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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.
Ibrutinib and venetoclax combo promising in frontline CLL
CHICAGO—Ibrutinib combined with venetoclax is showing promising clinical activity in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to investigators for the CAPTIVATE study.
In the first 30 patients, 77% of treatment-naïve patients had undetected minimal residual disease (MRD; <10-4 cells) in the blood and 86% showed a similar response in the bone marrow.
The overall response rate (ORR) was 100% in 11 evaluable patients. The investigators reported this initial data at the 2018 Annual Meeting of the American Society of Clinical Oncology (abstract 7502).
“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” said William G. Wierda, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, who presented the findings at ASCO.
Ibrutinib, a Bruton-kinase inhibitor, has already been approved for the treatment of CLL and venetoclax, a Bcl-2 inhibitor, is currently used to treat relapsed del 17p CLL.
Venetoclax in combination with rituximab was recently approved by the US Food and Drug Administration to treat patients with CLL or small lymphocytic lymphoma whether or not patients have del 17p.
With complementary mechanisms of action and preclinical studies suggesting synergy with the combination, CAPTIVATE was designed to test the efficacy of the oral combination given for 12 cycles.
Study design
CAPTIVATE (NCT02910583) is an ongoing phase 2 study that enrolled 164 patients with treatment-naïve CLL. Patients first received 3 cycles of ibrutinib monotherapy at the standard dose. This was intended to debulk the disease and reduce risk for venetoclax-associated tumor lysis syndrome (TLS).
Venetoclax 400 mg was initiated at cycle 4. After 12 cycles of the combination, patients with confirmed MRD negativity were randomized to receive ibrutinib with a placebo or to continue with the combination therapy.
In this initial report, Dr Wierda highlighted safety data for all 164 enrolled patients and efficacy data for the first 30 patients who had 6 cycles of combination therapy (MRD assessment cohort).
Dr Wierda also reported bone marrow data for the first 14 patients, who received a total of 12 cycles of the combination and represent the safety run-in cohort.
Ibrutinib and venetoclax show promising activity
Median age of patients was 58 years; about 2/3 of patients had unmutated IGHV and 1/3 had a creatine clearance of <80 mL/min.
Of 164 patients, 95% remain on therapy, with discontinuations reported for adverse events; one patient had disease progression to Richter’s transformation.
For the MRD evaluation, all 30 patients had 6 months of combination therapy and continue on treatment.
As expected, lead-in with ibrutinib monotherapy debulked the disease.
Investigators observed a reduction in the proportion of patients at high risk for TLS (24% to 3%) and an increase in the proportion of patients at low risk for TLS (12% to 29%).
A similar picture emerged for debulking of lymph node disease. No patient developed clinical TLS.
Other adverse events were consistent with the safety profile of single-agent ibrutinib and venetoclax. No new safety signals were seen.
After 6 cycles of the combination, blood MRD negativity was reported in 77% of the patients in the MRD assessment cohort.
In the safety-run in cohort of 14 patients, blood MRD negativity was reported in 86% of patients after 12 cycles and 93% of patients after 15 cycles of the combination. In these patients, bone marrow MRD negativity was achieved in 86%.
After 12 cycles of combination therapy, the objective response rate was 100% for 11 of the 14 evaluable patients from the safety run-in cohort: 6 patients showed complete remission (CR) or CR with incomplete blood count recovery (CRi) for a CR/CRi of 55%. All patients had confirmed undetectable MRD.
Investigators considered these responses promising and an assessment of the full treatment plan and durability of response are awaited.
The study was sponsored by Pharmacyclics.
CHICAGO—Ibrutinib combined with venetoclax is showing promising clinical activity in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to investigators for the CAPTIVATE study.
In the first 30 patients, 77% of treatment-naïve patients had undetected minimal residual disease (MRD; <10-4 cells) in the blood and 86% showed a similar response in the bone marrow.
The overall response rate (ORR) was 100% in 11 evaluable patients. The investigators reported this initial data at the 2018 Annual Meeting of the American Society of Clinical Oncology (abstract 7502).
“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” said William G. Wierda, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, who presented the findings at ASCO.
Ibrutinib, a Bruton-kinase inhibitor, has already been approved for the treatment of CLL and venetoclax, a Bcl-2 inhibitor, is currently used to treat relapsed del 17p CLL.
Venetoclax in combination with rituximab was recently approved by the US Food and Drug Administration to treat patients with CLL or small lymphocytic lymphoma whether or not patients have del 17p.
With complementary mechanisms of action and preclinical studies suggesting synergy with the combination, CAPTIVATE was designed to test the efficacy of the oral combination given for 12 cycles.
Study design
CAPTIVATE (NCT02910583) is an ongoing phase 2 study that enrolled 164 patients with treatment-naïve CLL. Patients first received 3 cycles of ibrutinib monotherapy at the standard dose. This was intended to debulk the disease and reduce risk for venetoclax-associated tumor lysis syndrome (TLS).
Venetoclax 400 mg was initiated at cycle 4. After 12 cycles of the combination, patients with confirmed MRD negativity were randomized to receive ibrutinib with a placebo or to continue with the combination therapy.
In this initial report, Dr Wierda highlighted safety data for all 164 enrolled patients and efficacy data for the first 30 patients who had 6 cycles of combination therapy (MRD assessment cohort).
Dr Wierda also reported bone marrow data for the first 14 patients, who received a total of 12 cycles of the combination and represent the safety run-in cohort.
Ibrutinib and venetoclax show promising activity
Median age of patients was 58 years; about 2/3 of patients had unmutated IGHV and 1/3 had a creatine clearance of <80 mL/min.
Of 164 patients, 95% remain on therapy, with discontinuations reported for adverse events; one patient had disease progression to Richter’s transformation.
For the MRD evaluation, all 30 patients had 6 months of combination therapy and continue on treatment.
As expected, lead-in with ibrutinib monotherapy debulked the disease.
Investigators observed a reduction in the proportion of patients at high risk for TLS (24% to 3%) and an increase in the proportion of patients at low risk for TLS (12% to 29%).
A similar picture emerged for debulking of lymph node disease. No patient developed clinical TLS.
Other adverse events were consistent with the safety profile of single-agent ibrutinib and venetoclax. No new safety signals were seen.
After 6 cycles of the combination, blood MRD negativity was reported in 77% of the patients in the MRD assessment cohort.
In the safety-run in cohort of 14 patients, blood MRD negativity was reported in 86% of patients after 12 cycles and 93% of patients after 15 cycles of the combination. In these patients, bone marrow MRD negativity was achieved in 86%.
After 12 cycles of combination therapy, the objective response rate was 100% for 11 of the 14 evaluable patients from the safety run-in cohort: 6 patients showed complete remission (CR) or CR with incomplete blood count recovery (CRi) for a CR/CRi of 55%. All patients had confirmed undetectable MRD.
Investigators considered these responses promising and an assessment of the full treatment plan and durability of response are awaited.
The study was sponsored by Pharmacyclics.
CHICAGO—Ibrutinib combined with venetoclax is showing promising clinical activity in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to investigators for the CAPTIVATE study.
In the first 30 patients, 77% of treatment-naïve patients had undetected minimal residual disease (MRD; <10-4 cells) in the blood and 86% showed a similar response in the bone marrow.
The overall response rate (ORR) was 100% in 11 evaluable patients. The investigators reported this initial data at the 2018 Annual Meeting of the American Society of Clinical Oncology (abstract 7502).
“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” said William G. Wierda, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, who presented the findings at ASCO.
Ibrutinib, a Bruton-kinase inhibitor, has already been approved for the treatment of CLL and venetoclax, a Bcl-2 inhibitor, is currently used to treat relapsed del 17p CLL.
Venetoclax in combination with rituximab was recently approved by the US Food and Drug Administration to treat patients with CLL or small lymphocytic lymphoma whether or not patients have del 17p.
With complementary mechanisms of action and preclinical studies suggesting synergy with the combination, CAPTIVATE was designed to test the efficacy of the oral combination given for 12 cycles.
Study design
CAPTIVATE (NCT02910583) is an ongoing phase 2 study that enrolled 164 patients with treatment-naïve CLL. Patients first received 3 cycles of ibrutinib monotherapy at the standard dose. This was intended to debulk the disease and reduce risk for venetoclax-associated tumor lysis syndrome (TLS).
Venetoclax 400 mg was initiated at cycle 4. After 12 cycles of the combination, patients with confirmed MRD negativity were randomized to receive ibrutinib with a placebo or to continue with the combination therapy.
In this initial report, Dr Wierda highlighted safety data for all 164 enrolled patients and efficacy data for the first 30 patients who had 6 cycles of combination therapy (MRD assessment cohort).
Dr Wierda also reported bone marrow data for the first 14 patients, who received a total of 12 cycles of the combination and represent the safety run-in cohort.
Ibrutinib and venetoclax show promising activity
Median age of patients was 58 years; about 2/3 of patients had unmutated IGHV and 1/3 had a creatine clearance of <80 mL/min.
Of 164 patients, 95% remain on therapy, with discontinuations reported for adverse events; one patient had disease progression to Richter’s transformation.
For the MRD evaluation, all 30 patients had 6 months of combination therapy and continue on treatment.
As expected, lead-in with ibrutinib monotherapy debulked the disease.
Investigators observed a reduction in the proportion of patients at high risk for TLS (24% to 3%) and an increase in the proportion of patients at low risk for TLS (12% to 29%).
A similar picture emerged for debulking of lymph node disease. No patient developed clinical TLS.
Other adverse events were consistent with the safety profile of single-agent ibrutinib and venetoclax. No new safety signals were seen.
After 6 cycles of the combination, blood MRD negativity was reported in 77% of the patients in the MRD assessment cohort.
