Leukemia, Myelodysplasia, Transplantation

ORLANDO – A combination of venetoclax (Venclexta) and the experimental BCL-2 inhibitor navitoclax showed good activity and acceptable safety in both children and adults with relapsed or refractory acute lymphoblastic leukemia or lymphoblastic lymphoma, investigators in a phase 1 trial reported.

Neil Osterweil/MDedge News

The overall rate of combined complete response (CR), CR with incomplete marrow recovery (CRi) or incomplete platelet recovery (CRp) was 49% among 45 patients: 24 with acute lymphoblastic leukemia of B-cell lineage (B-ALL), 18 with T-cell lineage ALL (T-ALL), and 3 with lymphoblastic lymphoma, reported Norman J. Lacayo, MD, from Stanford (Calif.) University.

“Venetoclax, navitoclax, and chemotherapy is well tolerated with few discontinuations for dose reductions due to adverse events in patients with relapsed/refractory ALL or lymphoblastic lymphoma. The preliminary efficacy was promising in this heavily pretreated population of patients, including pediatric patients and patients with prior stem cell transplantation of CAR [chimeric antigen receptor] T-cell therapy,” he said at the annual meeting of the American Society of Hematology.

Venetoclax is a highly selective inhibitor of the B-cell lymphoma 2 (BCL-2) pathway. Navitoclax inhibits BCL-2, the BCL–extra large (BCL-XL) transmembrane molecule, and the apoptotic protein BCL-W, but was associated with dose-limiting toxicities when used at standard doses in monotherapy, he noted.

To see whether adding venetoclax to low-dose navitoclax could be safe and have synergistic activity against BCL-2, Dr. Lacayo and colleagues are conducting a phase 1, open-label, dose-escalation study of patients aged 4 years and older with relapsed/refractory ALL or lymphoblastic lymphoma.

Patients receive the weight-adjusted equivalent of 200 mg venetoclax on day 1, and 400 mg equivalent daily thereafter. Beginning on day 3, patients receive oral navitoclax daily at doses of 25, 50, or 100 mg for patients weighing 45 kg or more, or 25 or 50 mg for patients weighing from 20 to less than 45 kg.

Patients can also receive two cycles of chemotherapy with asparaginase, vincristine, and dexamethasone, with additional cycles allowed at the investigators’ discretion.

The patients reported on at ASH 2019 had received a median of 4 prior lines of therapy (range, 1-10).

After a median time on study of 8 months, preliminary efficacy – a secondary endpoint of this phase 1 trial – was promising, Dr. Lacayo said. The CR rate was 25% among patients with B-ALL, 11% in patients with T-ALL, and 67% (two of three patients) with lymphoblastic lymphoma. The respective CRi rates were 13%, 17%, and 0%, and respective CRp rates were 17%, 11%, and 0%.

In addition, 3 of 24 patients (13%) with B-ALL had a partial response, as did 1 patient with lymphoblastic lymphoma.

The median time to first response was about 1.1 months. The median duration of response was 9.1 months for patients with B-ALL, 4.2 months for patients with T-ALL, and had not been reached among patients with lymphoblastic leukemia.

The median overall survival was 9.7 months for patients with B-ALL, 6.8 months for those with T-ALL, and not reached for those with lymphoblastic leukemia.

In all, 6 of 24 patients with B-ALL, 3 of 18 with T-ALL, and 2 of 3 with lymphoblastic leukemia survived long enough to proceed to stem cell transplantation or CAR T-cell therapy.

Analysis of the combination’s safety, the primary endpoint, showed that 58% of patients had grade 3-4 adverse events (AEs) related to venetoclax, and 42% had grade 3-4 AEs related to navitoclax. Four patients had to discontinue the combination because of treatment-related AEs.

Dose-limiting toxicities, which occurred in seven patients, included delayed count recovery, drug-induced liver injury, intestinal ischemia, and increase in serum bilirubin.

One patient died from an intestinal ischemic event deemed to be related to the combination, and seven other patients had fatal adverse events considered not related to the study drugs. The causes of death included sepsis, septic shock, cardiac arrest, and neurotoxicity.

The investigators are enrolling an expansion cohort to see whether a 21-day dosing schedule of venetoclax with 50 mg navitoclax, or 25 mg for patients under 45 kg, could improve count recovery time.

The study was funded by AbbVie. Dr. Lacayo reported having no conflict of interests to disclose. Several coauthors are AbbVie employees.

SOURCE: Lacayo NJ et al. ASH 2019, Abstract 285.

ORLANDO – A combination of venetoclax (Venclexta) and the experimental BCL-2 inhibitor navitoclax showed good activity and acceptable safety in both children and adults with relapsed or refractory acute lymphoblastic leukemia or lymphoblastic lymphoma, investigators in a phase 1 trial reported.

Neil Osterweil/MDedge News

The overall rate of combined complete response (CR), CR with incomplete marrow recovery (CRi) or incomplete platelet recovery (CRp) was 49% among 45 patients: 24 with acute lymphoblastic leukemia of B-cell lineage (B-ALL), 18 with T-cell lineage ALL (T-ALL), and 3 with lymphoblastic lymphoma, reported Norman J. Lacayo, MD, from Stanford (Calif.) University.

“Venetoclax, navitoclax, and chemotherapy is well tolerated with few discontinuations for dose reductions due to adverse events in patients with relapsed/refractory ALL or lymphoblastic lymphoma. The preliminary efficacy was promising in this heavily pretreated population of patients, including pediatric patients and patients with prior stem cell transplantation of CAR [chimeric antigen receptor] T-cell therapy,” he said at the annual meeting of the American Society of Hematology.

Venetoclax is a highly selective inhibitor of the B-cell lymphoma 2 (BCL-2) pathway. Navitoclax inhibits BCL-2, the BCL–extra large (BCL-XL) transmembrane molecule, and the apoptotic protein BCL-W, but was associated with dose-limiting toxicities when used at standard doses in monotherapy, he noted.

To see whether adding venetoclax to low-dose navitoclax could be safe and have synergistic activity against BCL-2, Dr. Lacayo and colleagues are conducting a phase 1, open-label, dose-escalation study of patients aged 4 years and older with relapsed/refractory ALL or lymphoblastic lymphoma.

Patients receive the weight-adjusted equivalent of 200 mg venetoclax on day 1, and 400 mg equivalent daily thereafter. Beginning on day 3, patients receive oral navitoclax daily at doses of 25, 50, or 100 mg for patients weighing 45 kg or more, or 25 or 50 mg for patients weighing from 20 to less than 45 kg.

Patients can also receive two cycles of chemotherapy with asparaginase, vincristine, and dexamethasone, with additional cycles allowed at the investigators’ discretion.

The patients reported on at ASH 2019 had received a median of 4 prior lines of therapy (range, 1-10).

After a median time on study of 8 months, preliminary efficacy – a secondary endpoint of this phase 1 trial – was promising, Dr. Lacayo said. The CR rate was 25% among patients with B-ALL, 11% in patients with T-ALL, and 67% (two of three patients) with lymphoblastic lymphoma. The respective CRi rates were 13%, 17%, and 0%, and respective CRp rates were 17%, 11%, and 0%.

