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M13-982 trial in del(17p) CLL: High, durable response rates to venetoclax
New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.
Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
That response was maintained at 1 year in 85% of participants.
The current findings, which represent data through April 2017 for those 107 patients from the main cohort, as well as for 51 patients in the safety expansion study, show an overall response rate of 77%, with 20% CR/CRi.
The median time to first response was 1 month, and time to CR/CRi was 9.8 months, they said.
Estimates at 24 months for duration of response, progression-free survival, and overall survival were 66%, 54%, and 73%, respectively.
Additionally, objective responses were seen in four of five previously untreated patients who were enrolled in the safety expansion, and two of them had complete remissions. One patient with best response of stable disease decided to discontinue treatment but remained in follow-up with stable disease.
“All patients were alive at the time of analysis and remain progression free,” the investigators wrote.
In 18 patients who received prior B-cell receptor pathway inhibitor (BCRi) therapy, the objective response rate was 61% and the complete remission rate was 11%, with 12-month, progression-free and overall survival estimates of 50% and 54%, respectively.
Treatment-emergent adverse events of any grade occurred in 98% of patients, and led to dosing interruption in 40% and dosing adjustment in 17%. The most common adverse event was neutropenia; grade 3/4 neutropenia occurred in 40% of patients.
Neutropenia lead to a dose reduction in 8% of patients and to treatment interruption in 6% of patients; no discontinuations were reported.
Infections occurred in 81% of 158 patients, and grade 3/4 infections occurred in 23%; these infections were consistent with the underlying disease, the investigators said.
Laboratory tumor lysis syndrome (TLS) occurred in 5% of patients, but there were no episodes of clinical TLS, they said, noting that five TLS patients required dose interruptions. TLS occurred in four patients with medium risk at screening and in four with high risk. All episodes of TLS occurred during initial dosing or ramp-up, and all resolved. Affected patients were able to resume venetoclax with dose escalation to 400 mg/day.
The rate of minimal residual disease negativity was 30% in the intention-to-treat population as demonstrated by flow cytometry and confirmed by next generation sequencing (NGS) in 21 of 29 patients with an evaluable matched time point specimen. Bone marrow MRD negativity was observed in 20 patients by flow cytometry, and in 9 patients by NGS.
When looking at flow cytometry and NGS data combined, the MRD negativity rate in peripheral blood was 25% overall and 40% in evaluable patients, and the MRD negativity rate in bone marrow was 11% overall and 24% in evaluable patients.
Of those who achieved CR/CRi, 69% were MRD negative in peripheral blood by flow cytometry, with a 24-month, progression-free survival estimate of 100%, and 13 of those had confirmed MRD-negative blood by NGS, 2 had MRD-positive blood by NGS at a matched flow cytometry assessment, and 7 were not evaluated by NGS. For the remaining CR/CRi patients, who were MRD-positive by flow cytometry, the 24-month progression-free survival estimate was 86%.
Study participants in the main cohort were adults with a median age of 67 years who had relapsed/refractory CLL with an indication for treatment by iwCLL criteria, del(17p), good performance status, adequate bone marrow function, and creatinine clearance of at least 50 mg/min. They received a single test dose of 20 mg on day 1, with gradual ramp up to 400 mg over 4-5 weeks based on laboratory assessments. All were hospitalized for the first 20 mg and 50 mg venetoclax doses during ramp up.
Those in the safety expansion were treated with once-daily oral venetoclax starting at a dose of 20 mg/day for 1 week and ramped up to 400 mg by week 5. To mitigate TLS risk, uric acid–lowering agents and hydration were started at least 72 hours prior to administering the first dose. Those with high TLS risk – and some with medium risk – were hospitalized for the first 20-mg and 50-mg doses. Those with low TLS risk – and most with medium risk – received initial venetoclax dosing in an outpatient setting.
“Continued follow-up of patients in this trial will provide additional data on the durability of response with venetoclax in patients with del(17p) CLL,” the investigators wrote.
This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.
Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
That response was maintained at 1 year in 85% of participants.
The current findings, which represent data through April 2017 for those 107 patients from the main cohort, as well as for 51 patients in the safety expansion study, show an overall response rate of 77%, with 20% CR/CRi.
The median time to first response was 1 month, and time to CR/CRi was 9.8 months, they said.
Estimates at 24 months for duration of response, progression-free survival, and overall survival were 66%, 54%, and 73%, respectively.
Additionally, objective responses were seen in four of five previously untreated patients who were enrolled in the safety expansion, and two of them had complete remissions. One patient with best response of stable disease decided to discontinue treatment but remained in follow-up with stable disease.
“All patients were alive at the time of analysis and remain progression free,” the investigators wrote.
In 18 patients who received prior B-cell receptor pathway inhibitor (BCRi) therapy, the objective response rate was 61% and the complete remission rate was 11%, with 12-month, progression-free and overall survival estimates of 50% and 54%, respectively.
Treatment-emergent adverse events of any grade occurred in 98% of patients, and led to dosing interruption in 40% and dosing adjustment in 17%. The most common adverse event was neutropenia; grade 3/4 neutropenia occurred in 40% of patients.
Neutropenia lead to a dose reduction in 8% of patients and to treatment interruption in 6% of patients; no discontinuations were reported.
Infections occurred in 81% of 158 patients, and grade 3/4 infections occurred in 23%; these infections were consistent with the underlying disease, the investigators said.
Laboratory tumor lysis syndrome (TLS) occurred in 5% of patients, but there were no episodes of clinical TLS, they said, noting that five TLS patients required dose interruptions. TLS occurred in four patients with medium risk at screening and in four with high risk. All episodes of TLS occurred during initial dosing or ramp-up, and all resolved. Affected patients were able to resume venetoclax with dose escalation to 400 mg/day.
The rate of minimal residual disease negativity was 30% in the intention-to-treat population as demonstrated by flow cytometry and confirmed by next generation sequencing (NGS) in 21 of 29 patients with an evaluable matched time point specimen. Bone marrow MRD negativity was observed in 20 patients by flow cytometry, and in 9 patients by NGS.
When looking at flow cytometry and NGS data combined, the MRD negativity rate in peripheral blood was 25% overall and 40% in evaluable patients, and the MRD negativity rate in bone marrow was 11% overall and 24% in evaluable patients.
Of those who achieved CR/CRi, 69% were MRD negative in peripheral blood by flow cytometry, with a 24-month, progression-free survival estimate of 100%, and 13 of those had confirmed MRD-negative blood by NGS, 2 had MRD-positive blood by NGS at a matched flow cytometry assessment, and 7 were not evaluated by NGS. For the remaining CR/CRi patients, who were MRD-positive by flow cytometry, the 24-month progression-free survival estimate was 86%.
Study participants in the main cohort were adults with a median age of 67 years who had relapsed/refractory CLL with an indication for treatment by iwCLL criteria, del(17p), good performance status, adequate bone marrow function, and creatinine clearance of at least 50 mg/min. They received a single test dose of 20 mg on day 1, with gradual ramp up to 400 mg over 4-5 weeks based on laboratory assessments. All were hospitalized for the first 20 mg and 50 mg venetoclax doses during ramp up.
Those in the safety expansion were treated with once-daily oral venetoclax starting at a dose of 20 mg/day for 1 week and ramped up to 400 mg by week 5. To mitigate TLS risk, uric acid–lowering agents and hydration were started at least 72 hours prior to administering the first dose. Those with high TLS risk – and some with medium risk – were hospitalized for the first 20-mg and 50-mg doses. Those with low TLS risk – and most with medium risk – received initial venetoclax dosing in an outpatient setting.
“Continued follow-up of patients in this trial will provide additional data on the durability of response with venetoclax in patients with del(17p) CLL,” the investigators wrote.
This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.
Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
That response was maintained at 1 year in 85% of participants.
The current findings, which represent data through April 2017 for those 107 patients from the main cohort, as well as for 51 patients in the safety expansion study, show an overall response rate of 77%, with 20% CR/CRi.
The median time to first response was 1 month, and time to CR/CRi was 9.8 months, they said.
Estimates at 24 months for duration of response, progression-free survival, and overall survival were 66%, 54%, and 73%, respectively.
Additionally, objective responses were seen in four of five previously untreated patients who were enrolled in the safety expansion, and two of them had complete remissions. One patient with best response of stable disease decided to discontinue treatment but remained in follow-up with stable disease.
“All patients were alive at the time of analysis and remain progression free,” the investigators wrote.
In 18 patients who received prior B-cell receptor pathway inhibitor (BCRi) therapy, the objective response rate was 61% and the complete remission rate was 11%, with 12-month, progression-free and overall survival estimates of 50% and 54%, respectively.
Treatment-emergent adverse events of any grade occurred in 98% of patients, and led to dosing interruption in 40% and dosing adjustment in 17%. The most common adverse event was neutropenia; grade 3/4 neutropenia occurred in 40% of patients.
Neutropenia lead to a dose reduction in 8% of patients and to treatment interruption in 6% of patients; no discontinuations were reported.
Infections occurred in 81% of 158 patients, and grade 3/4 infections occurred in 23%; these infections were consistent with the underlying disease, the investigators said.