In the safety-run in cohort of 14 patients, blood MRD negativity was reported in 86% of patients after 12 cycles and 93% of patients after 15 cycles of the combination. In these patients, bone marrow MRD negativity was achieved in 86%.
After 12 cycles of combination therapy, the objective response rate was 100% for 11 of the 14 evaluable patients from the safety run-in cohort: 6 patients showed complete remission (CR) or CR with incomplete blood count recovery (CRi) for a CR/CRi of 55%. All patients had confirmed undetectable MRD.
Investigators considered these responses promising and an assessment of the full treatment plan and durability of response are awaited.
The study was sponsored by Pharmacyclics.
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).
FDA approves venetoclax for CLL/SLL with or without del 17p
The US Food and Drug Administration (FDA) has approved venetoclax tablets (Venclexta ®) in combination with rituximab to treat patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received 1 prior therapy.
The combination is approved for patients with or without deletion of 17p (del 17p).
The FDA based its approval on the phase 3 MURANO trial, in which venetoclax in combination with rituximab (VEN+R) significantly improved progression-free survival (PFS) in relapsed or refractory CLL patients compared to the chemoimmunotherapy regimen of bendamustine plus rituximab(B+R).
This approval, according to the drug’s developers, makes venetoclax plus rituximab the first oral-based, chemotherapy-free combination with a fixed treatment duration for CLL.
The FDA has also converted venetoclax's accelerated approval to a full approval. The drug was previously granted accelerated approval as a single agent for the treatment of people with CLL with 17p deletion.
Venetoclax is being developed by AbbVie and Roche and jointly commercialized by AbbVie and Genentech in the US and by AbbVie outside the US.
Phase 3 MURANO trial (NCT02005471)
The multicenter, open-label trial randomized 389 patients to VEN+R (194 patients) or B+R (195 patients). Median age of the patients was 65 years (range, 22 – 85).
Patients in the VEN+R arm completed a 5-week ramp-up of venetoclax followed by venetoclax 400 mg once daily for 24 months measured from the rituximab start date.
Tumor lysis syndrome (TLS), caused by a rapid reduction in tumor volume, is an identified risk with venetoclax treatment. The dose ramp-up was intended to mitigate this risk.
Rituximab was initiated after venetoclax ramp-up and given for 6 cycles (375 mg/m2 intravenously on cycle 1 day 1 and 500 mg/m2 intravenously on day 1 of cycles 2-6, with a 28-day cycle length).
Patients in the B+R arm received 6 cycles of B+R (bendamustine 70 mg/m2 on days 1 and 2 of each 28-day cycle and rituximab at the above described dose and schedule).
Efficacy was based on PFS as assessed by an independent review committee.
After a median follow-up of 23 months, the median PFS was not reached in the VEN+R arm and was 18.1 months in the B+R arm (P<0.0001).
The overall response rate was 92% for patients treated with VEN+R compared to 72% for those treated with B+R.
Safety
The most common adverse events (AEs) in the VEN+R arms that occurred in 20% or more patients were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), cough (22%), and nausea (21%).
Grade 3 or 4 neutropenia developed in 64% of patients, and grade 4 neutropenia in 31%.
Serious adverse events (SAEs) developed in 46% of patients and serious infections in 21%, consisting most frequently of pneumonia (9%).
The incidence of TLS was 3%, occurring in 6 of 194 patients.
In the VEN+R arm, discontinuations due to any AEs occurred in 16% of patients, dose reductions in 15%, and dose interruptions in 71%.
Neutropenia led to dose interruptions in 46% of patients and discontinuations in 3%. Thrombocytopenia led to discontinuations in 3% of patients.
Fatal AEs that occurred in the absence of disease progression and within 30 days of the last VEN+R treatment and/or 90 days of the last rituximab infusion were reported in 2% (4/194) of patients.
In the B+R arm, AEs led to treatment discontinuations in 10% of patients, dose reductions in 15%, and dose interruptions in 40 %.
Investigators previously reported data from the phase 3 MURANO study as a late-breaking abstract at the 2017 ASH Annual Meeting and published the findings in NEJM.
John Seymour, MBBS, PhD, lead investigator of the MURANO study, said in the corporate release, the approval "validates the results seen in the phase 3 trial, including the significant improvement in progression-free survival over a standard of care comparator arm."
"Progression-free survival is considered a gold standard for demonstrating clinical benefit in oncology," he added.
Full prescribing information for venetoclax is available here.
The US Food and Drug Administration (FDA) has approved venetoclax tablets (Venclexta ®) in combination with rituximab to treat patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received 1 prior therapy.
The combination is approved for patients with or without deletion of 17p (del 17p).
The FDA based its approval on the phase 3 MURANO trial, in which venetoclax in combination with rituximab (VEN+R) significantly improved progression-free survival (PFS) in relapsed or refractory CLL patients compared to the chemoimmunotherapy regimen of bendamustine plus rituximab(B+R).
This approval, according to the drug’s developers, makes venetoclax plus rituximab the first oral-based, chemotherapy-free combination with a fixed treatment duration for CLL.
The FDA has also converted venetoclax's accelerated approval to a full approval. The drug was previously granted accelerated approval as a single agent for the treatment of people with CLL with 17p deletion.
Venetoclax is being developed by AbbVie and Roche and jointly commercialized by AbbVie and Genentech in the US and by AbbVie outside the US.
Phase 3 MURANO trial (NCT02005471)
The multicenter, open-label trial randomized 389 patients to VEN+R (194 patients) or B+R (195 patients). Median age of the patients was 65 years (range, 22 – 85).
Patients in the VEN+R arm completed a 5-week ramp-up of venetoclax followed by venetoclax 400 mg once daily for 24 months measured from the rituximab start date.
Tumor lysis syndrome (TLS), caused by a rapid reduction in tumor volume, is an identified risk with venetoclax treatment. The dose ramp-up was intended to mitigate this risk.
Rituximab was initiated after venetoclax ramp-up and given for 6 cycles (375 mg/m2 intravenously on cycle 1 day 1 and 500 mg/m2 intravenously on day 1 of cycles 2-6, with a 28-day cycle length).
Patients in the B+R arm received 6 cycles of B+R (bendamustine 70 mg/m2 on days 1 and 2 of each 28-day cycle and rituximab at the above described dose and schedule).
Efficacy was based on PFS as assessed by an independent review committee.
After a median follow-up of 23 months, the median PFS was not reached in the VEN+R arm and was 18.1 months in the B+R arm (P<0.0001).
The overall response rate was 92% for patients treated with VEN+R compared to 72% for those treated with B+R.
Safety
The most common adverse events (AEs) in the VEN+R arms that occurred in 20% or more patients were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), cough (22%), and nausea (21%).
Grade 3 or 4 neutropenia developed in 64% of patients, and grade 4 neutropenia in 31%.
Serious adverse events (SAEs) developed in 46% of patients and serious infections in 21%, consisting most frequently of pneumonia (9%).
The incidence of TLS was 3%, occurring in 6 of 194 patients.
In the VEN+R arm, discontinuations due to any AEs occurred in 16% of patients, dose reductions in 15%, and dose interruptions in 71%.
Neutropenia led to dose interruptions in 46% of patients and discontinuations in 3%. Thrombocytopenia led to discontinuations in 3% of patients.
Fatal AEs that occurred in the absence of disease progression and within 30 days of the last VEN+R treatment and/or 90 days of the last rituximab infusion were reported in 2% (4/194) of patients.
In the B+R arm, AEs led to treatment discontinuations in 10% of patients, dose reductions in 15%, and dose interruptions in 40 %.
Investigators previously reported data from the phase 3 MURANO study as a late-breaking abstract at the 2017 ASH Annual Meeting and published the findings in NEJM.
John Seymour, MBBS, PhD, lead investigator of the MURANO study, said in the corporate release, the approval "validates the results seen in the phase 3 trial, including the significant improvement in progression-free survival over a standard of care comparator arm."
"Progression-free survival is considered a gold standard for demonstrating clinical benefit in oncology," he added.
Full prescribing information for venetoclax is available here.
The US Food and Drug Administration (FDA) has approved venetoclax tablets (Venclexta ®) in combination with rituximab to treat patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received 1 prior therapy.
The combination is approved for patients with or without deletion of 17p (del 17p).
The FDA based its approval on the phase 3 MURANO trial, in which venetoclax in combination with rituximab (VEN+R) significantly improved progression-free survival (PFS) in relapsed or refractory CLL patients compared to the chemoimmunotherapy regimen of bendamustine plus rituximab(B+R).
This approval, according to the drug’s developers, makes venetoclax plus rituximab the first oral-based, chemotherapy-free combination with a fixed treatment duration for CLL.
The FDA has also converted venetoclax's accelerated approval to a full approval. The drug was previously granted accelerated approval as a single agent for the treatment of people with CLL with 17p deletion.
Venetoclax is being developed by AbbVie and Roche and jointly commercialized by AbbVie and Genentech in the US and by AbbVie outside the US.
Phase 3 MURANO trial (NCT02005471)
The multicenter, open-label trial randomized 389 patients to VEN+R (194 patients) or B+R (195 patients). Median age of the patients was 65 years (range, 22 – 85).
Patients in the VEN+R arm completed a 5-week ramp-up of venetoclax followed by venetoclax 400 mg once daily for 24 months measured from the rituximab start date.
Tumor lysis syndrome (TLS), caused by a rapid reduction in tumor volume, is an identified risk with venetoclax treatment. The dose ramp-up was intended to mitigate this risk.
Rituximab was initiated after venetoclax ramp-up and given for 6 cycles (375 mg/m2 intravenously on cycle 1 day 1 and 500 mg/m2 intravenously on day 1 of cycles 2-6, with a 28-day cycle length).