In addition, 3 of 24 patients (13%) with B-ALL had a partial response, as did 1 patient with lymphoblastic lymphoma.

The median time to first response was about 1.1 months. The median duration of response was 9.1 months for patients with B-ALL, 4.2 months for patients with T-ALL, and had not been reached among patients with lymphoblastic leukemia.

The median overall survival was 9.7 months for patients with B-ALL, 6.8 months for those with T-ALL, and not reached for those with lymphoblastic leukemia.

In all, 6 of 24 patients with B-ALL, 3 of 18 with T-ALL, and 2 of 3 with lymphoblastic leukemia survived long enough to proceed to stem cell transplantation or CAR T-cell therapy.

Analysis of the combination’s safety, the primary endpoint, showed that 58% of patients had grade 3-4 adverse events (AEs) related to venetoclax, and 42% had grade 3-4 AEs related to navitoclax. Four patients had to discontinue the combination because of treatment-related AEs.

Dose-limiting toxicities, which occurred in seven patients, included delayed count recovery, drug-induced liver injury, intestinal ischemia, and increase in serum bilirubin.

One patient died from an intestinal ischemic event deemed to be related to the combination, and seven other patients had fatal adverse events considered not related to the study drugs. The causes of death included sepsis, septic shock, cardiac arrest, and neurotoxicity.

The investigators are enrolling an expansion cohort to see whether a 21-day dosing schedule of venetoclax with 50 mg navitoclax, or 25 mg for patients under 45 kg, could improve count recovery time.

The study was funded by AbbVie. Dr. Lacayo reported having no conflict of interests to disclose. Several coauthors are AbbVie employees.

SOURCE: Lacayo NJ et al. ASH 2019, Abstract 285.

ORLANDO – A combination of venetoclax (Venclexta) and the experimental BCL-2 inhibitor navitoclax showed good activity and acceptable safety in both children and adults with relapsed or refractory acute lymphoblastic leukemia or lymphoblastic lymphoma, investigators in a phase 1 trial reported.

Neil Osterweil/MDedge News

The overall rate of combined complete response (CR), CR with incomplete marrow recovery (CRi) or incomplete platelet recovery (CRp) was 49% among 45 patients: 24 with acute lymphoblastic leukemia of B-cell lineage (B-ALL), 18 with T-cell lineage ALL (T-ALL), and 3 with lymphoblastic lymphoma, reported Norman J. Lacayo, MD, from Stanford (Calif.) University.

“Venetoclax, navitoclax, and chemotherapy is well tolerated with few discontinuations for dose reductions due to adverse events in patients with relapsed/refractory ALL or lymphoblastic lymphoma. The preliminary efficacy was promising in this heavily pretreated population of patients, including pediatric patients and patients with prior stem cell transplantation of CAR [chimeric antigen receptor] T-cell therapy,” he said at the annual meeting of the American Society of Hematology.

Venetoclax is a highly selective inhibitor of the B-cell lymphoma 2 (BCL-2) pathway. Navitoclax inhibits BCL-2, the BCL–extra large (BCL-XL) transmembrane molecule, and the apoptotic protein BCL-W, but was associated with dose-limiting toxicities when used at standard doses in monotherapy, he noted.

To see whether adding venetoclax to low-dose navitoclax could be safe and have synergistic activity against BCL-2, Dr. Lacayo and colleagues are conducting a phase 1, open-label, dose-escalation study of patients aged 4 years and older with relapsed/refractory ALL or lymphoblastic lymphoma.

Patients receive the weight-adjusted equivalent of 200 mg venetoclax on day 1, and 400 mg equivalent daily thereafter. Beginning on day 3, patients receive oral navitoclax daily at doses of 25, 50, or 100 mg for patients weighing 45 kg or more, or 25 or 50 mg for patients weighing from 20 to less than 45 kg.

Patients can also receive two cycles of chemotherapy with asparaginase, vincristine, and dexamethasone, with additional cycles allowed at the investigators’ discretion.

The patients reported on at ASH 2019 had received a median of 4 prior lines of therapy (range, 1-10).

After a median time on study of 8 months, preliminary efficacy – a secondary endpoint of this phase 1 trial – was promising, Dr. Lacayo said. The CR rate was 25% among patients with B-ALL, 11% in patients with T-ALL, and 67% (two of three patients) with lymphoblastic lymphoma. The respective CRi rates were 13%, 17%, and 0%, and respective CRp rates were 17%, 11%, and 0%.

In addition, 3 of 24 patients (13%) with B-ALL had a partial response, as did 1 patient with lymphoblastic lymphoma.

The median time to first response was about 1.1 months. The median duration of response was 9.1 months for patients with B-ALL, 4.2 months for patients with T-ALL, and had not been reached among patients with lymphoblastic leukemia.

The median overall survival was 9.7 months for patients with B-ALL, 6.8 months for those with T-ALL, and not reached for those with lymphoblastic leukemia.

In all, 6 of 24 patients with B-ALL, 3 of 18 with T-ALL, and 2 of 3 with lymphoblastic leukemia survived long enough to proceed to stem cell transplantation or CAR T-cell therapy.

Analysis of the combination’s safety, the primary endpoint, showed that 58% of patients had grade 3-4 adverse events (AEs) related to venetoclax, and 42% had grade 3-4 AEs related to navitoclax. Four patients had to discontinue the combination because of treatment-related AEs.

Dose-limiting toxicities, which occurred in seven patients, included delayed count recovery, drug-induced liver injury, intestinal ischemia, and increase in serum bilirubin.

One patient died from an intestinal ischemic event deemed to be related to the combination, and seven other patients had fatal adverse events considered not related to the study drugs. The causes of death included sepsis, septic shock, cardiac arrest, and neurotoxicity.

The investigators are enrolling an expansion cohort to see whether a 21-day dosing schedule of venetoclax with 50 mg navitoclax, or 25 mg for patients under 45 kg, could improve count recovery time.

The study was funded by AbbVie. Dr. Lacayo reported having no conflict of interests to disclose. Several coauthors are AbbVie employees.

SOURCE: Lacayo NJ et al. ASH 2019, Abstract 285.

ORLANDO – A front-line chemotherapy-free induction-consolidation protocol that combines dasatinib and blinatumomab for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resulted in high survival and molecular response rates in the phase 2 D-ALBA trial.

Sharon Worcester/MDedge News

At a median follow-up of 14.3 months, 61 of 63 patients enrolled in the multicenter trial had completed induction with the second-generation tyrosine kinase inhibitor (TKI) dasatinib, 60 had received the first cycle of treatment with the bispecific monoclonal antibody blinatumomab, and 56, 45, 36, and 25 had received second, third, fourth, and fifth cycles of blinatumomab, respectively, Sabina Chiaretti, MD, PhD, reported at the annual meeting of the American Society of Hematology.

The molecular response rate at the end of induction on day 85 was 29%, said Dr. Chiaretti of the department of translational and precision medicine, Sapienza University, Rome.

“Even more importantly, at the primary endpoint [the end of the second cycle of blinatumomab], 60% of patients were molecular responders,” she said.

