival (PFS) in lenalidomide-exposed patients with relapsed or refractory (R/R) multiple myeloma (MM), a new study reveals.
Up until now, pomalidomide and dexamethasone (Pd) had been the only therapy investigated exclusively after lenalidomide therapy, according to Paul G. Richardson, MD.
Now, he said, “a triple combination of PVd demonstrated promising activity in early phase clinical trials of lenalidomide-refractory patients.”
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented the findings of the phase 3 OPTIMISMM trial (abstract 8001) at the 2018 ASCO Annual Meeting.
The oral immunomodulatory agent pomalidomide, a standard-of-care treatment in R/R MM, has demonstrated synergistic anti-myeloma activity with dexamethasone and proteasome inhibitors.
A combination of pomalidomide and dexamethasone is indicated for MM patients after 2 or more prior therapies, including lenalidomide and a proteasome inhibitor.
“Lenalidomide is an established therapy in newly diagnosed multiple myeloma,” Dr Richardson explained. “Therefore, patients for whom lenalidomide is no longer a treatment option represent a clinically relevant population with unmet need.”
Phase 3 OPTIMISMM trial (NCT01734928)
Dr Richardson reported the final PFS and safety data from the first phase 3 pomalidomide triplet trial comparing PVd against bortezomib and dexamethasone (Vd) in an entirely post-lenalidomide treated population.
The 559 patients had 1 to 3 prior lines of therapy and 2 or more cycles of prior lenalidomide. They were randomized to receive PVd (281 patients, median age 67 years) or Vd (278 patients, median age 68 years).
In 21-day cycles, patients received pomalidomide 4 mg per day on days 1-14 (PVd arm only); bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1-8 and on day 1 and 8 of cycles 9 and higher; and dexamethasone 20 mg per day (10 mg for those over age 75) on the days of and after bortezomib.
The primary endpoint was PFS.
Results
After a median follow-up of 16 months, “PVd reduced the risk of progression or death by 39% compared with Vd,” Dr Richardson said.
Median PFS was 11.2 months in the PVd group and 7.1 months in the Vd group. Overall survival data are not mature.
The overall response rate was significantly higher with PVd (82.2%) vs Vd (50%).
And the overall response rate was even higher in patients with only 1 prior line of therapy (90.1% vs 54.8%, respectively).
“PVd led to deeper responses with higher stringent complete response/complete response and more very good partial responses than Vd,” Dr Richardson noted.
“PFS was improved with PVd vs Vd across patient subgroups and regardless of lenalidomide refractoriness. The PFS benefit with PVd was maintained through the next line of therapy.”
He reported longer treatment duration and exposure with PVd compared with Vd.
Safety
The safety profile was consistent with known toxicities associated with pomalidomide and low-dose dexamethasone, he said.
Most common grade 3/4 treatment-emergent adverse events were higher with PVd than Vd, including neutropenia (42% vs 9%) and infections (31% vs 18%).
In conclusion, Dr Richardson said, “These results support the use of PVd in first relapse in patients with relapsed/refractory multiple myeloma and prior exposure to lenalidomide.”
Future analyses of the data will include correlatives, minimal residual disease, and quality of life, he said.
The trial was sponsored by Celgene.
CHICAGO—The addition of pomalidomide to bortezomib and low‐dose dexamethasone (PVd) significantly improves progression-free survival (PFS) in lenalidomide-exposed patients with relapsed or refractory (R/R) multiple myeloma (MM), a new study reveals.
Up until now, pomalidomide and dexamethasone (Pd) had been the only therapy investigated exclusively after lenalidomide therapy, according to Paul G. Richardson, MD.
Now, he said, “a triple combination of PVd demonstrated promising activity in early phase clinical trials of lenalidomide-refractory patients.”
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented the findings of the phase 3 OPTIMISMM trial (abstract 8001) at the 2018 ASCO Annual Meeting.
The oral immunomodulatory agent pomalidomide, a standard-of-care treatment in R/R MM, has demonstrated synergistic anti-myeloma activity with dexamethasone and proteasome inhibitors.
A combination of pomalidomide and dexamethasone is indicated for MM patients after 2 or more prior therapies, including lenalidomide and a proteasome inhibitor.
“Lenalidomide is an established therapy in newly diagnosed multiple myeloma,” Dr Richardson explained. “Therefore, patients for whom lenalidomide is no longer a treatment option represent a clinically relevant population with unmet need.”
Phase 3 OPTIMISMM trial (NCT01734928)
Dr Richardson reported the final PFS and safety data from the first phase 3 pomalidomide triplet trial comparing PVd against bortezomib and dexamethasone (Vd) in an entirely post-lenalidomide treated population.
The 559 patients had 1 to 3 prior lines of therapy and 2 or more cycles of prior lenalidomide. They were randomized to receive PVd (281 patients, median age 67 years) or Vd (278 patients, median age 68 years).
In 21-day cycles, patients received pomalidomide 4 mg per day on days 1-14 (PVd arm only); bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1-8 and on day 1 and 8 of cycles 9 and higher; and dexamethasone 20 mg per day (10 mg for those over age 75) on the days of and after bortezomib.
The primary endpoint was PFS.
Results
After a median follow-up of 16 months, “PVd reduced the risk of progression or death by 39% compared with Vd,” Dr Richardson said.
Median PFS was 11.2 months in the PVd group and 7.1 months in the Vd group. Overall survival data are not mature.
The overall response rate was significantly higher with PVd (82.2%) vs Vd (50%).
And the overall response rate was even higher in patients with only 1 prior line of therapy (90.1% vs 54.8%, respectively).
“PVd led to deeper responses with higher stringent complete response/complete response and more very good partial responses than Vd,” Dr Richardson noted.
“PFS was improved with PVd vs Vd across patient subgroups and regardless of lenalidomide refractoriness. The PFS benefit with PVd was maintained through the next line of therapy.”
He reported longer treatment duration and exposure with PVd compared with Vd.
Safety
The safety profile was consistent with known toxicities associated with pomalidomide and low-dose dexamethasone, he said.
Most common grade 3/4 treatment-emergent adverse events were higher with PVd than Vd, including neutropenia (42% vs 9%) and infections (31% vs 18%).
In conclusion, Dr Richardson said, “These results support the use of PVd in first relapse in patients with relapsed/refractory multiple myeloma and prior exposure to lenalidomide.”
Future analyses of the data will include correlatives, minimal residual disease, and quality of life, he said.
The trial was sponsored by Celgene.
Once-weekly carfilzomib combo improves PFS in R/R MM
CHICAGO—A once-weekly regimen of carfilzomib plus dexamethasone shows a favorable benefit-risk profile for patients with relapsed or refractory (R/R) multiple myeloma (MM), according to a new study.
“The more convenient dosing schedule can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” said investigator Maria-Victoria Mateos, MD, of the Hospital Clinico Universitario de Salamanca-IBSAL in Salamanca, Spain.
Dr Mateos presented results of the randomized, phase 3 study (abstract 8000) at the 2018 ASCO Annual Meeting. The results were also published in The Lancet.
Twice-weekly carfilzomib at 27 mg/m2 is approved as a single agent and in combination with lenalidomide or dexamethasone for the treatment of relapsed/refractory MM.
To develop a more convenient carfilzomib regimen, once-weekly carfilzomib plus dexamethasone was assessed in the phase 1/2 CHAMPION-1 study, showing good response rates (77%) and a median PFS of 12.6 months.
At ASCO, Dr Mateos presented the results from the pre-planned interim analysis of the phase 3 ARROW study (NCT02412878), comparing the two-drug regimen once-weekly vs twice-weekly.
Study design
The 478 patients, median age 66 years, had 2 to 3 prior therapies and prior exposure to a proteasome inhibitor and an immunomodulatory agent. Baseline characteristics were generally balanced, she said.