Patients in the B+R arm received 6 cycles of B+R (bendamustine 70 mg/m2 on days 1 and 2 of each 28-day cycle and rituximab at the above described dose and schedule).
Efficacy was based on PFS as assessed by an independent review committee.
After a median follow-up of 23 months, the median PFS was not reached in the VEN+R arm and was 18.1 months in the B+R arm (P<0.0001).
The overall response rate was 92% for patients treated with VEN+R compared to 72% for those treated with B+R.
Safety
The most common adverse events (AEs) in the VEN+R arms that occurred in 20% or more patients were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), cough (22%), and nausea (21%).
Grade 3 or 4 neutropenia developed in 64% of patients, and grade 4 neutropenia in 31%.
Serious adverse events (SAEs) developed in 46% of patients and serious infections in 21%, consisting most frequently of pneumonia (9%).
The incidence of TLS was 3%, occurring in 6 of 194 patients.
In the VEN+R arm, discontinuations due to any AEs occurred in 16% of patients, dose reductions in 15%, and dose interruptions in 71%.
Neutropenia led to dose interruptions in 46% of patients and discontinuations in 3%. Thrombocytopenia led to discontinuations in 3% of patients.
Fatal AEs that occurred in the absence of disease progression and within 30 days of the last VEN+R treatment and/or 90 days of the last rituximab infusion were reported in 2% (4/194) of patients.
In the B+R arm, AEs led to treatment discontinuations in 10% of patients, dose reductions in 15%, and dose interruptions in 40 %.
Investigators previously reported data from the phase 3 MURANO study as a late-breaking abstract at the 2017 ASH Annual Meeting and published the findings in NEJM.
John Seymour, MBBS, PhD, lead investigator of the MURANO study, said in the corporate release, the approval "validates the results seen in the phase 3 trial, including the significant improvement in progression-free survival over a standard of care comparator arm."
"Progression-free survival is considered a gold standard for demonstrating clinical benefit in oncology," he added.
Full prescribing information for venetoclax is available here.
Polatuzumab plus BR improves efficacy in DLBCL
CHICAGO—Polatuzumab vedotin, when added to bendamustine (B) and rituximab (R), significantly improved response and survival rates in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 2 study.
By contrast, there were no such improvements in a cohort of follicular lymphoma (FL) patients, at least in short-term follow-up, investigator Laurie Helen Sehn, MD, of the BC Cancer Agency in Vancouver, Canada, said at the 2018 ASCO Annual Meeting.
However, the improvement in overall survival in DLBCL patients is “remarkable,” Dr Sehn affirmed in an oral presentation (abstract 7507).
“Based on these encouraging results, polatuzumab vedotin has received breakthrough therapy designation and priority medicines designation by the FDA and EMA for patients with relapsed or refractory DLBCL,” she said.
Polatuzumab-BR study (NCT02257567)
The study by Dr Sehn and colleagues included a cohort of 80 DLBCL patients randomized to BR or polatuzumab-BR for 6 planned 21-day cycles.
Investigators randomized another cohort of 80 FL patients to BR or polatuzumab-BR for 6 planned 28-day cycles.
The primary endpoint was complete response (CR) assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) at 6 to 8 weeks after the end of treatment.
DLBCL patients
A total of 40% of polatuzumab-BR-treated DLBCL patients achieved CR at the end of treatment, versus 15% of BR-treated patients (P=0.012).
That CR improvement translated into a significantly higher progression-free survival (PFS) (6.7 months for polatuzumab-BR vs 2.0 months for BR, P<0.0001) and overall survival (11.8 months versus 4.7 months, P=0.0008), according to Dr Sehn.
The FDG-PET CR rates were higher in the polatuzumab-BR arm regardless of the number of prior lines of treatment for DLBCL, and regardless of relapsed versus refractory status, Dr. Sehn added.
FL patients
By contrast, in the FL cohort, the FDG-PET CR rate was high for both arms, at 69% for polatuzumab-BR and 63% for BR.
And there was no significant difference in progression-free survival (P=0.58) with “relatively short-term follow-up,” she said.
Adverse events
The most common grades 3 – 5 adverse events for both DLBCL and FL patients were higher in the polatuzumab-BR arm than the BR arm and included cytopenias, febrile neutropenia, and infections.
Serious AEs were also higher in the polatuzumab-BR arm and included febrile neutropenia for both FL and DLBCL patients and infection for FL patients.
Five percent of FL patients and 18% of DLBCL had a grade 5 event.
Commentary
Whether polatuzumab vedotin will change treatment paradigms for DLBCL patients may be answered by the ongoing POLARIX study, according to Alison Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.
The randomized phase 3 POLARIX study (abstract TPS7589) is comparing polatuzumab plus R-CHP to R-CHOP in patients with previously untreated DLBCL.
“Certainly, there are patients who do very well with R-CHOP chemotherapy alone, and so we need to learn whether this is necessary for all patients, or only the high-risk patients,” Dr Moskowitz said in a talk at ASCO commenting on the results of the polatuzumab-BR study.
Hoffman-LaRoche is the sponsor of the study.
CHICAGO—Polatuzumab vedotin, when added to bendamustine (B) and rituximab (R), significantly improved response and survival rates in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 2 study.
By contrast, there were no such improvements in a cohort of follicular lymphoma (FL) patients, at least in short-term follow-up, investigator Laurie Helen Sehn, MD, of the BC Cancer Agency in Vancouver, Canada, said at the 2018 ASCO Annual Meeting.
However, the improvement in overall survival in DLBCL patients is “remarkable,” Dr Sehn affirmed in an oral presentation (abstract 7507).
“Based on these encouraging results, polatuzumab vedotin has received breakthrough therapy designation and priority medicines designation by the FDA and EMA for patients with relapsed or refractory DLBCL,” she said.
Polatuzumab-BR study (NCT02257567)
The study by Dr Sehn and colleagues included a cohort of 80 DLBCL patients randomized to BR or polatuzumab-BR for 6 planned 21-day cycles.
Investigators randomized another cohort of 80 FL patients to BR or polatuzumab-BR for 6 planned 28-day cycles.
The primary endpoint was complete response (CR) assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) at 6 to 8 weeks after the end of treatment.
DLBCL patients
A total of 40% of polatuzumab-BR-treated DLBCL patients achieved CR at the end of treatment, versus 15% of BR-treated patients (P=0.012).
That CR improvement translated into a significantly higher progression-free survival (PFS) (6.7 months for polatuzumab-BR vs 2.0 months for BR, P<0.0001) and overall survival (11.8 months versus 4.7 months, P=0.0008), according to Dr Sehn.
The FDG-PET CR rates were higher in the polatuzumab-BR arm regardless of the number of prior lines of treatment for DLBCL, and regardless of relapsed versus refractory status, Dr. Sehn added.
FL patients
By contrast, in the FL cohort, the FDG-PET CR rate was high for both arms, at 69% for polatuzumab-BR and 63% for BR.
And there was no significant difference in progression-free survival (P=0.58) with “relatively short-term follow-up,” she said.
Adverse events
The most common grades 3 – 5 adverse events for both DLBCL and FL patients were higher in the polatuzumab-BR arm than the BR arm and included cytopenias, febrile neutropenia, and infections.
Serious AEs were also higher in the polatuzumab-BR arm and included febrile neutropenia for both FL and DLBCL patients and infection for FL patients.
Five percent of FL patients and 18% of DLBCL had a grade 5 event.
Commentary
Whether polatuzumab vedotin will change treatment paradigms for DLBCL patients may be answered by the ongoing POLARIX study, according to Alison Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.
The randomized phase 3 POLARIX study (abstract TPS7589) is comparing polatuzumab plus R-CHP to R-CHOP in patients with previously untreated DLBCL.
“Certainly, there are patients who do very well with R-CHOP chemotherapy alone, and so we need to learn whether this is necessary for all patients, or only the high-risk patients,” Dr Moskowitz said in a talk at ASCO commenting on the results of the polatuzumab-BR study.
Hoffman-LaRoche is the sponsor of the study.
CHICAGO—Polatuzumab vedotin, when added to bendamustine (B) and rituximab (R), significantly improved response and survival rates in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 2 study.
By contrast, there were no such improvements in a cohort of follicular lymphoma (FL) patients, at least in short-term follow-up, investigator Laurie Helen Sehn, MD, of the BC Cancer Agency in Vancouver, Canada, said at the 2018 ASCO Annual Meeting.
However, the improvement in overall survival in DLBCL patients is “remarkable,” Dr Sehn affirmed in an oral presentation (abstract 7507).
“Based on these encouraging results, polatuzumab vedotin has received breakthrough therapy designation and priority medicines designation by the FDA and EMA for patients with relapsed or refractory DLBCL,” she said.
Polatuzumab-BR study (NCT02257567)
The study by Dr Sehn and colleagues included a cohort of 80 DLBCL patients randomized to BR or polatuzumab-BR for 6 planned 21-day cycles.
Investigators randomized another cohort of 80 FL patients to BR or polatuzumab-BR for 6 planned 28-day cycles.
The primary endpoint was complete response (CR) assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) at 6 to 8 weeks after the end of treatment.
DLBCL patients
A total of 40% of polatuzumab-BR-treated DLBCL patients achieved CR at the end of treatment, versus 15% of BR-treated patients (P=0.012).
That CR improvement translated into a significantly higher progression-free survival (PFS) (6.7 months for polatuzumab-BR vs 2.0 months for BR, P<0.0001) and overall survival (11.8 months versus 4.7 months, P=0.0008), according to Dr Sehn.