Of note, the molecular response rate continued to increase with additional blinatumomab cycles; the rate was 79% after cycle 4, she said.

The overall survival (OS) and disease-free survival (DFS) rates also were “very exciting and promising” at 92.5% and 89.7%, respectively, she added.

DFS did not differ significantly based on molecular response at day 85 (100% vs. 87.4% in those with vs. without a molecular response; P = .154), but patients with p190 fusion protein had slightly worse DFS, compared with those who had p210 or both p190 and p210 fusion protein (83.5% vs. 100%; P = .48).

Study participants included adult Ph+ ALL patients with a median age of 54.5 years (range of 24.1-81.7 years) who were enrolled between May 2017 and January 2019; 54% were women and the median white blood cell count was 42 x10⁹/L.

The percentage of study subjects with the p190, p210, and both p190/p210 fusion proteins was 65.1%, 27%, and 7.9% respectively, Dr. Chiaretti said.

Treatment included dasatinib at a dose of 140 mg/day as induction for 85 days along with steroids, which were started 7 days prior to induction and continued for a total of 31 days. Those who had a complete hematologic response (CHR) after induction received postinduction consolidation treatment with blinatumomab at a flat dose of 28 mcg/day for at least 2 cycles, and up to 3 additional cycles were allowed at physician discretion based on molecular response.

During the course of the study, 156 adverse events occurred, including 50 serious adverse events. The latter most often involved infections, including 6 cytomegalovirus infections and 6 cases of prolonged fever; one of those cases was likely related to blinatumomab.

Two patients died, including an 80-year-old woman who died during induction, and a patient who was in CHR. Six relapses occurred, including one that involved a major protocol violation; three were extramedullary.

Additional analyses in this study showed that the most frequent copy number aberration was, as expected based on the available literature, IKZF1 deletion, which was present in 25 of 46 available samples (54%). Of those, 11 (23.9%) were found to have the IKZF1-plus signature, defined as IKZF1 and/or PAX5 and/or CDKN2A/B deletions, she said.

Further, ABL1 mutational analysis conducted in 15 patients with evidence of MRD increase showed that 8 were wild type and 7 were mutated – with 6 of the 7 represented by the gatekeeper mutation T315I, and one by an E255K mutation. All but 1 mutation occurred in p190 cases prior to the start of blinatumomab.

Of note, and in line with prior findings, blinatumomab was effective for reducing or eradicating the MRD levels in these difficult-to-treat patients, Dr. Chiaretti said.

An analysis of the immunologic compartment carried out in 12 patients who completed all 5 cycles of blinatumomab showed a significant increase in the rate of CD8+ T cells (29% vs. 19.8% before the start of blinatumomab; P = .04) and a significant reduction in the rate of Tregs (3.7% vs. 11% before blinatumomab; P = .02), she added.

The findings of this study to date – with some patients having more than 2 years of follow-up – are notable given the high rates of molecular response and survival, Dr. Chiaretti said.

Outcomes in patients with Ph+ ALL were generally poor before the introduction of TKIs, but “the scenario completely changed,” she explained.

“In general, all TKI-based treatments – with or without chemotherapy – have led to overall survival rates in the range of 50% ... which means that we still need to improve our clinical management,” she said. “Another finding that became clear is the fact that patients who achieve MRD-negative status have a significantly better outcome than those who do not.”

The D-ALBA trial was designed with the aim of increasing the rate of MRD negativity in newly diagnosed patients using dasatinib and blinatumomab, and the results demonstrate that this chemotherapy-free induction/consolidation approach is feasible in the front-line setting for adult Ph+ ALL patients, she said, adding that “it is strongly effective in inducing high rates of MRD negativity, and it results in much better survival rates.”

The findings with respect to IKZF1-plus cases and ABL1 mutations underscore the need for further work, she said.

“We still have to face some challenging cases,” she explained. “This study, as others before, really proves that IKZF1-plus cases are very difficult to treat; they require intensification and probably alternative strategies.”

Dr. Chiaretti reported membership on a board of directors or advisory committee for Pfizer, Incyte, Amgen, and Shire.

[email protected]

SOURCE: Chiaretti S et al. ASH 2019, Abstract 740.

ORLANDO – A front-line chemotherapy-free induction-consolidation protocol that combines dasatinib and blinatumomab for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resulted in high survival and molecular response rates in the phase 2 D-ALBA trial.

Sharon Worcester/MDedge News

At a median follow-up of 14.3 months, 61 of 63 patients enrolled in the multicenter trial had completed induction with the second-generation tyrosine kinase inhibitor (TKI) dasatinib, 60 had received the first cycle of treatment with the bispecific monoclonal antibody blinatumomab, and 56, 45, 36, and 25 had received second, third, fourth, and fifth cycles of blinatumomab, respectively, Sabina Chiaretti, MD, PhD, reported at the annual meeting of the American Society of Hematology.

The molecular response rate at the end of induction on day 85 was 29%, said Dr. Chiaretti of the department of translational and precision medicine, Sapienza University, Rome.

“Even more importantly, at the primary endpoint [the end of the second cycle of blinatumomab], 60% of patients were molecular responders,” she said.

Of note, the molecular response rate continued to increase with additional blinatumomab cycles; the rate was 79% after cycle 4, she said.

The overall survival (OS) and disease-free survival (DFS) rates also were “very exciting and promising” at 92.5% and 89.7%, respectively, she added.

DFS did not differ significantly based on molecular response at day 85 (100% vs. 87.4% in those with vs. without a molecular response; P = .154), but patients with p190 fusion protein had slightly worse DFS, compared with those who had p210 or both p190 and p210 fusion protein (83.5% vs. 100%; P = .48).

Study participants included adult Ph+ ALL patients with a median age of 54.5 years (range of 24.1-81.7 years) who were enrolled between May 2017 and January 2019; 54% were women and the median white blood cell count was 42 x10⁹/L.

The percentage of study subjects with the p190, p210, and both p190/p210 fusion proteins was 65.1%, 27%, and 7.9% respectively, Dr. Chiaretti said.

Treatment included dasatinib at a dose of 140 mg/day as induction for 85 days along with steroids, which were started 7 days prior to induction and continued for a total of 31 days. Those who had a complete hematologic response (CHR) after induction received postinduction consolidation treatment with blinatumomab at a flat dose of 28 mcg/day for at least 2 cycles, and up to 3 additional cycles were allowed at physician discretion based on molecular response.

During the course of the study, 156 adverse events occurred, including 50 serious adverse events. The latter most often involved infections, including 6 cytomegalovirus infections and 6 cases of prolonged fever; one of those cases was likely related to blinatumomab.

Two patients died, including an 80-year-old woman who died during induction, and a patient who was in CHR. Six relapses occurred, including one that involved a major protocol violation; three were extramedullary.

Additional analyses in this study showed that the most frequent copy number aberration was, as expected based on the available literature, IKZF1 deletion, which was present in 25 of 46 available samples (54%). Of those, 11 (23.9%) were found to have the IKZF1-plus signature, defined as IKZF1 and/or PAX5 and/or CDKN2A/B deletions, she said.

