Leukemia, Myelodysplasia, Transplantation

Acute myeloid leukemia (AML) consists of at least 11 disease classes that represent distinct paths in the evolution of AML and have prognostic implications, based on an analysis of somatic driver mutations in 1,540 patients.

In total, 5,234 driver mutations were identified in 76 genes or regions, with 96% of patients having at least one mutation and 86% having two or more mutations. However, nearly one-half of the cohort did not fall into one of the molecular groups defined by the World Health Organization in 2008.

“The characterization of many new leukemia genes, multiple driver mutations per patient, and complex co-mutation patterns prompted us to reevaluate genomic classification of AML from the beginning,” wrote Elli Papaemmanuil, Ph.D., a molecular geneticist at Memorial Sloan Kettering, New York, and of the Cancer Genome Project, Wellcome Trust Sanger Institute, and her colleagues (N Engl J Med. 2016 Jun 9; 374:2209-21).

The team developed a Bayesian statistical model to define 11 mutually exclusive subtypes based on patterns of co-mutations. The schema unambiguously classified 1,236 of 1,540 patients (80%) into a single subgroup and 56 (4%) into two or more groups. A subset of patients (166, 11%) remained unclassified, possibly due to mutations in genes not sequenced in the study.

NPM1-mutated AML was the largest class (27% of the cohort), followed by the chromatin-spliceosome group (18% of the cohort) that included mutations in genes regulating RNA splicing (SRSF2, SF3B1, U2AF1, and ZRSR2), chromatin (ASXL1, STAG2, BCOR, MLL^PTD, EZH2, and PHF6), or transcription (RUNX1). Another subgroup consisted of mutations in TP53, as well as complex karyotype alterations, cytogenetically visible copy-number alterations (aneuploidies), or a combination. While broader than previous classifications, such as “monosomal karyotype AML” and “complex karyotype AML,” this group emerged from correlated chromosomal abnormalities and was mutually exclusive of other class-defining lesions. In general, patients in this group were older and had fewer RAS pathway mutations.

The groups had considerable differences in clinical presentation and overall survival, according to the report. The TP53-aneuploidy subgroup had poor outcomes, as previously described. Patients in the chromatin-spliceosome group had lower rates of response to induction chemotherapy, higher relapse rates, and poorer long-term outcomes, compared with other groups. Most of these patients (84%) would be classified as intermediate risk under current guidelines, but the characteristics were more similar to those of subgroups with adverse outcomes.

Overall survival was correlated with the number of driver mutations, and deleterious affects of mutations often were found to be additive. In some cases, complex gene interactions accounted for variation in outcomes, suggesting the clinical effect of some driver mutations may depend on the occurrence of co-mutations in a wider genomic context.

Acute myeloid leukemia (AML) consists of at least 11 disease classes that represent distinct paths in the evolution of AML and have prognostic implications, based on an analysis of somatic driver mutations in 1,540 patients.

In total, 5,234 driver mutations were identified in 76 genes or regions, with 96% of patients having at least one mutation and 86% having two or more mutations. However, nearly one-half of the cohort did not fall into one of the molecular groups defined by the World Health Organization in 2008.

“The characterization of many new leukemia genes, multiple driver mutations per patient, and complex co-mutation patterns prompted us to reevaluate genomic classification of AML from the beginning,” wrote Elli Papaemmanuil, Ph.D., a molecular geneticist at Memorial Sloan Kettering, New York, and of the Cancer Genome Project, Wellcome Trust Sanger Institute, and her colleagues (N Engl J Med. 2016 Jun 9; 374:2209-21).

The team developed a Bayesian statistical model to define 11 mutually exclusive subtypes based on patterns of co-mutations. The schema unambiguously classified 1,236 of 1,540 patients (80%) into a single subgroup and 56 (4%) into two or more groups. A subset of patients (166, 11%) remained unclassified, possibly due to mutations in genes not sequenced in the study.

NPM1-mutated AML was the largest class (27% of the cohort), followed by the chromatin-spliceosome group (18% of the cohort) that included mutations in genes regulating RNA splicing (SRSF2, SF3B1, U2AF1, and ZRSR2), chromatin (ASXL1, STAG2, BCOR, MLL^PTD, EZH2, and PHF6), or transcription (RUNX1). Another subgroup consisted of mutations in TP53, as well as complex karyotype alterations, cytogenetically visible copy-number alterations (aneuploidies), or a combination. While broader than previous classifications, such as “monosomal karyotype AML” and “complex karyotype AML,” this group emerged from correlated chromosomal abnormalities and was mutually exclusive of other class-defining lesions. In general, patients in this group were older and had fewer RAS pathway mutations.

The groups had considerable differences in clinical presentation and overall survival, according to the report. The TP53-aneuploidy subgroup had poor outcomes, as previously described. Patients in the chromatin-spliceosome group had lower rates of response to induction chemotherapy, higher relapse rates, and poorer long-term outcomes, compared with other groups. Most of these patients (84%) would be classified as intermediate risk under current guidelines, but the characteristics were more similar to those of subgroups with adverse outcomes.

Overall survival was correlated with the number of driver mutations, and deleterious affects of mutations often were found to be additive. In some cases, complex gene interactions accounted for variation in outcomes, suggesting the clinical effect of some driver mutations may depend on the occurrence of co-mutations in a wider genomic context.

Acute myeloid leukemia (AML) consists of at least 11 disease classes that represent distinct paths in the evolution of AML and have prognostic implications, based on an analysis of somatic driver mutations in 1,540 patients.

In total, 5,234 driver mutations were identified in 76 genes or regions, with 96% of patients having at least one mutation and 86% having two or more mutations. However, nearly one-half of the cohort did not fall into one of the molecular groups defined by the World Health Organization in 2008.

“The characterization of many new leukemia genes, multiple driver mutations per patient, and complex co-mutation patterns prompted us to reevaluate genomic classification of AML from the beginning,” wrote Elli Papaemmanuil, Ph.D., a molecular geneticist at Memorial Sloan Kettering, New York, and of the Cancer Genome Project, Wellcome Trust Sanger Institute, and her colleagues (N Engl J Med. 2016 Jun 9; 374:2209-21).

The team developed a Bayesian statistical model to define 11 mutually exclusive subtypes based on patterns of co-mutations. The schema unambiguously classified 1,236 of 1,540 patients (80%) into a single subgroup and 56 (4%) into two or more groups. A subset of patients (166, 11%) remained unclassified, possibly due to mutations in genes not sequenced in the study.

NPM1-mutated AML was the largest class (27% of the cohort), followed by the chromatin-spliceosome group (18% of the cohort) that included mutations in genes regulating RNA splicing (SRSF2, SF3B1, U2AF1, and ZRSR2), chromatin (ASXL1, STAG2, BCOR, MLL^PTD, EZH2, and PHF6), or transcription (RUNX1). Another subgroup consisted of mutations in TP53, as well as complex karyotype alterations, cytogenetically visible copy-number alterations (aneuploidies), or a combination. While broader than previous classifications, such as “monosomal karyotype AML” and “complex karyotype AML,” this group emerged from correlated chromosomal abnormalities and was mutually exclusive of other class-defining lesions. In general, patients in this group were older and had fewer RAS pathway mutations.

The groups had considerable differences in clinical presentation and overall survival, according to the report. The TP53-aneuploidy subgroup had poor outcomes, as previously described. Patients in the chromatin-spliceosome group had lower rates of response to induction chemotherapy, higher relapse rates, and poorer long-term outcomes, compared with other groups. Most of these patients (84%) would be classified as intermediate risk under current guidelines, but the characteristics were more similar to those of subgroups with adverse outcomes.

Overall survival was correlated with the number of driver mutations, and deleterious affects of mutations often were found to be additive. In some cases, complex gene interactions accounted for variation in outcomes, suggesting the clinical effect of some driver mutations may depend on the occurrence of co-mutations in a wider genomic context.

COPENHAGEN – A year after stopping tyrosine kinase inhibitor therapy, more than half of patients with chronic myeloid leukemia (CML) in a large clinical trial remained in deep molecular remission.

Among 750 patients with CML in remission for at least 1 year before study entry, 62% retained a treatment response 6 months after stopping a tyrosine kinase inhibitor (TKI) such as imatinib (Gleevec) and 56% retained responses 1 year after being off their drugs, reported Dr. Johan Richter of Lund (Sweden) University at the annual congress of the European Hematology Association.

“About 6 years of therapy [with imatinib] would be optimal for therapy prior to a stop attempt,” he said at a briefing prior to the presentation of data at the congress.

Although in clinical practice patients with CML may remain on a TKI indefinitely, results from small clinical trials have suggested that in 40%-60% of patients with deep molecular responses (MR4.0 or better), TKIs can be safely stopped, Dr. Richter noted.

To get a better handle on when it might be safe to stop a TKI and under what conditions, EURO-SKI investigators enrolled 868 adults with CML in chronic phase from 11 countries, 750 of whom had complete data for the analysis.

In all, 94% of patients had received imatinib in the first line, 2% received dasatinib (Sprycel), and 4% had received nilotinib (Tasigna). Of this group, 115 had switched to a second-line agent due to intolerance of the first-line drug.

The median time from diagnosis was 7.7 years. The median duration of therapy was 7.6 years, and the median duration of MR4 before stopping was 4.7 years.

As noted, among 750 patients assessable for molecular relapse–free survival, 62% remained in remission at 6 months after stopping the TKI, as did 56% at 12 months, 52% at 24 months, and 49% at 36 months.

For patients who resumed therapy, the median time to restart was 4.1 months.

To see whether they could identify any factors prognostic for relapse after stopping a TKI, the investigators used data on 448 patients in the study who were treated with imatinib.

In univariate analysis there was no significant association between molecular relapse–free survival at 6 months and either age, gender, depth of molecular response, or any standard risk scores.

The only significant predictors of molecular remission status at 6 months were duration of imatinib therapy and duration of molecular response before stopping.

The odds ratio for treatment duration was 1.16, indicating that each additional year of imatinib treatment is associated with a 16% increase in the likelihood that a patient would remain in deep molecular remission 6 months after stopping.

The investigators used the minimal P value approach to determine the cutoff of approximately 6 years, based on a molecular relapse–free survival at 6 months of 65.5% for patients who remained on imatinib for more than 5.8 years, compared with 42.6% for those who were on it for 5.8 years or less.

Although the study is ongoing, to date more than 80% of patients who had a loss of deep molecular remission after stopping their TKI regained the remission after resuming therapy, Dr. Richter said.

Dr. Richter said in an interview that longer follow-up will be needed to confirm their findings, and that patients who were sensitive to TKIs prior to stopping therapy remained sensitive when restarting, suggesting that treatment interruption does not increase the likelihood of drug resistance.