The FDG-PET CR rates were higher in the polatuzumab-BR arm regardless of the number of prior lines of treatment for DLBCL, and regardless of relapsed versus refractory status, Dr. Sehn added.
FL patients
By contrast, in the FL cohort, the FDG-PET CR rate was high for both arms, at 69% for polatuzumab-BR and 63% for BR.
And there was no significant difference in progression-free survival (P=0.58) with “relatively short-term follow-up,” she said.
Adverse events
The most common grades 3 – 5 adverse events for both DLBCL and FL patients were higher in the polatuzumab-BR arm than the BR arm and included cytopenias, febrile neutropenia, and infections.
Serious AEs were also higher in the polatuzumab-BR arm and included febrile neutropenia for both FL and DLBCL patients and infection for FL patients.
Five percent of FL patients and 18% of DLBCL had a grade 5 event.
Commentary
Whether polatuzumab vedotin will change treatment paradigms for DLBCL patients may be answered by the ongoing POLARIX study, according to Alison Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.
The randomized phase 3 POLARIX study (abstract TPS7589) is comparing polatuzumab plus R-CHP to R-CHOP in patients with previously untreated DLBCL.
“Certainly, there are patients who do very well with R-CHOP chemotherapy alone, and so we need to learn whether this is necessary for all patients, or only the high-risk patients,” Dr Moskowitz said in a talk at ASCO commenting on the results of the polatuzumab-BR study.
Hoffman-LaRoche is the sponsor of the study.
Single-agent acalabrutinib ‘impressive’ in patients with WM
CHICAGO—Acalabrutinib monotherapy was highly effective in Waldenström’s macroglobulinemia (WM) in a phase 2 study, investigator Roger Owen, MD, reported at the 2018 ASCO Annual Meeting.
The BTK inhibitor was effective in both treatment-naïve and relapsed/refractory patients, with overall response rates for both groups in excess of 90%, and “amazing” major response rates—partial response or better—of approximately 80%, Dr Owen said.
Dr Owen, of the St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust in Leeds, UK, reported the findings as abstract 7501.*
Durations of response were excellent, according to Dr Owen, who also reported 2-year progression-free survival of 90% in treatment-naïve patients and 82% in relapsed/refractory patients.
The safety profile was favorable, with most adverse events of low grade, and a very limited number of dropouts due to adverse events, according to the investigator.
“I think this study clearly demonstrates the highly effective nature of acalabrutinib in Waldenström’s macroglobulinemia,” Dr Owen stated.
Acalabrutinib is a selective BTK inhibitor with minimal off-target activity, he said. The BTK inhibitor ibrutinib also has demonstrated activity in Waldenström’s, but has been associated with toxicities such as atrial fibrillation and bleeding, he noted.
In this phase 2 acalabrutinib study (NCT02180724), which included 14 treatment-naïve and 92 relapsed/refractory patients, atrial fibrillation occurred in 5 patients. However, 4 of those cases were grade 1-2, and only one was grade 3, according to Dr Owen.
Investigators observed grade 3 hypertension in 3 relapsed/refractory patients.
Bleeding events occurred in more than half of patients, though only 3 of those events were grade 3, and no patient discontinued treatment due to a bleeding episode.
These efficacy results are “impressive,” and the fact that very few cardiac events were seen is important, said Bruce D. Cheson, MD, of Georgetown University Medical Center in Washington, DC.
Dr Cheson commented on the acalabrutinib results in his presentation during ASCO on non-chemotherapy treatments for lymphoid malignancies.
“One can construct a non-chemo algorithm now for Waldenström’s, for patients who are MYD88 mutated, which is more than 90% of patients,” he said. “Right now ibrutinib, and perhaps in the future acalabrutinib, can be the initial therapy with or without rituximab based on the results of ongoing trials.”
However, single non-chemotherapy agents will not be sufficient to achieve cure of lymphoid malignancies, Dr Cheson added.
“We need to carefully develop rational combinations, identifying biomarkers for response, for resistance, for toxicity,” he said.
The study was sponsored by Acerta Pharma BV.
*Data presented at the meeting differ from the abstract.
CHICAGO—Acalabrutinib monotherapy was highly effective in Waldenström’s macroglobulinemia (WM) in a phase 2 study, investigator Roger Owen, MD, reported at the 2018 ASCO Annual Meeting.
The BTK inhibitor was effective in both treatment-naïve and relapsed/refractory patients, with overall response rates for both groups in excess of 90%, and “amazing” major response rates—partial response or better—of approximately 80%, Dr Owen said.
Dr Owen, of the St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust in Leeds, UK, reported the findings as abstract 7501.*
Durations of response were excellent, according to Dr Owen, who also reported 2-year progression-free survival of 90% in treatment-naïve patients and 82% in relapsed/refractory patients.
The safety profile was favorable, with most adverse events of low grade, and a very limited number of dropouts due to adverse events, according to the investigator.
“I think this study clearly demonstrates the highly effective nature of acalabrutinib in Waldenström’s macroglobulinemia,” Dr Owen stated.
Acalabrutinib is a selective BTK inhibitor with minimal off-target activity, he said. The BTK inhibitor ibrutinib also has demonstrated activity in Waldenström’s, but has been associated with toxicities such as atrial fibrillation and bleeding, he noted.
In this phase 2 acalabrutinib study (NCT02180724), which included 14 treatment-naïve and 92 relapsed/refractory patients, atrial fibrillation occurred in 5 patients. However, 4 of those cases were grade 1-2, and only one was grade 3, according to Dr Owen.
Investigators observed grade 3 hypertension in 3 relapsed/refractory patients.
Bleeding events occurred in more than half of patients, though only 3 of those events were grade 3, and no patient discontinued treatment due to a bleeding episode.
These efficacy results are “impressive,” and the fact that very few cardiac events were seen is important, said Bruce D. Cheson, MD, of Georgetown University Medical Center in Washington, DC.
Dr Cheson commented on the acalabrutinib results in his presentation during ASCO on non-chemotherapy treatments for lymphoid malignancies.
“One can construct a non-chemo algorithm now for Waldenström’s, for patients who are MYD88 mutated, which is more than 90% of patients,” he said. “Right now ibrutinib, and perhaps in the future acalabrutinib, can be the initial therapy with or without rituximab based on the results of ongoing trials.”
However, single non-chemotherapy agents will not be sufficient to achieve cure of lymphoid malignancies, Dr Cheson added.
“We need to carefully develop rational combinations, identifying biomarkers for response, for resistance, for toxicity,” he said.
The study was sponsored by Acerta Pharma BV.
*Data presented at the meeting differ from the abstract.
CHICAGO—Acalabrutinib monotherapy was highly effective in Waldenström’s macroglobulinemia (WM) in a phase 2 study, investigator Roger Owen, MD, reported at the 2018 ASCO Annual Meeting.
The BTK inhibitor was effective in both treatment-naïve and relapsed/refractory patients, with overall response rates for both groups in excess of 90%, and “amazing” major response rates—partial response or better—of approximately 80%, Dr Owen said.
Dr Owen, of the St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust in Leeds, UK, reported the findings as abstract 7501.*
Durations of response were excellent, according to Dr Owen, who also reported 2-year progression-free survival of 90% in treatment-naïve patients and 82% in relapsed/refractory patients.
The safety profile was favorable, with most adverse events of low grade, and a very limited number of dropouts due to adverse events, according to the investigator.
“I think this study clearly demonstrates the highly effective nature of acalabrutinib in Waldenström’s macroglobulinemia,” Dr Owen stated.
Acalabrutinib is a selective BTK inhibitor with minimal off-target activity, he said. The BTK inhibitor ibrutinib also has demonstrated activity in Waldenström’s, but has been associated with toxicities such as atrial fibrillation and bleeding, he noted.
In this phase 2 acalabrutinib study (NCT02180724), which included 14 treatment-naïve and 92 relapsed/refractory patients, atrial fibrillation occurred in 5 patients. However, 4 of those cases were grade 1-2, and only one was grade 3, according to Dr Owen.
Investigators observed grade 3 hypertension in 3 relapsed/refractory patients.
Bleeding events occurred in more than half of patients, though only 3 of those events were grade 3, and no patient discontinued treatment due to a bleeding episode.
These efficacy results are “impressive,” and the fact that very few cardiac events were seen is important, said Bruce D. Cheson, MD, of Georgetown University Medical Center in Washington, DC.
Dr Cheson commented on the acalabrutinib results in his presentation during ASCO on non-chemotherapy treatments for lymphoid malignancies.
“One can construct a non-chemo algorithm now for Waldenström’s, for patients who are MYD88 mutated, which is more than 90% of patients,” he said. “Right now ibrutinib, and perhaps in the future acalabrutinib, can be the initial therapy with or without rituximab based on the results of ongoing trials.”
However, single non-chemotherapy agents will not be sufficient to achieve cure of lymphoid malignancies, Dr Cheson added.
“We need to carefully develop rational combinations, identifying biomarkers for response, for resistance, for toxicity,” he said.
The study was sponsored by Acerta Pharma BV.
*Data presented at the meeting differ from the abstract.
Older, cheaper drug formulation to remain available
The 140 mg capsules of Imbruvica® (ibrutinib) will remain on the market, according to Pharmacyclics LLC.
Pharmacyclics (an AbbVie company) and Janssen had planned to discontinue the capsules after introducing a single-tablet formulation of Imbruvica earlier this year.
However, the companies received negative feedback about the discontinuation and decided to keep the 140 mg capsules on the market.
In February, the US Food and Drug Administration (FDA) approved a single-tablet formulation of Imbruvica that is available in 4 doses—140 mg, 280 mg, 420 mg, and 560 mg.
Pharmacyclics and Janssen introduced this formulation to enable a once-a-day dosing regimen. The companies said the goal with the new formulation was to improve adherence because some patients had to take 3 or 4 pills every day to get the recommended dose of Imbruvica.