Investigators randomized patients to receive either once- or twice-weekly carfilzomib plus dexamethasone.
The once-weekly group received carfilzomib 20 mg/m2 intravenously on day 1 of cycle 1 and 70 mg/m2 on days 1, 8, and 15 of all subsequent cycles.
The twice-weekly group received the same carfilzomib dose on day 1, cycle 1 and 27 mg/m2 on days 8, 9, 15, and 16 thereafter. All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles), and day 22 (cycles 1–9 only).
The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate, overall survival, safety, and pharmacokinetics.
Results
The study met the primary endpoint of PFS, with a median PFS for the once-weekly dose of 11.2 months and 7.6 months for the twice-weekly dose.
In addition, “patients who received once-weekly carfilzomib plus dexamethasone achieved a statistically significant higher overall response rate (62.9%) than patients who received the twice-weekly dose (40.8%),” Dr Mateos said.
Similarly, more patients achieved a complete response or better (7.1%) with the once-weekly dose than the twice-weekly dose (1.7%).
Safety
The overall safety profile was comparable between the 2 treatment groups and no new safety risks were identified.
Grade 3 or higher adverse events occurred in 67.6% (once-weekly) and 61.7% (twice-weekly) of patients.
Treatment-related grade 5 adverse events occurred in 5 patients (2.1%) in the once-weekly group and in 2 patients (0.9%) in the twice-weekly group.
The incidence of grade 3 or higher hypertension and cardiac failure was similar in both groups.
“Exposure-adjusted incidence of grade 3 or higher adverse events was slightly higher in the once-weekly vs the twice-weekly group,” Dr Mateos explained, “but the exposure-adjusted incidence for severe adverse events and adverse events leading to discontinuation of carfilzomib or death were similar between the treatment groups,” she said.
The ARROW study was supported by Amgen Inc.
CHICAGO—A once-weekly regimen of carfilzomib plus dexamethasone shows a favorable benefit-risk profile for patients with relapsed or refractory (R/R) multiple myeloma (MM), according to a new study.
“The more convenient dosing schedule can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” said investigator Maria-Victoria Mateos, MD, of the Hospital Clinico Universitario de Salamanca-IBSAL in Salamanca, Spain.
Dr Mateos presented results of the randomized, phase 3 study (abstract 8000) at the 2018 ASCO Annual Meeting. The results were also published in The Lancet.
Twice-weekly carfilzomib at 27 mg/m2 is approved as a single agent and in combination with lenalidomide or dexamethasone for the treatment of relapsed/refractory MM.
To develop a more convenient carfilzomib regimen, once-weekly carfilzomib plus dexamethasone was assessed in the phase 1/2 CHAMPION-1 study, showing good response rates (77%) and a median PFS of 12.6 months.
At ASCO, Dr Mateos presented the results from the pre-planned interim analysis of the phase 3 ARROW study (NCT02412878), comparing the two-drug regimen once-weekly vs twice-weekly.
Study design
The 478 patients, median age 66 years, had 2 to 3 prior therapies and prior exposure to a proteasome inhibitor and an immunomodulatory agent. Baseline characteristics were generally balanced, she said.
Investigators randomized patients to receive either once- or twice-weekly carfilzomib plus dexamethasone.
The once-weekly group received carfilzomib 20 mg/m2 intravenously on day 1 of cycle 1 and 70 mg/m2 on days 1, 8, and 15 of all subsequent cycles.
The twice-weekly group received the same carfilzomib dose on day 1, cycle 1 and 27 mg/m2 on days 8, 9, 15, and 16 thereafter. All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles), and day 22 (cycles 1–9 only).
The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate, overall survival, safety, and pharmacokinetics.
Results
The study met the primary endpoint of PFS, with a median PFS for the once-weekly dose of 11.2 months and 7.6 months for the twice-weekly dose.
In addition, “patients who received once-weekly carfilzomib plus dexamethasone achieved a statistically significant higher overall response rate (62.9%) than patients who received the twice-weekly dose (40.8%),” Dr Mateos said.
Similarly, more patients achieved a complete response or better (7.1%) with the once-weekly dose than the twice-weekly dose (1.7%).
Safety
The overall safety profile was comparable between the 2 treatment groups and no new safety risks were identified.
Grade 3 or higher adverse events occurred in 67.6% (once-weekly) and 61.7% (twice-weekly) of patients.
Treatment-related grade 5 adverse events occurred in 5 patients (2.1%) in the once-weekly group and in 2 patients (0.9%) in the twice-weekly group.
The incidence of grade 3 or higher hypertension and cardiac failure was similar in both groups.
“Exposure-adjusted incidence of grade 3 or higher adverse events was slightly higher in the once-weekly vs the twice-weekly group,” Dr Mateos explained, “but the exposure-adjusted incidence for severe adverse events and adverse events leading to discontinuation of carfilzomib or death were similar between the treatment groups,” she said.
The ARROW study was supported by Amgen Inc.
CHICAGO—A once-weekly regimen of carfilzomib plus dexamethasone shows a favorable benefit-risk profile for patients with relapsed or refractory (R/R) multiple myeloma (MM), according to a new study.
“The more convenient dosing schedule can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” said investigator Maria-Victoria Mateos, MD, of the Hospital Clinico Universitario de Salamanca-IBSAL in Salamanca, Spain.
Dr Mateos presented results of the randomized, phase 3 study (abstract 8000) at the 2018 ASCO Annual Meeting. The results were also published in The Lancet.
Twice-weekly carfilzomib at 27 mg/m2 is approved as a single agent and in combination with lenalidomide or dexamethasone for the treatment of relapsed/refractory MM.
To develop a more convenient carfilzomib regimen, once-weekly carfilzomib plus dexamethasone was assessed in the phase 1/2 CHAMPION-1 study, showing good response rates (77%) and a median PFS of 12.6 months.
At ASCO, Dr Mateos presented the results from the pre-planned interim analysis of the phase 3 ARROW study (NCT02412878), comparing the two-drug regimen once-weekly vs twice-weekly.
Study design
The 478 patients, median age 66 years, had 2 to 3 prior therapies and prior exposure to a proteasome inhibitor and an immunomodulatory agent. Baseline characteristics were generally balanced, she said.
Investigators randomized patients to receive either once- or twice-weekly carfilzomib plus dexamethasone.
The once-weekly group received carfilzomib 20 mg/m2 intravenously on day 1 of cycle 1 and 70 mg/m2 on days 1, 8, and 15 of all subsequent cycles.
The twice-weekly group received the same carfilzomib dose on day 1, cycle 1 and 27 mg/m2 on days 8, 9, 15, and 16 thereafter. All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles), and day 22 (cycles 1–9 only).
The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate, overall survival, safety, and pharmacokinetics.
Results
The study met the primary endpoint of PFS, with a median PFS for the once-weekly dose of 11.2 months and 7.6 months for the twice-weekly dose.
In addition, “patients who received once-weekly carfilzomib plus dexamethasone achieved a statistically significant higher overall response rate (62.9%) than patients who received the twice-weekly dose (40.8%),” Dr Mateos said.
Similarly, more patients achieved a complete response or better (7.1%) with the once-weekly dose than the twice-weekly dose (1.7%).
Safety
The overall safety profile was comparable between the 2 treatment groups and no new safety risks were identified.
Grade 3 or higher adverse events occurred in 67.6% (once-weekly) and 61.7% (twice-weekly) of patients.
Treatment-related grade 5 adverse events occurred in 5 patients (2.1%) in the once-weekly group and in 2 patients (0.9%) in the twice-weekly group.
The incidence of grade 3 or higher hypertension and cardiac failure was similar in both groups.
“Exposure-adjusted incidence of grade 3 or higher adverse events was slightly higher in the once-weekly vs the twice-weekly group,” Dr Mateos explained, “but the exposure-adjusted incidence for severe adverse events and adverse events leading to discontinuation of carfilzomib or death were similar between the treatment groups,” she said.