Further, ABL1 mutational analysis conducted in 15 patients with evidence of MRD increase showed that 8 were wild type and 7 were mutated – with 6 of the 7 represented by the gatekeeper mutation T315I, and one by an E255K mutation. All but 1 mutation occurred in p190 cases prior to the start of blinatumomab.

Of note, and in line with prior findings, blinatumomab was effective for reducing or eradicating the MRD levels in these difficult-to-treat patients, Dr. Chiaretti said.

An analysis of the immunologic compartment carried out in 12 patients who completed all 5 cycles of blinatumomab showed a significant increase in the rate of CD8+ T cells (29% vs. 19.8% before the start of blinatumomab; P = .04) and a significant reduction in the rate of Tregs (3.7% vs. 11% before blinatumomab; P = .02), she added.

The findings of this study to date – with some patients having more than 2 years of follow-up – are notable given the high rates of molecular response and survival, Dr. Chiaretti said.

Outcomes in patients with Ph+ ALL were generally poor before the introduction of TKIs, but “the scenario completely changed,” she explained.

“In general, all TKI-based treatments – with or without chemotherapy – have led to overall survival rates in the range of 50% ... which means that we still need to improve our clinical management,” she said. “Another finding that became clear is the fact that patients who achieve MRD-negative status have a significantly better outcome than those who do not.”

The D-ALBA trial was designed with the aim of increasing the rate of MRD negativity in newly diagnosed patients using dasatinib and blinatumomab, and the results demonstrate that this chemotherapy-free induction/consolidation approach is feasible in the front-line setting for adult Ph+ ALL patients, she said, adding that “it is strongly effective in inducing high rates of MRD negativity, and it results in much better survival rates.”

The findings with respect to IKZF1-plus cases and ABL1 mutations underscore the need for further work, she said.

“We still have to face some challenging cases,” she explained. “This study, as others before, really proves that IKZF1-plus cases are very difficult to treat; they require intensification and probably alternative strategies.”

Dr. Chiaretti reported membership on a board of directors or advisory committee for Pfizer, Incyte, Amgen, and Shire.

[email protected]

SOURCE: Chiaretti S et al. ASH 2019, Abstract 740.

ORLANDO – A front-line chemotherapy-free induction-consolidation protocol that combines dasatinib and blinatumomab for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resulted in high survival and molecular response rates in the phase 2 D-ALBA trial.

Sharon Worcester/MDedge News

At a median follow-up of 14.3 months, 61 of 63 patients enrolled in the multicenter trial had completed induction with the second-generation tyrosine kinase inhibitor (TKI) dasatinib, 60 had received the first cycle of treatment with the bispecific monoclonal antibody blinatumomab, and 56, 45, 36, and 25 had received second, third, fourth, and fifth cycles of blinatumomab, respectively, Sabina Chiaretti, MD, PhD, reported at the annual meeting of the American Society of Hematology.

The molecular response rate at the end of induction on day 85 was 29%, said Dr. Chiaretti of the department of translational and precision medicine, Sapienza University, Rome.

“Even more importantly, at the primary endpoint [the end of the second cycle of blinatumomab], 60% of patients were molecular responders,” she said.

Of note, the molecular response rate continued to increase with additional blinatumomab cycles; the rate was 79% after cycle 4, she said.

The overall survival (OS) and disease-free survival (DFS) rates also were “very exciting and promising” at 92.5% and 89.7%, respectively, she added.

DFS did not differ significantly based on molecular response at day 85 (100% vs. 87.4% in those with vs. without a molecular response; P = .154), but patients with p190 fusion protein had slightly worse DFS, compared with those who had p210 or both p190 and p210 fusion protein (83.5% vs. 100%; P = .48).

Study participants included adult Ph+ ALL patients with a median age of 54.5 years (range of 24.1-81.7 years) who were enrolled between May 2017 and January 2019; 54% were women and the median white blood cell count was 42 x10⁹/L.

The percentage of study subjects with the p190, p210, and both p190/p210 fusion proteins was 65.1%, 27%, and 7.9% respectively, Dr. Chiaretti said.

Treatment included dasatinib at a dose of 140 mg/day as induction for 85 days along with steroids, which were started 7 days prior to induction and continued for a total of 31 days. Those who had a complete hematologic response (CHR) after induction received postinduction consolidation treatment with blinatumomab at a flat dose of 28 mcg/day for at least 2 cycles, and up to 3 additional cycles were allowed at physician discretion based on molecular response.

During the course of the study, 156 adverse events occurred, including 50 serious adverse events. The latter most often involved infections, including 6 cytomegalovirus infections and 6 cases of prolonged fever; one of those cases was likely related to blinatumomab.

Two patients died, including an 80-year-old woman who died during induction, and a patient who was in CHR. Six relapses occurred, including one that involved a major protocol violation; three were extramedullary.

Additional analyses in this study showed that the most frequent copy number aberration was, as expected based on the available literature, IKZF1 deletion, which was present in 25 of 46 available samples (54%). Of those, 11 (23.9%) were found to have the IKZF1-plus signature, defined as IKZF1 and/or PAX5 and/or CDKN2A/B deletions, she said.

Further, ABL1 mutational analysis conducted in 15 patients with evidence of MRD increase showed that 8 were wild type and 7 were mutated – with 6 of the 7 represented by the gatekeeper mutation T315I, and one by an E255K mutation. All but 1 mutation occurred in p190 cases prior to the start of blinatumomab.

Of note, and in line with prior findings, blinatumomab was effective for reducing or eradicating the MRD levels in these difficult-to-treat patients, Dr. Chiaretti said.

An analysis of the immunologic compartment carried out in 12 patients who completed all 5 cycles of blinatumomab showed a significant increase in the rate of CD8+ T cells (29% vs. 19.8% before the start of blinatumomab; P = .04) and a significant reduction in the rate of Tregs (3.7% vs. 11% before blinatumomab; P = .02), she added.

The findings of this study to date – with some patients having more than 2 years of follow-up – are notable given the high rates of molecular response and survival, Dr. Chiaretti said.

Outcomes in patients with Ph+ ALL were generally poor before the introduction of TKIs, but “the scenario completely changed,” she explained.

“In general, all TKI-based treatments – with or without chemotherapy – have led to overall survival rates in the range of 50% ... which means that we still need to improve our clinical management,” she said. “Another finding that became clear is the fact that patients who achieve MRD-negative status have a significantly better outcome than those who do not.”

The D-ALBA trial was designed with the aim of increasing the rate of MRD negativity in newly diagnosed patients using dasatinib and blinatumomab, and the results demonstrate that this chemotherapy-free induction/consolidation approach is feasible in the front-line setting for adult Ph+ ALL patients, she said, adding that “it is strongly effective in inducing high rates of MRD negativity, and it results in much better survival rates.”

The findings with respect to IKZF1-plus cases and ABL1 mutations underscore the need for further work, she said.

“We still have to face some challenging cases,” she explained. “This study, as others before, really proves that IKZF1-plus cases are very difficult to treat; they require intensification and probably alternative strategies.”

Dr. Chiaretti reported membership on a board of directors or advisory committee for Pfizer, Incyte, Amgen, and Shire.