Coprincipal investigator Dr. Francois-Xavier Mahon of Bordeaux University in France, noted that in the STIM (Stop Imatinib)–1 and –2 trials, the estimated annual savings to the French health care system were 20 million euros ($22.6 million).

COPENHAGEN – A year after stopping tyrosine kinase inhibitor therapy, more than half of patients with chronic myeloid leukemia (CML) in a large clinical trial remained in deep molecular remission.

Among 750 patients with CML in remission for at least 1 year before study entry, 62% retained a treatment response 6 months after stopping a tyrosine kinase inhibitor (TKI) such as imatinib (Gleevec) and 56% retained responses 1 year after being off their drugs, reported Dr. Johan Richter of Lund (Sweden) University at the annual congress of the European Hematology Association.

“About 6 years of therapy [with imatinib] would be optimal for therapy prior to a stop attempt,” he said at a briefing prior to the presentation of data at the congress.

Although in clinical practice patients with CML may remain on a TKI indefinitely, results from small clinical trials have suggested that in 40%-60% of patients with deep molecular responses (MR4.0 or better), TKIs can be safely stopped, Dr. Richter noted.

To get a better handle on when it might be safe to stop a TKI and under what conditions, EURO-SKI investigators enrolled 868 adults with CML in chronic phase from 11 countries, 750 of whom had complete data for the analysis.

In all, 94% of patients had received imatinib in the first line, 2% received dasatinib (Sprycel), and 4% had received nilotinib (Tasigna). Of this group, 115 had switched to a second-line agent due to intolerance of the first-line drug.

The median time from diagnosis was 7.7 years. The median duration of therapy was 7.6 years, and the median duration of MR4 before stopping was 4.7 years.

As noted, among 750 patients assessable for molecular relapse–free survival, 62% remained in remission at 6 months after stopping the TKI, as did 56% at 12 months, 52% at 24 months, and 49% at 36 months.

For patients who resumed therapy, the median time to restart was 4.1 months.

To see whether they could identify any factors prognostic for relapse after stopping a TKI, the investigators used data on 448 patients in the study who were treated with imatinib.

In univariate analysis there was no significant association between molecular relapse–free survival at 6 months and either age, gender, depth of molecular response, or any standard risk scores.

The only significant predictors of molecular remission status at 6 months were duration of imatinib therapy and duration of molecular response before stopping.

The odds ratio for treatment duration was 1.16, indicating that each additional year of imatinib treatment is associated with a 16% increase in the likelihood that a patient would remain in deep molecular remission 6 months after stopping.

The investigators used the minimal P value approach to determine the cutoff of approximately 6 years, based on a molecular relapse–free survival at 6 months of 65.5% for patients who remained on imatinib for more than 5.8 years, compared with 42.6% for those who were on it for 5.8 years or less.

Although the study is ongoing, to date more than 80% of patients who had a loss of deep molecular remission after stopping their TKI regained the remission after resuming therapy, Dr. Richter said.

Dr. Richter said in an interview that longer follow-up will be needed to confirm their findings, and that patients who were sensitive to TKIs prior to stopping therapy remained sensitive when restarting, suggesting that treatment interruption does not increase the likelihood of drug resistance.

Coprincipal investigator Dr. Francois-Xavier Mahon of Bordeaux University in France, noted that in the STIM (Stop Imatinib)–1 and –2 trials, the estimated annual savings to the French health care system were 20 million euros ($22.6 million).

COPENHAGEN – A year after stopping tyrosine kinase inhibitor therapy, more than half of patients with chronic myeloid leukemia (CML) in a large clinical trial remained in deep molecular remission.

Among 750 patients with CML in remission for at least 1 year before study entry, 62% retained a treatment response 6 months after stopping a tyrosine kinase inhibitor (TKI) such as imatinib (Gleevec) and 56% retained responses 1 year after being off their drugs, reported Dr. Johan Richter of Lund (Sweden) University at the annual congress of the European Hematology Association.

“About 6 years of therapy [with imatinib] would be optimal for therapy prior to a stop attempt,” he said at a briefing prior to the presentation of data at the congress.

Although in clinical practice patients with CML may remain on a TKI indefinitely, results from small clinical trials have suggested that in 40%-60% of patients with deep molecular responses (MR4.0 or better), TKIs can be safely stopped, Dr. Richter noted.

To get a better handle on when it might be safe to stop a TKI and under what conditions, EURO-SKI investigators enrolled 868 adults with CML in chronic phase from 11 countries, 750 of whom had complete data for the analysis.

In all, 94% of patients had received imatinib in the first line, 2% received dasatinib (Sprycel), and 4% had received nilotinib (Tasigna). Of this group, 115 had switched to a second-line agent due to intolerance of the first-line drug.

The median time from diagnosis was 7.7 years. The median duration of therapy was 7.6 years, and the median duration of MR4 before stopping was 4.7 years.

As noted, among 750 patients assessable for molecular relapse–free survival, 62% remained in remission at 6 months after stopping the TKI, as did 56% at 12 months, 52% at 24 months, and 49% at 36 months.

For patients who resumed therapy, the median time to restart was 4.1 months.

To see whether they could identify any factors prognostic for relapse after stopping a TKI, the investigators used data on 448 patients in the study who were treated with imatinib.

In univariate analysis there was no significant association between molecular relapse–free survival at 6 months and either age, gender, depth of molecular response, or any standard risk scores.

The only significant predictors of molecular remission status at 6 months were duration of imatinib therapy and duration of molecular response before stopping.

The odds ratio for treatment duration was 1.16, indicating that each additional year of imatinib treatment is associated with a 16% increase in the likelihood that a patient would remain in deep molecular remission 6 months after stopping.

The investigators used the minimal P value approach to determine the cutoff of approximately 6 years, based on a molecular relapse–free survival at 6 months of 65.5% for patients who remained on imatinib for more than 5.8 years, compared with 42.6% for those who were on it for 5.8 years or less.

Although the study is ongoing, to date more than 80% of patients who had a loss of deep molecular remission after stopping their TKI regained the remission after resuming therapy, Dr. Richter said.

Dr. Richter said in an interview that longer follow-up will be needed to confirm their findings, and that patients who were sensitive to TKIs prior to stopping therapy remained sensitive when restarting, suggesting that treatment interruption does not increase the likelihood of drug resistance.

Coprincipal investigator Dr. Francois-Xavier Mahon of Bordeaux University in France, noted that in the STIM (Stop Imatinib)–1 and –2 trials, the estimated annual savings to the French health care system were 20 million euros ($22.6 million).

Copenhagen – The monoclonal antibody blinatumomab nearly doubled overall survival compared with standard chemotherapy among patients with relapsed or refractory B-cell precursor leukemia negative for the Philadelphia chromosome, investigators reported.

Among 405 patients enrolled in the TOWER study, a multicenter, open-label phase III trial, median overall survival for patients treated with blinatumomab (Blincyto) was 7.7 months, compared with 4.0 months for patients treated with one of four standard chemotherapy regimens (P = .012) reported Dr. Max S. Topp of Universitätsklinikum in Würzburg, Germany.

“Blinatumomab is the first immunotherapy agent to demonstrate an overall survival benefit when compared to chemotherapy in patients relapsing with adult acute lymphoblastic leukemia. It increases almost twofold the overall survival when compared to standard care. This was consistent in all subgroups that we were looking at, regardless of age, prior salvage therapy, or patients relapsing after an allo-transplantation,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

The trial was halted early, after a preplanned interim analysis showed a clear survival benefit with blinatumomab.

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. As previously reported, it has induced high complete remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

In May 2015, the Food and Drug Administration granted blinatumomab accelerated approval for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

In the TOWER trial, patients with relapsed/refractory BCP-ALL were randomly assigned on a 2:1 basis to receive either blinatumomab (271 patients) or standard chemotherapy (134), consisting of the investigator’s choice of one of four defined regimens (based on either anthracyclines, histone deacetylase inhibitors, high-dose methotrexate, or clofarabine).

The patients were further stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT).

Patients assigned to receive blinatumomab received it in 6-week cycles consisting of continuous infusions of 9 mcg/day in week 1 of cycle 1, then 28 mcg/day for weeks 3-4, followed by 2 weeks off. Patients were pretreated with dexamethasone for prophylaxis against the cytokine release syndrome.

Patients whose disease was in remission following two induction cycles could be continued on therapy until relapse.

As noted, the trial was halted early, after 248 patients had died; the primary analysis had been planned to occur after 330 patients had died.

In addition to the superior survival rates, blinatumomab was associated with a higher rate of complete responses (39% vs. 19%, P less than .001) and combined complete responses, complete hematologic responses, and complete responses with incomplete recovery of counts (46% vs. 28%, P = .001).

In all, 19% of patients assigned to blinatumomab and 17% assigned to chemotherapy died on study. Grade 3 or greater adverse events included neutropenia (38% of patients and 58%, respectively), infections (34% and 52%), neurologic events (9% and 8%), and the cytokine release syndrome (5% vs. 0%).

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing, asked Dr. Topp whether there were plans to use blinatumomab earlier in the course of disease.

Dr. Topp agreed that it might be a valuable addition to upfront therapy, noting that blinatumomab has been shown in a small percentage of patients who are positive for minimal residual disease to convert to being negative for minimal residual disease, and that this conversion was associated with improved overall survival.

Copenhagen – The monoclonal antibody blinatumomab nearly doubled overall survival compared with standard chemotherapy among patients with relapsed or refractory B-cell precursor leukemia negative for the Philadelphia chromosome, investigators reported.

Among 405 patients enrolled in the TOWER study, a multicenter, open-label phase III trial, median overall survival for patients treated with blinatumomab (Blincyto) was 7.7 months, compared with 4.0 months for patients treated with one of four standard chemotherapy regimens (P = .012) reported Dr. Max S. Topp of Universitätsklinikum in Würzburg, Germany.

“Blinatumomab is the first immunotherapy agent to demonstrate an overall survival benefit when compared to chemotherapy in patients relapsing with adult acute lymphoblastic leukemia. It increases almost twofold the overall survival when compared to standard care. This was consistent in all subgroups that we were looking at, regardless of age, prior salvage therapy, or patients relapsing after an allo-transplantation,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

The trial was halted early, after a preplanned interim analysis showed a clear survival benefit with blinatumomab.

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. As previously reported, it has induced high complete remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

In May 2015, the Food and Drug Administration granted blinatumomab accelerated approval for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

In the TOWER trial, patients with relapsed/refractory BCP-ALL were randomly assigned on a 2:1 basis to receive either blinatumomab (271 patients) or standard chemotherapy (134), consisting of the investigator’s choice of one of four defined regimens (based on either anthracyclines, histone deacetylase inhibitors, high-dose methotrexate, or clofarabine).

The patients were further stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT).