The ARROW study was supported by Amgen Inc.
Team develops new scoring systems for PMF
ATLANTA—Two novel prognostic scoring systems can help clinicians decide how to treat certain patients with primary myelofibrosis (PMF), according to a new study.
The scoring systems, which build upon the International Prognostic Scoring System (IPSS), were developed for use in PMF patients age 70 and younger who are potential candidates for hematopoietic stem cell transplant (HSCT).
One of the scoring systems—MIPSS70—integrates clinical, histologic, and molecular information. The other—MIPSS70-plus—also includes cytogenetic information.
Alessandro M. Vannucchi, MD, of the University of Florence in Italy, presented details on these prognostic scoring systems at the 2017 ASH Annual Meeting (abstract 200*).
The information was published simultaneously in the Journal of Clinical Oncology.
Dr Vannucchi noted that, in PMF, survival is currently predicted by the IPSS, the dynamic IPSS, and the dynamic IPSS-plus.
“The IPSS score is used at the time of diagnosis, while the dynamic IPSS or dynamic IPSS-plus are used to provide survival estimates at the time of patient referral,” he explained. “In clinical practice, these prognostic risk scores are mainly used for [HSCT] decision-making in younger patients.”
Driver mutations and other myeloid neoplasm-associated mutations provide prognostic information that is independent of the IPSS/dynamic IPSS/dynamic IPSS-plus scoring systems.
The degree of bone marrow fibrosis and cytogenetic abnormalities configuring an unfavorable category also contribute prognostic information that is independent of these scoring systems.
With this in mind, Dr Vannucchi and his colleagues set out to develop an updated prognostic score that included molecular information (MIPSS70) and, if possible, cytogenetic information (MIPSS70-plus) for PMF patients age 70 and younger who are potential candidates for HSCT.
The researchers developed 2 prognostic models using a training/validation cohort approach.
For MIPSS70, the training cohort included 490 patients from 6 Italian institutions associated with the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative project (AGIMM group), and the validation cohort included 211 patients from the Mayo Clinic in Rochester, Minnesota.
For MIPSS70-plus, the training cohort included 315 patients from the Mayo Clinic, and the validation cohort included 261 patients from the AGIMM group.
Using the MIPSS70 risk score in the validation cohort, the 5-year overall survival rate was 96% in low-risk, 67% in intermediate-risk, and 34% in high-risk patients.
“MIPSS70 performed better than IPSS in predicting survival,” Dr Vannucchi said. “About 30% of patients who were high-risk with MIPPS70 were missed by IPSS.”
Using the MIPSS70-plus risk score in the validation cohort, the 5-year overall survival rate was 100% in low-risk, 90% in intermediate-risk, 76% in high-risk, and 46.5% in very high-risk patients.
The MIPSS70-plus risk score also identified patients at very high risk for leukemic transformation, Dr Vannucchi said.
Furthermore, both MIPSS70 and MIPSS70-plus remained predictive of survival when the researchers evaluated patients older than 70 years of age.
“The new MIPSS70 and MIPSS70-plus scores include modern disease-associated risk variables pertinent to both pre-PMF and overt-PMF according to the 2016 WHO classification,” Dr Vannucchi said. “They integrate prognostically relevant clinical, cytogenetic, and mutation data and provide complementary systems of improved risk stratification for transplantation-age patients with PMF.”
Dr Vannucchi disclosed membership in speaker’s bureaus with Gilead, Shire, and Novartis, and research funding and membership on Board of Directors or advisory committees with Novartis. 
*Data in the presentation differ from the abstract.
ATLANTA—Two novel prognostic scoring systems can help clinicians decide how to treat certain patients with primary myelofibrosis (PMF), according to a new study.
The scoring systems, which build upon the International Prognostic Scoring System (IPSS), were developed for use in PMF patients age 70 and younger who are potential candidates for hematopoietic stem cell transplant (HSCT).
One of the scoring systems—MIPSS70—integrates clinical, histologic, and molecular information. The other—MIPSS70-plus—also includes cytogenetic information.
Alessandro M. Vannucchi, MD, of the University of Florence in Italy, presented details on these prognostic scoring systems at the 2017 ASH Annual Meeting (abstract 200*).
The information was published simultaneously in the Journal of Clinical Oncology.
Dr Vannucchi noted that, in PMF, survival is currently predicted by the IPSS, the dynamic IPSS, and the dynamic IPSS-plus.
“The IPSS score is used at the time of diagnosis, while the dynamic IPSS or dynamic IPSS-plus are used to provide survival estimates at the time of patient referral,” he explained. “In clinical practice, these prognostic risk scores are mainly used for [HSCT] decision-making in younger patients.”
Driver mutations and other myeloid neoplasm-associated mutations provide prognostic information that is independent of the IPSS/dynamic IPSS/dynamic IPSS-plus scoring systems.
The degree of bone marrow fibrosis and cytogenetic abnormalities configuring an unfavorable category also contribute prognostic information that is independent of these scoring systems.
With this in mind, Dr Vannucchi and his colleagues set out to develop an updated prognostic score that included molecular information (MIPSS70) and, if possible, cytogenetic information (MIPSS70-plus) for PMF patients age 70 and younger who are potential candidates for HSCT.
The researchers developed 2 prognostic models using a training/validation cohort approach.
For MIPSS70, the training cohort included 490 patients from 6 Italian institutions associated with the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative project (AGIMM group), and the validation cohort included 211 patients from the Mayo Clinic in Rochester, Minnesota.
For MIPSS70-plus, the training cohort included 315 patients from the Mayo Clinic, and the validation cohort included 261 patients from the AGIMM group.
Using the MIPSS70 risk score in the validation cohort, the 5-year overall survival rate was 96% in low-risk, 67% in intermediate-risk, and 34% in high-risk patients.
“MIPSS70 performed better than IPSS in predicting survival,” Dr Vannucchi said. “About 30% of patients who were high-risk with MIPPS70 were missed by IPSS.”
Using the MIPSS70-plus risk score in the validation cohort, the 5-year overall survival rate was 100% in low-risk, 90% in intermediate-risk, 76% in high-risk, and 46.5% in very high-risk patients.
The MIPSS70-plus risk score also identified patients at very high risk for leukemic transformation, Dr Vannucchi said.
Furthermore, both MIPSS70 and MIPSS70-plus remained predictive of survival when the researchers evaluated patients older than 70 years of age.
“The new MIPSS70 and MIPSS70-plus scores include modern disease-associated risk variables pertinent to both pre-PMF and overt-PMF according to the 2016 WHO classification,” Dr Vannucchi said. “They integrate prognostically relevant clinical, cytogenetic, and mutation data and provide complementary systems of improved risk stratification for transplantation-age patients with PMF.”
Dr Vannucchi disclosed membership in speaker’s bureaus with Gilead, Shire, and Novartis, and research funding and membership on Board of Directors or advisory committees with Novartis.
*Data in the presentation differ from the abstract.
ATLANTA—Two novel prognostic scoring systems can help clinicians decide how to treat certain patients with primary myelofibrosis (PMF), according to a new study.
The scoring systems, which build upon the International Prognostic Scoring System (IPSS), were developed for use in PMF patients age 70 and younger who are potential candidates for hematopoietic stem cell transplant (HSCT).
One of the scoring systems—MIPSS70—integrates clinical, histologic, and molecular information. The other—MIPSS70-plus—also includes cytogenetic information.
Alessandro M. Vannucchi, MD, of the University of Florence in Italy, presented details on these prognostic scoring systems at the 2017 ASH Annual Meeting (abstract 200*).
The information was published simultaneously in the Journal of Clinical Oncology.
Dr Vannucchi noted that, in PMF, survival is currently predicted by the IPSS, the dynamic IPSS, and the dynamic IPSS-plus.