Laboratory tumor lysis syndrome (TLS) occurred in 5% of patients, but there were no episodes of clinical TLS, they said, noting that five TLS patients required dose interruptions. TLS occurred in four patients with medium risk at screening and in four with high risk. All episodes of TLS occurred during initial dosing or ramp-up, and all resolved. Affected patients were able to resume venetoclax with dose escalation to 400 mg/day.
The rate of minimal residual disease negativity was 30% in the intention-to-treat population as demonstrated by flow cytometry and confirmed by next generation sequencing (NGS) in 21 of 29 patients with an evaluable matched time point specimen. Bone marrow MRD negativity was observed in 20 patients by flow cytometry, and in 9 patients by NGS.
When looking at flow cytometry and NGS data combined, the MRD negativity rate in peripheral blood was 25% overall and 40% in evaluable patients, and the MRD negativity rate in bone marrow was 11% overall and 24% in evaluable patients.
Of those who achieved CR/CRi, 69% were MRD negative in peripheral blood by flow cytometry, with a 24-month, progression-free survival estimate of 100%, and 13 of those had confirmed MRD-negative blood by NGS, 2 had MRD-positive blood by NGS at a matched flow cytometry assessment, and 7 were not evaluated by NGS. For the remaining CR/CRi patients, who were MRD-positive by flow cytometry, the 24-month progression-free survival estimate was 86%.
Study participants in the main cohort were adults with a median age of 67 years who had relapsed/refractory CLL with an indication for treatment by iwCLL criteria, del(17p), good performance status, adequate bone marrow function, and creatinine clearance of at least 50 mg/min. They received a single test dose of 20 mg on day 1, with gradual ramp up to 400 mg over 4-5 weeks based on laboratory assessments. All were hospitalized for the first 20 mg and 50 mg venetoclax doses during ramp up.
Those in the safety expansion were treated with once-daily oral venetoclax starting at a dose of 20 mg/day for 1 week and ramped up to 400 mg by week 5. To mitigate TLS risk, uric acid–lowering agents and hydration were started at least 72 hours prior to administering the first dose. Those with high TLS risk – and some with medium risk – were hospitalized for the first 20-mg and 50-mg doses. Those with low TLS risk – and most with medium risk – received initial venetoclax dosing in an outpatient setting.
“Continued follow-up of patients in this trial will provide additional data on the durability of response with venetoclax in patients with del(17p) CLL,” the investigators wrote.
This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
AT THE iwCLL MEETING
Key clinical point:
Major finding: At April 2017 data analysis, the overall response rate was 77% with 20% CR/CRi.
Data source: The phase 2 open-label M13-982 Trial and safety expansion cohort of 158 total patients.
Disclosures: This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
First-line obinutuzumab monotherapy in CLL linked to good response, reduced toxicity
NEW YORK – Obinutuzumab monotherapy was effective for the first-line treatment of chronic lymphocytic leukemia in a small study of patients with a high rate of unmutated immunoglobulin heavy-chain variable region (IGHV) genes.
The overall response rate to obinutuzumab, a type 2 anti-CD20 humanized monoclonal antibody, was 100% in 20 previously untreated patients. Median progression-free survival was 30 months, and no deaths occurred at a median of 23 months follow-up, Nathan D. Gay, MD, reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL).
The good results imply that initial monotherapy may be an alternative approach that limits the toxicity associated with the recommended combination of chlorambucil and obinutuzumab.
At the time of analysis, 3 of the 20 patients (15%) had relapsed, and the mean time to next line therapy was 29 months,” Dr. Gay of Oregon Health & Science University, Portland and his colleagues wrote. Minimal residual disease (MRD) analysis completed in 16 patients showed that 5 (31%) were MRD-negative 6 months after the completion of therapy.
Study participants were adults with a median age of 62.5 years and a median cumulative illness rating scale score of 6.5 on the 0-56 scale. Most (80%) had unmutated IGHV and none harbored 17p deletion. All met iwCLL diagnostic criteria for CLL based on peripheral blood counts and flow cytometry,
All but one patient received 6 cycles of intravenous obinutuzumab given at 100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15 of the first cycle, and 1000 mg on day 1 for cycles 2-6.
The remaining patient discontinued treatment after two cycles because of grade 4 neutropenia.
Obinutuzumab is approved for use in combination with oral chlorambucil in patients with previously untreated CLL. The approval was based on the CLL11 study, which demonstrated improved overall response, complete response rate, and peripheral blood MRD negativity rates with obinutuzumab plus chlorambucil, vs. rituximab plus chlorambucil, the authors said. Based on those findings, obinutuzumab plus chlorambucil is considered a standard of care option in treatment-naive CLL lacking del(17p)/TP53 mutation in patients who are not candidates for first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR).
However, while chlorambucil is generally well tolerated, it has limited efficacy and is associated with overall grade 3-4 toxicity of about 44%. Obinutuzumab has significant single-agent activity in previously untreated CLL and was shown in a recent phase 2 dose-response study to be associated with an overall response rate of 49%-67% and complete response rates of 5%-20%, but data on the efficacy of first line obinutuzumab monotherapy using standard dosing outside of a clinical trial are lacking, they said.
The current study represents an analysis of all patients treated with first line obinutuzumab monotherapy at Oregon Health & Science University.
In the current study, the most common side effects were infusion reactions and cytopenias. Grade 3 or higher neutropenia, anemia, and thrombocytopenia occurred in 32%, 11%, and 32% of patients, respectively, and one patient developed a grade 3 infection.
“In our cohort of patients with untreated CLL, we found first line obinutuzumab monotherapy to be very effective and well tolerated,” they wrote, noting that this was true despite a high rate of unmutated IGHV. “These data, using first-line obinutuzumab monotherapy, compare favorably with combination therapy with chlorambucil.
“Omitting chlorambucil from this combination in favor of initial obinutuzumab monotherapy may eliminate the short- and long-term toxicity associated with the use of chemotherapy,” they concluded.
The authors reported having no disclosures.
NEW YORK – Obinutuzumab monotherapy was effective for the first-line treatment of chronic lymphocytic leukemia in a small study of patients with a high rate of unmutated immunoglobulin heavy-chain variable region (IGHV) genes.
The overall response rate to obinutuzumab, a type 2 anti-CD20 humanized monoclonal antibody, was 100% in 20 previously untreated patients. Median progression-free survival was 30 months, and no deaths occurred at a median of 23 months follow-up, Nathan D. Gay, MD, reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL).
The good results imply that initial monotherapy may be an alternative approach that limits the toxicity associated with the recommended combination of chlorambucil and obinutuzumab.
At the time of analysis, 3 of the 20 patients (15%) had relapsed, and the mean time to next line therapy was 29 months,” Dr. Gay of Oregon Health & Science University, Portland and his colleagues wrote. Minimal residual disease (MRD) analysis completed in 16 patients showed that 5 (31%) were MRD-negative 6 months after the completion of therapy.
Study participants were adults with a median age of 62.5 years and a median cumulative illness rating scale score of 6.5 on the 0-56 scale. Most (80%) had unmutated IGHV and none harbored 17p deletion. All met iwCLL diagnostic criteria for CLL based on peripheral blood counts and flow cytometry,
All but one patient received 6 cycles of intravenous obinutuzumab given at 100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15 of the first cycle, and 1000 mg on day 1 for cycles 2-6.
The remaining patient discontinued treatment after two cycles because of grade 4 neutropenia.
Obinutuzumab is approved for use in combination with oral chlorambucil in patients with previously untreated CLL. The approval was based on the CLL11 study, which demonstrated improved overall response, complete response rate, and peripheral blood MRD negativity rates with obinutuzumab plus chlorambucil, vs. rituximab plus chlorambucil, the authors said. Based on those findings, obinutuzumab plus chlorambucil is considered a standard of care option in treatment-naive CLL lacking del(17p)/TP53 mutation in patients who are not candidates for first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR).
However, while chlorambucil is generally well tolerated, it has limited efficacy and is associated with overall grade 3-4 toxicity of about 44%. Obinutuzumab has significant single-agent activity in previously untreated CLL and was shown in a recent phase 2 dose-response study to be associated with an overall response rate of 49%-67% and complete response rates of 5%-20%, but data on the efficacy of first line obinutuzumab monotherapy using standard dosing outside of a clinical trial are lacking, they said.
The current study represents an analysis of all patients treated with first line obinutuzumab monotherapy at Oregon Health & Science University.
In the current study, the most common side effects were infusion reactions and cytopenias. Grade 3 or higher neutropenia, anemia, and thrombocytopenia occurred in 32%, 11%, and 32% of patients, respectively, and one patient developed a grade 3 infection.
“In our cohort of patients with untreated CLL, we found first line obinutuzumab monotherapy to be very effective and well tolerated,” they wrote, noting that this was true despite a high rate of unmutated IGHV. “These data, using first-line obinutuzumab monotherapy, compare favorably with combination therapy with chlorambucil.
“Omitting chlorambucil from this combination in favor of initial obinutuzumab monotherapy may eliminate the short- and long-term toxicity associated with the use of chemotherapy,” they concluded.
The authors reported having no disclosures.
NEW YORK – Obinutuzumab monotherapy was effective for the first-line treatment of chronic lymphocytic leukemia in a small study of patients with a high rate of unmutated immunoglobulin heavy-chain variable region (IGHV) genes.