Patients assigned to receive blinatumomab received it in 6-week cycles consisting of continuous infusions of 9 mcg/day in week 1 of cycle 1, then 28 mcg/day for weeks 3-4, followed by 2 weeks off. Patients were pretreated with dexamethasone for prophylaxis against the cytokine release syndrome.

Patients whose disease was in remission following two induction cycles could be continued on therapy until relapse.

As noted, the trial was halted early, after 248 patients had died; the primary analysis had been planned to occur after 330 patients had died.

In addition to the superior survival rates, blinatumomab was associated with a higher rate of complete responses (39% vs. 19%, P less than .001) and combined complete responses, complete hematologic responses, and complete responses with incomplete recovery of counts (46% vs. 28%, P = .001).

In all, 19% of patients assigned to blinatumomab and 17% assigned to chemotherapy died on study. Grade 3 or greater adverse events included neutropenia (38% of patients and 58%, respectively), infections (34% and 52%), neurologic events (9% and 8%), and the cytokine release syndrome (5% vs. 0%).

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing, asked Dr. Topp whether there were plans to use blinatumomab earlier in the course of disease.

Dr. Topp agreed that it might be a valuable addition to upfront therapy, noting that blinatumomab has been shown in a small percentage of patients who are positive for minimal residual disease to convert to being negative for minimal residual disease, and that this conversion was associated with improved overall survival.

Copenhagen – The monoclonal antibody blinatumomab nearly doubled overall survival compared with standard chemotherapy among patients with relapsed or refractory B-cell precursor leukemia negative for the Philadelphia chromosome, investigators reported.

Among 405 patients enrolled in the TOWER study, a multicenter, open-label phase III trial, median overall survival for patients treated with blinatumomab (Blincyto) was 7.7 months, compared with 4.0 months for patients treated with one of four standard chemotherapy regimens (P = .012) reported Dr. Max S. Topp of Universitätsklinikum in Würzburg, Germany.

“Blinatumomab is the first immunotherapy agent to demonstrate an overall survival benefit when compared to chemotherapy in patients relapsing with adult acute lymphoblastic leukemia. It increases almost twofold the overall survival when compared to standard care. This was consistent in all subgroups that we were looking at, regardless of age, prior salvage therapy, or patients relapsing after an allo-transplantation,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

The trial was halted early, after a preplanned interim analysis showed a clear survival benefit with blinatumomab.

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. As previously reported, it has induced high complete remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

In May 2015, the Food and Drug Administration granted blinatumomab accelerated approval for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

In the TOWER trial, patients with relapsed/refractory BCP-ALL were randomly assigned on a 2:1 basis to receive either blinatumomab (271 patients) or standard chemotherapy (134), consisting of the investigator’s choice of one of four defined regimens (based on either anthracyclines, histone deacetylase inhibitors, high-dose methotrexate, or clofarabine).

The patients were further stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT).

Patients assigned to receive blinatumomab received it in 6-week cycles consisting of continuous infusions of 9 mcg/day in week 1 of cycle 1, then 28 mcg/day for weeks 3-4, followed by 2 weeks off. Patients were pretreated with dexamethasone for prophylaxis against the cytokine release syndrome.

Patients whose disease was in remission following two induction cycles could be continued on therapy until relapse.

As noted, the trial was halted early, after 248 patients had died; the primary analysis had been planned to occur after 330 patients had died.

In addition to the superior survival rates, blinatumomab was associated with a higher rate of complete responses (39% vs. 19%, P less than .001) and combined complete responses, complete hematologic responses, and complete responses with incomplete recovery of counts (46% vs. 28%, P = .001).

In all, 19% of patients assigned to blinatumomab and 17% assigned to chemotherapy died on study. Grade 3 or greater adverse events included neutropenia (38% of patients and 58%, respectively), infections (34% and 52%), neurologic events (9% and 8%), and the cytokine release syndrome (5% vs. 0%).

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing, asked Dr. Topp whether there were plans to use blinatumomab earlier in the course of disease.

Dr. Topp agreed that it might be a valuable addition to upfront therapy, noting that blinatumomab has been shown in a small percentage of patients who are positive for minimal residual disease to convert to being negative for minimal residual disease, and that this conversion was associated with improved overall survival.

Genome testing

Photo courtesy of NIGMS

Using patient samples from 3 prospective multicenter clinical trials of the German-Austrian AML Study Group, researchers have identified 5234 driver mutations involving 76 genes or regions in 1540 patients with acute myeloid leukemia (AML).

They say the sample size afforded a more comprehensive analysis than previously conducted, and as a result, they found patients were divided into at least 11 subgroups of AML.

They also identified 3 genomic categories beyond the existing World Health Organization (WHO) subgroups. These genomic categories are chromatin–spliceosome mutations, TP53–aneuploidy, and provisionally, IDH2^R172 mutations.

Their study, led by scientists at the Wellcome Trust Sanger Institute and international collaborators, could have an impact on clinical trial design and improve the way patients are diagnosed and treated in the future.

The scientists stated in their published paper that 736 patients (48%) in their study would not have fit into the molecular groups included in the 2008 WHO classification of adult AML. This prompted them to reevaluate genomic classification of AML from the beginning.

“We have shown that AML is an umbrella term for a group of at least 11 different types of leukemia,” said Peter Campbell, MBChB, PhD, co-leader of the study. “We can now start to decode these genetics to shape clinical trials and develop diagnostics.”

The scientists found NPM1-mutated AML to be the largest class in their cohort, accounting for 27% of the patients.

The second largest subgroup--the chromatin-spliceosome group—accounted for 18% of patients, the TP53-aneuploidy group accounted for 13%, and the IDH2^R172 mutations for 1%.

The study also showed that most patients had a unique combination of genetic changes driving their leukemia. This genetic complexity helps explain why AML shows such variability in survival rates among patients.

Under their new schema, the scientists were able to unambiguously classify 80% of the 1540 patients with driver mutations in a single subgroup. Fifty-six of the patients (4%) met criteria for 2 or more categories, primarily in the TP53-aneuploidy and chromatin-spliceosome groups.

They were not able to classify 11% of patients with driver mutations. They explained that these patients might have had mutations in drivers that were either not sequenced or had mutations that were missed.

The scientists applied their classification schema to an independent cohort from the Cancer Genome Atlas (TCGA). The new schema was able to replicate the absence of overlap among subgroups, and relative frequencies of the mutations were equivalent to those in the AML cohort.

“For the first time we untangled the genetic complexity seen in most AML cancer genomes into distinct evolutionary paths that lead to AML,” joint first author Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center in New York, said.

“By understanding these paths, we can help develop more appropriate treatments for individual patients with AML. We are now extending such studies across other leukemias."

The investigators recommend prospective clinical trials to further validate the schema.

The work was supported by the Wellcome Trust, Bundesministerium fur Bildung und Forschung, Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft, the European Hematology Association, Amgen and the Kay Kendall Leukaemia Fund.

Genome testing

Photo courtesy of NIGMS

Using patient samples from 3 prospective multicenter clinical trials of the German-Austrian AML Study Group, researchers have identified 5234 driver mutations involving 76 genes or regions in 1540 patients with acute myeloid leukemia (AML).

They say the sample size afforded a more comprehensive analysis than previously conducted, and as a result, they found patients were divided into at least 11 subgroups of AML.

They also identified 3 genomic categories beyond the existing World Health Organization (WHO) subgroups. These genomic categories are chromatin–spliceosome mutations, TP53–aneuploidy, and provisionally, IDH2^R172 mutations.

Their study, led by scientists at the Wellcome Trust Sanger Institute and international collaborators, could have an impact on clinical trial design and improve the way patients are diagnosed and treated in the future.

The scientists stated in their published paper that 736 patients (48%) in their study would not have fit into the molecular groups included in the 2008 WHO classification of adult AML. This prompted them to reevaluate genomic classification of AML from the beginning.

“We have shown that AML is an umbrella term for a group of at least 11 different types of leukemia,” said Peter Campbell, MBChB, PhD, co-leader of the study. “We can now start to decode these genetics to shape clinical trials and develop diagnostics.”

The scientists found NPM1-mutated AML to be the largest class in their cohort, accounting for 27% of the patients.

The second largest subgroup--the chromatin-spliceosome group—accounted for 18% of patients, the TP53-aneuploidy group accounted for 13%, and the IDH2^R172 mutations for 1%.

The study also showed that most patients had a unique combination of genetic changes driving their leukemia. This genetic complexity helps explain why AML shows such variability in survival rates among patients.

Under their new schema, the scientists were able to unambiguously classify 80% of the 1540 patients with driver mutations in a single subgroup. Fifty-six of the patients (4%) met criteria for 2 or more categories, primarily in the TP53-aneuploidy and chromatin-spliceosome groups.

They were not able to classify 11% of patients with driver mutations. They explained that these patients might have had mutations in drivers that were either not sequenced or had mutations that were missed.

The scientists applied their classification schema to an independent cohort from the Cancer Genome Atlas (TCGA). The new schema was able to replicate the absence of overlap among subgroups, and relative frequencies of the mutations were equivalent to those in the AML cohort.

“For the first time we untangled the genetic complexity seen in most AML cancer genomes into distinct evolutionary paths that lead to AML,” joint first author Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center in New York, said.

“By understanding these paths, we can help develop more appropriate treatments for individual patients with AML. We are now extending such studies across other leukemias."

The investigators recommend prospective clinical trials to further validate the schema.

The work was supported by the Wellcome Trust, Bundesministerium fur Bildung und Forschung, Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft, the European Hematology Association, Amgen and the Kay Kendall Leukaemia Fund.

Genome testing

Photo courtesy of NIGMS

Using patient samples from 3 prospective multicenter clinical trials of the German-Austrian AML Study Group, researchers have identified 5234 driver mutations involving 76 genes or regions in 1540 patients with acute myeloid leukemia (AML).

They say the sample size afforded a more comprehensive analysis than previously conducted, and as a result, they found patients were divided into at least 11 subgroups of AML.

They also identified 3 genomic categories beyond the existing World Health Organization (WHO) subgroups. These genomic categories are chromatin–spliceosome mutations, TP53–aneuploidy, and provisionally, IDH2^R172 mutations.

Their study, led by scientists at the Wellcome Trust Sanger Institute and international collaborators, could have an impact on clinical trial design and improve the way patients are diagnosed and treated in the future.

The scientists stated in their published paper that 736 patients (48%) in their study would not have fit into the molecular groups included in the 2008 WHO classification of adult AML. This prompted them to reevaluate genomic classification of AML from the beginning.

“We have shown that AML is an umbrella term for a group of at least 11 different types of leukemia,” said Peter Campbell, MBChB, PhD, co-leader of the study. “We can now start to decode these genetics to shape clinical trials and develop diagnostics.”

The scientists found NPM1-mutated AML to be the largest class in their cohort, accounting for 27% of the patients.