“The IPSS score is used at the time of diagnosis, while the dynamic IPSS or dynamic IPSS-plus are used to provide survival estimates at the time of patient referral,” he explained. “In clinical practice, these prognostic risk scores are mainly used for [HSCT] decision-making in younger patients.”
Driver mutations and other myeloid neoplasm-associated mutations provide prognostic information that is independent of the IPSS/dynamic IPSS/dynamic IPSS-plus scoring systems.
The degree of bone marrow fibrosis and cytogenetic abnormalities configuring an unfavorable category also contribute prognostic information that is independent of these scoring systems.
With this in mind, Dr Vannucchi and his colleagues set out to develop an updated prognostic score that included molecular information (MIPSS70) and, if possible, cytogenetic information (MIPSS70-plus) for PMF patients age 70 and younger who are potential candidates for HSCT.
The researchers developed 2 prognostic models using a training/validation cohort approach.
For MIPSS70, the training cohort included 490 patients from 6 Italian institutions associated with the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative project (AGIMM group), and the validation cohort included 211 patients from the Mayo Clinic in Rochester, Minnesota.
For MIPSS70-plus, the training cohort included 315 patients from the Mayo Clinic, and the validation cohort included 261 patients from the AGIMM group.
Using the MIPSS70 risk score in the validation cohort, the 5-year overall survival rate was 96% in low-risk, 67% in intermediate-risk, and 34% in high-risk patients.
“MIPSS70 performed better than IPSS in predicting survival,” Dr Vannucchi said. “About 30% of patients who were high-risk with MIPPS70 were missed by IPSS.”
Using the MIPSS70-plus risk score in the validation cohort, the 5-year overall survival rate was 100% in low-risk, 90% in intermediate-risk, 76% in high-risk, and 46.5% in very high-risk patients.
The MIPSS70-plus risk score also identified patients at very high risk for leukemic transformation, Dr Vannucchi said.
Furthermore, both MIPSS70 and MIPSS70-plus remained predictive of survival when the researchers evaluated patients older than 70 years of age.
“The new MIPSS70 and MIPSS70-plus scores include modern disease-associated risk variables pertinent to both pre-PMF and overt-PMF according to the 2016 WHO classification,” Dr Vannucchi said. “They integrate prognostically relevant clinical, cytogenetic, and mutation data and provide complementary systems of improved risk stratification for transplantation-age patients with PMF.”
Dr Vannucchi disclosed membership in speaker’s bureaus with Gilead, Shire, and Novartis, and research funding and membership on Board of Directors or advisory committees with Novartis.
*Data in the presentation differ from the abstract.
Allo-HSCT leads to long-term survival in MF
ATLANTA—One of the largest single-center studies of fludarabine/melphalan-based allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients with myelofibrosis (MF) shows excellent overall survival (OS) with a low risk of relapse, according to investigators.
Allo-HSCT is the only potential curative treatment modality for MF.
However, it is associated with risks of transplant-related morbidity and mortality from graft-versus-host disease (GVHD), infection, graft rejection, and regimen-related toxicities.
This necessitates careful patient selection and intense peri-transplant management, said study investigator Haris Ali, MD, of the City of Hope Medical Center in Duarte, California.
He noted that there has been a 5-fold increase in allo-HSCT in the last 2 decades, mainly among older patients, due to the increase in reduced-intensity conditioning.
At the 2017 ASH Annual Meeting (in abstract 199), Dr Ali reported on a cohort of 110 MF patients who underwent allo-HSCT with fludarabine/melphalan conditioning at City of Hope between 2004 and 2017.
The patients, 58 with primary MF and 52 with secondary MF, were without prior acute leukemic transformation. They were a median age of 58.5 at the time of transplant, with a median interval of 15.2 months from MF diagnosis.
Virtually all (n=107) received peripheral blood stem cells, and 3 were transplanted with bone marrow as the stem cell source. Forty-nine allo-HSCT donors were matched related, 32 were matched unrelated, 27 were mismatched unrelated, 1 was mismatched relative, and 1 was haploidentical family.
Three-quarters of the patients had intermediate-2 or high-risk disease. Of the 110 patients, 16 had splenectomy prior to allo-HSCT. All but 2 patients engrafted.
After a median follow-up of 56.8 months, the 2-year OS rate was 74%, and the 5-year OS rate was 65%.
Non-relapse mortality at 2 years was 12%. At 5 years, it was 24%.
“The risk of non-relapse mortality was acceptable, considering the relatively older age of a large subset of patients; nearly half were over age 60 at allo-HSCT,” Dr Ali said.
In a univariate analysis, mismatched donors and matched unrelated donors were significantly associated with worse OS compared with matched related donors.
The cumulative incidence of relapse was 17% at 2 years and 5 years.
Splenectomy prior to transplant was associated with higher relapse risk, Dr Ali noted.
“Cytogenetic abnormalities were not associated with transplant relapse or other outcomes in our cohort,” he added.
Mutational changes are being tested in pre-transplant samples and will be reported at a later date.
The incidence of grade 2-4 and 3-4 acute GVHD at 100 days was 45% and 17%, respectively.
At 36 months, the cumulative incidence of all chronic GVHD was 66%. For extensive chronic GVHD, it was 59%.
“Interestingly, prior use of ruxolitinib increased the risk of grade 3-4 acute GVHD, possibly due to known inflammatory cytokine rebound,” Dr Ali said.
Extended use of ruxolitinib until day 30 or longer is currently being evaluated in a prospective trial at City of Hope (NCT02917096).
Dr Ali disclosed consulting fees from Incyte.
ATLANTA—One of the largest single-center studies of fludarabine/melphalan-based allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients with myelofibrosis (MF) shows excellent overall survival (OS) with a low risk of relapse, according to investigators.
Allo-HSCT is the only potential curative treatment modality for MF.
However, it is associated with risks of transplant-related morbidity and mortality from graft-versus-host disease (GVHD), infection, graft rejection, and regimen-related toxicities.
This necessitates careful patient selection and intense peri-transplant management, said study investigator Haris Ali, MD, of the City of Hope Medical Center in Duarte, California.
He noted that there has been a 5-fold increase in allo-HSCT in the last 2 decades, mainly among older patients, due to the increase in reduced-intensity conditioning.
At the 2017 ASH Annual Meeting (in abstract 199), Dr Ali reported on a cohort of 110 MF patients who underwent allo-HSCT with fludarabine/melphalan conditioning at City of Hope between 2004 and 2017.
The patients, 58 with primary MF and 52 with secondary MF, were without prior acute leukemic transformation. They were a median age of 58.5 at the time of transplant, with a median interval of 15.2 months from MF diagnosis.
Virtually all (n=107) received peripheral blood stem cells, and 3 were transplanted with bone marrow as the stem cell source. Forty-nine allo-HSCT donors were matched related, 32 were matched unrelated, 27 were mismatched unrelated, 1 was mismatched relative, and 1 was haploidentical family.
Three-quarters of the patients had intermediate-2 or high-risk disease. Of the 110 patients, 16 had splenectomy prior to allo-HSCT. All but 2 patients engrafted.
After a median follow-up of 56.8 months, the 2-year OS rate was 74%, and the 5-year OS rate was 65%.
Non-relapse mortality at 2 years was 12%. At 5 years, it was 24%.
“The risk of non-relapse mortality was acceptable, considering the relatively older age of a large subset of patients; nearly half were over age 60 at allo-HSCT,” Dr Ali said.
In a univariate analysis, mismatched donors and matched unrelated donors were significantly associated with worse OS compared with matched related donors.
The cumulative incidence of relapse was 17% at 2 years and 5 years.
Splenectomy prior to transplant was associated with higher relapse risk, Dr Ali noted.