The overall response rate to obinutuzumab, a type 2 anti-CD20 humanized monoclonal antibody, was 100% in 20 previously untreated patients. Median progression-free survival was 30 months, and no deaths occurred at a median of 23 months follow-up, Nathan D. Gay, MD, reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL).
The good results imply that initial monotherapy may be an alternative approach that limits the toxicity associated with the recommended combination of chlorambucil and obinutuzumab.
At the time of analysis, 3 of the 20 patients (15%) had relapsed, and the mean time to next line therapy was 29 months,” Dr. Gay of Oregon Health & Science University, Portland and his colleagues wrote. Minimal residual disease (MRD) analysis completed in 16 patients showed that 5 (31%) were MRD-negative 6 months after the completion of therapy.
Study participants were adults with a median age of 62.5 years and a median cumulative illness rating scale score of 6.5 on the 0-56 scale. Most (80%) had unmutated IGHV and none harbored 17p deletion. All met iwCLL diagnostic criteria for CLL based on peripheral blood counts and flow cytometry,
All but one patient received 6 cycles of intravenous obinutuzumab given at 100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15 of the first cycle, and 1000 mg on day 1 for cycles 2-6.
The remaining patient discontinued treatment after two cycles because of grade 4 neutropenia.
Obinutuzumab is approved for use in combination with oral chlorambucil in patients with previously untreated CLL. The approval was based on the CLL11 study, which demonstrated improved overall response, complete response rate, and peripheral blood MRD negativity rates with obinutuzumab plus chlorambucil, vs. rituximab plus chlorambucil, the authors said. Based on those findings, obinutuzumab plus chlorambucil is considered a standard of care option in treatment-naive CLL lacking del(17p)/TP53 mutation in patients who are not candidates for first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR).
However, while chlorambucil is generally well tolerated, it has limited efficacy and is associated with overall grade 3-4 toxicity of about 44%. Obinutuzumab has significant single-agent activity in previously untreated CLL and was shown in a recent phase 2 dose-response study to be associated with an overall response rate of 49%-67% and complete response rates of 5%-20%, but data on the efficacy of first line obinutuzumab monotherapy using standard dosing outside of a clinical trial are lacking, they said.
The current study represents an analysis of all patients treated with first line obinutuzumab monotherapy at Oregon Health & Science University.
In the current study, the most common side effects were infusion reactions and cytopenias. Grade 3 or higher neutropenia, anemia, and thrombocytopenia occurred in 32%, 11%, and 32% of patients, respectively, and one patient developed a grade 3 infection.
“In our cohort of patients with untreated CLL, we found first line obinutuzumab monotherapy to be very effective and well tolerated,” they wrote, noting that this was true despite a high rate of unmutated IGHV. “These data, using first-line obinutuzumab monotherapy, compare favorably with combination therapy with chlorambucil.
“Omitting chlorambucil from this combination in favor of initial obinutuzumab monotherapy may eliminate the short- and long-term toxicity associated with the use of chemotherapy,” they concluded.
The authors reported having no disclosures.
AT THE iwCLL MEETING
Key clinical point:
Major finding: Overall response rate, 100%; median progression-free survival, 30 months.
Data source: A study of 20 patients treated with obinutuzumab monotherapy.
Disclosures: The authors reported having no disclosures.
NF-kB inhibitor IT-901 shows promise in Richter syndrome
NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.
The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.
In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”
That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”
“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”
The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.
Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).
For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.
In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.
Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.
IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.
These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.
The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.
Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.
The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.
Dr. Vaisitti has received research funding from Immune Target.
NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.
The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.
In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”
That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”
“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”
The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.
Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).
For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.
In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.
Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.
IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.
These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.
The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.
Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.
The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.
Dr. Vaisitti has received research funding from Immune Target.
NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.
The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.
In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”
That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”
“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”
The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.
Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).
For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.
In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.
Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.
IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.
These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.
The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.
Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.
The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.
Dr. Vaisitti has received research funding from Immune Target.
AT THE iwCLL MEETING
Key clinical point:
Major finding: IT-901 induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.
Data source: In vitro and in vivo analyses.
Disclosures: Dr. Vaisitti has received research funding from Immune Target.
Telomere length predicts FCR response in CLL patients
NEW YORK – Telomere length reliably predicts response to fludarabine-cyclophosphamide-rituximab (FCR) treatment in patients with chronic lymphocytic leukemia, according to an analysis of 278 samples from the ARCTIC and ADMIRE clinical trials of FCR in previously untreated CLL.
The findings were particularly pronounced in the immunoglobulin heavy-chain variable region gene (IGHV)–mutated patients and suggest a role for telomere measurement as a predictive tool in risk-adapted clinical trials, Kevin Norris reported in a poster at the annual International Workshop on Chronic Lymphocytic Leukemia.
Short telomere length was associated with quicker time to progression (median of 3.9 years vs. 5.5 years; hazard ratio[HR], 2.04) and reduced overall survival (OS) (median of 5.5 years vs. OS not reached; HR, 2.1), compared with long telomere length. IGHV-mutated patients with short telomeres were more than five times more likely to relapse (median progression-free survival 2.97 vs. PFS not reached; HR, 5.1), and more than four times more likely to die than were patients with long telomere length (median OS, 4.15 years vs. OS not reached; HR, 4.16), said Mr. Norris, a research associate at Cardiff (Wales) University.
The association between telomere length and FCR response was less pronounced among IGHV-unmutated patients, but those with short telomeres in this group still had an inferior response and shorter survival, compared with those with long telomeres (HR, 1.6 and 1.6, respectively), he noted.
Mr. Norris also noted that in contrast to the telomere length findings, CD38 expression and b2-microglobulin were not predictive of time to progression or OS.
“In multivariate analysis, telomere length was the dominant covariable for both PFS (HR, 2.58) and OS (HR, 2.84); when telomere length was entered into the model no other variable retained independent prognostic significance,” he and his colleagues wrote.
Telomere length in this analysis was assessed by use of the high throughput single telomere length analysis (HT-STELA) assay.
It has recently been shown that a proportion of IGHV-mutated CLL patients treated with FCR can achieve long-term remissions. The current findings demonstrate that these patients can be accurately identified by measuring telomere length, the investigators said, noting that they saw a similar pattern in patients in the UK CLL4 trial who were treated with fludarabine and cyclophosphamide
“Our results demonstrate that telomere length is the major determinant of response and survival following treatment with FCR,” they wrote. “IGHV-mutated patients with longer telomeres have a high probability of achieving a long-term remission following treatment with FCR (greater than 81% survival after 5 years). Equally, IGHV-mutated patients with short dysfunctional telomeres show a markedly inferior response to FCR and should be considered for alternative treatment options in the frontline setting.”
Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.
NEW YORK – Telomere length reliably predicts response to fludarabine-cyclophosphamide-rituximab (FCR) treatment in patients with chronic lymphocytic leukemia, according to an analysis of 278 samples from the ARCTIC and ADMIRE clinical trials of FCR in previously untreated CLL.
The findings were particularly pronounced in the immunoglobulin heavy-chain variable region gene (IGHV)–mutated patients and suggest a role for telomere measurement as a predictive tool in risk-adapted clinical trials, Kevin Norris reported in a poster at the annual International Workshop on Chronic Lymphocytic Leukemia.
Short telomere length was associated with quicker time to progression (median of 3.9 years vs. 5.5 years; hazard ratio[HR], 2.04) and reduced overall survival (OS) (median of 5.5 years vs. OS not reached; HR, 2.1), compared with long telomere length. IGHV-mutated patients with short telomeres were more than five times more likely to relapse (median progression-free survival 2.97 vs. PFS not reached; HR, 5.1), and more than four times more likely to die than were patients with long telomere length (median OS, 4.15 years vs. OS not reached; HR, 4.16), said Mr. Norris, a research associate at Cardiff (Wales) University.
The association between telomere length and FCR response was less pronounced among IGHV-unmutated patients, but those with short telomeres in this group still had an inferior response and shorter survival, compared with those with long telomeres (HR, 1.6 and 1.6, respectively), he noted.
Mr. Norris also noted that in contrast to the telomere length findings, CD38 expression and b2-microglobulin were not predictive of time to progression or OS.
“In multivariate analysis, telomere length was the dominant covariable for both PFS (HR, 2.58) and OS (HR, 2.84); when telomere length was entered into the model no other variable retained independent prognostic significance,” he and his colleagues wrote.
Telomere length in this analysis was assessed by use of the high throughput single telomere length analysis (HT-STELA) assay.
It has recently been shown that a proportion of IGHV-mutated CLL patients treated with FCR can achieve long-term remissions. The current findings demonstrate that these patients can be accurately identified by measuring telomere length, the investigators said, noting that they saw a similar pattern in patients in the UK CLL4 trial who were treated with fludarabine and cyclophosphamide
“Our results demonstrate that telomere length is the major determinant of response and survival following treatment with FCR,” they wrote. “IGHV-mutated patients with longer telomeres have a high probability of achieving a long-term remission following treatment with FCR (greater than 81% survival after 5 years). Equally, IGHV-mutated patients with short dysfunctional telomeres show a markedly inferior response to FCR and should be considered for alternative treatment options in the frontline setting.”
Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.