The second largest subgroup--the chromatin-spliceosome group—accounted for 18% of patients, the TP53-aneuploidy group accounted for 13%, and the IDH2^R172 mutations for 1%.

The study also showed that most patients had a unique combination of genetic changes driving their leukemia. This genetic complexity helps explain why AML shows such variability in survival rates among patients.

Under their new schema, the scientists were able to unambiguously classify 80% of the 1540 patients with driver mutations in a single subgroup. Fifty-six of the patients (4%) met criteria for 2 or more categories, primarily in the TP53-aneuploidy and chromatin-spliceosome groups.

They were not able to classify 11% of patients with driver mutations. They explained that these patients might have had mutations in drivers that were either not sequenced or had mutations that were missed.

The scientists applied their classification schema to an independent cohort from the Cancer Genome Atlas (TCGA). The new schema was able to replicate the absence of overlap among subgroups, and relative frequencies of the mutations were equivalent to those in the AML cohort.

“For the first time we untangled the genetic complexity seen in most AML cancer genomes into distinct evolutionary paths that lead to AML,” joint first author Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center in New York, said.

“By understanding these paths, we can help develop more appropriate treatments for individual patients with AML. We are now extending such studies across other leukemias."

The investigators recommend prospective clinical trials to further validate the schema.

The work was supported by the Wellcome Trust, Bundesministerium fur Bildung und Forschung, Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft, the European Hematology Association, Amgen and the Kay Kendall Leukaemia Fund.

Patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitors (TKIs) had 1.7 times the rate of arterial or venous vascular events of population-based controls in a large retrospective cohort study.

In addition, second-generation TKIs were associated with higher rates of myocardial infarction than was first-generation imatinib, Dr. Torsten Dahlén of Karolinska University Hospital Solna, Stockholm, and his associates reported. Although absolute numbers of cardiovascular events were low, physicians “should be aware of these risk factors when initiating TKI therapy in patients with CML,” the authors wrote in a study published online June 13 in the Annals of Internal Medicine .

Tyrosine kinase inhibitors have “revolutionized” the prognosis of CML and are generally well tolerated, the researchers noted. But case reports and follow-up studies of clinical trial participants have raised concerns about cardiovascular toxicities with second-generation TKIs, such as nilotinib, they added.

To further study the issue, the investigators compared 896 patients in Sweden who were diagnosed with CML between 2002 and 2012 with 4,438 age- and sex-matched controls from the national population register. By crosschecking both groups against a national patient database, the investigators calculated rates of venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular ischemia, and other arterial thromboses (Ann. Intern. Med. 2016 Jun 13. doi: 10.7326/M15-2306).

A total of 846 CML patients (94%) received a TKI during a median of 4.2 years of follow-up, the investigators reported. First-line therapy usually consisted of imatinib (89%), followed by nilotinib (9%) and dasatinib (1%).

The TKI cohort had 78 arterial and venous events during 3,969 person-years of follow-up, compared with 250 events during 21,917 person-years of follow-up for controls, for a statistically significant incidence rate ratio (IRR) of 1.7 (95% confidence interval, 1.3-2.2). Individual IRRs for arterial and venous events also reached statistical significance at 1.5 (95% CI, 1.1-2.1) and 2.0 (95% CI, 1.2-3.3), respectively. Deep venous thrombosis and myocardial infarction accounted for most of the excess risk, with IRRs of 2.2 (95% CI, 1.1-4.4) and 1.9 (95% CI, 1.3-2.7), respectively.

When investigators looked only at the TKI cohort, they found that the rates of arterial thromboembolic events were highest for nilotinib (29 events per 1,000 person-years), followed by dasatinib (19 events per 1,000 person-years) and imatinib (13 events per 1,000 person-years). Nilotinib also was associated with a substantially higher rate of all arterial and venous events (42/1,000 person-years) than dasatinib (20/1,000 person-years) and imatinib (16/1,000 person-years).

Furthermore, nilotinib and dasatinib were associated with higher rates of myocardial infarctions (29 and 19 per 1,000 person-years, respectively) and cerebrovascular ischemic events (11 and 4 events per 1,000 person-years, respectively) than was imatinib (8 events per 1,000 person-years and 4 events per 1,000 person-years, respectively). However, the absolute numbers of events were too small to allow for statistical comparisons, the researchers said.

“The observed increase in thrombotic events may be related to CML itself, the treatment administered, or both,” they noted, but “the prevalence of myocardial infarction in patients with CML before diagnosis was similar to that of the control population, [which] might indicate a treatment-related association.”

Among the 31 patients on TKIs who had a myocardial infarction, 26 (84%) had been previously diagnosed with at least one risk factor for cardiovascular disease, including diabetes (19%), atrial fibrillation (26%), angina pectoris (39%), hypertension (55%), and hyperlipidemia (23%).

Most patients who received nilotinib or dasatinib had previously received imatinib, meaning that they could have had more advanced disease that increased their risk of adverse events, according to the researchers.

“The small number of events also leads us to exercise caution in drawing any strong conclusions,” they added. “Future data from the Swedish CML register will provide more robust evidence regarding the risks of individual drugs as exposure time increases.”

The researchers received no funding for the work. Dr. Dahlén disclosed grant support from Merck outside the submitted work. Two coinvestigators disclosed ties to Ariad, Bristol-Myers, Novartis, and Squibb.

Patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitors (TKIs) had 1.7 times the rate of arterial or venous vascular events of population-based controls in a large retrospective cohort study.

In addition, second-generation TKIs were associated with higher rates of myocardial infarction than was first-generation imatinib, Dr. Torsten Dahlén of Karolinska University Hospital Solna, Stockholm, and his associates reported. Although absolute numbers of cardiovascular events were low, physicians “should be aware of these risk factors when initiating TKI therapy in patients with CML,” the authors wrote in a study published online June 13 in the Annals of Internal Medicine .

Tyrosine kinase inhibitors have “revolutionized” the prognosis of CML and are generally well tolerated, the researchers noted. But case reports and follow-up studies of clinical trial participants have raised concerns about cardiovascular toxicities with second-generation TKIs, such as nilotinib, they added.

To further study the issue, the investigators compared 896 patients in Sweden who were diagnosed with CML between 2002 and 2012 with 4,438 age- and sex-matched controls from the national population register. By crosschecking both groups against a national patient database, the investigators calculated rates of venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular ischemia, and other arterial thromboses (Ann. Intern. Med. 2016 Jun 13. doi: 10.7326/M15-2306).

A total of 846 CML patients (94%) received a TKI during a median of 4.2 years of follow-up, the investigators reported. First-line therapy usually consisted of imatinib (89%), followed by nilotinib (9%) and dasatinib (1%).

The TKI cohort had 78 arterial and venous events during 3,969 person-years of follow-up, compared with 250 events during 21,917 person-years of follow-up for controls, for a statistically significant incidence rate ratio (IRR) of 1.7 (95% confidence interval, 1.3-2.2). Individual IRRs for arterial and venous events also reached statistical significance at 1.5 (95% CI, 1.1-2.1) and 2.0 (95% CI, 1.2-3.3), respectively. Deep venous thrombosis and myocardial infarction accounted for most of the excess risk, with IRRs of 2.2 (95% CI, 1.1-4.4) and 1.9 (95% CI, 1.3-2.7), respectively.

When investigators looked only at the TKI cohort, they found that the rates of arterial thromboembolic events were highest for nilotinib (29 events per 1,000 person-years), followed by dasatinib (19 events per 1,000 person-years) and imatinib (13 events per 1,000 person-years). Nilotinib also was associated with a substantially higher rate of all arterial and venous events (42/1,000 person-years) than dasatinib (20/1,000 person-years) and imatinib (16/1,000 person-years).

Furthermore, nilotinib and dasatinib were associated with higher rates of myocardial infarctions (29 and 19 per 1,000 person-years, respectively) and cerebrovascular ischemic events (11 and 4 events per 1,000 person-years, respectively) than was imatinib (8 events per 1,000 person-years and 4 events per 1,000 person-years, respectively). However, the absolute numbers of events were too small to allow for statistical comparisons, the researchers said.

“The observed increase in thrombotic events may be related to CML itself, the treatment administered, or both,” they noted, but “the prevalence of myocardial infarction in patients with CML before diagnosis was similar to that of the control population, [which] might indicate a treatment-related association.”

Among the 31 patients on TKIs who had a myocardial infarction, 26 (84%) had been previously diagnosed with at least one risk factor for cardiovascular disease, including diabetes (19%), atrial fibrillation (26%), angina pectoris (39%), hypertension (55%), and hyperlipidemia (23%).

Most patients who received nilotinib or dasatinib had previously received imatinib, meaning that they could have had more advanced disease that increased their risk of adverse events, according to the researchers.

“The small number of events also leads us to exercise caution in drawing any strong conclusions,” they added. “Future data from the Swedish CML register will provide more robust evidence regarding the risks of individual drugs as exposure time increases.”

The researchers received no funding for the work. Dr. Dahlén disclosed grant support from Merck outside the submitted work. Two coinvestigators disclosed ties to Ariad, Bristol-Myers, Novartis, and Squibb.

Patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitors (TKIs) had 1.7 times the rate of arterial or venous vascular events of population-based controls in a large retrospective cohort study.

In addition, second-generation TKIs were associated with higher rates of myocardial infarction than was first-generation imatinib, Dr. Torsten Dahlén of Karolinska University Hospital Solna, Stockholm, and his associates reported. Although absolute numbers of cardiovascular events were low, physicians “should be aware of these risk factors when initiating TKI therapy in patients with CML,” the authors wrote in a study published online June 13 in the Annals of Internal Medicine .

Tyrosine kinase inhibitors have “revolutionized” the prognosis of CML and are generally well tolerated, the researchers noted. But case reports and follow-up studies of clinical trial participants have raised concerns about cardiovascular toxicities with second-generation TKIs, such as nilotinib, they added.

To further study the issue, the investigators compared 896 patients in Sweden who were diagnosed with CML between 2002 and 2012 with 4,438 age- and sex-matched controls from the national population register. By crosschecking both groups against a national patient database, the investigators calculated rates of venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular ischemia, and other arterial thromboses (Ann. Intern. Med. 2016 Jun 13. doi: 10.7326/M15-2306).

A total of 846 CML patients (94%) received a TKI during a median of 4.2 years of follow-up, the investigators reported. First-line therapy usually consisted of imatinib (89%), followed by nilotinib (9%) and dasatinib (1%).

The TKI cohort had 78 arterial and venous events during 3,969 person-years of follow-up, compared with 250 events during 21,917 person-years of follow-up for controls, for a statistically significant incidence rate ratio (IRR) of 1.7 (95% confidence interval, 1.3-2.2). Individual IRRs for arterial and venous events also reached statistical significance at 1.5 (95% CI, 1.1-2.1) and 2.0 (95% CI, 1.2-3.3), respectively. Deep venous thrombosis and myocardial infarction accounted for most of the excess risk, with IRRs of 2.2 (95% CI, 1.1-4.4) and 1.9 (95% CI, 1.3-2.7), respectively.