[email protected]

SOURCE: Chiaretti S et al. ASH 2019, Abstract 740.

New data suggest an increased risk of leukemia among responders who worked at the World Trade Center site after the attacks on Sept. 11, 2001.

Courtesy Andrea Booher/FEMA News Photo

Previous studies have shown that 9/11 responders have a higher incidence of cancers than does the general population. The current study is the first to show a higher incidence of leukemia among responders. It also shows a higher incidence of thyroid and prostate cancers as well as all cancer types combined.

These findings were published in JNCI Cancer Spectrum.

“This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods,” study author Susan L, Teitelbaum, PhD, of the Icahn School of Medicine at Mount Sinai, New York, said in a press release.

“Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study.”

Dr. Teitelbaum and colleagues evaluated responders enrolled in the World Trade Center Health Program General Responder Cohort from when it was established in July 2002 through the end of follow-up, which was Dec. 31, 2013, for New York residents and Dec. 31, 2012, for residents of other states.

To be eligible for the cohort, responders must have worked on the World Trade Center rescue and recovery effort a minimum of 4 hours in the first 4 days from Sept. 11, 2001, 24 hours in September 2001, or 80 hours from September through December 2001. Responders also had to complete at least one monitoring visit.

Responders’ data were linked to data from cancer registries in New York, New Jersey, Pennsylvania, and Connecticut (where most responders lived at the time of the attacks), as well as Florida and North Carolina (where responders were known to retire). The responders were linked to the registries using probabilistic matching algorithms, which made use of information such as patient name, address, social security number, sex, race, and birth date.

The researchers noted that patients who enrolled in the General Responder Cohort had their cancer certified for federally funded treatment, and this factor might result in “sicker members disproportionately self-selecting into the program.” To reduce this potential bias, the researchers conducted a restricted analysis in which counts of cancer cases and person-years of observation began 6 months after responder enrollment.

The researchers analyzed data on 28,729 responders who primarily worked in protective services (49.0%) and construction (20.8%). Responders spent a median of 52 days on the rescue and recovery effort, and 44.4% of them had some exposure to the dust cloud caused by the collapse of the towers.

In the restricted analysis, there were 1,072 cancers observed in 999 responders. Compared with the general population, responders had a significantly higher incidence of all cancers combined, with a standardized incidence ratio (SIR) of 1.09.

Responders had a significantly higher incidence of prostate cancer (SIR,1.25), thyroid cancer (SIR, 2.19), and leukemia (SIR, 1.41). The leukemia category included acute myeloid leukemia (SIR,1.58) and chronic lymphocytic leukemia (SIR, 1.08).

“Although other studies have revealed elevated SIRs for other hematologic malignancies, this is the first reported, statistically significant, elevated SIR for leukemia,” the researchers wrote. “Leukemia is known to occur after exposure to occupational carcinogens, including benzene (burning jet fuel and other sources at the [World Trade Center] site), possibly at low levels of exposure and with a latency of several years from exposure.”

A multivariate analysis showed no association between cancer incidence and the length of time responders spent on the rescue and recovery effort or the intensity of their exposure to the dust cloud or debris pile.

The analysis did show an elevated risk of all cancers combined with each 1-year increase in responder age (hazard ratio, 1.09), among male responders (HR, 1.21), and among responders who smoked at baseline (HR, 1.29).

This research was supported by the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The researchers disclosed no conflicts of interest.
 

[email protected]

SOURCE: Shapiro MZ et al. JNCI Cancer Spectr. 2020 Jan 14. doi: 10.1093/jncics/pkz090.

New data suggest an increased risk of leukemia among responders who worked at the World Trade Center site after the attacks on Sept. 11, 2001.

Courtesy Andrea Booher/FEMA News Photo

Previous studies have shown that 9/11 responders have a higher incidence of cancers than does the general population. The current study is the first to show a higher incidence of leukemia among responders. It also shows a higher incidence of thyroid and prostate cancers as well as all cancer types combined.

These findings were published in JNCI Cancer Spectrum.

“This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods,” study author Susan L, Teitelbaum, PhD, of the Icahn School of Medicine at Mount Sinai, New York, said in a press release.

“Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study.”

Dr. Teitelbaum and colleagues evaluated responders enrolled in the World Trade Center Health Program General Responder Cohort from when it was established in July 2002 through the end of follow-up, which was Dec. 31, 2013, for New York residents and Dec. 31, 2012, for residents of other states.

To be eligible for the cohort, responders must have worked on the World Trade Center rescue and recovery effort a minimum of 4 hours in the first 4 days from Sept. 11, 2001, 24 hours in September 2001, or 80 hours from September through December 2001. Responders also had to complete at least one monitoring visit.

Responders’ data were linked to data from cancer registries in New York, New Jersey, Pennsylvania, and Connecticut (where most responders lived at the time of the attacks), as well as Florida and North Carolina (where responders were known to retire). The responders were linked to the registries using probabilistic matching algorithms, which made use of information such as patient name, address, social security number, sex, race, and birth date.

The researchers noted that patients who enrolled in the General Responder Cohort had their cancer certified for federally funded treatment, and this factor might result in “sicker members disproportionately self-selecting into the program.” To reduce this potential bias, the researchers conducted a restricted analysis in which counts of cancer cases and person-years of observation began 6 months after responder enrollment.

The researchers analyzed data on 28,729 responders who primarily worked in protective services (49.0%) and construction (20.8%). Responders spent a median of 52 days on the rescue and recovery effort, and 44.4% of them had some exposure to the dust cloud caused by the collapse of the towers.

In the restricted analysis, there were 1,072 cancers observed in 999 responders. Compared with the general population, responders had a significantly higher incidence of all cancers combined, with a standardized incidence ratio (SIR) of 1.09.

Responders had a significantly higher incidence of prostate cancer (SIR,1.25), thyroid cancer (SIR, 2.19), and leukemia (SIR, 1.41). The leukemia category included acute myeloid leukemia (SIR,1.58) and chronic lymphocytic leukemia (SIR, 1.08).

“Although other studies have revealed elevated SIRs for other hematologic malignancies, this is the first reported, statistically significant, elevated SIR for leukemia,” the researchers wrote. “Leukemia is known to occur after exposure to occupational carcinogens, including benzene (burning jet fuel and other sources at the [World Trade Center] site), possibly at low levels of exposure and with a latency of several years from exposure.”

A multivariate analysis showed no association between cancer incidence and the length of time responders spent on the rescue and recovery effort or the intensity of their exposure to the dust cloud or debris pile.

The analysis did show an elevated risk of all cancers combined with each 1-year increase in responder age (hazard ratio, 1.09), among male responders (HR, 1.21), and among responders who smoked at baseline (HR, 1.29).

This research was supported by the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The researchers disclosed no conflicts of interest.
 

[email protected]

SOURCE: Shapiro MZ et al. JNCI Cancer Spectr. 2020 Jan 14. doi: 10.1093/jncics/pkz090.

New data suggest an increased risk of leukemia among responders who worked at the World Trade Center site after the attacks on Sept. 11, 2001.