NEW YORK – Telomere length reliably predicts response to fludarabine-cyclophosphamide-rituximab (FCR) treatment in patients with chronic lymphocytic leukemia, according to an analysis of 278 samples from the ARCTIC and ADMIRE clinical trials of FCR in previously untreated CLL.
The findings were particularly pronounced in the immunoglobulin heavy-chain variable region gene (IGHV)–mutated patients and suggest a role for telomere measurement as a predictive tool in risk-adapted clinical trials, Kevin Norris reported in a poster at the annual International Workshop on Chronic Lymphocytic Leukemia.
Short telomere length was associated with quicker time to progression (median of 3.9 years vs. 5.5 years; hazard ratio[HR], 2.04) and reduced overall survival (OS) (median of 5.5 years vs. OS not reached; HR, 2.1), compared with long telomere length. IGHV-mutated patients with short telomeres were more than five times more likely to relapse (median progression-free survival 2.97 vs. PFS not reached; HR, 5.1), and more than four times more likely to die than were patients with long telomere length (median OS, 4.15 years vs. OS not reached; HR, 4.16), said Mr. Norris, a research associate at Cardiff (Wales) University.
The association between telomere length and FCR response was less pronounced among IGHV-unmutated patients, but those with short telomeres in this group still had an inferior response and shorter survival, compared with those with long telomeres (HR, 1.6 and 1.6, respectively), he noted.
Mr. Norris also noted that in contrast to the telomere length findings, CD38 expression and b2-microglobulin were not predictive of time to progression or OS.
“In multivariate analysis, telomere length was the dominant covariable for both PFS (HR, 2.58) and OS (HR, 2.84); when telomere length was entered into the model no other variable retained independent prognostic significance,” he and his colleagues wrote.
Telomere length in this analysis was assessed by use of the high throughput single telomere length analysis (HT-STELA) assay.
It has recently been shown that a proportion of IGHV-mutated CLL patients treated with FCR can achieve long-term remissions. The current findings demonstrate that these patients can be accurately identified by measuring telomere length, the investigators said, noting that they saw a similar pattern in patients in the UK CLL4 trial who were treated with fludarabine and cyclophosphamide
“Our results demonstrate that telomere length is the major determinant of response and survival following treatment with FCR,” they wrote. “IGHV-mutated patients with longer telomeres have a high probability of achieving a long-term remission following treatment with FCR (greater than 81% survival after 5 years). Equally, IGHV-mutated patients with short dysfunctional telomeres show a markedly inferior response to FCR and should be considered for alternative treatment options in the frontline setting.”
Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.
AT THE iwCLL MEETING
Key clinical point:
Major finding: Short vs. long telomere length was associated with quicker time to progression and reduced overall survival (hazard ratios, 2.04 and 2.1, respectively).
Data source: An analysis of 278 samples from the ARCTIC and ADMIRE trials.
Disclosures: Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.
NOTCH1 mutation predicts reduced ofatumumab efficacy in CLL
NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.
Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).
The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.
The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.
Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.
“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.
In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.
However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.
CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.
Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).
Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.
With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).
This effect was not explained by CD20 expression levels, Dr. Tausch said.
The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.
“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.
Dr. Tausch reported receiving research support from Novartis.
NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.
Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).
The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.
The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.
Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.
“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.
In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.
However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.
CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.
Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).
Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.
With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).
This effect was not explained by CD20 expression levels, Dr. Tausch said.
The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.
“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.
Dr. Tausch reported receiving research support from Novartis.
NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.
Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).
The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.
The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.
Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.
“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.
In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.
However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.
CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.
Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).
Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.
With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).
This effect was not explained by CD20 expression levels, Dr. Tausch said.
The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.
“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.
Dr. Tausch reported receiving research support from Novartis.
AT iwCLL MEETING
Key clinical point:
Major finding: Ofatumumab was beneficial in patients with NOTCH1 wild-type, but not in patients with NOTCH1 mutation (hazard ratios, 0.64 and 0.86, respectively).
Data source: A mutation analysis of 325 DNA samples from patients in the phase III COMPLEMENT 2 trial.
Disclosures: Dr. Tausch reported receiving research support from Novartis.
iFCG achieves high MRD-negative remission in untreated CLL
NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.
NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.
NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.
AT THE IWCLL MEETING
Key clinical point:
Major finding: The overall response rate was 100%, and 83% of patients achieved MRD-negativity after three courses.
Data source: 29 patients from an investigator-initiated phase II trial.
Disclosures: Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis, Novimmune, and Adaptive Biotechnologies.
ECG finding predicts AFib in ibrutinib-treated CLL
NEW YORK – A left atrial abnormality on a pretreatment electrocardiogram (ECG) is a moderately specific and sensitive finding that independently predicts risk for developing atrial fibrillation in chronic lymphocytic leukemia patients starting on ibrutinib, findings from a retrospective cohort study indicate.
ECGs are inexpensive and available in most physician’s offices. Routinely checking for a left atrial abnormality before starting ibrutinib would identify a patient subgroup that would benefit from increased monitoring and allow for proactive intervention strategies to reduce complications should atrial fibrillation develop, Anthony Mato, MD, said at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
Prior studies, including the RESONATE and RESONATE 2 trials, have clearly demonstrated a link between ibrutinib exposure and the development of AFib. Long-term follow-up data suggest an estimated incidence of 9% to 11%.
Dr. Mato and his colleagues used a case-control design within a two-center retrospective cohort study to test the hypothesis that pre-ibrutinib left atrial abnormality, as determined by the ECG, can identify patients at increased risk for AFib during ibrutinib-based therapy.
Of 153 consecutive CLL patients who were treated with ibrutinib 420 mg/day, 11% developed new AFib at a median of 7 months after starting treatment. Discontinuation of ibrutinib because of AFib was low, with less than 2% of the entire cohort discontinuing treatment.
Based on findings in 20 case patients and 24 controls with an available pretreatment ECG, the presence of a left atrial abnormality before ibrutinib therapy was associated with a nine times increased risk of subsequently developing AFib.
“We looked at baseline hypertension, coronary disease, diabetes, age, and sex, and, although hypertension, coronary disease, and age appeared to have some effect, they weren’t as significant as left atrial abnormality” for predicting risk of AFib, Dr. Mato noted.
On multivariate analysis, controlling for hypertension, coronary disease, and age, a left atrial abnormality continued to be a significant predictor of AFib (odds ratio, 6.6).
“We then wanted to make this more practical for clinicians who may potentially perform an ECG to estimate risk,” he said, noting that ECG test characteristics associated with left atrial abnormality were defined: Sensitivity was estimated to be 79%, specificity was 71%, positive and negative likelihood ratios were 2.7 and 0.3, respectively. Positive predictive value was 68%, and negative predictive value was 81%.
The area under the ROC curve for this single predictor was 75%, he said.
The median age of the cohort at CLL diagnosis was 61 years, and the median age at ibrutinib start was 70. Patients had undergone a median of 2 prior lines of therapy, and 87% were treated in the relapsed/refractory setting.
The median follow-up was 17 months, and the median time from CLL diagnosis to the start of ibrutinib was 73 months.
Cardiovascular characteristics prior to treatment included smoking or former smoking in 49%, hypertension in 42%, hyperlipidemia in 39%, diabetes in 17%, coronary artery disease in 12%, and valvular heart disease in 5%.
Controls were matched to cases on baseline characteristics, and only those with no pretreatment history of AFib, a pretreatment ECG, and therapeutic ibrutinib dosing (420 mg/day for at least 4 months) were included.
To minimize bias, all ECGs were reviewed by a cardio-oncologist blinded to clinical outcomes.
The findings need prospective validation, as they are limited by the retrospective study design, lack of balance with respect to cardiovascular characteristics among cases and controls, a small number of atrial fibrillation cases, and variable timing of pre-ibrutinib ECG, he said.
Patients should be educated about the signs and symptoms of AFib. “The development of AFib during ibrutinib treatment should not prevent its continuation. These patients should be managed medically,” he added.
Dr. Mato reported having no disclosures.
NEW YORK – A left atrial abnormality on a pretreatment electrocardiogram (ECG) is a moderately specific and sensitive finding that independently predicts risk for developing atrial fibrillation in chronic lymphocytic leukemia patients starting on ibrutinib, findings from a retrospective cohort study indicate.
ECGs are inexpensive and available in most physician’s offices. Routinely checking for a left atrial abnormality before starting ibrutinib would identify a patient subgroup that would benefit from increased monitoring and allow for proactive intervention strategies to reduce complications should atrial fibrillation develop, Anthony Mato, MD, said at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
Prior studies, including the RESONATE and RESONATE 2 trials, have clearly demonstrated a link between ibrutinib exposure and the development of AFib. Long-term follow-up data suggest an estimated incidence of 9% to 11%.
Dr. Mato and his colleagues used a case-control design within a two-center retrospective cohort study to test the hypothesis that pre-ibrutinib left atrial abnormality, as determined by the ECG, can identify patients at increased risk for AFib during ibrutinib-based therapy.
Of 153 consecutive CLL patients who were treated with ibrutinib 420 mg/day, 11% developed new AFib at a median of 7 months after starting treatment. Discontinuation of ibrutinib because of AFib was low, with less than 2% of the entire cohort discontinuing treatment.