When investigators looked only at the TKI cohort, they found that the rates of arterial thromboembolic events were highest for nilotinib (29 events per 1,000 person-years), followed by dasatinib (19 events per 1,000 person-years) and imatinib (13 events per 1,000 person-years). Nilotinib also was associated with a substantially higher rate of all arterial and venous events (42/1,000 person-years) than dasatinib (20/1,000 person-years) and imatinib (16/1,000 person-years).

Furthermore, nilotinib and dasatinib were associated with higher rates of myocardial infarctions (29 and 19 per 1,000 person-years, respectively) and cerebrovascular ischemic events (11 and 4 events per 1,000 person-years, respectively) than was imatinib (8 events per 1,000 person-years and 4 events per 1,000 person-years, respectively). However, the absolute numbers of events were too small to allow for statistical comparisons, the researchers said.

“The observed increase in thrombotic events may be related to CML itself, the treatment administered, or both,” they noted, but “the prevalence of myocardial infarction in patients with CML before diagnosis was similar to that of the control population, [which] might indicate a treatment-related association.”

Among the 31 patients on TKIs who had a myocardial infarction, 26 (84%) had been previously diagnosed with at least one risk factor for cardiovascular disease, including diabetes (19%), atrial fibrillation (26%), angina pectoris (39%), hypertension (55%), and hyperlipidemia (23%).

Most patients who received nilotinib or dasatinib had previously received imatinib, meaning that they could have had more advanced disease that increased their risk of adverse events, according to the researchers.

“The small number of events also leads us to exercise caution in drawing any strong conclusions,” they added. “Future data from the Swedish CML register will provide more robust evidence regarding the risks of individual drugs as exposure time increases.”

The researchers received no funding for the work. Dr. Dahlén disclosed grant support from Merck outside the submitted work. Two coinvestigators disclosed ties to Ariad, Bristol-Myers, Novartis, and Squibb.

ASCO Annual Meeting 2016
© ASCO/Matt Herp

CHICAGO—Nearly 60% of chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib maintain treatment-free remission for 48 weeks after stopping treatment, according to a new study, ENESTop, presented at the 2016 ASCO Annual Meeting (abstract 7054). 

Treatment-free remission (TFR)—stopping tyrosine kinase inhibitor therapy after achieving a sustained deep molecular response—is an emerging treatment goal for patients with CML in chronic phase (CML-CP).

Results from Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) demonstrated that patients on long-term imatinib who had not achieved MR4.5 were more likely to achieve this response by switching to nilotinib than by remaining on imatinib. 

“This suggests that, compared with remaining on imatinib, switching to nilotinib may enable more of these patients to reach a molecular response level required for attempting to achieve TFR in clinical trials,” said lead author Timothy Hughes, MD, of University of Adelaide in Australia. 

ENESTop is the first study, providing the largest set of prospective TFR data to date, to specifically assess TFR in patients who achieved a sustained deep molecular response after switching from imatinib to nilotinib. 

The trial evaluated 126 patients who were able to achieve a sustained deep molecular response with nilotinib, but not with prior imatinib therapy.

The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of major molecular response (MMR) within 48 weeks of nilotinib discontinuation in the TFR phase. 

Some 57.9% patients who achieved a sustained deep molecular response following at least three years of nilotinib therapy maintained a molecular response 48 weeks after stopping treatment.

Of the 51 patients with confirmed loss of MR4.0 or loss of MMR who restarted nilotinib, 98.0% regained at least MMR, with 94.1% regaining MR4.0 and 92.2% regaining MR4.5. 

By weeks 12 and 13 of treatment reinitiation with nilotinib, half of retreated patients already achieved MR4.0 and MR4.5, respectively. 

One patient entered the treatment reinitiation phase, but did not regain MMR by 20 weeks and discontinued the study. 

“MR4.5 achieved following the switch from imatinib to nilotinib,” Dr Hughes said, “was durable in most patients; more than three quarters of enrolled patients were eligible to enter the TFR phase.”

No new safety signals were observed, Dr Hughes said. Consistent with reports in imatinib-treated patients, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking nilotinib in the consolidation phase. 

Dr Hughes said the results suggest “TFR can be maintained in the majority of patients who achieve a sustained deep molecular response with nilotinib following switch from imatinib.”

He continued, “The results from ENESTop, together with those from ENESTcmr, show that a higher proportion of patients switching to nilotinib achieve MR 4.5, suggesting that a higher proportion of patients switching to nilotinib will achieve TFR compared with patients continuing on imatinib.”

Novartis is the sponsor of ENESTop and the manufacturer of imatinib (Gleevec) and nilotinib (Tasigna). Dr Hughes disclosed that he has received honoraria and research funding from Novartis.

ASCO Annual Meeting 2016
© ASCO/Matt Herp

CHICAGO—Nearly 60% of chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib maintain treatment-free remission for 48 weeks after stopping treatment, according to a new study, ENESTop, presented at the 2016 ASCO Annual Meeting (abstract 7054). 

Treatment-free remission (TFR)—stopping tyrosine kinase inhibitor therapy after achieving a sustained deep molecular response—is an emerging treatment goal for patients with CML in chronic phase (CML-CP).

Results from Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) demonstrated that patients on long-term imatinib who had not achieved MR4.5 were more likely to achieve this response by switching to nilotinib than by remaining on imatinib. 

“This suggests that, compared with remaining on imatinib, switching to nilotinib may enable more of these patients to reach a molecular response level required for attempting to achieve TFR in clinical trials,” said lead author Timothy Hughes, MD, of University of Adelaide in Australia. 

ENESTop is the first study, providing the largest set of prospective TFR data to date, to specifically assess TFR in patients who achieved a sustained deep molecular response after switching from imatinib to nilotinib. 

The trial evaluated 126 patients who were able to achieve a sustained deep molecular response with nilotinib, but not with prior imatinib therapy.

The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of major molecular response (MMR) within 48 weeks of nilotinib discontinuation in the TFR phase. 

Some 57.9% patients who achieved a sustained deep molecular response following at least three years of nilotinib therapy maintained a molecular response 48 weeks after stopping treatment.

Of the 51 patients with confirmed loss of MR4.0 or loss of MMR who restarted nilotinib, 98.0% regained at least MMR, with 94.1% regaining MR4.0 and 92.2% regaining MR4.5. 

By weeks 12 and 13 of treatment reinitiation with nilotinib, half of retreated patients already achieved MR4.0 and MR4.5, respectively. 

One patient entered the treatment reinitiation phase, but did not regain MMR by 20 weeks and discontinued the study. 

“MR4.5 achieved following the switch from imatinib to nilotinib,” Dr Hughes said, “was durable in most patients; more than three quarters of enrolled patients were eligible to enter the TFR phase.”

No new safety signals were observed, Dr Hughes said. Consistent with reports in imatinib-treated patients, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking nilotinib in the consolidation phase. 

Dr Hughes said the results suggest “TFR can be maintained in the majority of patients who achieve a sustained deep molecular response with nilotinib following switch from imatinib.”

He continued, “The results from ENESTop, together with those from ENESTcmr, show that a higher proportion of patients switching to nilotinib achieve MR 4.5, suggesting that a higher proportion of patients switching to nilotinib will achieve TFR compared with patients continuing on imatinib.”

Novartis is the sponsor of ENESTop and the manufacturer of imatinib (Gleevec) and nilotinib (Tasigna). Dr Hughes disclosed that he has received honoraria and research funding from Novartis.

ASCO Annual Meeting 2016
© ASCO/Matt Herp

CHICAGO—Nearly 60% of chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib maintain treatment-free remission for 48 weeks after stopping treatment, according to a new study, ENESTop, presented at the 2016 ASCO Annual Meeting (abstract 7054). 

Treatment-free remission (TFR)—stopping tyrosine kinase inhibitor therapy after achieving a sustained deep molecular response—is an emerging treatment goal for patients with CML in chronic phase (CML-CP).

Results from Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) demonstrated that patients on long-term imatinib who had not achieved MR4.5 were more likely to achieve this response by switching to nilotinib than by remaining on imatinib. 

“This suggests that, compared with remaining on imatinib, switching to nilotinib may enable more of these patients to reach a molecular response level required for attempting to achieve TFR in clinical trials,” said lead author Timothy Hughes, MD, of University of Adelaide in Australia. 

ENESTop is the first study, providing the largest set of prospective TFR data to date, to specifically assess TFR in patients who achieved a sustained deep molecular response after switching from imatinib to nilotinib. 

The trial evaluated 126 patients who were able to achieve a sustained deep molecular response with nilotinib, but not with prior imatinib therapy.

The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of major molecular response (MMR) within 48 weeks of nilotinib discontinuation in the TFR phase. 

Some 57.9% patients who achieved a sustained deep molecular response following at least three years of nilotinib therapy maintained a molecular response 48 weeks after stopping treatment.

Of the 51 patients with confirmed loss of MR4.0 or loss of MMR who restarted nilotinib, 98.0% regained at least MMR, with 94.1% regaining MR4.0 and 92.2% regaining MR4.5. 

By weeks 12 and 13 of treatment reinitiation with nilotinib, half of retreated patients already achieved MR4.0 and MR4.5, respectively. 

One patient entered the treatment reinitiation phase, but did not regain MMR by 20 weeks and discontinued the study. 

“MR4.5 achieved following the switch from imatinib to nilotinib,” Dr Hughes said, “was durable in most patients; more than three quarters of enrolled patients were eligible to enter the TFR phase.”

No new safety signals were observed, Dr Hughes said. Consistent with reports in imatinib-treated patients, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking nilotinib in the consolidation phase. 

Dr Hughes said the results suggest “TFR can be maintained in the majority of patients who achieve a sustained deep molecular response with nilotinib following switch from imatinib.”

He continued, “The results from ENESTop, together with those from ENESTcmr, show that a higher proportion of patients switching to nilotinib achieve MR 4.5, suggesting that a higher proportion of patients switching to nilotinib will achieve TFR compared with patients continuing on imatinib.”

Novartis is the sponsor of ENESTop and the manufacturer of imatinib (Gleevec) and nilotinib (Tasigna). Dr Hughes disclosed that he has received honoraria and research funding from Novartis.

Hagop M. Kantarjian, MD
Photo courtesy of MDACC

In multiple categories, the antibody-drug conjuagate inotuzumab ozogamicin achieved significantly better results than the standard of care in the treatment of adults with acute lymphoblastic leukemia (ALL). 

Patients in the inotuzumab arm experienced a higher rate of complete remissions, a greater frequency of achieving minimal residual disease negativity, and longer progression-free survival and overall survival. 