“Cytogenetic abnormalities were not associated with transplant relapse or other outcomes in our cohort,” he added.
Mutational changes are being tested in pre-transplant samples and will be reported at a later date.
The incidence of grade 2-4 and 3-4 acute GVHD at 100 days was 45% and 17%, respectively.
At 36 months, the cumulative incidence of all chronic GVHD was 66%. For extensive chronic GVHD, it was 59%.
“Interestingly, prior use of ruxolitinib increased the risk of grade 3-4 acute GVHD, possibly due to known inflammatory cytokine rebound,” Dr Ali said.
Extended use of ruxolitinib until day 30 or longer is currently being evaluated in a prospective trial at City of Hope (NCT02917096).
Dr Ali disclosed consulting fees from Incyte.
ATLANTA—One of the largest single-center studies of fludarabine/melphalan-based allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients with myelofibrosis (MF) shows excellent overall survival (OS) with a low risk of relapse, according to investigators.
Allo-HSCT is the only potential curative treatment modality for MF.
However, it is associated with risks of transplant-related morbidity and mortality from graft-versus-host disease (GVHD), infection, graft rejection, and regimen-related toxicities.
This necessitates careful patient selection and intense peri-transplant management, said study investigator Haris Ali, MD, of the City of Hope Medical Center in Duarte, California.
He noted that there has been a 5-fold increase in allo-HSCT in the last 2 decades, mainly among older patients, due to the increase in reduced-intensity conditioning.
At the 2017 ASH Annual Meeting (in abstract 199), Dr Ali reported on a cohort of 110 MF patients who underwent allo-HSCT with fludarabine/melphalan conditioning at City of Hope between 2004 and 2017.
The patients, 58 with primary MF and 52 with secondary MF, were without prior acute leukemic transformation. They were a median age of 58.5 at the time of transplant, with a median interval of 15.2 months from MF diagnosis.
Virtually all (n=107) received peripheral blood stem cells, and 3 were transplanted with bone marrow as the stem cell source. Forty-nine allo-HSCT donors were matched related, 32 were matched unrelated, 27 were mismatched unrelated, 1 was mismatched relative, and 1 was haploidentical family.
Three-quarters of the patients had intermediate-2 or high-risk disease. Of the 110 patients, 16 had splenectomy prior to allo-HSCT. All but 2 patients engrafted.
After a median follow-up of 56.8 months, the 2-year OS rate was 74%, and the 5-year OS rate was 65%.
Non-relapse mortality at 2 years was 12%. At 5 years, it was 24%.
“The risk of non-relapse mortality was acceptable, considering the relatively older age of a large subset of patients; nearly half were over age 60 at allo-HSCT,” Dr Ali said.
In a univariate analysis, mismatched donors and matched unrelated donors were significantly associated with worse OS compared with matched related donors.
The cumulative incidence of relapse was 17% at 2 years and 5 years.
Splenectomy prior to transplant was associated with higher relapse risk, Dr Ali noted.
“Cytogenetic abnormalities were not associated with transplant relapse or other outcomes in our cohort,” he added.
Mutational changes are being tested in pre-transplant samples and will be reported at a later date.
The incidence of grade 2-4 and 3-4 acute GVHD at 100 days was 45% and 17%, respectively.
At 36 months, the cumulative incidence of all chronic GVHD was 66%. For extensive chronic GVHD, it was 59%.
“Interestingly, prior use of ruxolitinib increased the risk of grade 3-4 acute GVHD, possibly due to known inflammatory cytokine rebound,” Dr Ali said.
Extended use of ruxolitinib until day 30 or longer is currently being evaluated in a prospective trial at City of Hope (NCT02917096).
Dr Ali disclosed consulting fees from Incyte.
Ruxolitinib improves survival for MF patients in CP-e
ATLANTA—A new study suggests the JAK2 inhibitor ruxolitinib has the potential to significantly improve survival in patients who have chronic phase (CP) myelofibrosis (MF), with or without elevated blasts.
In this retrospective study, researchers found evidence to suggest that MF patients in CP with elevated blasts (CP-e) should be considered a high-risk group.
However, ruxolitinib significantly improved overall survival (OS) in CP-e patients—who had 5% to 9% blasts in the bone marrow or peripheral blood—and in patients with CP and less than 5% blasts.
On the other hand, ruxolitinib had no impact on the rate of progression to acute myeloid leukemia (AML) in CP or CP-e patients.
Lucia Masarova, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these findings at the 2017 ASH Annual Meeting (abstract 201).
Clinical characteristics of MF CP-e patients are not well described, and the outcome of available therapy in this population is largely unknown. Therefore, Dr Masarova and her colleagues set out to evaluate the effects of ruxolitinib on CP-e patients.
The team conducted a retrospective chart review of 1199 MF patients, 832 with primary MF, 169 with post-essential thrombocythemia MF, and 198 with post-polycythemia vera MF. About two-thirds of the patients were newly diagnosed.
The majority of patients (85%, n=1020) were in CP with less than 5% blasts, 10% (n=123) were in CP-e, and 5% (n=56) were in accelerated phase (AP, 10% to 19% blasts).
CP-e patients had similar clinical characteristics as patients in AP. Both groups had higher white blood cell counts; lower hemoglobin and platelets; and more frequent splenomegaly, systemic symptoms, and presence of abnormal and unfavorable karyotype than CP patients.
Among the 1030 treated patients, ruxolitinib was used in 30% (n=328), including 28% of CP patients (n=289), 27% of CP-e patients (n=33), and 11% of AP patients (n=6). The median treatment duration was about 22 months in the CP and CP-e groups.
After a median follow-up of 27 months, half the patients studied had died.
“Patients in the [CP-e] group had similar OS as those in AP, which was inferior to patients in CP,” Dr Masarova said.
The median OS was 48 months for the entire cohort, 56 months in the CP group, 34 months in the CP-e group, and 23 months in the AP group.
One-year OS rates were 86% for the CP group, 73% for the CP-e group, and 65% for the AP group. Five-year OS rates were 46%, 24%, and 21%, respectively.
CP and CP-e patients had superior OS if they had received ruxolitinib.
Among CP patients, the median OS was 61 months in those who received ruxolitinib and 54 months in those who did not (hazard ratio=0.85, P=0.002).
Among CP-e patients, the median OS was 54 months in those who received ruxolitinib and 27 months in those who did not (hazard ratio=0.50, P=0.001).
Ruxolitinib had no impact on OS in AP patients, which was 23 months with or without the drug. However, Dr Masarova noted that the AP patient numbers were small.
Progression to AML occurred in 9% of patients overall (n=139), 9% in the CP group, 20% in the CP-e group, and 39% in the AP group.
Ruxolitinib had no impact on the rate of AML progression, which was 9% in CP patients, with and without the drug.
In CP-e patients, AML progression occurred in 22% of those who received ruxolitinib and 18% of those who did not.
“The [CP-e] patients are similar to AP patients, with adverse clinical characteristics, inferior OS, and a 20% to 40% AML rate,” Dr Masarova said. “Ruxolitinib improves survival of [CP-e] patients, which is similar to CP patients on the drug.”
CP-e patients should be considered a high-risk population, she said, adding “we need to find new, better treatments for these patients.”
Dr Masarova had no disclosures.
ATLANTA—A new study suggests the JAK2 inhibitor ruxolitinib has the potential to significantly improve survival in patients who have chronic phase (CP) myelofibrosis (MF), with or without elevated blasts.
In this retrospective study, researchers found evidence to suggest that MF patients in CP with elevated blasts (CP-e) should be considered a high-risk group.
However, ruxolitinib significantly improved overall survival (OS) in CP-e patients—who had 5% to 9% blasts in the bone marrow or peripheral blood—and in patients with CP and less than 5% blasts.
On the other hand, ruxolitinib had no impact on the rate of progression to acute myeloid leukemia (AML) in CP or CP-e patients.