Based on findings in 20 case patients and 24 controls with an available pretreatment ECG, the presence of a left atrial abnormality before ibrutinib therapy was associated with a nine times increased risk of subsequently developing AFib.
“We looked at baseline hypertension, coronary disease, diabetes, age, and sex, and, although hypertension, coronary disease, and age appeared to have some effect, they weren’t as significant as left atrial abnormality” for predicting risk of AFib, Dr. Mato noted.
On multivariate analysis, controlling for hypertension, coronary disease, and age, a left atrial abnormality continued to be a significant predictor of AFib (odds ratio, 6.6).
“We then wanted to make this more practical for clinicians who may potentially perform an ECG to estimate risk,” he said, noting that ECG test characteristics associated with left atrial abnormality were defined: Sensitivity was estimated to be 79%, specificity was 71%, positive and negative likelihood ratios were 2.7 and 0.3, respectively. Positive predictive value was 68%, and negative predictive value was 81%.
The area under the ROC curve for this single predictor was 75%, he said.
The median age of the cohort at CLL diagnosis was 61 years, and the median age at ibrutinib start was 70. Patients had undergone a median of 2 prior lines of therapy, and 87% were treated in the relapsed/refractory setting.
The median follow-up was 17 months, and the median time from CLL diagnosis to the start of ibrutinib was 73 months.
Cardiovascular characteristics prior to treatment included smoking or former smoking in 49%, hypertension in 42%, hyperlipidemia in 39%, diabetes in 17%, coronary artery disease in 12%, and valvular heart disease in 5%.
Controls were matched to cases on baseline characteristics, and only those with no pretreatment history of AFib, a pretreatment ECG, and therapeutic ibrutinib dosing (420 mg/day for at least 4 months) were included.
To minimize bias, all ECGs were reviewed by a cardio-oncologist blinded to clinical outcomes.
The findings need prospective validation, as they are limited by the retrospective study design, lack of balance with respect to cardiovascular characteristics among cases and controls, a small number of atrial fibrillation cases, and variable timing of pre-ibrutinib ECG, he said.
Patients should be educated about the signs and symptoms of AFib. “The development of AFib during ibrutinib treatment should not prevent its continuation. These patients should be managed medically,” he added.
Dr. Mato reported having no disclosures.
NEW YORK – A left atrial abnormality on a pretreatment electrocardiogram (ECG) is a moderately specific and sensitive finding that independently predicts risk for developing atrial fibrillation in chronic lymphocytic leukemia patients starting on ibrutinib, findings from a retrospective cohort study indicate.
ECGs are inexpensive and available in most physician’s offices. Routinely checking for a left atrial abnormality before starting ibrutinib would identify a patient subgroup that would benefit from increased monitoring and allow for proactive intervention strategies to reduce complications should atrial fibrillation develop, Anthony Mato, MD, said at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
Prior studies, including the RESONATE and RESONATE 2 trials, have clearly demonstrated a link between ibrutinib exposure and the development of AFib. Long-term follow-up data suggest an estimated incidence of 9% to 11%.
Dr. Mato and his colleagues used a case-control design within a two-center retrospective cohort study to test the hypothesis that pre-ibrutinib left atrial abnormality, as determined by the ECG, can identify patients at increased risk for AFib during ibrutinib-based therapy.
Of 153 consecutive CLL patients who were treated with ibrutinib 420 mg/day, 11% developed new AFib at a median of 7 months after starting treatment. Discontinuation of ibrutinib because of AFib was low, with less than 2% of the entire cohort discontinuing treatment.
Based on findings in 20 case patients and 24 controls with an available pretreatment ECG, the presence of a left atrial abnormality before ibrutinib therapy was associated with a nine times increased risk of subsequently developing AFib.
“We looked at baseline hypertension, coronary disease, diabetes, age, and sex, and, although hypertension, coronary disease, and age appeared to have some effect, they weren’t as significant as left atrial abnormality” for predicting risk of AFib, Dr. Mato noted.
On multivariate analysis, controlling for hypertension, coronary disease, and age, a left atrial abnormality continued to be a significant predictor of AFib (odds ratio, 6.6).
“We then wanted to make this more practical for clinicians who may potentially perform an ECG to estimate risk,” he said, noting that ECG test characteristics associated with left atrial abnormality were defined: Sensitivity was estimated to be 79%, specificity was 71%, positive and negative likelihood ratios were 2.7 and 0.3, respectively. Positive predictive value was 68%, and negative predictive value was 81%.
The area under the ROC curve for this single predictor was 75%, he said.
The median age of the cohort at CLL diagnosis was 61 years, and the median age at ibrutinib start was 70. Patients had undergone a median of 2 prior lines of therapy, and 87% were treated in the relapsed/refractory setting.
The median follow-up was 17 months, and the median time from CLL diagnosis to the start of ibrutinib was 73 months.
Cardiovascular characteristics prior to treatment included smoking or former smoking in 49%, hypertension in 42%, hyperlipidemia in 39%, diabetes in 17%, coronary artery disease in 12%, and valvular heart disease in 5%.
Controls were matched to cases on baseline characteristics, and only those with no pretreatment history of AFib, a pretreatment ECG, and therapeutic ibrutinib dosing (420 mg/day for at least 4 months) were included.
To minimize bias, all ECGs were reviewed by a cardio-oncologist blinded to clinical outcomes.
The findings need prospective validation, as they are limited by the retrospective study design, lack of balance with respect to cardiovascular characteristics among cases and controls, a small number of atrial fibrillation cases, and variable timing of pre-ibrutinib ECG, he said.
Patients should be educated about the signs and symptoms of AFib. “The development of AFib during ibrutinib treatment should not prevent its continuation. These patients should be managed medically,” he added.
Dr. Mato reported having no disclosures.
AT THE IWCLL MEETING
Key clinical point:
Major finding: Left atrial abnormality as measured using ECG was a significant predictor of AFIB (adjusted odds ratio, 6.6).
Data source: A case-control study of 44 patients within a retrospective cohort.
Disclosures: Dr. Mato reported having no disclosures.
In good-candidate CLL, don’t wait too long for alloHCT
NEW YORK – Allogeneic hematopoietic stem cell transplantation (alloHCT) using HLA-compatible donors results in excellent long-term progression-free survival in younger high-risk chronic lymphocytic leukemia (CLL) patients, an analysis of data from a European Society for Blood and Marrow Transplantation registry cohort suggests.
AlloHCT may, in some patients, be preferable to sequential targeted therapy, according to Michel van Gelder, MD.
This is especially true for those progressing with Richter’s syndrome, who comprise about one-third of patients, he noted.
“On the other hand, allogeneic stem cell transplantation can induce prolonged progression-free survival,” said Dr. van Gelder of Maastricht (the Netherlands) University Medical Center.
Further, most alloHCT patients become minimal residual disease negative, which predicts prolonged progression-free survival (PFS).
“The down-side, of course, is nonrelapse mortality,” he said, noting that NRM depends on factors such as age, performance status, and HLA match.
In a recent risk factor analysis currently pending publication, he and his colleagues found, in a large group of patients, that age, performance status, remission at time of transplant, donor relationship, HLA and sex match each had an impact on 5-year PFS after alloHCT.
The more risk factors a patient had, the worse the outcome, he said.
Based on current knowledge, the place for alloHCT in CLL treatment is in patients with high-risk cytogenetics. Patients can be treated first with a kinase inhibitor or venetoclax followed by transplant, or they can wait for progression and then do the transplant, he said.
Those without high risk cytogenetics but with short PFS after treatment with a kinase inhibitor or venetoclax may also be candidates for alloHCT, he added.
“Preferably they should be young [and] have a good matched donor and low comorbidity,” he said.
In the current study, the focus was on younger CLL patients. “We tried to identify factors that predict for a low 2-year NRM and a high 8-year PFS. We studied the impact of high risk cytogenetics, and, for this study, we chose del(17p) and del(11q), and we tried to officialize the PFS, the relapse incidence, and the nonrelapse mortality of so-called ‘good transplant risk CLL patients’ with these high cytogenetic risk factors,” he explained.
In 197 patients under age 50 years (median 46 years) with a median follow-up of 90 months in an updated EBMT registry cohort, the most important relevant prognostic factor for 2-year NRM was the donor HLA match (adjusted hazard ratio, 2.5 for a matched unrelated donor, 4.0 for a partially matched unrelated donor, both vs. a matched sibling), and predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio, 1.7), and partially HLA matched unrelated donor (HR, 2.8).
High-risk cytogenetics did not significantly impact 8-year PFS, Dr. van Gelder said, noting that this confirms findings from prior studies.
Most of the patients included in the analysis were fludarabine refractory, 70% had del(17p), 35% had del(11q), and the median number of prior treatments was 3. Additionally, 12% had previous autologous transplant, 62% had remission at time of transplant, and most had good performance status, he said.
Conditioning regimens varied by site, 42% of patients had an HLA-matched sibling donor, and 50% had a matched unrelated donor.
Based on the regression model, a reference patient with high risk cytogenetics (del[17p] and/or del[11q]) and good transplant characteristics (age 46 years, no prior autologous stem cell transplantation, remission at the time of alloHCT and HLA- and sex-matched sibling donor) was created. A reference patient with poor transplant characteristics (not in remission at the time of transplant, with an unrelated, non-sex-matched donor) was also created. The predicted 2-year NRM for the good transplant risk patient was 12.1%, and 8-year PFS was more than 50%, Dr. van Gelder said.