However, veno-occlusive liver disease occurred more frequently in the inotuzumab-treated patients. 

Inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, received breakthrough designation for ALL from the US Food and Drug Administration last October.

For this phase 3 trial, called INO-VATE, investigators randomized 326 patients to receive inotuzumab or the investigator’s choice of standard therapy. The first 218 patients, 109 in each arm, were included in the intent-to-treat analysis of complete remission.

Hagop M. Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, presented the findings at the European Hematology Association meeting as abstract LB2233*. The study was simultaneously published in NEJM. Data cited here are based on the published paper.

Patients had to be 18 years of age or older and had to have relapsed or refractory disease with 5% or more blasts in the bone marrow. They had to be CD22-positive and could be either Philadelphia chromosome positive or negative. Patients had to be scheduled for their first or second salvage therapy. 

No cross-over between the groups was allowed.

The primary endpoints were complete remission including complete remission with incomplete hematologic recovery, and overall survival.

Treatments

Patients in the inotuzumab arm received the drug intravenously at a starting dose of 1.8 mg/m² per cycle for up to 6 cycles. Once a patient achieved complete remission or remission with incomplete hematologic recovery, the dose per cycle was reduced to 1.5 mg/m².

Patients in the standard therapy arm could receive one of three regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor), cytarabine plus mitoxantrone, or high-dose cytarabine. These regimens were chosen because they are commonly used for the treatment of relapsed or refractory ALL.

Patient characteristics

Patients in both arms were a median age of 47, range 18 – 79. And a little more than a third in each arm were 55 or older. Most patients were white, and about half had an ECOG performance status of 1.

Almost three quarters of the patients in each arm had bone marrow blasts of 50% or more.

Results

Patients in the inotuzumab arm received a median of 3 cycles of therapy and those in the standard therapy arm received a median of 1 cycle. 

More patients in the inotuzumab arm received treatment for 2 or more cycles (73%) compared to the standard therapy arm (22%), a finding the investigators said was expected.

Dose reductions were more common in the inotuzumab arm (12%) compared with the standard therapy arm (3%). 

More inotuzumab-treated patients discontinued therapy due to achieving complete remission (35%) than in the standard arm (15%).

And fewer patients in the inotuzumab arm (10%) discontinued treatment because of resistant disease than in the standard arm (40%).

Efficacy

The rate of complete remission, including incomplete hematologic recovery, was significantly higher in the inotuzumab group (80.7%) than in the standard group (29.4%), P<0.001.

In both groups, patients who achieved complete remission, including those with incomplete hematologic recovery, did so at the end of cycle 1. 

"Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier,” Dr Kantarjian noted, “and just 18 to 25 percent in those who relapse later." 

"Patients in the inotuzumab ozogamicin study,” he continued, “had remission rates of 58% higher than previously reported, possibly due to patients being treated later in the disease course."

Among the complete responders, significantly more patients achieved minimal residual disease (MRD) negativity in the inotuzumab arm (78.4%) than in the standard therapy group (28.1%), P<0.001.

The median duration of remission was 4.6 months in the inotuzumab arm and 3.1 months in the standard therapy group, P=0.03.

And more patients treated with inotuzumab (41%) proceeded to stem cell transplant directly after treatment than in the standard therapy group (11%), P<0.001.

"Given that stem cell transplant is considered the only curative treatment option,” Dr Kantarjian said, “the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging."

Survival

The intention-to-treat survival analysis included 164 patients in the inotuzumab arm and 162 in the standard therapy arm.

Progression-free survival (PFS) was significantly longer in the inotuzumab arm than in the standard therapy arm, a median of 5.0 months compared to 1.8 months, respectively, P<0.001.

The second primary objective of longer overall survival at the prespecified boundary of P=0.0208 was not met. Median overall survival was 7.7 months in the inotuzumab arm and 6.7 months in the standard therapy group, P=0.04.

Safety

In both treatment groups, the most common hematologic adverse events of any cause occurring during treatment were cytopenias.

Thrombocytopenia of grade 3 or higher was lower in the inotuzumab arm (37%) than in the standard therapy arm (59%).

Febrile neutropenia of grade 3 or higher occurred in 24% of inotuzumab-treated patients compared with 49% of patients in the standard therapy group. 

In the inotuzumab group, the most common non-hematologic adverse events of any grade included nausea (32%), headache (28%), and pyrexia (27%). Grade 3 or higher nausea, headache, and pyrexia occurred in 2%, 1%, and 4%, respectively.

In the standard therapy arm, the most common non-hematologic events of any grade included nausea (47%), pyrexia (43%), and diarrhea (40%). Grade 3 or higher nausea, pyrexia, and diarrhea occurred in 0%, 5%, and 1%, respectively. 

Febrile neutropenia was the most frequently reported serious adverse event, occurring in 12% of the inotuzumab-treated patients and 18% in the standard therapy group.

And liver-related adverse events were more common in the inotuzumab arm. 

The most frequent liver-related adverse event of any grade was increased aspartate aminotransferase level, 20% in the inotuzumab group and 10% in the standard therapy group, hyperbilirubinemia, 15% and 10%, respectively, and increased alanine aminotransferase level, 14% and 11%, respectively. 

Veno-occlusive liver disease (VOD) occurred more frequently with inotuzumab (11%, 15 patients) compared with standard therapy (1%, 1 patient). And cases were reported up to 2 years after randomization. 

Five of the 15 patients developed VOD during or shortly after inotuzumab treatment. No cases of VOD occurred during the administration of standard therapy. 

Seventeen deaths occurred during treatment in the inotuzumab arm and 11 in the standard therapy arm. Four deaths in the inotuzumab group and 2 in the standard therapy group were believed to be treatment-related. 

The study was funded by Pfizer.

*Data in the abstract differ from those published in NEJM.

Hagop M. Kantarjian, MD
Photo courtesy of MDACC

In multiple categories, the antibody-drug conjuagate inotuzumab ozogamicin achieved significantly better results than the standard of care in the treatment of adults with acute lymphoblastic leukemia (ALL). 

Patients in the inotuzumab arm experienced a higher rate of complete remissions, a greater frequency of achieving minimal residual disease negativity, and longer progression-free survival and overall survival. 

However, veno-occlusive liver disease occurred more frequently in the inotuzumab-treated patients. 

Inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, received breakthrough designation for ALL from the US Food and Drug Administration last October.

For this phase 3 trial, called INO-VATE, investigators randomized 326 patients to receive inotuzumab or the investigator’s choice of standard therapy. The first 218 patients, 109 in each arm, were included in the intent-to-treat analysis of complete remission.

Hagop M. Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, presented the findings at the European Hematology Association meeting as abstract LB2233*. The study was simultaneously published in NEJM. Data cited here are based on the published paper.

Patients had to be 18 years of age or older and had to have relapsed or refractory disease with 5% or more blasts in the bone marrow. They had to be CD22-positive and could be either Philadelphia chromosome positive or negative. Patients had to be scheduled for their first or second salvage therapy. 

No cross-over between the groups was allowed.

The primary endpoints were complete remission including complete remission with incomplete hematologic recovery, and overall survival.

Treatments

Patients in the inotuzumab arm received the drug intravenously at a starting dose of 1.8 mg/m² per cycle for up to 6 cycles. Once a patient achieved complete remission or remission with incomplete hematologic recovery, the dose per cycle was reduced to 1.5 mg/m².

Patients in the standard therapy arm could receive one of three regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor), cytarabine plus mitoxantrone, or high-dose cytarabine. These regimens were chosen because they are commonly used for the treatment of relapsed or refractory ALL.

Patient characteristics

Patients in both arms were a median age of 47, range 18 – 79. And a little more than a third in each arm were 55 or older. Most patients were white, and about half had an ECOG performance status of 1.

Almost three quarters of the patients in each arm had bone marrow blasts of 50% or more.

Results

Patients in the inotuzumab arm received a median of 3 cycles of therapy and those in the standard therapy arm received a median of 1 cycle. 

More patients in the inotuzumab arm received treatment for 2 or more cycles (73%) compared to the standard therapy arm (22%), a finding the investigators said was expected.

Dose reductions were more common in the inotuzumab arm (12%) compared with the standard therapy arm (3%). 

More inotuzumab-treated patients discontinued therapy due to achieving complete remission (35%) than in the standard arm (15%).

And fewer patients in the inotuzumab arm (10%) discontinued treatment because of resistant disease than in the standard arm (40%).

Efficacy

The rate of complete remission, including incomplete hematologic recovery, was significantly higher in the inotuzumab group (80.7%) than in the standard group (29.4%), P<0.001.

In both groups, patients who achieved complete remission, including those with incomplete hematologic recovery, did so at the end of cycle 1. 

"Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier,” Dr Kantarjian noted, “and just 18 to 25 percent in those who relapse later." 

"Patients in the inotuzumab ozogamicin study,” he continued, “had remission rates of 58% higher than previously reported, possibly due to patients being treated later in the disease course."

Among the complete responders, significantly more patients achieved minimal residual disease (MRD) negativity in the inotuzumab arm (78.4%) than in the standard therapy group (28.1%), P<0.001.

The median duration of remission was 4.6 months in the inotuzumab arm and 3.1 months in the standard therapy group, P=0.03.

And more patients treated with inotuzumab (41%) proceeded to stem cell transplant directly after treatment than in the standard therapy group (11%), P<0.001.

"Given that stem cell transplant is considered the only curative treatment option,” Dr Kantarjian said, “the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging."

Survival

The intention-to-treat survival analysis included 164 patients in the inotuzumab arm and 162 in the standard therapy arm.

Progression-free survival (PFS) was significantly longer in the inotuzumab arm than in the standard therapy arm, a median of 5.0 months compared to 1.8 months, respectively, P<0.001.

The second primary objective of longer overall survival at the prespecified boundary of P=0.0208 was not met. Median overall survival was 7.7 months in the inotuzumab arm and 6.7 months in the standard therapy group, P=0.04.

Safety

In both treatment groups, the most common hematologic adverse events of any cause occurring during treatment were cytopenias.

Thrombocytopenia of grade 3 or higher was lower in the inotuzumab arm (37%) than in the standard therapy arm (59%).

Febrile neutropenia of grade 3 or higher occurred in 24% of inotuzumab-treated patients compared with 49% of patients in the standard therapy group. 

In the inotuzumab group, the most common non-hematologic adverse events of any grade included nausea (32%), headache (28%), and pyrexia (27%). Grade 3 or higher nausea, headache, and pyrexia occurred in 2%, 1%, and 4%, respectively.

In the standard therapy arm, the most common non-hematologic events of any grade included nausea (47%), pyrexia (43%), and diarrhea (40%). Grade 3 or higher nausea, pyrexia, and diarrhea occurred in 0%, 5%, and 1%, respectively. 