Lucia Masarova, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these findings at the 2017 ASH Annual Meeting (abstract 201).
Clinical characteristics of MF CP-e patients are not well described, and the outcome of available therapy in this population is largely unknown. Therefore, Dr Masarova and her colleagues set out to evaluate the effects of ruxolitinib on CP-e patients.
The team conducted a retrospective chart review of 1199 MF patients, 832 with primary MF, 169 with post-essential thrombocythemia MF, and 198 with post-polycythemia vera MF. About two-thirds of the patients were newly diagnosed.
The majority of patients (85%, n=1020) were in CP with less than 5% blasts, 10% (n=123) were in CP-e, and 5% (n=56) were in accelerated phase (AP, 10% to 19% blasts).
CP-e patients had similar clinical characteristics as patients in AP. Both groups had higher white blood cell counts; lower hemoglobin and platelets; and more frequent splenomegaly, systemic symptoms, and presence of abnormal and unfavorable karyotype than CP patients.
Among the 1030 treated patients, ruxolitinib was used in 30% (n=328), including 28% of CP patients (n=289), 27% of CP-e patients (n=33), and 11% of AP patients (n=6). The median treatment duration was about 22 months in the CP and CP-e groups.
After a median follow-up of 27 months, half the patients studied had died.
“Patients in the [CP-e] group had similar OS as those in AP, which was inferior to patients in CP,” Dr Masarova said.
The median OS was 48 months for the entire cohort, 56 months in the CP group, 34 months in the CP-e group, and 23 months in the AP group.
One-year OS rates were 86% for the CP group, 73% for the CP-e group, and 65% for the AP group. Five-year OS rates were 46%, 24%, and 21%, respectively.
CP and CP-e patients had superior OS if they had received ruxolitinib.
Among CP patients, the median OS was 61 months in those who received ruxolitinib and 54 months in those who did not (hazard ratio=0.85, P=0.002).
Among CP-e patients, the median OS was 54 months in those who received ruxolitinib and 27 months in those who did not (hazard ratio=0.50, P=0.001).
Ruxolitinib had no impact on OS in AP patients, which was 23 months with or without the drug. However, Dr Masarova noted that the AP patient numbers were small.
Progression to AML occurred in 9% of patients overall (n=139), 9% in the CP group, 20% in the CP-e group, and 39% in the AP group.
Ruxolitinib had no impact on the rate of AML progression, which was 9% in CP patients, with and without the drug.
In CP-e patients, AML progression occurred in 22% of those who received ruxolitinib and 18% of those who did not.
“The [CP-e] patients are similar to AP patients, with adverse clinical characteristics, inferior OS, and a 20% to 40% AML rate,” Dr Masarova said. “Ruxolitinib improves survival of [CP-e] patients, which is similar to CP patients on the drug.”
CP-e patients should be considered a high-risk population, she said, adding “we need to find new, better treatments for these patients.”
Dr Masarova had no disclosures.
ATLANTA—A new study suggests the JAK2 inhibitor ruxolitinib has the potential to significantly improve survival in patients who have chronic phase (CP) myelofibrosis (MF), with or without elevated blasts.
In this retrospective study, researchers found evidence to suggest that MF patients in CP with elevated blasts (CP-e) should be considered a high-risk group.
However, ruxolitinib significantly improved overall survival (OS) in CP-e patients—who had 5% to 9% blasts in the bone marrow or peripheral blood—and in patients with CP and less than 5% blasts.
On the other hand, ruxolitinib had no impact on the rate of progression to acute myeloid leukemia (AML) in CP or CP-e patients.
Lucia Masarova, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these findings at the 2017 ASH Annual Meeting (abstract 201).
Clinical characteristics of MF CP-e patients are not well described, and the outcome of available therapy in this population is largely unknown. Therefore, Dr Masarova and her colleagues set out to evaluate the effects of ruxolitinib on CP-e patients.
The team conducted a retrospective chart review of 1199 MF patients, 832 with primary MF, 169 with post-essential thrombocythemia MF, and 198 with post-polycythemia vera MF. About two-thirds of the patients were newly diagnosed.
The majority of patients (85%, n=1020) were in CP with less than 5% blasts, 10% (n=123) were in CP-e, and 5% (n=56) were in accelerated phase (AP, 10% to 19% blasts).
CP-e patients had similar clinical characteristics as patients in AP. Both groups had higher white blood cell counts; lower hemoglobin and platelets; and more frequent splenomegaly, systemic symptoms, and presence of abnormal and unfavorable karyotype than CP patients.
Among the 1030 treated patients, ruxolitinib was used in 30% (n=328), including 28% of CP patients (n=289), 27% of CP-e patients (n=33), and 11% of AP patients (n=6). The median treatment duration was about 22 months in the CP and CP-e groups.
After a median follow-up of 27 months, half the patients studied had died.
“Patients in the [CP-e] group had similar OS as those in AP, which was inferior to patients in CP,” Dr Masarova said.
The median OS was 48 months for the entire cohort, 56 months in the CP group, 34 months in the CP-e group, and 23 months in the AP group.
One-year OS rates were 86% for the CP group, 73% for the CP-e group, and 65% for the AP group. Five-year OS rates were 46%, 24%, and 21%, respectively.
CP and CP-e patients had superior OS if they had received ruxolitinib.
Among CP patients, the median OS was 61 months in those who received ruxolitinib and 54 months in those who did not (hazard ratio=0.85, P=0.002).
Among CP-e patients, the median OS was 54 months in those who received ruxolitinib and 27 months in those who did not (hazard ratio=0.50, P=0.001).
Ruxolitinib had no impact on OS in AP patients, which was 23 months with or without the drug. However, Dr Masarova noted that the AP patient numbers were small.
Progression to AML occurred in 9% of patients overall (n=139), 9% in the CP group, 20% in the CP-e group, and 39% in the AP group.
Ruxolitinib had no impact on the rate of AML progression, which was 9% in CP patients, with and without the drug.
In CP-e patients, AML progression occurred in 22% of those who received ruxolitinib and 18% of those who did not.
“The [CP-e] patients are similar to AP patients, with adverse clinical characteristics, inferior OS, and a 20% to 40% AML rate,” Dr Masarova said. “Ruxolitinib improves survival of [CP-e] patients, which is similar to CP patients on the drug.”
CP-e patients should be considered a high-risk population, she said, adding “we need to find new, better treatments for these patients.”
Dr Masarova had no disclosures.
Neurotoxicity needs separate treatment from CRS in CAR T-cell therapy
CHICAGO – The neurotoxicity in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL) treated with CD19 CAR T cells is a separate process from cytokine release syndrome (CRS) and needs to be treated separately, according to a new study presented at the American Society of Clinical Oncology annual meeting (abstract 3019).
CD19-specific CAR-modified T cells produce high, durable anti-tumor activity, but can be associated with treatment-related toxicities, including CRS and neurotoxicity.
Neurotoxicity is poorly understood and it hasn't been clear where to focus further research, said Bianca Santomasso, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
Dr Santomasso and colleagues had conducted a phase 1 study using autologous 19-CAR T cells in adult patients with relapsing/refractory B-ALL, with high response rates.
To gain a better understanding of CD19 CAR T-cell-associated neurotoxicity, they analyzed clinical and research parameters after stratifying patients by neurotoxicity grade.
At ASCO, she reported neurologic symptom presentation in 51 adult patients with relapsed/refractory B-ALL who were treated with CAR T cells following conditioning chemotherapy, along with cerebrospinal fluid (CSF) data and neuroimaging findings associated with neurotoxicity.
Of the 51 patients treated, 10 patients (20%) developed mild neurologic symptoms (grade 1 or 2) and 21 patients (41%) developed severe neurotoxicity (grade 3 or 4).