For the poor risk patient, 2-year NRM was 37%, and PFS was below 50%, he said.
“So, in conclusion ... good transplant risk young patients with a low nonrelapse mortality and high 8-year progression-free survival can be identified,” he said.
The problem in clinical practice is determining whether – and when – to do a transplant in a young patient, he continued.
“There are a lot of possibilities. Nobody knows, of course, what is the best regimen, but a problem in these patients is that, if they have progression with Richter’s transformation, then you are lost,” he said. “So, if you would like to prevent this, and you have a patient with a low nonrelapse mortality risk, maybe it is better to do the transplant before.”
As for whether alloHCT can be done after kinase inhibitor therapy, the data are limited, but data presented at EBMT 2017 suggest the approach is feasible and effective. In 43 younger patients who underwent alloHCT after ibrutinib treatment, including 37% with TP53 mutation, the 1-year NRM and PFS rates were 9% and 63%, which is “in the same range as in the era before kinase inhibitors,” Dr. van Gelder said regarding the abstract presented by Peter Dreger, MD.
In 32 patients who underwent alloHCT after idelalisib treatment, including 44% with del(17p)/del(11q) and 85% in remission at the time of alloHCT, early follow-up showed that 6-month NRM and PFS was 7% and 83%, respectively, according to another abstract presented by Johannes Schetelig, MD.
“It’s all about balancing the risks. On the one hand you can use sequential therapies. On the other, if you have patients with high-risk cytogenetics [and] CLL in remission and you have a well-matched donor, maybe you should consider the transplant earlier, Dr. van Gelder said. “If you have a good transplant patient in remission, I would propose [that you] don’t wait too long.”
Dr. van Gelder reported having no relevant disclosures.
NEW YORK – Allogeneic hematopoietic stem cell transplantation (alloHCT) using HLA-compatible donors results in excellent long-term progression-free survival in younger high-risk chronic lymphocytic leukemia (CLL) patients, an analysis of data from a European Society for Blood and Marrow Transplantation registry cohort suggests.
AlloHCT may, in some patients, be preferable to sequential targeted therapy, according to Michel van Gelder, MD.
This is especially true for those progressing with Richter’s syndrome, who comprise about one-third of patients, he noted.
“On the other hand, allogeneic stem cell transplantation can induce prolonged progression-free survival,” said Dr. van Gelder of Maastricht (the Netherlands) University Medical Center.
Further, most alloHCT patients become minimal residual disease negative, which predicts prolonged progression-free survival (PFS).
“The down-side, of course, is nonrelapse mortality,” he said, noting that NRM depends on factors such as age, performance status, and HLA match.
In a recent risk factor analysis currently pending publication, he and his colleagues found, in a large group of patients, that age, performance status, remission at time of transplant, donor relationship, HLA and sex match each had an impact on 5-year PFS after alloHCT.
The more risk factors a patient had, the worse the outcome, he said.
Based on current knowledge, the place for alloHCT in CLL treatment is in patients with high-risk cytogenetics. Patients can be treated first with a kinase inhibitor or venetoclax followed by transplant, or they can wait for progression and then do the transplant, he said.
Those without high risk cytogenetics but with short PFS after treatment with a kinase inhibitor or venetoclax may also be candidates for alloHCT, he added.
“Preferably they should be young [and] have a good matched donor and low comorbidity,” he said.
In the current study, the focus was on younger CLL patients. “We tried to identify factors that predict for a low 2-year NRM and a high 8-year PFS. We studied the impact of high risk cytogenetics, and, for this study, we chose del(17p) and del(11q), and we tried to officialize the PFS, the relapse incidence, and the nonrelapse mortality of so-called ‘good transplant risk CLL patients’ with these high cytogenetic risk factors,” he explained.
In 197 patients under age 50 years (median 46 years) with a median follow-up of 90 months in an updated EBMT registry cohort, the most important relevant prognostic factor for 2-year NRM was the donor HLA match (adjusted hazard ratio, 2.5 for a matched unrelated donor, 4.0 for a partially matched unrelated donor, both vs. a matched sibling), and predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio, 1.7), and partially HLA matched unrelated donor (HR, 2.8).
High-risk cytogenetics did not significantly impact 8-year PFS, Dr. van Gelder said, noting that this confirms findings from prior studies.
Most of the patients included in the analysis were fludarabine refractory, 70% had del(17p), 35% had del(11q), and the median number of prior treatments was 3. Additionally, 12% had previous autologous transplant, 62% had remission at time of transplant, and most had good performance status, he said.
Conditioning regimens varied by site, 42% of patients had an HLA-matched sibling donor, and 50% had a matched unrelated donor.
Based on the regression model, a reference patient with high risk cytogenetics (del[17p] and/or del[11q]) and good transplant characteristics (age 46 years, no prior autologous stem cell transplantation, remission at the time of alloHCT and HLA- and sex-matched sibling donor) was created. A reference patient with poor transplant characteristics (not in remission at the time of transplant, with an unrelated, non-sex-matched donor) was also created. The predicted 2-year NRM for the good transplant risk patient was 12.1%, and 8-year PFS was more than 50%, Dr. van Gelder said.
For the poor risk patient, 2-year NRM was 37%, and PFS was below 50%, he said.
“So, in conclusion ... good transplant risk young patients with a low nonrelapse mortality and high 8-year progression-free survival can be identified,” he said.
The problem in clinical practice is determining whether – and when – to do a transplant in a young patient, he continued.
“There are a lot of possibilities. Nobody knows, of course, what is the best regimen, but a problem in these patients is that, if they have progression with Richter’s transformation, then you are lost,” he said. “So, if you would like to prevent this, and you have a patient with a low nonrelapse mortality risk, maybe it is better to do the transplant before.”
As for whether alloHCT can be done after kinase inhibitor therapy, the data are limited, but data presented at EBMT 2017 suggest the approach is feasible and effective. In 43 younger patients who underwent alloHCT after ibrutinib treatment, including 37% with TP53 mutation, the 1-year NRM and PFS rates were 9% and 63%, which is “in the same range as in the era before kinase inhibitors,” Dr. van Gelder said regarding the abstract presented by Peter Dreger, MD.
In 32 patients who underwent alloHCT after idelalisib treatment, including 44% with del(17p)/del(11q) and 85% in remission at the time of alloHCT, early follow-up showed that 6-month NRM and PFS was 7% and 83%, respectively, according to another abstract presented by Johannes Schetelig, MD.
“It’s all about balancing the risks. On the one hand you can use sequential therapies. On the other, if you have patients with high-risk cytogenetics [and] CLL in remission and you have a well-matched donor, maybe you should consider the transplant earlier, Dr. van Gelder said. “If you have a good transplant patient in remission, I would propose [that you] don’t wait too long.”
Dr. van Gelder reported having no relevant disclosures.
NEW YORK – Allogeneic hematopoietic stem cell transplantation (alloHCT) using HLA-compatible donors results in excellent long-term progression-free survival in younger high-risk chronic lymphocytic leukemia (CLL) patients, an analysis of data from a European Society for Blood and Marrow Transplantation registry cohort suggests.
AlloHCT may, in some patients, be preferable to sequential targeted therapy, according to Michel van Gelder, MD.
This is especially true for those progressing with Richter’s syndrome, who comprise about one-third of patients, he noted.
“On the other hand, allogeneic stem cell transplantation can induce prolonged progression-free survival,” said Dr. van Gelder of Maastricht (the Netherlands) University Medical Center.
Further, most alloHCT patients become minimal residual disease negative, which predicts prolonged progression-free survival (PFS).
“The down-side, of course, is nonrelapse mortality,” he said, noting that NRM depends on factors such as age, performance status, and HLA match.
In a recent risk factor analysis currently pending publication, he and his colleagues found, in a large group of patients, that age, performance status, remission at time of transplant, donor relationship, HLA and sex match each had an impact on 5-year PFS after alloHCT.
The more risk factors a patient had, the worse the outcome, he said.
Based on current knowledge, the place for alloHCT in CLL treatment is in patients with high-risk cytogenetics. Patients can be treated first with a kinase inhibitor or venetoclax followed by transplant, or they can wait for progression and then do the transplant, he said.
Those without high risk cytogenetics but with short PFS after treatment with a kinase inhibitor or venetoclax may also be candidates for alloHCT, he added.
“Preferably they should be young [and] have a good matched donor and low comorbidity,” he said.
In the current study, the focus was on younger CLL patients. “We tried to identify factors that predict for a low 2-year NRM and a high 8-year PFS. We studied the impact of high risk cytogenetics, and, for this study, we chose del(17p) and del(11q), and we tried to officialize the PFS, the relapse incidence, and the nonrelapse mortality of so-called ‘good transplant risk CLL patients’ with these high cytogenetic risk factors,” he explained.
In 197 patients under age 50 years (median 46 years) with a median follow-up of 90 months in an updated EBMT registry cohort, the most important relevant prognostic factor for 2-year NRM was the donor HLA match (adjusted hazard ratio, 2.5 for a matched unrelated donor, 4.0 for a partially matched unrelated donor, both vs. a matched sibling), and predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio, 1.7), and partially HLA matched unrelated donor (HR, 2.8).