After introducing the new formulation, Pharmacyclics and Janssen planned to discontinue the 140 mg capsules.
Critics spoke out against this change in an article published in The Cancer Letter. They noted that discontinuing the old formulation would mean price increases for some patients. That’s because the single-tablet formulation of Imbruvica has the same price regardless of dose—$400 per tablet.
Patients on lower doses of Imbruvica would experience an increase in cost if they switched from the capsules to the tablet formulation. In fact, costs could triple for patients on the 140 mg dose.
Pharmacyclics argued that most patients on Imbruvica—those taking the 420 mg and 560 mg doses—would see no increase in out-of-pocket costs when transitioning to the single-tablet formulation. And patients on the 560 mg dose would likely see a decrease in their out-of-pocket costs.
However, critics pointed to results of a recent pilot study, which indicated that the recommended dose of Imbruvica for patients with chronic lymphocytic leukemia (CLL)—420 mg—may be too high. The results suggested that CLL patients could receive lower doses of Imbruvica without a reduction in efficacy.
Therefore, keeping the 140 mg capsules on the market could mean lower costs for some CLL patients.
In addition to voicing concerns about costs, the critics pointed out that discontinuing the 140 mg capsules of Imbruvica would make it more difficult to adjust patients’ doses when needed.
Pharmacyclics said its YOU&i™ Dose Exchange Program can aid healthcare professionals in adjusting doses before patients have finished their current pack of Imbruvica. Patients would receive a “rapid shipment” of their new dose at no additional cost.
But the critics said this program “creates a barrier to optimal prescribing for some patients” and urged the FDA to review the safety of the program.
Roughly a month after the critics made this recommendation in The Cancer Letter article, Pharmacyclics announced that the 140 mg capsules of Imbruvica would remain on the market.
The 140 mg capsules of Imbruvica® (ibrutinib) will remain on the market, according to Pharmacyclics LLC.
Pharmacyclics (an AbbVie company) and Janssen had planned to discontinue the capsules after introducing a single-tablet formulation of Imbruvica earlier this year.
However, the companies received negative feedback about the discontinuation and decided to keep the 140 mg capsules on the market.
In February, the US Food and Drug Administration (FDA) approved a single-tablet formulation of Imbruvica that is available in 4 doses—140 mg, 280 mg, 420 mg, and 560 mg.
Pharmacyclics and Janssen introduced this formulation to enable a once-a-day dosing regimen. The companies said the goal with the new formulation was to improve adherence because some patients had to take 3 or 4 pills every day to get the recommended dose of Imbruvica.
After introducing the new formulation, Pharmacyclics and Janssen planned to discontinue the 140 mg capsules.
Critics spoke out against this change in an article published in The Cancer Letter. They noted that discontinuing the old formulation would mean price increases for some patients. That’s because the single-tablet formulation of Imbruvica has the same price regardless of dose—$400 per tablet.
Patients on lower doses of Imbruvica would experience an increase in cost if they switched from the capsules to the tablet formulation. In fact, costs could triple for patients on the 140 mg dose.
Pharmacyclics argued that most patients on Imbruvica—those taking the 420 mg and 560 mg doses—would see no increase in out-of-pocket costs when transitioning to the single-tablet formulation. And patients on the 560 mg dose would likely see a decrease in their out-of-pocket costs.
However, critics pointed to results of a recent pilot study, which indicated that the recommended dose of Imbruvica for patients with chronic lymphocytic leukemia (CLL)—420 mg—may be too high. The results suggested that CLL patients could receive lower doses of Imbruvica without a reduction in efficacy.
Therefore, keeping the 140 mg capsules on the market could mean lower costs for some CLL patients.
In addition to voicing concerns about costs, the critics pointed out that discontinuing the 140 mg capsules of Imbruvica would make it more difficult to adjust patients’ doses when needed.
Pharmacyclics said its YOU&i™ Dose Exchange Program can aid healthcare professionals in adjusting doses before patients have finished their current pack of Imbruvica. Patients would receive a “rapid shipment” of their new dose at no additional cost.
But the critics said this program “creates a barrier to optimal prescribing for some patients” and urged the FDA to review the safety of the program.
Roughly a month after the critics made this recommendation in The Cancer Letter article, Pharmacyclics announced that the 140 mg capsules of Imbruvica would remain on the market.
The 140 mg capsules of Imbruvica® (ibrutinib) will remain on the market, according to Pharmacyclics LLC.
Pharmacyclics (an AbbVie company) and Janssen had planned to discontinue the capsules after introducing a single-tablet formulation of Imbruvica earlier this year.
However, the companies received negative feedback about the discontinuation and decided to keep the 140 mg capsules on the market.
In February, the US Food and Drug Administration (FDA) approved a single-tablet formulation of Imbruvica that is available in 4 doses—140 mg, 280 mg, 420 mg, and 560 mg.
Pharmacyclics and Janssen introduced this formulation to enable a once-a-day dosing regimen. The companies said the goal with the new formulation was to improve adherence because some patients had to take 3 or 4 pills every day to get the recommended dose of Imbruvica.
After introducing the new formulation, Pharmacyclics and Janssen planned to discontinue the 140 mg capsules.
Critics spoke out against this change in an article published in The Cancer Letter. They noted that discontinuing the old formulation would mean price increases for some patients. That’s because the single-tablet formulation of Imbruvica has the same price regardless of dose—$400 per tablet.
Patients on lower doses of Imbruvica would experience an increase in cost if they switched from the capsules to the tablet formulation. In fact, costs could triple for patients on the 140 mg dose.
Pharmacyclics argued that most patients on Imbruvica—those taking the 420 mg and 560 mg doses—would see no increase in out-of-pocket costs when transitioning to the single-tablet formulation. And patients on the 560 mg dose would likely see a decrease in their out-of-pocket costs.
However, critics pointed to results of a recent pilot study, which indicated that the recommended dose of Imbruvica for patients with chronic lymphocytic leukemia (CLL)—420 mg—may be too high. The results suggested that CLL patients could receive lower doses of Imbruvica without a reduction in efficacy.
Therefore, keeping the 140 mg capsules on the market could mean lower costs for some CLL patients.
In addition to voicing concerns about costs, the critics pointed out that discontinuing the 140 mg capsules of Imbruvica would make it more difficult to adjust patients’ doses when needed.
Pharmacyclics said its YOU&i™ Dose Exchange Program can aid healthcare professionals in adjusting doses before patients have finished their current pack of Imbruvica. Patients would receive a “rapid shipment” of their new dose at no additional cost.
But the critics said this program “creates a barrier to optimal prescribing for some patients” and urged the FDA to review the safety of the program.
Roughly a month after the critics made this recommendation in The Cancer Letter article, Pharmacyclics announced that the 140 mg capsules of Imbruvica would remain on the market.
Regimen can improve DFS in newly diagnosed T-ALL
The addition of nelarabine can improve treatment outcomes for certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to a phase 3 trial.
Patients with newly diagnosed, intermediate- or high-risk T-ALL had a significant improvement in 4-year disease-free survival (DFS) if they received nelarabine in addition to chemotherapy and cranial irradiation.
The DFS benefit with nelarabine was significant for patients who received high-dose methotrexate but not for those who received escalating-dose methotrexate.
This study also included patients with T-cell lymphoblastic lymphoma (T-LL), and they did not experience an improvement in DFS with the addition of nelarabine.
Kimberly Dunsmore, MD, of Virginia Tech Carilion School of Medicine in Roanoke, presented these results in a press briefing in advance of the 2018 ASCO Annual Meeting. Additional results are scheduled to be presented at the meeting as abstract 10500.
This research was supported by the National Cancer Institute/National Institutes of Health and St. Baldrick’s Foundation. The researchers’ disclosures are listed with the abstract.
Patients and treatment
The trial enrolled 1895 patients, ages 1 to 30, who were newly diagnosed with T-ALL (94%) or T-LL (6%).
Patients received standard 4-drug induction chemotherapy, and 1307 of these patients were then randomized to 1 of 4 treatment arms.
Regardless of which arm they were randomized to, patients received an 11-drug chemotherapy regimen—the augmented Berlin-Frankfurt-Munster regimen. Intermediate- and high-risk patients in all 4 arms also received cranial irradiation.
In the first treatment arm, T-LL (n=58) and T-ALL (n=372) patients received escalating-dose methotrexate without leucovorin rescue and pegaspargase (C-MTX).
In the second treatment arm, patients with intermediate- and high-risk T-ALL (n=147) and T-LL (n=60) received C-MTX plus nelarabine (six 5-day courses at 650 mg/m2/day).
In the third arm, T-ALL patients (n=451) received high-dose methotrexate with leucovorin rescue (HD-MTX). T-LL patients were not eligible for this arm or the fourth treatment arm.
In the fourth arm, intermediate- and high-risk T-ALL patients (n=219) received HD-MTX and nelarabine (same schedule as above). This included 43 T-ALL patients who had induction failure and were assigned to this arm non-randomly.
Results
For T-ALL patients, the 4-year disease-free survival (DFS) rate was 84%, and the 4-year overall survival rate was 90%.
There was a significant improvement in DFS for T-ALL patients who received nelarabine compared to those who did not—89% and 83%, respectively (P=0.0332).
“Historically, about 80% of people [with T-ALL] live at least 4 years after being treated for their disease, but we felt we could and must do better,” Dr Dunsmore said. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”
Dr Dunsmore also noted that patients who received nelarabine had fewer central nervous system relapses.
Among T-ALL patients who received C-MTX, there was no significant difference in DFS for those who received nelarabine and those who did not—92% and 90%, respectively (P=0.3825).