Febrile neutropenia was the most frequently reported serious adverse event, occurring in 12% of the inotuzumab-treated patients and 18% in the standard therapy group.

And liver-related adverse events were more common in the inotuzumab arm. 

The most frequent liver-related adverse event of any grade was increased aspartate aminotransferase level, 20% in the inotuzumab group and 10% in the standard therapy group, hyperbilirubinemia, 15% and 10%, respectively, and increased alanine aminotransferase level, 14% and 11%, respectively. 

Veno-occlusive liver disease (VOD) occurred more frequently with inotuzumab (11%, 15 patients) compared with standard therapy (1%, 1 patient). And cases were reported up to 2 years after randomization. 

Five of the 15 patients developed VOD during or shortly after inotuzumab treatment. No cases of VOD occurred during the administration of standard therapy. 

Seventeen deaths occurred during treatment in the inotuzumab arm and 11 in the standard therapy arm. Four deaths in the inotuzumab group and 2 in the standard therapy group were believed to be treatment-related. 

The study was funded by Pfizer.

*Data in the abstract differ from those published in NEJM.

Hagop M. Kantarjian, MD
Photo courtesy of MDACC

In multiple categories, the antibody-drug conjuagate inotuzumab ozogamicin achieved significantly better results than the standard of care in the treatment of adults with acute lymphoblastic leukemia (ALL). 

Patients in the inotuzumab arm experienced a higher rate of complete remissions, a greater frequency of achieving minimal residual disease negativity, and longer progression-free survival and overall survival. 

However, veno-occlusive liver disease occurred more frequently in the inotuzumab-treated patients. 

Inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, received breakthrough designation for ALL from the US Food and Drug Administration last October.

For this phase 3 trial, called INO-VATE, investigators randomized 326 patients to receive inotuzumab or the investigator’s choice of standard therapy. The first 218 patients, 109 in each arm, were included in the intent-to-treat analysis of complete remission.

Hagop M. Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, presented the findings at the European Hematology Association meeting as abstract LB2233*. The study was simultaneously published in NEJM. Data cited here are based on the published paper.

Patients had to be 18 years of age or older and had to have relapsed or refractory disease with 5% or more blasts in the bone marrow. They had to be CD22-positive and could be either Philadelphia chromosome positive or negative. Patients had to be scheduled for their first or second salvage therapy. 

No cross-over between the groups was allowed.

The primary endpoints were complete remission including complete remission with incomplete hematologic recovery, and overall survival.

Treatments

Patients in the inotuzumab arm received the drug intravenously at a starting dose of 1.8 mg/m² per cycle for up to 6 cycles. Once a patient achieved complete remission or remission with incomplete hematologic recovery, the dose per cycle was reduced to 1.5 mg/m².

Patients in the standard therapy arm could receive one of three regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor), cytarabine plus mitoxantrone, or high-dose cytarabine. These regimens were chosen because they are commonly used for the treatment of relapsed or refractory ALL.

Patient characteristics

Patients in both arms were a median age of 47, range 18 – 79. And a little more than a third in each arm were 55 or older. Most patients were white, and about half had an ECOG performance status of 1.

Almost three quarters of the patients in each arm had bone marrow blasts of 50% or more.

Results

Patients in the inotuzumab arm received a median of 3 cycles of therapy and those in the standard therapy arm received a median of 1 cycle. 

More patients in the inotuzumab arm received treatment for 2 or more cycles (73%) compared to the standard therapy arm (22%), a finding the investigators said was expected.

Dose reductions were more common in the inotuzumab arm (12%) compared with the standard therapy arm (3%). 

More inotuzumab-treated patients discontinued therapy due to achieving complete remission (35%) than in the standard arm (15%).

And fewer patients in the inotuzumab arm (10%) discontinued treatment because of resistant disease than in the standard arm (40%).

Efficacy

The rate of complete remission, including incomplete hematologic recovery, was significantly higher in the inotuzumab group (80.7%) than in the standard group (29.4%), P<0.001.

In both groups, patients who achieved complete remission, including those with incomplete hematologic recovery, did so at the end of cycle 1. 

"Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier,” Dr Kantarjian noted, “and just 18 to 25 percent in those who relapse later." 

"Patients in the inotuzumab ozogamicin study,” he continued, “had remission rates of 58% higher than previously reported, possibly due to patients being treated later in the disease course."

Among the complete responders, significantly more patients achieved minimal residual disease (MRD) negativity in the inotuzumab arm (78.4%) than in the standard therapy group (28.1%), P<0.001.

The median duration of remission was 4.6 months in the inotuzumab arm and 3.1 months in the standard therapy group, P=0.03.

And more patients treated with inotuzumab (41%) proceeded to stem cell transplant directly after treatment than in the standard therapy group (11%), P<0.001.

"Given that stem cell transplant is considered the only curative treatment option,” Dr Kantarjian said, “the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging."

Survival

The intention-to-treat survival analysis included 164 patients in the inotuzumab arm and 162 in the standard therapy arm.

Progression-free survival (PFS) was significantly longer in the inotuzumab arm than in the standard therapy arm, a median of 5.0 months compared to 1.8 months, respectively, P<0.001.

The second primary objective of longer overall survival at the prespecified boundary of P=0.0208 was not met. Median overall survival was 7.7 months in the inotuzumab arm and 6.7 months in the standard therapy group, P=0.04.

Safety

In both treatment groups, the most common hematologic adverse events of any cause occurring during treatment were cytopenias.

Thrombocytopenia of grade 3 or higher was lower in the inotuzumab arm (37%) than in the standard therapy arm (59%).

Febrile neutropenia of grade 3 or higher occurred in 24% of inotuzumab-treated patients compared with 49% of patients in the standard therapy group. 

In the inotuzumab group, the most common non-hematologic adverse events of any grade included nausea (32%), headache (28%), and pyrexia (27%). Grade 3 or higher nausea, headache, and pyrexia occurred in 2%, 1%, and 4%, respectively.

In the standard therapy arm, the most common non-hematologic events of any grade included nausea (47%), pyrexia (43%), and diarrhea (40%). Grade 3 or higher nausea, pyrexia, and diarrhea occurred in 0%, 5%, and 1%, respectively. 

Febrile neutropenia was the most frequently reported serious adverse event, occurring in 12% of the inotuzumab-treated patients and 18% in the standard therapy group.

And liver-related adverse events were more common in the inotuzumab arm. 

The most frequent liver-related adverse event of any grade was increased aspartate aminotransferase level, 20% in the inotuzumab group and 10% in the standard therapy group, hyperbilirubinemia, 15% and 10%, respectively, and increased alanine aminotransferase level, 14% and 11%, respectively. 

Veno-occlusive liver disease (VOD) occurred more frequently with inotuzumab (11%, 15 patients) compared with standard therapy (1%, 1 patient). And cases were reported up to 2 years after randomization. 

Five of the 15 patients developed VOD during or shortly after inotuzumab treatment. No cases of VOD occurred during the administration of standard therapy. 

Seventeen deaths occurred during treatment in the inotuzumab arm and 11 in the standard therapy arm. Four deaths in the inotuzumab group and 2 in the standard therapy group were believed to be treatment-related. 

The study was funded by Pfizer.

*Data in the abstract differ from those published in NEJM.

DNA helix
Image courtesy Spencer Phillips

Using next-generation sequencing (NGS) technology, a team of researchers has discovered 2 new subtypes of pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL).

The 2 new subtypes, called DUX4-rearranged and ETV6/RUNX1-like, may improve risk stratification and targeted therapeutic options for treatment of the disease, the researchers say.

Previous studies have defined 6 major groups of ALL in children. The 2 new types can now be added to these groups.

The research team performed RNA sequencing in a population-based series of 195 pediatric BCP ALL cases, all under 18 years.

They found gene fusions present in 65% of BCP ALL cases. They also identified several new fusions along with the 2 novel subtypes.

The DUX4-rearranged subtype occurs “when a gene called DUX4, which is normally inactive in blood cells, becomes activated when the gene is relocated in the genome,” corresponding author Henrik Lilljebjörn, of Lund University in Sweden, said.

The DUX4-rearranged subtype was represented in 4% of the cases. It led to overexpression of DUX4 and frequently occurred together with intragenic ERG deletions.

The team observed a borderline significance (P=0.051) for age in cases with DUX4 rearrangements. Those with DUX4 rearrangements tended to be from older patients compared to cases lacking the fusion, with a median age of 6.5 year versus 4 years, respectively. The authors noted that this association needs to be confirmed in larger cohorts.

The ETV6/RUNX1-like subtype “resembles a previously known type of childhood leukemia,”Lilljebjörn said, “but is caused by other genetic mutations."

The ETV6/RUNX1-like subtype was represented in 3% of the BCP ALL cases.

According to the team, if all known subtypes are taken into consideration, “98% of the BCP ALL cases could be classified into distinct genetic subtypes with a known underlying driver mutation, or, less commonly, with a rare in-frame gene fusion,” they wrote.

“Finding the critical mutations in the diseased cells,” principal investigator Thoas Fioretos, MD, PhD, of Lund University, explained, “is an important condition for understanding the mechanisms of the disease and ultimately discovering new therapies.”

The investigators published their work in Nature Communications.

The research was funded mainly by The Swedish Childhood Cancer Foundation, The Swedish Cancer Society, The Swedish Research Council, the Faculty of Medicine at Lund University and Region Skåne.

DNA helix
Image courtesy Spencer Phillips

Using next-generation sequencing (NGS) technology, a team of researchers has discovered 2 new subtypes of pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL).

The 2 new subtypes, called DUX4-rearranged and ETV6/RUNX1-like, may improve risk stratification and targeted therapeutic options for treatment of the disease, the researchers say.

Previous studies have defined 6 major groups of ALL in children. The 2 new types can now be added to these groups.

The research team performed RNA sequencing in a population-based series of 195 pediatric BCP ALL cases, all under 18 years.

They found gene fusions present in 65% of BCP ALL cases. They also identified several new fusions along with the 2 novel subtypes.

The DUX4-rearranged subtype occurs “when a gene called DUX4, which is normally inactive in blood cells, becomes activated when the gene is relocated in the genome,” corresponding author Henrik Lilljebjörn, of Lund University in Sweden, said.

The DUX4-rearranged subtype was represented in 4% of the cases. It led to overexpression of DUX4 and frequently occurred together with intragenic ERG deletions.

The team observed a borderline significance (P=0.051) for age in cases with DUX4 rearrangements. Those with DUX4 rearrangements tended to be from older patients compared to cases lacking the fusion, with a median age of 6.5 year versus 4 years, respectively. The authors noted that this association needs to be confirmed in larger cohorts.

The ETV6/RUNX1-like subtype “resembles a previously known type of childhood leukemia,”Lilljebjörn said, “but is caused by other genetic mutations."