No grade 5 neurotoxicity or diffuse cerebral edema occurred and, in all but one case, neurologic symptoms fully resolved.
Fourteen patients (27.4%) developed severe CRS; 6 patients received tocilizumab alone, 13 patients tocilizumab plus steroids, 4 patients steroids alone, and 29 patients supportive care.
The cytokines IL-6, IL-8, IL-10, interferon gamma, and granulocyte-colony stimulating factor were elevated in CSF over serum at the time of neurotoxicity and correlated with CSF protein levels.
“We found no significant correlation between neurotoxicity grade and the CAR T-cell concentration in the CSF during neurotoxicity,” Dr Santomasso said. “Instead, CSF protein level was correlated with neurotoxicity grade.”
Neurotoxicity was associated with peak CAR T-cell expansion in the blood and peak serum levels of several cytokines associated with T-cell activation or proliferation, she said.
“CAR T cells traffic to the CSF of patients with all grades of neurotoxicity, including grade 0, and there is no significant correlation between CAR T cells in CSF at the time of acute neurotoxicity and grade of neurotoxicity,” Dr Santomasso reported. “This suggests that neurotoxicity is not directly mediated by CAR T cells, which cross into the spinal fluid.”
Some chemokines/cytokines are elevated in CSF relative to serum, suggesting CNS-specific production of these factors, she said.
“Clinicians treating these patients tend to lump CRS and neurotoxicity together. Now we have an increasing understanding that these adverse events are separated in time and possibly in underlying pathology,” said Dr Santomasso.
“Even when patients recover from CRS, they could still be at risk for neurotoxicity.”
She noted that the neurotoxicity symptoms that B-ALL patients develop in the setting of CAR T cells are manageable.
In a subset of patients with severe neurotoxicity, T2/FLAIR changes were observed, which resolved with steroids and neurologic symptom resolution.
CHICAGO – The neurotoxicity in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL) treated with CD19 CAR T cells is a separate process from cytokine release syndrome (CRS) and needs to be treated separately, according to a new study presented at the American Society of Clinical Oncology annual meeting (abstract 3019).
CD19-specific CAR-modified T cells produce high, durable anti-tumor activity, but can be associated with treatment-related toxicities, including CRS and neurotoxicity.
Neurotoxicity is poorly understood and it hasn't been clear where to focus further research, said Bianca Santomasso, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
Dr Santomasso and colleagues had conducted a phase 1 study using autologous 19-CAR T cells in adult patients with relapsing/refractory B-ALL, with high response rates.
To gain a better understanding of CD19 CAR T-cell-associated neurotoxicity, they analyzed clinical and research parameters after stratifying patients by neurotoxicity grade.
At ASCO, she reported neurologic symptom presentation in 51 adult patients with relapsed/refractory B-ALL who were treated with CAR T cells following conditioning chemotherapy, along with cerebrospinal fluid (CSF) data and neuroimaging findings associated with neurotoxicity.
Of the 51 patients treated, 10 patients (20%) developed mild neurologic symptoms (grade 1 or 2) and 21 patients (41%) developed severe neurotoxicity (grade 3 or 4).
No grade 5 neurotoxicity or diffuse cerebral edema occurred and, in all but one case, neurologic symptoms fully resolved.
Fourteen patients (27.4%) developed severe CRS; 6 patients received tocilizumab alone, 13 patients tocilizumab plus steroids, 4 patients steroids alone, and 29 patients supportive care.
The cytokines IL-6, IL-8, IL-10, interferon gamma, and granulocyte-colony stimulating factor were elevated in CSF over serum at the time of neurotoxicity and correlated with CSF protein levels.
“We found no significant correlation between neurotoxicity grade and the CAR T-cell concentration in the CSF during neurotoxicity,” Dr Santomasso said. “Instead, CSF protein level was correlated with neurotoxicity grade.”
Neurotoxicity was associated with peak CAR T-cell expansion in the blood and peak serum levels of several cytokines associated with T-cell activation or proliferation, she said.
“CAR T cells traffic to the CSF of patients with all grades of neurotoxicity, including grade 0, and there is no significant correlation between CAR T cells in CSF at the time of acute neurotoxicity and grade of neurotoxicity,” Dr Santomasso reported. “This suggests that neurotoxicity is not directly mediated by CAR T cells, which cross into the spinal fluid.”
Some chemokines/cytokines are elevated in CSF relative to serum, suggesting CNS-specific production of these factors, she said.
“Clinicians treating these patients tend to lump CRS and neurotoxicity together. Now we have an increasing understanding that these adverse events are separated in time and possibly in underlying pathology,” said Dr Santomasso.
“Even when patients recover from CRS, they could still be at risk for neurotoxicity.”
She noted that the neurotoxicity symptoms that B-ALL patients develop in the setting of CAR T cells are manageable.
In a subset of patients with severe neurotoxicity, T2/FLAIR changes were observed, which resolved with steroids and neurologic symptom resolution.
CHICAGO – The neurotoxicity in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL) treated with CD19 CAR T cells is a separate process from cytokine release syndrome (CRS) and needs to be treated separately, according to a new study presented at the American Society of Clinical Oncology annual meeting (abstract 3019).
CD19-specific CAR-modified T cells produce high, durable anti-tumor activity, but can be associated with treatment-related toxicities, including CRS and neurotoxicity.
Neurotoxicity is poorly understood and it hasn't been clear where to focus further research, said Bianca Santomasso, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
Dr Santomasso and colleagues had conducted a phase 1 study using autologous 19-CAR T cells in adult patients with relapsing/refractory B-ALL, with high response rates.
To gain a better understanding of CD19 CAR T-cell-associated neurotoxicity, they analyzed clinical and research parameters after stratifying patients by neurotoxicity grade.
At ASCO, she reported neurologic symptom presentation in 51 adult patients with relapsed/refractory B-ALL who were treated with CAR T cells following conditioning chemotherapy, along with cerebrospinal fluid (CSF) data and neuroimaging findings associated with neurotoxicity.
Of the 51 patients treated, 10 patients (20%) developed mild neurologic symptoms (grade 1 or 2) and 21 patients (41%) developed severe neurotoxicity (grade 3 or 4).
No grade 5 neurotoxicity or diffuse cerebral edema occurred and, in all but one case, neurologic symptoms fully resolved.
Fourteen patients (27.4%) developed severe CRS; 6 patients received tocilizumab alone, 13 patients tocilizumab plus steroids, 4 patients steroids alone, and 29 patients supportive care.
The cytokines IL-6, IL-8, IL-10, interferon gamma, and granulocyte-colony stimulating factor were elevated in CSF over serum at the time of neurotoxicity and correlated with CSF protein levels.
“We found no significant correlation between neurotoxicity grade and the CAR T-cell concentration in the CSF during neurotoxicity,” Dr Santomasso said. “Instead, CSF protein level was correlated with neurotoxicity grade.”
Neurotoxicity was associated with peak CAR T-cell expansion in the blood and peak serum levels of several cytokines associated with T-cell activation or proliferation, she said.
“CAR T cells traffic to the CSF of patients with all grades of neurotoxicity, including grade 0, and there is no significant correlation between CAR T cells in CSF at the time of acute neurotoxicity and grade of neurotoxicity,” Dr Santomasso reported. “This suggests that neurotoxicity is not directly mediated by CAR T cells, which cross into the spinal fluid.”
Some chemokines/cytokines are elevated in CSF relative to serum, suggesting CNS-specific production of these factors, she said.
“Clinicians treating these patients tend to lump CRS and neurotoxicity together. Now we have an increasing understanding that these adverse events are separated in time and possibly in underlying pathology,” said Dr Santomasso.
“Even when patients recover from CRS, they could still be at risk for neurotoxicity.”
She noted that the neurotoxicity symptoms that B-ALL patients develop in the setting of CAR T cells are manageable.