However, for patients who received HD-MTX, the difference in DFS was significant. The DFS rate was 86% in patients who received nelarabine and 78% in those who did not (P=0.024).
For the T-ALL patients who failed induction and were assigned to HD-MTX and nelarabine, the 4-year DFS rate was 55%.
Patients with T-LL did not benefit from the addition of nelarabine. The 4-year DFS rate was 85% in the nelarabine recipients and 89% in non-recipients (P=0.2788).
There were no significant differences in overall toxicity or peripheral neurotoxicity between the treatment arms.
Dr Dunsmore said the next step with this research will be to examine the implications and potential benefits of using nelarabine in treatment protocols that do not include cranial radiation.
The addition of nelarabine can improve treatment outcomes for certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to a phase 3 trial.
Patients with newly diagnosed, intermediate- or high-risk T-ALL had a significant improvement in 4-year disease-free survival (DFS) if they received nelarabine in addition to chemotherapy and cranial irradiation.
The DFS benefit with nelarabine was significant for patients who received high-dose methotrexate but not for those who received escalating-dose methotrexate.
This study also included patients with T-cell lymphoblastic lymphoma (T-LL), and they did not experience an improvement in DFS with the addition of nelarabine.
Kimberly Dunsmore, MD, of Virginia Tech Carilion School of Medicine in Roanoke, presented these results in a press briefing in advance of the 2018 ASCO Annual Meeting. Additional results are scheduled to be presented at the meeting as abstract 10500.
This research was supported by the National Cancer Institute/National Institutes of Health and St. Baldrick’s Foundation. The researchers’ disclosures are listed with the abstract.
Patients and treatment
The trial enrolled 1895 patients, ages 1 to 30, who were newly diagnosed with T-ALL (94%) or T-LL (6%).
Patients received standard 4-drug induction chemotherapy, and 1307 of these patients were then randomized to 1 of 4 treatment arms.
Regardless of which arm they were randomized to, patients received an 11-drug chemotherapy regimen—the augmented Berlin-Frankfurt-Munster regimen. Intermediate- and high-risk patients in all 4 arms also received cranial irradiation.
In the first treatment arm, T-LL (n=58) and T-ALL (n=372) patients received escalating-dose methotrexate without leucovorin rescue and pegaspargase (C-MTX).
In the second treatment arm, patients with intermediate- and high-risk T-ALL (n=147) and T-LL (n=60) received C-MTX plus nelarabine (six 5-day courses at 650 mg/m2/day).
In the third arm, T-ALL patients (n=451) received high-dose methotrexate with leucovorin rescue (HD-MTX). T-LL patients were not eligible for this arm or the fourth treatment arm.
In the fourth arm, intermediate- and high-risk T-ALL patients (n=219) received HD-MTX and nelarabine (same schedule as above). This included 43 T-ALL patients who had induction failure and were assigned to this arm non-randomly.
Results
For T-ALL patients, the 4-year disease-free survival (DFS) rate was 84%, and the 4-year overall survival rate was 90%.
There was a significant improvement in DFS for T-ALL patients who received nelarabine compared to those who did not—89% and 83%, respectively (P=0.0332).
“Historically, about 80% of people [with T-ALL] live at least 4 years after being treated for their disease, but we felt we could and must do better,” Dr Dunsmore said. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”
Dr Dunsmore also noted that patients who received nelarabine had fewer central nervous system relapses.
Among T-ALL patients who received C-MTX, there was no significant difference in DFS for those who received nelarabine and those who did not—92% and 90%, respectively (P=0.3825).
However, for patients who received HD-MTX, the difference in DFS was significant. The DFS rate was 86% in patients who received nelarabine and 78% in those who did not (P=0.024).
For the T-ALL patients who failed induction and were assigned to HD-MTX and nelarabine, the 4-year DFS rate was 55%.
Patients with T-LL did not benefit from the addition of nelarabine. The 4-year DFS rate was 85% in the nelarabine recipients and 89% in non-recipients (P=0.2788).
There were no significant differences in overall toxicity or peripheral neurotoxicity between the treatment arms.
Dr Dunsmore said the next step with this research will be to examine the implications and potential benefits of using nelarabine in treatment protocols that do not include cranial radiation.
The addition of nelarabine can improve treatment outcomes for certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to a phase 3 trial.
Patients with newly diagnosed, intermediate- or high-risk T-ALL had a significant improvement in 4-year disease-free survival (DFS) if they received nelarabine in addition to chemotherapy and cranial irradiation.
The DFS benefit with nelarabine was significant for patients who received high-dose methotrexate but not for those who received escalating-dose methotrexate.
This study also included patients with T-cell lymphoblastic lymphoma (T-LL), and they did not experience an improvement in DFS with the addition of nelarabine.
Kimberly Dunsmore, MD, of Virginia Tech Carilion School of Medicine in Roanoke, presented these results in a press briefing in advance of the 2018 ASCO Annual Meeting. Additional results are scheduled to be presented at the meeting as abstract 10500.
This research was supported by the National Cancer Institute/National Institutes of Health and St. Baldrick’s Foundation. The researchers’ disclosures are listed with the abstract.
Patients and treatment
The trial enrolled 1895 patients, ages 1 to 30, who were newly diagnosed with T-ALL (94%) or T-LL (6%).
Patients received standard 4-drug induction chemotherapy, and 1307 of these patients were then randomized to 1 of 4 treatment arms.
Regardless of which arm they were randomized to, patients received an 11-drug chemotherapy regimen—the augmented Berlin-Frankfurt-Munster regimen. Intermediate- and high-risk patients in all 4 arms also received cranial irradiation.
In the first treatment arm, T-LL (n=58) and T-ALL (n=372) patients received escalating-dose methotrexate without leucovorin rescue and pegaspargase (C-MTX).
In the second treatment arm, patients with intermediate- and high-risk T-ALL (n=147) and T-LL (n=60) received C-MTX plus nelarabine (six 5-day courses at 650 mg/m2/day).
In the third arm, T-ALL patients (n=451) received high-dose methotrexate with leucovorin rescue (HD-MTX). T-LL patients were not eligible for this arm or the fourth treatment arm.
In the fourth arm, intermediate- and high-risk T-ALL patients (n=219) received HD-MTX and nelarabine (same schedule as above). This included 43 T-ALL patients who had induction failure and were assigned to this arm non-randomly.
Results
For T-ALL patients, the 4-year disease-free survival (DFS) rate was 84%, and the 4-year overall survival rate was 90%.
There was a significant improvement in DFS for T-ALL patients who received nelarabine compared to those who did not—89% and 83%, respectively (P=0.0332).
“Historically, about 80% of people [with T-ALL] live at least 4 years after being treated for their disease, but we felt we could and must do better,” Dr Dunsmore said. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”
Dr Dunsmore also noted that patients who received nelarabine had fewer central nervous system relapses.
Among T-ALL patients who received C-MTX, there was no significant difference in DFS for those who received nelarabine and those who did not—92% and 90%, respectively (P=0.3825).
However, for patients who received HD-MTX, the difference in DFS was significant. The DFS rate was 86% in patients who received nelarabine and 78% in those who did not (P=0.024).
For the T-ALL patients who failed induction and were assigned to HD-MTX and nelarabine, the 4-year DFS rate was 55%.
Patients with T-LL did not benefit from the addition of nelarabine. The 4-year DFS rate was 85% in the nelarabine recipients and 89% in non-recipients (P=0.2788).
There were no significant differences in overall toxicity or peripheral neurotoxicity between the treatment arms.
Dr Dunsmore said the next step with this research will be to examine the implications and potential benefits of using nelarabine in treatment protocols that do not include cranial radiation.
Umbralisib has ‘distinct’ safety profile
Phase 1 trial results suggest umbralisib, a PI3Kδ/CK1ε inhibitor, can be safe and active in patients with relapsed or refractory B-cell malignancies.
Researchers said the safety profile of umbralisib “was distinct from that of other PI3Kδ inhibitors,” as it produced few immune-mediated adverse events (AEs).
Umbralisib also produced an objective response rate of 37% in the entire study cohort, 80% in patients with chronic lymphocytic leukemia (CLL), 53% in patients with follicular lymphoma (FL), and 31% in patients with diffuse large B-cell lymphoma (DLBCL).
These results were published in The Lancet Oncology. The study was sponsored by TG Therapeutics, Inc.
The trial enrolled 90 patients between January 17, 2013, and January 14, 2016.
There were 24 patients with CLL, 22 with FL, 16 with DLBCL, 11 with Hodgkin lymphoma, 6 with mantle cell lymphoma, 5 with marginal zone lymphoma, 3 with Waldenstrom’s macroglobulinemia, 2 with T-cell lymphoma, and 1 with hairy cell leukemia.
The median number of prior therapies was 3 (range, 2-5), and 49% of patients were refractory to previous therapy.
Treatment
Patients took umbralisib once daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.
Initially, patients took the drug in a fasting state at doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In April 2014, the researchers did a second dose-escalation with a micronized formulation of umbralisib, taken with food, at doses of 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In August, 2014, all patients who were still on the study transitioned to the 800 mg dose of the micronized formulation. This was the recommended phase 2 dose.
At the data cutoff in November 2016, 44 patients (49%) had received umbralisib for more than 6 cycles, and 23 (26%) had received the drug for more than 12 cycles. Thirteen patients (14%) were still taking umbralisib at the end of the study.
Most patients who stopped treatment did so because of disease progression (n=50, 56%) or AEs (n=9, 10%).
“We are pleased to have treated the first patient ever with umbralisib over 5 years ago and believe it has an important place in the treatment landscape for patients with hematologic malignancies,” said study author Howard A. Burris, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
“Several patients from this phase 1 study are still on study today, approaching 5 years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent.”