High-risk cytogenetics did not significantly impact 8-year PFS, Dr. van Gelder said, noting that this confirms findings from prior studies.
Most of the patients included in the analysis were fludarabine refractory, 70% had del(17p), 35% had del(11q), and the median number of prior treatments was 3. Additionally, 12% had previous autologous transplant, 62% had remission at time of transplant, and most had good performance status, he said.
Conditioning regimens varied by site, 42% of patients had an HLA-matched sibling donor, and 50% had a matched unrelated donor.
Based on the regression model, a reference patient with high risk cytogenetics (del[17p] and/or del[11q]) and good transplant characteristics (age 46 years, no prior autologous stem cell transplantation, remission at the time of alloHCT and HLA- and sex-matched sibling donor) was created. A reference patient with poor transplant characteristics (not in remission at the time of transplant, with an unrelated, non-sex-matched donor) was also created. The predicted 2-year NRM for the good transplant risk patient was 12.1%, and 8-year PFS was more than 50%, Dr. van Gelder said.
For the poor risk patient, 2-year NRM was 37%, and PFS was below 50%, he said.
“So, in conclusion ... good transplant risk young patients with a low nonrelapse mortality and high 8-year progression-free survival can be identified,” he said.
The problem in clinical practice is determining whether – and when – to do a transplant in a young patient, he continued.
“There are a lot of possibilities. Nobody knows, of course, what is the best regimen, but a problem in these patients is that, if they have progression with Richter’s transformation, then you are lost,” he said. “So, if you would like to prevent this, and you have a patient with a low nonrelapse mortality risk, maybe it is better to do the transplant before.”
As for whether alloHCT can be done after kinase inhibitor therapy, the data are limited, but data presented at EBMT 2017 suggest the approach is feasible and effective. In 43 younger patients who underwent alloHCT after ibrutinib treatment, including 37% with TP53 mutation, the 1-year NRM and PFS rates were 9% and 63%, which is “in the same range as in the era before kinase inhibitors,” Dr. van Gelder said regarding the abstract presented by Peter Dreger, MD.
In 32 patients who underwent alloHCT after idelalisib treatment, including 44% with del(17p)/del(11q) and 85% in remission at the time of alloHCT, early follow-up showed that 6-month NRM and PFS was 7% and 83%, respectively, according to another abstract presented by Johannes Schetelig, MD.
“It’s all about balancing the risks. On the one hand you can use sequential therapies. On the other, if you have patients with high-risk cytogenetics [and] CLL in remission and you have a well-matched donor, maybe you should consider the transplant earlier, Dr. van Gelder said. “If you have a good transplant patient in remission, I would propose [that you] don’t wait too long.”
Dr. van Gelder reported having no relevant disclosures.
AT THE IWCLL MEETING
Key clinical point:
Major finding: The predicted 2-year nonrelapse mortality was 12.1% for a patient who is a good transplant risk and predicted 8-year PFS was more than 50%.
Data source: An analysis of updated registry data for 197 patients.
Disclosures: Dr. van Gelder reported having no relevant disclosures
Ibrutinib response in CLL/SLL less affected by select risk factors
NEW YORK – Risk factors associated with poor outcomes in chronic lymphocytic leukemia/small lymphocytic leukemia patients treated with standard therapies appear to have less relevance with ibrutinib treatment, according to an integrated analysis of data from the randomized, phase III RESONATE, RESONATE 2, and HELIOS trials.
In the combined analysis, at a median follow-up of 21 months, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and complete response rate (CRR) were better in ibrutinib-treated patients than in comparator-treated patients – and, in the ibrutinib-treated patients, the outcomes did not differ based on the adverse genomic factors examined, Thomas J. Kipps, MD, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The trials compared well with each other, but differed in terms of number of prior therapies received by patients, he said. Furthermore, the analysis did not examine the effect of del(17p); patients with that deletion were included only in the RESONATE trial.
In RESONATE, ibrutinib was superior to ofatumumab in relapsed/refractory CLL/SLL. In RESONATE 2, ibrutinib was superior to chlorambucil in treatment-naive patients with CLL/SLL. In HELIOS, ibrutinib with bendamustine/rituximab was superior to placebo with bendamustine/rituximab in patients with relapsed/refractory CLL/SLL.
In the new multivariate analysis of the pooled data from these trials – adjusting for the four genomic risk factors and age, sex, ECOG performance status, cytopenia, lactate dehydrogenase (LDH), bulky disease, and number of prior therapies – only having had one or more vs. no prior therapies, and having two or more vs. one prior therapies was associated with shorter PFS and OS in ibrutinib-treated patients, with a trend toward significance.
In comparator-treated patients, however, unmutated IGHV, del(11q), complex karyotype, male sex, two or more prior therapies, and bulky disease all were associated with significantly shorter PFS. Complex karyotype, male sex, bulky disease, ECOG performance status greater than 1, and elevated LDH were associated with significantly shorter OS.
“We need to debate on what the significance of this is and how that can be incorporated into our idea about first-line therapies,” said Dr. Kipps, who was an investigator in both RESONATE trials and is a professor of medicine at the University of California, San Diego.
In univariate analysis of data from ibrutinib-treated patients, unmutated IGHV, del(11q), trisomy 12, and complex karyotype were generally not associated with shorter PFS, OS, or lower ORR or CRR.
Overall survival with and without unmutated IGHV was 78% and 84%, respectively; with and without trisomy 12 was 82% and 80%, respectively; and with and without complex karyotype was 77% and 78%, respectively.
ORR, for example, was comparable in the presence (90%) and absence (89%) of unmutated IGHV in ibrutinib-treated patients, as was CRR, at 29% and 26%, respectively.
In the presence and absence of trisomy 12, ORR was 85% and 91%, respectively; CRR was 33% and 22%.
In the presence and absence of complex karyotype, ORR was 88% and 89%, respectively, and CRR was 18% and 24%.
In the presence and absence of del(11q), ORR was 91% and 90%, respectively, and CRR was 22% and 27%.
The only difference that reached statistical significance was the complete response rate with trisomy 12, which favored the presence of trisomy 12.
Interestingly, the ibrutinib-treated patients with del(11q) had a trend toward longer PFS and OS, compared with those without del(11q), said Dr. Kipps.
At 36 months, PFS was 74% with the presence of del(11q) and 68% with the absence of del(11q) (hazard ratio, 0.73 vs. 1.88 in comparator-treated patients), and overall survival at 42 months was 80% in patients with del(11q) and 78% in those without del(11q) (HR, 0.73), Dr. Kipps said.
“The [finding in the] patients with the complex karyotype was a bit surprising, and I think this requires further analysis,” he said, explaining that complex karyotype actually was associated with a shorter PFS in patients treated on the comparator arm, and that this finding conflicts with earlier data.
The findings suggest ibrutinib-treated patients with trisomy 12, for reasons that are unclear, had a significantly higher complete response rate, but not greater PFS or OS vs. those without trisomy 12, Dr. Kipps said.
“It’s also interesting that ... unmutated antibody genes or del(11q) or complex karyotype were adverse prognostic factors in patients treated with comparator treatments, but not necessarily in patients treated with ibrutinib-based therapy,” he said.
Furthermore, although a prior phase II study involving heavily pretreated patients suggested that del(11q) may have adverse prognostic influence on PFS, that finding may not be borne out in patients with fewer lines of prior therapy.
The findings suggest that genomic risk factors associated with poor outcomes with initial chemoimmunotherapy may be less apparent in patients treated with ibrutinib.
“I think this is important, because it may then turn a prognostic factor into a predictive factor, meaning, a predictor of adverse outcomes for a given type of therapy as opposed to adverse prognostic value overall,” he concluded.
Ibrutinib (Imbruvica, Pharmacyclics) was approved by the Food and Drug Administration in January 2015 for the treatment of CLL after previous therapy. Dr. Kipps has received research funding from and/or served as a consultant or advisor for AbbVie, Genentech, Gilead, and Pharmacyclics, an AbbVie company.
[email protected]
NEW YORK – Risk factors associated with poor outcomes in chronic lymphocytic leukemia/small lymphocytic leukemia patients treated with standard therapies appear to have less relevance with ibrutinib treatment, according to an integrated analysis of data from the randomized, phase III RESONATE, RESONATE 2, and HELIOS trials.
In the combined analysis, at a median follow-up of 21 months, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and complete response rate (CRR) were better in ibrutinib-treated patients than in comparator-treated patients – and, in the ibrutinib-treated patients, the outcomes did not differ based on the adverse genomic factors examined, Thomas J. Kipps, MD, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The trials compared well with each other, but differed in terms of number of prior therapies received by patients, he said. Furthermore, the analysis did not examine the effect of del(17p); patients with that deletion were included only in the RESONATE trial.
In RESONATE, ibrutinib was superior to ofatumumab in relapsed/refractory CLL/SLL. In RESONATE 2, ibrutinib was superior to chlorambucil in treatment-naive patients with CLL/SLL. In HELIOS, ibrutinib with bendamustine/rituximab was superior to placebo with bendamustine/rituximab in patients with relapsed/refractory CLL/SLL.