In a subset of patients with severe neurotoxicity, T2/FLAIR changes were observed, which resolved with steroids and neurologic symptom resolution.
CAR T cells plus ibrutinib induce CLL remissions
CHICAGO—Chimeric antigen receptor (CAR) T cells combined with ibrutinib enhance T-cell function and can induce complete remission (CR) in patients with chronic lymphocytic leukemia (CLL), researchers report.
Many CLL patients receive ibrutinib treatment, which is well tolerated, but few patients achieve CR.
Immunotherapy with anti-CD19 CAR T cells has induced CR in 25% - 45% of patients with CLL, Saar Gill, MD, of the University of Pennsylvania in Philadelphia, told Hematology Times, and these CRs tend to be durable.
So investigators conducted a pilot trial in 10 patients to test whether combining anti-CD19 CAR T cells with ibrutinib would enhance the CR rate.
Dr Gill reported the findings of the pilot trial at the ASCO 2017 Annual Meeting (abstract 7509).
The patients must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation.
T cells were lentivirally transduced to express a CAR that included humanized anti-CD19.
Patients were lymphodepleted 1 week before infusion, and ibrutinib was continued throughout the trial.
After a median follow-up of 6 months, 8 of the 9 evaluable patients show absence of CLL in the bone marrow by flow cytometry or minimal residual disease (MRD) negative, and all remain in marrow CR at last follow-up, Dr Gill said.
Radiologic responses are less clear-cut and may require longer follow-up.
“All but 1 patient achieved MRD with deep sequencing. We have deep response in the bone marrow,” Dr Gill said. He also noted that the treatment was well tolerated.
Cytokine release syndrome (CRS) developed in 9 patients: grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. One patient developed grade 4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required.
There was modest residual splenomegaly in 3 of 5 patients, and adenopathy resolved in 4 of 6 patients, with progression in 1 patient.
Ibrutinib reduced CRS apparently by blocking cytokine production by T cells, said Dr Gill, adding, “The combination led to improved efficacy without increased toxicity.”
Ibrutinib may make CAR T-cell therapy more feasible.
Patients who receive ibrutinib for 6 months have a better T-cell response.
“This opens up future discussions of bringing CAR T-cell therapy earlier into CLL treatment,” said Dr Gill.
He envisions patients receiving ibrutinib for 6 months, which would allow time to manufacture T cells, and then have a T-cell infusion.
“Once patients achieve MRD, then we can discuss the possibility of stopping ibrutinib therapy,” he said.
“Most patients remain on ibrutinib, but longer follow-up may show whether remissions are sustained off ibrutinib.”
The researchers have ongoing plans to treat 25 patients with CTL19 plus ibrutinib in a continuation of this trial.
Dr Gill said longer follow-up will reveal the durability of these results “and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy.”
CHICAGO—Chimeric antigen receptor (CAR) T cells combined with ibrutinib enhance T-cell function and can induce complete remission (CR) in patients with chronic lymphocytic leukemia (CLL), researchers report.
Many CLL patients receive ibrutinib treatment, which is well tolerated, but few patients achieve CR.
Immunotherapy with anti-CD19 CAR T cells has induced CR in 25% - 45% of patients with CLL, Saar Gill, MD, of the University of Pennsylvania in Philadelphia, told Hematology Times, and these CRs tend to be durable.
So investigators conducted a pilot trial in 10 patients to test whether combining anti-CD19 CAR T cells with ibrutinib would enhance the CR rate.
Dr Gill reported the findings of the pilot trial at the ASCO 2017 Annual Meeting (abstract 7509).
The patients must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation.
T cells were lentivirally transduced to express a CAR that included humanized anti-CD19.
Patients were lymphodepleted 1 week before infusion, and ibrutinib was continued throughout the trial.
After a median follow-up of 6 months, 8 of the 9 evaluable patients show absence of CLL in the bone marrow by flow cytometry or minimal residual disease (MRD) negative, and all remain in marrow CR at last follow-up, Dr Gill said.
Radiologic responses are less clear-cut and may require longer follow-up.
“All but 1 patient achieved MRD with deep sequencing. We have deep response in the bone marrow,” Dr Gill said. He also noted that the treatment was well tolerated.
Cytokine release syndrome (CRS) developed in 9 patients: grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. One patient developed grade 4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required.
There was modest residual splenomegaly in 3 of 5 patients, and adenopathy resolved in 4 of 6 patients, with progression in 1 patient.
Ibrutinib reduced CRS apparently by blocking cytokine production by T cells, said Dr Gill, adding, “The combination led to improved efficacy without increased toxicity.”
Ibrutinib may make CAR T-cell therapy more feasible.
Patients who receive ibrutinib for 6 months have a better T-cell response.
“This opens up future discussions of bringing CAR T-cell therapy earlier into CLL treatment,” said Dr Gill.
He envisions patients receiving ibrutinib for 6 months, which would allow time to manufacture T cells, and then have a T-cell infusion.
“Once patients achieve MRD, then we can discuss the possibility of stopping ibrutinib therapy,” he said.
“Most patients remain on ibrutinib, but longer follow-up may show whether remissions are sustained off ibrutinib.”
The researchers have ongoing plans to treat 25 patients with CTL19 plus ibrutinib in a continuation of this trial.
Dr Gill said longer follow-up will reveal the durability of these results “and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy.”
CHICAGO—Chimeric antigen receptor (CAR) T cells combined with ibrutinib enhance T-cell function and can induce complete remission (CR) in patients with chronic lymphocytic leukemia (CLL), researchers report.
Many CLL patients receive ibrutinib treatment, which is well tolerated, but few patients achieve CR.
Immunotherapy with anti-CD19 CAR T cells has induced CR in 25% - 45% of patients with CLL, Saar Gill, MD, of the University of Pennsylvania in Philadelphia, told Hematology Times, and these CRs tend to be durable.
So investigators conducted a pilot trial in 10 patients to test whether combining anti-CD19 CAR T cells with ibrutinib would enhance the CR rate.
Dr Gill reported the findings of the pilot trial at the ASCO 2017 Annual Meeting (abstract 7509).
The patients must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation.
T cells were lentivirally transduced to express a CAR that included humanized anti-CD19.
Patients were lymphodepleted 1 week before infusion, and ibrutinib was continued throughout the trial.
After a median follow-up of 6 months, 8 of the 9 evaluable patients show absence of CLL in the bone marrow by flow cytometry or minimal residual disease (MRD) negative, and all remain in marrow CR at last follow-up, Dr Gill said.
Radiologic responses are less clear-cut and may require longer follow-up.
“All but 1 patient achieved MRD with deep sequencing. We have deep response in the bone marrow,” Dr Gill said. He also noted that the treatment was well tolerated.
Cytokine release syndrome (CRS) developed in 9 patients: grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. One patient developed grade 4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required.
There was modest residual splenomegaly in 3 of 5 patients, and adenopathy resolved in 4 of 6 patients, with progression in 1 patient.
Ibrutinib reduced CRS apparently by blocking cytokine production by T cells, said Dr Gill, adding, “The combination led to improved efficacy without increased toxicity.”
Ibrutinib may make CAR T-cell therapy more feasible.
Patients who receive ibrutinib for 6 months have a better T-cell response.
“This opens up future discussions of bringing CAR T-cell therapy earlier into CLL treatment,” said Dr Gill.
He envisions patients receiving ibrutinib for 6 months, which would allow time to manufacture T cells, and then have a T-cell infusion.
“Once patients achieve MRD, then we can discuss the possibility of stopping ibrutinib therapy,” he said.
“Most patients remain on ibrutinib, but longer follow-up may show whether remissions are sustained off ibrutinib.”
The researchers have ongoing plans to treat 25 patients with CTL19 plus ibrutinib in a continuation of this trial.
Dr Gill said longer follow-up will reveal the durability of these results “and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy.”