Safety
Dose-limiting toxicities (DLTs) occurred in 4 patients. One DLT was grade 3 maculopapular rash in a patient receiving the 800 mg dose of the initial formulation.
Another DLT was grade 3 hypokalemia in a patient receiving 1800 mg of the initial formulation. A third DLT was grade 3 fatigue, which occurred in 2 patients receiving 1800 mg of the micronized formulation.
Because of these toxicities, the maximum tolerated dose was 1200 mg of the micronized formulation.
The most common treatment-emergent AEs were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).
Serious AEs considered at least possibly related to umbralisib were pneumonia (3%), lung infection (1%), febrile neutropenia (1%), and colitis (2%).
Treatment discontinuation due to AEs considered at least possibly related to umbralisib occurred in 6 patients (7%). Two patients had grade 3 colitis, 2 had increased ALT/AST (grade 1 and grade 4), 1 had grade 2 diarrhea, and 1 had grade 3 fatigue.
There were no treatment-related deaths.
The researchers said the safety profile of umbralisib was distinct from that of other PI3Kδ inhibitors, as patients in this trial had fewer occurrences of autoimmune-like toxicities, such as colitis.
“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3Kδ and CK1ε,” said study author Owen O’Connor, MD, PhD, of Columbia Presbyterian Medical Center in New York, New York.
“The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3Kδ inhibitors.”
Response
The objective response rate was 37%, with 33 patients achieving a response and 3 patients having a complete response (CR).
Sixteen CLL patients responded (80%), all with partial responses (PRs). Four DLBCL patients responded (31%), all with PRs. And 9 FL patients responded (53%), 2 with CRs.
The remaining CR occurred in a Hodgkin lymphoma patient, and this was the only response in this patient group.
One patient with marginal zone lymphoma had a PR, as did 1 patient with mantle cell lymphoma. All other patients had stable disease or progressed.
The mean duration of response was 13.4 months in the CLL patients, 6.4 months in the DLBCL patients, and 9.3 months in the FL patients.
Phase 1 trial results suggest umbralisib, a PI3Kδ/CK1ε inhibitor, can be safe and active in patients with relapsed or refractory B-cell malignancies.
Researchers said the safety profile of umbralisib “was distinct from that of other PI3Kδ inhibitors,” as it produced few immune-mediated adverse events (AEs).
Umbralisib also produced an objective response rate of 37% in the entire study cohort, 80% in patients with chronic lymphocytic leukemia (CLL), 53% in patients with follicular lymphoma (FL), and 31% in patients with diffuse large B-cell lymphoma (DLBCL).
These results were published in The Lancet Oncology. The study was sponsored by TG Therapeutics, Inc.
The trial enrolled 90 patients between January 17, 2013, and January 14, 2016.
There were 24 patients with CLL, 22 with FL, 16 with DLBCL, 11 with Hodgkin lymphoma, 6 with mantle cell lymphoma, 5 with marginal zone lymphoma, 3 with Waldenstrom’s macroglobulinemia, 2 with T-cell lymphoma, and 1 with hairy cell leukemia.
The median number of prior therapies was 3 (range, 2-5), and 49% of patients were refractory to previous therapy.
Treatment
Patients took umbralisib once daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.
Initially, patients took the drug in a fasting state at doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In April 2014, the researchers did a second dose-escalation with a micronized formulation of umbralisib, taken with food, at doses of 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In August, 2014, all patients who were still on the study transitioned to the 800 mg dose of the micronized formulation. This was the recommended phase 2 dose.
At the data cutoff in November 2016, 44 patients (49%) had received umbralisib for more than 6 cycles, and 23 (26%) had received the drug for more than 12 cycles. Thirteen patients (14%) were still taking umbralisib at the end of the study.
Most patients who stopped treatment did so because of disease progression (n=50, 56%) or AEs (n=9, 10%).
“We are pleased to have treated the first patient ever with umbralisib over 5 years ago and believe it has an important place in the treatment landscape for patients with hematologic malignancies,” said study author Howard A. Burris, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
“Several patients from this phase 1 study are still on study today, approaching 5 years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent.”
Safety
Dose-limiting toxicities (DLTs) occurred in 4 patients. One DLT was grade 3 maculopapular rash in a patient receiving the 800 mg dose of the initial formulation.
Another DLT was grade 3 hypokalemia in a patient receiving 1800 mg of the initial formulation. A third DLT was grade 3 fatigue, which occurred in 2 patients receiving 1800 mg of the micronized formulation.
Because of these toxicities, the maximum tolerated dose was 1200 mg of the micronized formulation.
The most common treatment-emergent AEs were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).
Serious AEs considered at least possibly related to umbralisib were pneumonia (3%), lung infection (1%), febrile neutropenia (1%), and colitis (2%).
Treatment discontinuation due to AEs considered at least possibly related to umbralisib occurred in 6 patients (7%). Two patients had grade 3 colitis, 2 had increased ALT/AST (grade 1 and grade 4), 1 had grade 2 diarrhea, and 1 had grade 3 fatigue.
There were no treatment-related deaths.
The researchers said the safety profile of umbralisib was distinct from that of other PI3Kδ inhibitors, as patients in this trial had fewer occurrences of autoimmune-like toxicities, such as colitis.
“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3Kδ and CK1ε,” said study author Owen O’Connor, MD, PhD, of Columbia Presbyterian Medical Center in New York, New York.
“The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3Kδ inhibitors.”
Response
The objective response rate was 37%, with 33 patients achieving a response and 3 patients having a complete response (CR).
Sixteen CLL patients responded (80%), all with partial responses (PRs). Four DLBCL patients responded (31%), all with PRs. And 9 FL patients responded (53%), 2 with CRs.
The remaining CR occurred in a Hodgkin lymphoma patient, and this was the only response in this patient group.
One patient with marginal zone lymphoma had a PR, as did 1 patient with mantle cell lymphoma. All other patients had stable disease or progressed.
The mean duration of response was 13.4 months in the CLL patients, 6.4 months in the DLBCL patients, and 9.3 months in the FL patients.
Phase 1 trial results suggest umbralisib, a PI3Kδ/CK1ε inhibitor, can be safe and active in patients with relapsed or refractory B-cell malignancies.
Researchers said the safety profile of umbralisib “was distinct from that of other PI3Kδ inhibitors,” as it produced few immune-mediated adverse events (AEs).
Umbralisib also produced an objective response rate of 37% in the entire study cohort, 80% in patients with chronic lymphocytic leukemia (CLL), 53% in patients with follicular lymphoma (FL), and 31% in patients with diffuse large B-cell lymphoma (DLBCL).
These results were published in The Lancet Oncology. The study was sponsored by TG Therapeutics, Inc.
The trial enrolled 90 patients between January 17, 2013, and January 14, 2016.
There were 24 patients with CLL, 22 with FL, 16 with DLBCL, 11 with Hodgkin lymphoma, 6 with mantle cell lymphoma, 5 with marginal zone lymphoma, 3 with Waldenstrom’s macroglobulinemia, 2 with T-cell lymphoma, and 1 with hairy cell leukemia.
The median number of prior therapies was 3 (range, 2-5), and 49% of patients were refractory to previous therapy.
Treatment
Patients took umbralisib once daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.
Initially, patients took the drug in a fasting state at doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In April 2014, the researchers did a second dose-escalation with a micronized formulation of umbralisib, taken with food, at doses of 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In August, 2014, all patients who were still on the study transitioned to the 800 mg dose of the micronized formulation. This was the recommended phase 2 dose.
At the data cutoff in November 2016, 44 patients (49%) had received umbralisib for more than 6 cycles, and 23 (26%) had received the drug for more than 12 cycles. Thirteen patients (14%) were still taking umbralisib at the end of the study.
Most patients who stopped treatment did so because of disease progression (n=50, 56%) or AEs (n=9, 10%).
“We are pleased to have treated the first patient ever with umbralisib over 5 years ago and believe it has an important place in the treatment landscape for patients with hematologic malignancies,” said study author Howard A. Burris, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
“Several patients from this phase 1 study are still on study today, approaching 5 years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent.”
Safety
Dose-limiting toxicities (DLTs) occurred in 4 patients. One DLT was grade 3 maculopapular rash in a patient receiving the 800 mg dose of the initial formulation.
Another DLT was grade 3 hypokalemia in a patient receiving 1800 mg of the initial formulation. A third DLT was grade 3 fatigue, which occurred in 2 patients receiving 1800 mg of the micronized formulation.
Because of these toxicities, the maximum tolerated dose was 1200 mg of the micronized formulation.
The most common treatment-emergent AEs were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).
Serious AEs considered at least possibly related to umbralisib were pneumonia (3%), lung infection (1%), febrile neutropenia (1%), and colitis (2%).
Treatment discontinuation due to AEs considered at least possibly related to umbralisib occurred in 6 patients (7%). Two patients had grade 3 colitis, 2 had increased ALT/AST (grade 1 and grade 4), 1 had grade 2 diarrhea, and 1 had grade 3 fatigue.
There were no treatment-related deaths.
The researchers said the safety profile of umbralisib was distinct from that of other PI3Kδ inhibitors, as patients in this trial had fewer occurrences of autoimmune-like toxicities, such as colitis.
“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3Kδ and CK1ε,” said study author Owen O’Connor, MD, PhD, of Columbia Presbyterian Medical Center in New York, New York.
“The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3Kδ inhibitors.”
Response
The objective response rate was 37%, with 33 patients achieving a response and 3 patients having a complete response (CR).
Sixteen CLL patients responded (80%), all with partial responses (PRs). Four DLBCL patients responded (31%), all with PRs. And 9 FL patients responded (53%), 2 with CRs.