Courtesy Andrea Booher/FEMA News Photo

Previous studies have shown that 9/11 responders have a higher incidence of cancers than does the general population. The current study is the first to show a higher incidence of leukemia among responders. It also shows a higher incidence of thyroid and prostate cancers as well as all cancer types combined.

These findings were published in JNCI Cancer Spectrum.

“This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods,” study author Susan L, Teitelbaum, PhD, of the Icahn School of Medicine at Mount Sinai, New York, said in a press release.

“Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study.”

Dr. Teitelbaum and colleagues evaluated responders enrolled in the World Trade Center Health Program General Responder Cohort from when it was established in July 2002 through the end of follow-up, which was Dec. 31, 2013, for New York residents and Dec. 31, 2012, for residents of other states.

To be eligible for the cohort, responders must have worked on the World Trade Center rescue and recovery effort a minimum of 4 hours in the first 4 days from Sept. 11, 2001, 24 hours in September 2001, or 80 hours from September through December 2001. Responders also had to complete at least one monitoring visit.

Responders’ data were linked to data from cancer registries in New York, New Jersey, Pennsylvania, and Connecticut (where most responders lived at the time of the attacks), as well as Florida and North Carolina (where responders were known to retire). The responders were linked to the registries using probabilistic matching algorithms, which made use of information such as patient name, address, social security number, sex, race, and birth date.

The researchers noted that patients who enrolled in the General Responder Cohort had their cancer certified for federally funded treatment, and this factor might result in “sicker members disproportionately self-selecting into the program.” To reduce this potential bias, the researchers conducted a restricted analysis in which counts of cancer cases and person-years of observation began 6 months after responder enrollment.

The researchers analyzed data on 28,729 responders who primarily worked in protective services (49.0%) and construction (20.8%). Responders spent a median of 52 days on the rescue and recovery effort, and 44.4% of them had some exposure to the dust cloud caused by the collapse of the towers.

In the restricted analysis, there were 1,072 cancers observed in 999 responders. Compared with the general population, responders had a significantly higher incidence of all cancers combined, with a standardized incidence ratio (SIR) of 1.09.

Responders had a significantly higher incidence of prostate cancer (SIR,1.25), thyroid cancer (SIR, 2.19), and leukemia (SIR, 1.41). The leukemia category included acute myeloid leukemia (SIR,1.58) and chronic lymphocytic leukemia (SIR, 1.08).

“Although other studies have revealed elevated SIRs for other hematologic malignancies, this is the first reported, statistically significant, elevated SIR for leukemia,” the researchers wrote. “Leukemia is known to occur after exposure to occupational carcinogens, including benzene (burning jet fuel and other sources at the [World Trade Center] site), possibly at low levels of exposure and with a latency of several years from exposure.”

A multivariate analysis showed no association between cancer incidence and the length of time responders spent on the rescue and recovery effort or the intensity of their exposure to the dust cloud or debris pile.

The analysis did show an elevated risk of all cancers combined with each 1-year increase in responder age (hazard ratio, 1.09), among male responders (HR, 1.21), and among responders who smoked at baseline (HR, 1.29).

This research was supported by the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The researchers disclosed no conflicts of interest.
 

[email protected]

SOURCE: Shapiro MZ et al. JNCI Cancer Spectr. 2020 Jan 14. doi: 10.1093/jncics/pkz090.

ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.

Neil Osterweil/MDedge News

“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).

The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.

The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.

The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.

Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.

The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.

For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.

In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.

They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.

At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.

“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.

Benjamin Pena/Medscape

In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.

“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.

The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.

SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.

ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.

Neil Osterweil/MDedge News

“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).

The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.

The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.

The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.

Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.

The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.

For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.

In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.

They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.

At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.

“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.

Benjamin Pena/Medscape

In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.

“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.

The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.

SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.

ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.

Neil Osterweil/MDedge News

“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).

The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.

The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.

The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.

Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.

The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.

For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.

In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.

They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.

At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.

“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.

Benjamin Pena/Medscape

In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.

“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.

The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.

SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.

ORLANDO – For adults with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL), the combination of hyper-CVAD chemotherapy and ponatinib is associated with high complete molecular response and 5-year overall survival rates, investigators reported.

Neil Osterweil/MDedge News

Long-term follow-up of 86 adults with Ph+ALL treated in the front line with chemotherapy plus ponatinib (Iclusig), a third-generation tyrosine kinase inhibitor (TKI), showed a complete remission (CR) rate of 100%, complete molecular remission (CMR) rate of 86%, and a 5-year overall survival (OS) rate of 74%, reported Nicholas J. Short, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Although we observed two treatment-related cardiovascular deaths with the original trial design, with almost 50 patients treated since instituting a risk-adapted dosing schedule with lower doses of ponatinib, no additional ponatinib-related deaths have been observed,” he said at the annual meeting of the American Society of Hematology.

The standard of care for adults with Ph+ALL is chemotherapy plus a TKI. With a first- or second-generation TKI plus chemotherapy, reported 5-year OS rates range from 35% to 50%.

“However, relapses are still common, and these are usually driven by the development of new resistance mutations in the ABL gene, particularly the T315I gatekeeper mutation which has been reported in up to 75% of patients at the time of relapse,” he said.

Ponatinib is a pan-BCR-ABL TKI with activity against ALL with T315I mutations, and the combination of this agent with hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has been associated with higher response rates than those seen with earlier-generation TKIs, as well as higher levels of minimal residual disease (MRD) negativity, he noted.

Dr. Short and colleagues hypothesized that, compared with the standard of care, hyper-CVAD plus ponatinib would be associated with higher MRD levels, low relapse rates by suppression of T315I subclones, decreased reliance on stem cell transplantation in first remission, and improved long-term survival.

To test this, they treated 86 adults with newly diagnosed Ph+ALL, including those who had undergone one or two previous courses of chemotherapy with a TKI other than ponatinib. The patients had Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no clinically significant cardiovascular disease.

The patients underwent eight cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. The first 37 patients were treated with, ponatinib 45 mg daily for the first 14 days of cycle 1, then continuously for subsequent cycles. Patients with CD20 expression of 20% or greater also received rituximab during the first four cycles. CNS prophylaxis was also administered with 12 doses of intrathecal chemotherapy with alternating methotrexate and cytarabine.

Patients who had a CR received maintenance with ponatinib and vincristine/prednisone monthly for 2 years, followed by ponatinib indefinitely.

Out of concern for vascular toxicity with long-term use of high-dose ponatinib, including the two deaths mentioned before, the protocol was amended after the first 37 patients were treated. The amended protocol reduced ponatinib to 30 mg starting at cycle 2, with further reduction to 15 mg once a CMR (absence of BCR-ABL on polymerase chain reaction) was achieved.

At a median follow-up of 44 months, the event-free survival rates – the primary endpoint – were 71% at 3 years and 68% at 5 years. The 3-year OS rate was 78%, and the 5-year OS rate was 74%.

All patients had complete remission and complete cytogenetic remission as assessed by conventional karyotyping. Additionally, 73 of 85 evaluable patients (86%) achieved a CMR at some point during therapy.