The ETV6/RUNX1-like subtype was represented in 3% of the BCP ALL cases.

According to the team, if all known subtypes are taken into consideration, “98% of the BCP ALL cases could be classified into distinct genetic subtypes with a known underlying driver mutation, or, less commonly, with a rare in-frame gene fusion,” they wrote.

“Finding the critical mutations in the diseased cells,” principal investigator Thoas Fioretos, MD, PhD, of Lund University, explained, “is an important condition for understanding the mechanisms of the disease and ultimately discovering new therapies.”

The investigators published their work in Nature Communications.

The research was funded mainly by The Swedish Childhood Cancer Foundation, The Swedish Cancer Society, The Swedish Research Council, the Faculty of Medicine at Lund University and Region Skåne.

DNA helix
Image courtesy Spencer Phillips

Using next-generation sequencing (NGS) technology, a team of researchers has discovered 2 new subtypes of pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL).

The 2 new subtypes, called DUX4-rearranged and ETV6/RUNX1-like, may improve risk stratification and targeted therapeutic options for treatment of the disease, the researchers say.

Previous studies have defined 6 major groups of ALL in children. The 2 new types can now be added to these groups.

The research team performed RNA sequencing in a population-based series of 195 pediatric BCP ALL cases, all under 18 years.

They found gene fusions present in 65% of BCP ALL cases. They also identified several new fusions along with the 2 novel subtypes.

The DUX4-rearranged subtype occurs “when a gene called DUX4, which is normally inactive in blood cells, becomes activated when the gene is relocated in the genome,” corresponding author Henrik Lilljebjörn, of Lund University in Sweden, said.

The DUX4-rearranged subtype was represented in 4% of the cases. It led to overexpression of DUX4 and frequently occurred together with intragenic ERG deletions.

The team observed a borderline significance (P=0.051) for age in cases with DUX4 rearrangements. Those with DUX4 rearrangements tended to be from older patients compared to cases lacking the fusion, with a median age of 6.5 year versus 4 years, respectively. The authors noted that this association needs to be confirmed in larger cohorts.

The ETV6/RUNX1-like subtype “resembles a previously known type of childhood leukemia,”Lilljebjörn said, “but is caused by other genetic mutations."

The ETV6/RUNX1-like subtype was represented in 3% of the BCP ALL cases.

According to the team, if all known subtypes are taken into consideration, “98% of the BCP ALL cases could be classified into distinct genetic subtypes with a known underlying driver mutation, or, less commonly, with a rare in-frame gene fusion,” they wrote.

“Finding the critical mutations in the diseased cells,” principal investigator Thoas Fioretos, MD, PhD, of Lund University, explained, “is an important condition for understanding the mechanisms of the disease and ultimately discovering new therapies.”

The investigators published their work in Nature Communications.

The research was funded mainly by The Swedish Childhood Cancer Foundation, The Swedish Cancer Society, The Swedish Research Council, the Faculty of Medicine at Lund University and Region Skåne.

MRI scan of the brain

New research has found that higher blood concentrations of methotrexate in pediatric leukemia patients during treatment results in difficulties with mental flexibility, organization, and related skills for the long-term survivors. 

And in patients with acute lymphoblastic leukemia (ALL) who had higher levels of methotrexate during treatment, brain imaging showed anatomical and functional changes in regions of the brain involved with executive functioning. Methotrexate is one of the few chemotherapy agents that crosses the blood–brain barrier. 

“This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors,” lead author Kevin Krull, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, said. 

“This information is essential for designing effective interventions to address the risk,” he said.

To examine the association between methotrexate exposure and neurocognitive outcomes, the investigators enrolled 218 long-term pediatric ALL survivors who participated in the St Jude Total Therapy XV clinical trial between 2000 and 2010. 

The patients had been treated with multidrug chemotherapy according to the Total Therapy XV protocol, which included intrathecal treatments with methotrexate, hydrocortisone, and cytarabine in addition to other chemotherapeutic agents.

Researchers calculated methotrexate concentrations by measuring blood levels of the drug before, during, and after treatment. They also checked blood levels of the amino acid homocysteine, a marker of methotrexate activity, and the chemotherapy agent dexamethasone.

All patients had survived at least 5 years from their diagnosis and were at least 8 years old when this study was conducted.

Investigators performed neurocognitive testing, functional magnetic resonance imaging (MRI) during a task, and structural MRI with diffusion tensor imaging.

At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis. Fifty-one percent were male, 74% were white, and 57% were in the low-risk treatment stratum.

Investigators found that the survivors’ intelligence was within normal limits compared with population expectations.

However, they found measures of executive function, processing speed, and memory to be less than population means, with a significance of P<0.02 after correction for false discovery rates.

And while impact of methotrexate varied, some survivors had executive functioning scores that indicated moderate to almost severe impairment. 

Investigators also found higher plasma methotrexate to be associated with higher functional MRI activity, thicker cortex, and higher activity in frontal brain regions, regions often associated with executive function.

The investigators found neurocognitive impairment also to be associated with these imaging findings .

The increased activity in the frontal lobe region suggests that survivors’ brains may be working harder to compensate for impaired cognitive function, the investigators believe.

When they adjusted for age or dose of leucovorin rescue, these associations did not change.

And consistent with the methotrexate exposure, elevated homocysteine levels during therapy were associated with poorer cognitive flexibility.

The authors noted that they did not find an association between other chemotherapy agents and neurocognitive function. 

“This information,” Dr Krull said, “is essential for designing effective intervention to address the risk.”

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Dr Krull said. “While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”

The investigators reported their findings in JCO.

MRI scan of the brain

New research has found that higher blood concentrations of methotrexate in pediatric leukemia patients during treatment results in difficulties with mental flexibility, organization, and related skills for the long-term survivors. 

And in patients with acute lymphoblastic leukemia (ALL) who had higher levels of methotrexate during treatment, brain imaging showed anatomical and functional changes in regions of the brain involved with executive functioning. Methotrexate is one of the few chemotherapy agents that crosses the blood–brain barrier. 

“This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors,” lead author Kevin Krull, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, said. 

“This information is essential for designing effective interventions to address the risk,” he said.

To examine the association between methotrexate exposure and neurocognitive outcomes, the investigators enrolled 218 long-term pediatric ALL survivors who participated in the St Jude Total Therapy XV clinical trial between 2000 and 2010. 

The patients had been treated with multidrug chemotherapy according to the Total Therapy XV protocol, which included intrathecal treatments with methotrexate, hydrocortisone, and cytarabine in addition to other chemotherapeutic agents.

Researchers calculated methotrexate concentrations by measuring blood levels of the drug before, during, and after treatment. They also checked blood levels of the amino acid homocysteine, a marker of methotrexate activity, and the chemotherapy agent dexamethasone.

All patients had survived at least 5 years from their diagnosis and were at least 8 years old when this study was conducted.

Investigators performed neurocognitive testing, functional magnetic resonance imaging (MRI) during a task, and structural MRI with diffusion tensor imaging.

At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis. Fifty-one percent were male, 74% were white, and 57% were in the low-risk treatment stratum.

Investigators found that the survivors’ intelligence was within normal limits compared with population expectations.

However, they found measures of executive function, processing speed, and memory to be less than population means, with a significance of P<0.02 after correction for false discovery rates.

And while impact of methotrexate varied, some survivors had executive functioning scores that indicated moderate to almost severe impairment. 

Investigators also found higher plasma methotrexate to be associated with higher functional MRI activity, thicker cortex, and higher activity in frontal brain regions, regions often associated with executive function.

The investigators found neurocognitive impairment also to be associated with these imaging findings .

The increased activity in the frontal lobe region suggests that survivors’ brains may be working harder to compensate for impaired cognitive function, the investigators believe.

When they adjusted for age or dose of leucovorin rescue, these associations did not change.

And consistent with the methotrexate exposure, elevated homocysteine levels during therapy were associated with poorer cognitive flexibility.

The authors noted that they did not find an association between other chemotherapy agents and neurocognitive function. 

“This information,” Dr Krull said, “is essential for designing effective intervention to address the risk.”

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Dr Krull said. “While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”

The investigators reported their findings in JCO.

MRI scan of the brain

New research has found that higher blood concentrations of methotrexate in pediatric leukemia patients during treatment results in difficulties with mental flexibility, organization, and related skills for the long-term survivors. 

And in patients with acute lymphoblastic leukemia (ALL) who had higher levels of methotrexate during treatment, brain imaging showed anatomical and functional changes in regions of the brain involved with executive functioning. Methotrexate is one of the few chemotherapy agents that crosses the blood–brain barrier. 

“This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors,” lead author Kevin Krull, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, said. 

“This information is essential for designing effective interventions to address the risk,” he said.

To examine the association between methotrexate exposure and neurocognitive outcomes, the investigators enrolled 218 long-term pediatric ALL survivors who participated in the St Jude Total Therapy XV clinical trial between 2000 and 2010. 

The patients had been treated with multidrug chemotherapy according to the Total Therapy XV protocol, which included intrathecal treatments with methotrexate, hydrocortisone, and cytarabine in addition to other chemotherapeutic agents.

Researchers calculated methotrexate concentrations by measuring blood levels of the drug before, during, and after treatment. They also checked blood levels of the amino acid homocysteine, a marker of methotrexate activity, and the chemotherapy agent dexamethasone.

All patients had survived at least 5 years from their diagnosis and were at least 8 years old when this study was conducted.

Investigators performed neurocognitive testing, functional magnetic resonance imaging (MRI) during a task, and structural MRI with diffusion tensor imaging.

At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis. Fifty-one percent were male, 74% were white, and 57% were in the low-risk treatment stratum.

Investigators found that the survivors’ intelligence was within normal limits compared with population expectations.

However, they found measures of executive function, processing speed, and memory to be less than population means, with a significance of P<0.02 after correction for false discovery rates.

And while impact of methotrexate varied, some survivors had executive functioning scores that indicated moderate to almost severe impairment. 

Investigators also found higher plasma methotrexate to be associated with higher functional MRI activity, thicker cortex, and higher activity in frontal brain regions, regions often associated with executive function.

The investigators found neurocognitive impairment also to be associated with these imaging findings .

The increased activity in the frontal lobe region suggests that survivors’ brains may be working harder to compensate for impaired cognitive function, the investigators believe.

When they adjusted for age or dose of leucovorin rescue, these associations did not change.

And consistent with the methotrexate exposure, elevated homocysteine levels during therapy were associated with poorer cognitive flexibility.

The authors noted that they did not find an association between other chemotherapy agents and neurocognitive function. 

“This information,” Dr Krull said, “is essential for designing effective intervention to address the risk.”

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Dr Krull said. “While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”

The investigators reported their findings in JCO.

Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy. 

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . .  is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.

Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy. 

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . .  is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.

Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy. 

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . .  is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.