The remaining CR occurred in a Hodgkin lymphoma patient, and this was the only response in this patient group.
One patient with marginal zone lymphoma had a PR, as did 1 patient with mantle cell lymphoma. All other patients had stable disease or progressed.
The mean duration of response was 13.4 months in the CLL patients, 6.4 months in the DLBCL patients, and 9.3 months in the FL patients.
Team identifies new prognostic factor for MF
New research suggests DNA sequencing can reveal which patients with early stage mycosis fungoides (MF) will develop aggressive disease.
By sequencing the T-cell receptor beta gene (TCRB) in skin biopsies from MF patients, investigators were able to measure the tumor clone frequency (TCF), or the percentage of all T cells that represent the MF clone.
The researchers found the TCF could predict progression-free survival (PFS) and overall survival (OS).
In fact, for patients with early stage MF, TCF was a stronger predictor of PFS than other established prognostic factors.
“While more work needs to be done, we think this approach has the potential to prospectively identify a subgroup of patients who are destined to develop aggressive, life-threatening disease and treat them in a more aggressive fashion with the intent to better manage and, ideally, cure their cancer,” said Thomas Kupper, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, we believe we can provide reassurance to patients with a low-risk (low TCF) profile that they are likely to survive indefinitely with conventional conservative therapies. As a physician who has treated this disease for decades, I am excited to be involved with work that so directly and profoundly affects the care and management of these patients.”
Dr Kupper and his colleagues described this work in Science Translational Medicine.
The researchers had previously published a study showing that high-throughput sequencing of the TCRB gene was an accurate way to diagnose cutaneous T-cell lymphoma (CTCL), including MF.
With the current study, the investigators set out to determine if the method could be used to predict progression and survival in patients with CTCL.
The team sequenced TCRB in lesional skin biopsies from 309 CTCL patients, most of whom had MF. The discovery cohort had 208 patients (177 with MF), and the validation cohort had 101 patients (87 with MF).
The sequencing produced a snapshot of the TCRB genes from a large number of cells at the site of the lesion. And the researchers could use this to measure TCF.
The team tested the association of TCF with prognosis in all CTCL patients in the discovery cohort and found a TCF greater than 25% in the skin was significantly associated with reduced PFS (P<0.001) and OS (P<0.001). Results were similar in the validation cohort (P<0.001 for PFS and OS).
The investigators also found that TCF was significantly associated with PFS (P<0.001) and OS (P<0.001) in MF patients but not in patients with Sézary syndrome. The team noted that they did not assess the predictive value of TCF in the blood of Sézary patients.
In a multivariable analysis, TCF was still significantly associated with PFS (P<0.001) and OS (P<0.001) in the MF patients.
The researchers also assessed potential prognostic variables in the early stage MF patients and found a TCF greater than 25% was a stronger predictor of PFS than any other established prognostic factor. This includes disease stage, presence of plaques, elevated lactate dehydrogenase, age, large-cell transformation, and CLIPI score.
“In reviewing the results, 2 different patients could have identical-looking skin lesions, but one might have a TCF of 8%, and one would have a TCF of 40%,” Dr Kupper noted. “The latter patient was highly likely to progress—something we would never have been able to predict before this discovery.”
“The TCF was independent of how thick or thin the skin lesions were. Most importantly, compared to all other currently used means of trying to predict which patients would progress, TCF was by far the most sensitive and specific.”
The high-throughput sequencing in this study was performed using ImmunoSEQ, an assay developed by Adaptive Biotechnologies. The company did not sponsor the study, but company employees were involved in the research.
New research suggests DNA sequencing can reveal which patients with early stage mycosis fungoides (MF) will develop aggressive disease.
By sequencing the T-cell receptor beta gene (TCRB) in skin biopsies from MF patients, investigators were able to measure the tumor clone frequency (TCF), or the percentage of all T cells that represent the MF clone.
The researchers found the TCF could predict progression-free survival (PFS) and overall survival (OS).
In fact, for patients with early stage MF, TCF was a stronger predictor of PFS than other established prognostic factors.
“While more work needs to be done, we think this approach has the potential to prospectively identify a subgroup of patients who are destined to develop aggressive, life-threatening disease and treat them in a more aggressive fashion with the intent to better manage and, ideally, cure their cancer,” said Thomas Kupper, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, we believe we can provide reassurance to patients with a low-risk (low TCF) profile that they are likely to survive indefinitely with conventional conservative therapies. As a physician who has treated this disease for decades, I am excited to be involved with work that so directly and profoundly affects the care and management of these patients.”
Dr Kupper and his colleagues described this work in Science Translational Medicine.
The researchers had previously published a study showing that high-throughput sequencing of the TCRB gene was an accurate way to diagnose cutaneous T-cell lymphoma (CTCL), including MF.
With the current study, the investigators set out to determine if the method could be used to predict progression and survival in patients with CTCL.
The team sequenced TCRB in lesional skin biopsies from 309 CTCL patients, most of whom had MF. The discovery cohort had 208 patients (177 with MF), and the validation cohort had 101 patients (87 with MF).
The sequencing produced a snapshot of the TCRB genes from a large number of cells at the site of the lesion. And the researchers could use this to measure TCF.
The team tested the association of TCF with prognosis in all CTCL patients in the discovery cohort and found a TCF greater than 25% in the skin was significantly associated with reduced PFS (P<0.001) and OS (P<0.001). Results were similar in the validation cohort (P<0.001 for PFS and OS).
The investigators also found that TCF was significantly associated with PFS (P<0.001) and OS (P<0.001) in MF patients but not in patients with Sézary syndrome. The team noted that they did not assess the predictive value of TCF in the blood of Sézary patients.
In a multivariable analysis, TCF was still significantly associated with PFS (P<0.001) and OS (P<0.001) in the MF patients.
The researchers also assessed potential prognostic variables in the early stage MF patients and found a TCF greater than 25% was a stronger predictor of PFS than any other established prognostic factor. This includes disease stage, presence of plaques, elevated lactate dehydrogenase, age, large-cell transformation, and CLIPI score.
“In reviewing the results, 2 different patients could have identical-looking skin lesions, but one might have a TCF of 8%, and one would have a TCF of 40%,” Dr Kupper noted. “The latter patient was highly likely to progress—something we would never have been able to predict before this discovery.”
“The TCF was independent of how thick or thin the skin lesions were. Most importantly, compared to all other currently used means of trying to predict which patients would progress, TCF was by far the most sensitive and specific.”
The high-throughput sequencing in this study was performed using ImmunoSEQ, an assay developed by Adaptive Biotechnologies. The company did not sponsor the study, but company employees were involved in the research.
New research suggests DNA sequencing can reveal which patients with early stage mycosis fungoides (MF) will develop aggressive disease.
By sequencing the T-cell receptor beta gene (TCRB) in skin biopsies from MF patients, investigators were able to measure the tumor clone frequency (TCF), or the percentage of all T cells that represent the MF clone.
The researchers found the TCF could predict progression-free survival (PFS) and overall survival (OS).
In fact, for patients with early stage MF, TCF was a stronger predictor of PFS than other established prognostic factors.
“While more work needs to be done, we think this approach has the potential to prospectively identify a subgroup of patients who are destined to develop aggressive, life-threatening disease and treat them in a more aggressive fashion with the intent to better manage and, ideally, cure their cancer,” said Thomas Kupper, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, we believe we can provide reassurance to patients with a low-risk (low TCF) profile that they are likely to survive indefinitely with conventional conservative therapies. As a physician who has treated this disease for decades, I am excited to be involved with work that so directly and profoundly affects the care and management of these patients.”
Dr Kupper and his colleagues described this work in Science Translational Medicine.
The researchers had previously published a study showing that high-throughput sequencing of the TCRB gene was an accurate way to diagnose cutaneous T-cell lymphoma (CTCL), including MF.
With the current study, the investigators set out to determine if the method could be used to predict progression and survival in patients with CTCL.
The team sequenced TCRB in lesional skin biopsies from 309 CTCL patients, most of whom had MF. The discovery cohort had 208 patients (177 with MF), and the validation cohort had 101 patients (87 with MF).
The sequencing produced a snapshot of the TCRB genes from a large number of cells at the site of the lesion. And the researchers could use this to measure TCF.
The team tested the association of TCF with prognosis in all CTCL patients in the discovery cohort and found a TCF greater than 25% in the skin was significantly associated with reduced PFS (P<0.001) and OS (P<0.001). Results were similar in the validation cohort (P<0.001 for PFS and OS).
The investigators also found that TCF was significantly associated with PFS (P<0.001) and OS (P<0.001) in MF patients but not in patients with Sézary syndrome. The team noted that they did not assess the predictive value of TCF in the blood of Sézary patients.
In a multivariable analysis, TCF was still significantly associated with PFS (P<0.001) and OS (P<0.001) in the MF patients.
The researchers also assessed potential prognostic variables in the early stage MF patients and found a TCF greater than 25% was a stronger predictor of PFS than any other established prognostic factor. This includes disease stage, presence of plaques, elevated lactate dehydrogenase, age, large-cell transformation, and CLIPI score.
“In reviewing the results, 2 different patients could have identical-looking skin lesions, but one might have a TCF of 8%, and one would have a TCF of 40%,” Dr Kupper noted. “The latter patient was highly likely to progress—something we would never have been able to predict before this discovery.”
“The TCF was independent of how thick or thin the skin lesions were. Most importantly, compared to all other currently used means of trying to predict which patients would progress, TCF was by far the most sensitive and specific.”
The high-throughput sequencing in this study was performed using ImmunoSEQ, an assay developed by Adaptive Biotechnologies. The company did not sponsor the study, but company employees were involved in the research.