CLL

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.

[email protected]

CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.

Ibrutinib monotherapy

In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.

Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.

Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.

The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.

The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).

The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.

The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.

“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”

Ibrutinib plus ublituximab and umbralisib

In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.

A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.

The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).

The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.

“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”

“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
 

Ibrutinib plus CAR-T cells

In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.

Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.

Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.

“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”

CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.

Ibrutinib monotherapy

In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.

Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.

Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.

The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.

The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).

The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.

The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.

“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”

Ibrutinib plus ublituximab and umbralisib

In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.

A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.

The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).

The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.

“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”

“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
 

Ibrutinib plus CAR-T cells

In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.

Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.

Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.

“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”

CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.

Ibrutinib monotherapy

In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.

Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.

Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.

The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.

The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).

The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.

The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.

“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”

Ibrutinib plus ublituximab and umbralisib

In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.

A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.

The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).

The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.

“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”

“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
 

Ibrutinib plus CAR-T cells

In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.

Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.

Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.

“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”

MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.

The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.

MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.

The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.

MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.

The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.

The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).

The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.

• Relapsed or refractory FL as a single agent.
• Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
• Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
• Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
• Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.

The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.

Rituxan Hycela is marketed by Genentech.

[email protected]

The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).

The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.

• Relapsed or refractory FL as a single agent.
• Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
• Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
• Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
• Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.

The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.

Rituxan Hycela is marketed by Genentech.

[email protected]

The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).

The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.

• Relapsed or refractory FL as a single agent.
• Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
• Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
• Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
• Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.

The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.

Rituxan Hycela is marketed by Genentech.

[email protected]

CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.

This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.

Mary Jo M. Dales

[email protected]

On Twitter @maryjodales

CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.

This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.

Mary Jo M. Dales

[email protected]

On Twitter @maryjodales

CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.

This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.

Mary Jo M. Dales

[email protected]

On Twitter @maryjodales

Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.

In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).

“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.

The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.

The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.

At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m² on days 1 and 2 every 28 days, unless this was contraindicated.

The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.

Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.

A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

Responses

In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.

Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.

In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.

Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.

The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.

At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.

Adverse events

In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events

Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.

Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.

There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.

Something other than venetoclax?

Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.

“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.

Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.

The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
 

Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.

In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).

“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.

The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.

The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.

At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m² on days 1 and 2 every 28 days, unless this was contraindicated.

The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.

Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.

A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

Responses

In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.

Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.

In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.

Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.

The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.

At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.

Adverse events

In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events

Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.

Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.

There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.

Something other than venetoclax?

Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.

“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.

Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.

The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
 

Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.

In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).

“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.

The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.

The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.

At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m² on days 1 and 2 every 28 days, unless this was contraindicated.

The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.

Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.

A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

Responses

In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.

Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.

In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.

Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.

The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.

At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.

Adverse events

In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events

Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.

Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.

There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.

Something other than venetoclax?

Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.

“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.

Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.

The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
 

LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.

One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.

LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.

One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.

LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.

One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.

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.

[email protected]

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.

[email protected]

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.

[email protected]