“We had previously reported that achievement of a complete molecular response by 3 months is associated with superior outcomes. Approximately three quarters of patients achieved this milestone,” Dr. Short said.

Grade 3 or greater adverse events of particular concern included transaminase elevations in 29% of patients, elevated bilirubin and pancreatitis in 15% each, and hypertension in 14%.

Four patients had grade 3 or greater venous thromboembolic or arterial events, including the two previously noted deaths from myocardial infarction, both of which occurred prior to the protocol amendment.

At the most recent follow-up, 11 patients had experienced relapse (no CNS-only relapses), and of this group, 5 died and 6 were still alive. Nineteen patients underwent hematopoietic stem cell transplant, and of this group, 13 were still alive and 6 died.

Causes of death in the nine patients who died while in CR included the two myocardial infarction deaths on study, three deaths from sepsis during consolidation, one from lung cancer, one from a head injury after a fall, one from myocardial infarction in a 79-year-old patient 4 years after stopping ponatinib (off study), and one from preexisting congestive heart failure in a 74-year-old patient.

In all, 47 patients were either in ongoing therapy or observation at last follow-up, including three patients who were transitioned to MRD-directed therapy including blinatumomab (Blincyto).

“As a next step, we are now evaluating lower-intensity regimens with ponatinib and blinatumomab in both the frontline and relapsed/refractory settings, with the goals of decreased chemotherapy-related toxicity, increased MRD-negativity rates, further decreased reliance on transplant, and improved long-term outcomes,” Dr. Short said.

The study was sponsored by MD Anderson with support from the National Cancer Institute. Dr. Short reported consulting for AstraZenca, honoraria from Amgen, and consulting and receiving research funding from Takeda Oncology.

SOURCE: Short NJ et al. ASH 2019, Abstract 283.

ORLANDO – For adults with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL), the combination of hyper-CVAD chemotherapy and ponatinib is associated with high complete molecular response and 5-year overall survival rates, investigators reported.

Neil Osterweil/MDedge News

Long-term follow-up of 86 adults with Ph+ALL treated in the front line with chemotherapy plus ponatinib (Iclusig), a third-generation tyrosine kinase inhibitor (TKI), showed a complete remission (CR) rate of 100%, complete molecular remission (CMR) rate of 86%, and a 5-year overall survival (OS) rate of 74%, reported Nicholas J. Short, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Although we observed two treatment-related cardiovascular deaths with the original trial design, with almost 50 patients treated since instituting a risk-adapted dosing schedule with lower doses of ponatinib, no additional ponatinib-related deaths have been observed,” he said at the annual meeting of the American Society of Hematology.

The standard of care for adults with Ph+ALL is chemotherapy plus a TKI. With a first- or second-generation TKI plus chemotherapy, reported 5-year OS rates range from 35% to 50%.

“However, relapses are still common, and these are usually driven by the development of new resistance mutations in the ABL gene, particularly the T315I gatekeeper mutation which has been reported in up to 75% of patients at the time of relapse,” he said.

Ponatinib is a pan-BCR-ABL TKI with activity against ALL with T315I mutations, and the combination of this agent with hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has been associated with higher response rates than those seen with earlier-generation TKIs, as well as higher levels of minimal residual disease (MRD) negativity, he noted.

Dr. Short and colleagues hypothesized that, compared with the standard of care, hyper-CVAD plus ponatinib would be associated with higher MRD levels, low relapse rates by suppression of T315I subclones, decreased reliance on stem cell transplantation in first remission, and improved long-term survival.

To test this, they treated 86 adults with newly diagnosed Ph+ALL, including those who had undergone one or two previous courses of chemotherapy with a TKI other than ponatinib. The patients had Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no clinically significant cardiovascular disease.

The patients underwent eight cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. The first 37 patients were treated with, ponatinib 45 mg daily for the first 14 days of cycle 1, then continuously for subsequent cycles. Patients with CD20 expression of 20% or greater also received rituximab during the first four cycles. CNS prophylaxis was also administered with 12 doses of intrathecal chemotherapy with alternating methotrexate and cytarabine.

Patients who had a CR received maintenance with ponatinib and vincristine/prednisone monthly for 2 years, followed by ponatinib indefinitely.

Out of concern for vascular toxicity with long-term use of high-dose ponatinib, including the two deaths mentioned before, the protocol was amended after the first 37 patients were treated. The amended protocol reduced ponatinib to 30 mg starting at cycle 2, with further reduction to 15 mg once a CMR (absence of BCR-ABL on polymerase chain reaction) was achieved.

At a median follow-up of 44 months, the event-free survival rates – the primary endpoint – were 71% at 3 years and 68% at 5 years. The 3-year OS rate was 78%, and the 5-year OS rate was 74%.

All patients had complete remission and complete cytogenetic remission as assessed by conventional karyotyping. Additionally, 73 of 85 evaluable patients (86%) achieved a CMR at some point during therapy.

“We had previously reported that achievement of a complete molecular response by 3 months is associated with superior outcomes. Approximately three quarters of patients achieved this milestone,” Dr. Short said.

Grade 3 or greater adverse events of particular concern included transaminase elevations in 29% of patients, elevated bilirubin and pancreatitis in 15% each, and hypertension in 14%.

Four patients had grade 3 or greater venous thromboembolic or arterial events, including the two previously noted deaths from myocardial infarction, both of which occurred prior to the protocol amendment.

At the most recent follow-up, 11 patients had experienced relapse (no CNS-only relapses), and of this group, 5 died and 6 were still alive. Nineteen patients underwent hematopoietic stem cell transplant, and of this group, 13 were still alive and 6 died.

Causes of death in the nine patients who died while in CR included the two myocardial infarction deaths on study, three deaths from sepsis during consolidation, one from lung cancer, one from a head injury after a fall, one from myocardial infarction in a 79-year-old patient 4 years after stopping ponatinib (off study), and one from preexisting congestive heart failure in a 74-year-old patient.

In all, 47 patients were either in ongoing therapy or observation at last follow-up, including three patients who were transitioned to MRD-directed therapy including blinatumomab (Blincyto).

“As a next step, we are now evaluating lower-intensity regimens with ponatinib and blinatumomab in both the frontline and relapsed/refractory settings, with the goals of decreased chemotherapy-related toxicity, increased MRD-negativity rates, further decreased reliance on transplant, and improved long-term outcomes,” Dr. Short said.

The study was sponsored by MD Anderson with support from the National Cancer Institute. Dr. Short reported consulting for AstraZenca, honoraria from Amgen, and consulting and receiving research funding from Takeda Oncology.

SOURCE: Short NJ et al. ASH 2019, Abstract 283.

ORLANDO – For adults with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL), the combination of hyper-CVAD chemotherapy and ponatinib is associated with high complete molecular response and 5-year overall survival rates, investigators reported.

Neil Osterweil/MDedge News

Long-term follow-up of 86 adults with Ph+ALL treated in the front line with chemotherapy plus ponatinib (Iclusig), a third-generation tyrosine kinase inhibitor (TKI), showed a complete remission (CR) rate of 100%, complete molecular remission (CMR) rate of 86%, and a 5-year overall survival (OS) rate of 74%, reported Nicholas J. Short, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Although we observed two treatment-related cardiovascular deaths with the original trial design, with almost 50 patients treated since instituting a risk-adapted dosing schedule with lower doses of ponatinib, no additional ponatinib-related deaths have been observed,” he said at the annual meeting of the American Society of Hematology.