In the new multivariate analysis of the pooled data from these trials – adjusting for the four genomic risk factors and age, sex, ECOG performance status, cytopenia, lactate dehydrogenase (LDH), bulky disease, and number of prior therapies – only having had one or more vs. no prior therapies, and having two or more vs. one prior therapies was associated with shorter PFS and OS in ibrutinib-treated patients, with a trend toward significance.
In comparator-treated patients, however, unmutated IGHV, del(11q), complex karyotype, male sex, two or more prior therapies, and bulky disease all were associated with significantly shorter PFS. Complex karyotype, male sex, bulky disease, ECOG performance status greater than 1, and elevated LDH were associated with significantly shorter OS.
“We need to debate on what the significance of this is and how that can be incorporated into our idea about first-line therapies,” said Dr. Kipps, who was an investigator in both RESONATE trials and is a professor of medicine at the University of California, San Diego.
In univariate analysis of data from ibrutinib-treated patients, unmutated IGHV, del(11q), trisomy 12, and complex karyotype were generally not associated with shorter PFS, OS, or lower ORR or CRR.
Overall survival with and without unmutated IGHV was 78% and 84%, respectively; with and without trisomy 12 was 82% and 80%, respectively; and with and without complex karyotype was 77% and 78%, respectively.
ORR, for example, was comparable in the presence (90%) and absence (89%) of unmutated IGHV in ibrutinib-treated patients, as was CRR, at 29% and 26%, respectively.
In the presence and absence of trisomy 12, ORR was 85% and 91%, respectively; CRR was 33% and 22%.
In the presence and absence of complex karyotype, ORR was 88% and 89%, respectively, and CRR was 18% and 24%.
In the presence and absence of del(11q), ORR was 91% and 90%, respectively, and CRR was 22% and 27%.
The only difference that reached statistical significance was the complete response rate with trisomy 12, which favored the presence of trisomy 12.
Interestingly, the ibrutinib-treated patients with del(11q) had a trend toward longer PFS and OS, compared with those without del(11q), said Dr. Kipps.
At 36 months, PFS was 74% with the presence of del(11q) and 68% with the absence of del(11q) (hazard ratio, 0.73 vs. 1.88 in comparator-treated patients), and overall survival at 42 months was 80% in patients with del(11q) and 78% in those without del(11q) (HR, 0.73), Dr. Kipps said.
“The [finding in the] patients with the complex karyotype was a bit surprising, and I think this requires further analysis,” he said, explaining that complex karyotype actually was associated with a shorter PFS in patients treated on the comparator arm, and that this finding conflicts with earlier data.
The findings suggest ibrutinib-treated patients with trisomy 12, for reasons that are unclear, had a significantly higher complete response rate, but not greater PFS or OS vs. those without trisomy 12, Dr. Kipps said.
“It’s also interesting that ... unmutated antibody genes or del(11q) or complex karyotype were adverse prognostic factors in patients treated with comparator treatments, but not necessarily in patients treated with ibrutinib-based therapy,” he said.
Furthermore, although a prior phase II study involving heavily pretreated patients suggested that del(11q) may have adverse prognostic influence on PFS, that finding may not be borne out in patients with fewer lines of prior therapy.
The findings suggest that genomic risk factors associated with poor outcomes with initial chemoimmunotherapy may be less apparent in patients treated with ibrutinib.
“I think this is important, because it may then turn a prognostic factor into a predictive factor, meaning, a predictor of adverse outcomes for a given type of therapy as opposed to adverse prognostic value overall,” he concluded.
Ibrutinib (Imbruvica, Pharmacyclics) was approved by the Food and Drug Administration in January 2015 for the treatment of CLL after previous therapy. Dr. Kipps has received research funding from and/or served as a consultant or advisor for AbbVie, Genentech, Gilead, and Pharmacyclics, an AbbVie company.
[email protected]
NEW YORK – Risk factors associated with poor outcomes in chronic lymphocytic leukemia/small lymphocytic leukemia patients treated with standard therapies appear to have less relevance with ibrutinib treatment, according to an integrated analysis of data from the randomized, phase III RESONATE, RESONATE 2, and HELIOS trials.
In the combined analysis, at a median follow-up of 21 months, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and complete response rate (CRR) were better in ibrutinib-treated patients than in comparator-treated patients – and, in the ibrutinib-treated patients, the outcomes did not differ based on the adverse genomic factors examined, Thomas J. Kipps, MD, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The trials compared well with each other, but differed in terms of number of prior therapies received by patients, he said. Furthermore, the analysis did not examine the effect of del(17p); patients with that deletion were included only in the RESONATE trial.
In RESONATE, ibrutinib was superior to ofatumumab in relapsed/refractory CLL/SLL. In RESONATE 2, ibrutinib was superior to chlorambucil in treatment-naive patients with CLL/SLL. In HELIOS, ibrutinib with bendamustine/rituximab was superior to placebo with bendamustine/rituximab in patients with relapsed/refractory CLL/SLL.
In the new multivariate analysis of the pooled data from these trials – adjusting for the four genomic risk factors and age, sex, ECOG performance status, cytopenia, lactate dehydrogenase (LDH), bulky disease, and number of prior therapies – only having had one or more vs. no prior therapies, and having two or more vs. one prior therapies was associated with shorter PFS and OS in ibrutinib-treated patients, with a trend toward significance.
In comparator-treated patients, however, unmutated IGHV, del(11q), complex karyotype, male sex, two or more prior therapies, and bulky disease all were associated with significantly shorter PFS. Complex karyotype, male sex, bulky disease, ECOG performance status greater than 1, and elevated LDH were associated with significantly shorter OS.
“We need to debate on what the significance of this is and how that can be incorporated into our idea about first-line therapies,” said Dr. Kipps, who was an investigator in both RESONATE trials and is a professor of medicine at the University of California, San Diego.
In univariate analysis of data from ibrutinib-treated patients, unmutated IGHV, del(11q), trisomy 12, and complex karyotype were generally not associated with shorter PFS, OS, or lower ORR or CRR.
Overall survival with and without unmutated IGHV was 78% and 84%, respectively; with and without trisomy 12 was 82% and 80%, respectively; and with and without complex karyotype was 77% and 78%, respectively.
ORR, for example, was comparable in the presence (90%) and absence (89%) of unmutated IGHV in ibrutinib-treated patients, as was CRR, at 29% and 26%, respectively.
In the presence and absence of trisomy 12, ORR was 85% and 91%, respectively; CRR was 33% and 22%.
In the presence and absence of complex karyotype, ORR was 88% and 89%, respectively, and CRR was 18% and 24%.
In the presence and absence of del(11q), ORR was 91% and 90%, respectively, and CRR was 22% and 27%.
The only difference that reached statistical significance was the complete response rate with trisomy 12, which favored the presence of trisomy 12.
Interestingly, the ibrutinib-treated patients with del(11q) had a trend toward longer PFS and OS, compared with those without del(11q), said Dr. Kipps.
At 36 months, PFS was 74% with the presence of del(11q) and 68% with the absence of del(11q) (hazard ratio, 0.73 vs. 1.88 in comparator-treated patients), and overall survival at 42 months was 80% in patients with del(11q) and 78% in those without del(11q) (HR, 0.73), Dr. Kipps said.
“The [finding in the] patients with the complex karyotype was a bit surprising, and I think this requires further analysis,” he said, explaining that complex karyotype actually was associated with a shorter PFS in patients treated on the comparator arm, and that this finding conflicts with earlier data.
The findings suggest ibrutinib-treated patients with trisomy 12, for reasons that are unclear, had a significantly higher complete response rate, but not greater PFS or OS vs. those without trisomy 12, Dr. Kipps said.
“It’s also interesting that ... unmutated antibody genes or del(11q) or complex karyotype were adverse prognostic factors in patients treated with comparator treatments, but not necessarily in patients treated with ibrutinib-based therapy,” he said.
Furthermore, although a prior phase II study involving heavily pretreated patients suggested that del(11q) may have adverse prognostic influence on PFS, that finding may not be borne out in patients with fewer lines of prior therapy.
The findings suggest that genomic risk factors associated with poor outcomes with initial chemoimmunotherapy may be less apparent in patients treated with ibrutinib.
“I think this is important, because it may then turn a prognostic factor into a predictive factor, meaning, a predictor of adverse outcomes for a given type of therapy as opposed to adverse prognostic value overall,” he concluded.
Ibrutinib (Imbruvica, Pharmacyclics) was approved by the Food and Drug Administration in January 2015 for the treatment of CLL after previous therapy. Dr. Kipps has received research funding from and/or served as a consultant or advisor for AbbVie, Genentech, Gilead, and Pharmacyclics, an AbbVie company.
[email protected]
AT THE IWCLL MEETING
Key clinical point:
Major finding: In ibrutinib-treated patients, overall survival with and without unmutated IGHV was 78% and 84%, respectively; with and without trisomy 12 was 82% and 80%, respectively; and with and without complex karyotype was 77% and 78%, respectively.
Data source: A pooled analysis of data from 1,210 patients from three randomized phase III trials.
Disclosures: Dr. Kipps has received research funding from and/or served as a consultant or advisor for AbbVie, Genentech, Gilead, and Pharmacyclics, an AbbVie company.