The standard of care for adults with Ph+ALL is chemotherapy plus a TKI. With a first- or second-generation TKI plus chemotherapy, reported 5-year OS rates range from 35% to 50%.

“However, relapses are still common, and these are usually driven by the development of new resistance mutations in the ABL gene, particularly the T315I gatekeeper mutation which has been reported in up to 75% of patients at the time of relapse,” he said.

Ponatinib is a pan-BCR-ABL TKI with activity against ALL with T315I mutations, and the combination of this agent with hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has been associated with higher response rates than those seen with earlier-generation TKIs, as well as higher levels of minimal residual disease (MRD) negativity, he noted.

Dr. Short and colleagues hypothesized that, compared with the standard of care, hyper-CVAD plus ponatinib would be associated with higher MRD levels, low relapse rates by suppression of T315I subclones, decreased reliance on stem cell transplantation in first remission, and improved long-term survival.

To test this, they treated 86 adults with newly diagnosed Ph+ALL, including those who had undergone one or two previous courses of chemotherapy with a TKI other than ponatinib. The patients had Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no clinically significant cardiovascular disease.

The patients underwent eight cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. The first 37 patients were treated with, ponatinib 45 mg daily for the first 14 days of cycle 1, then continuously for subsequent cycles. Patients with CD20 expression of 20% or greater also received rituximab during the first four cycles. CNS prophylaxis was also administered with 12 doses of intrathecal chemotherapy with alternating methotrexate and cytarabine.

Patients who had a CR received maintenance with ponatinib and vincristine/prednisone monthly for 2 years, followed by ponatinib indefinitely.

Out of concern for vascular toxicity with long-term use of high-dose ponatinib, including the two deaths mentioned before, the protocol was amended after the first 37 patients were treated. The amended protocol reduced ponatinib to 30 mg starting at cycle 2, with further reduction to 15 mg once a CMR (absence of BCR-ABL on polymerase chain reaction) was achieved.

At a median follow-up of 44 months, the event-free survival rates – the primary endpoint – were 71% at 3 years and 68% at 5 years. The 3-year OS rate was 78%, and the 5-year OS rate was 74%.

All patients had complete remission and complete cytogenetic remission as assessed by conventional karyotyping. Additionally, 73 of 85 evaluable patients (86%) achieved a CMR at some point during therapy.

“We had previously reported that achievement of a complete molecular response by 3 months is associated with superior outcomes. Approximately three quarters of patients achieved this milestone,” Dr. Short said.

Grade 3 or greater adverse events of particular concern included transaminase elevations in 29% of patients, elevated bilirubin and pancreatitis in 15% each, and hypertension in 14%.

Four patients had grade 3 or greater venous thromboembolic or arterial events, including the two previously noted deaths from myocardial infarction, both of which occurred prior to the protocol amendment.

At the most recent follow-up, 11 patients had experienced relapse (no CNS-only relapses), and of this group, 5 died and 6 were still alive. Nineteen patients underwent hematopoietic stem cell transplant, and of this group, 13 were still alive and 6 died.

Causes of death in the nine patients who died while in CR included the two myocardial infarction deaths on study, three deaths from sepsis during consolidation, one from lung cancer, one from a head injury after a fall, one from myocardial infarction in a 79-year-old patient 4 years after stopping ponatinib (off study), and one from preexisting congestive heart failure in a 74-year-old patient.

In all, 47 patients were either in ongoing therapy or observation at last follow-up, including three patients who were transitioned to MRD-directed therapy including blinatumomab (Blincyto).

“As a next step, we are now evaluating lower-intensity regimens with ponatinib and blinatumomab in both the frontline and relapsed/refractory settings, with the goals of decreased chemotherapy-related toxicity, increased MRD-negativity rates, further decreased reliance on transplant, and improved long-term outcomes,” Dr. Short said.

The study was sponsored by MD Anderson with support from the National Cancer Institute. Dr. Short reported consulting for AstraZenca, honoraria from Amgen, and consulting and receiving research funding from Takeda Oncology.

SOURCE: Short NJ et al. ASH 2019, Abstract 283.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated manageable toxicity and promising clinical activity in the phase 1 portion of a trial enrolling heavily pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, according to an investigator.

Andrew D. Bowser/MDedge News

The overall response rate exceeded 80%, and most patients in response at 6 months had maintained that response at the 9-month mark, said Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif.

“Clinical responses were rapid, improved with time, and were deep and durable,” Dr. Siddiqi said at the annual meeting of the American Society of Hematology.

These findings have provided justification for conducting the phase 2 portion of the study, which is currently enrolling at the higher of two dose levels evaluated in phase 1, she added.

Dr. Siddiqi reported on a total of 23 patients enrolled in the study, known as TRANSCEND CLL 004. All patients had relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and had received at least two prior therapies, including ibrutinib, while about one-third had failed venetoclax as well.

The median patient age was 66 years, and 83% had high-risk features, according to Dr. Siddiqi, who said patients had received a median of five prior lines of therapy.

Nine patients were treated at dose level 1, or 50 x 10⁶ CAR+ T cells, while 14 were treated at dose level 2, or 100 x 10⁶ CAR+ T cells. Two patients experienced grade 3 or 4 dose-limiting toxicities at the second level, including hypertension in one patient, and encephalopathy, muscle weakness, and tumor lysis syndrome (TLS) in the other.

Cytokine release syndrome (CRS) occurred in 17 patients, though only two cases reached grade 3. Neurologic adverse events were seen in nine patients, of which five were grade 3 or 4.

SOURCE: Siddiqi T et al. ASH 2019, Abstract 503.

ORLANDO – Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated manageable toxicity and promising clinical activity in the phase 1 portion of a trial enrolling heavily pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, according to an investigator.

Andrew D. Bowser/MDedge News

The overall response rate exceeded 80%, and most patients in response at 6 months had maintained that response at the 9-month mark, said Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif.

“Clinical responses were rapid, improved with time, and were deep and durable,” Dr. Siddiqi said at the annual meeting of the American Society of Hematology.

These findings have provided justification for conducting the phase 2 portion of the study, which is currently enrolling at the higher of two dose levels evaluated in phase 1, she added.

Dr. Siddiqi reported on a total of 23 patients enrolled in the study, known as TRANSCEND CLL 004. All patients had relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and had received at least two prior therapies, including ibrutinib, while about one-third had failed venetoclax as well.

The median patient age was 66 years, and 83% had high-risk features, according to Dr. Siddiqi, who said patients had received a median of five prior lines of therapy.

Nine patients were treated at dose level 1, or 50 x 10⁶ CAR+ T cells, while 14 were treated at dose level 2, or 100 x 10⁶ CAR+ T cells. Two patients experienced grade 3 or 4 dose-limiting toxicities at the second level, including hypertension in one patient, and encephalopathy, muscle weakness, and tumor lysis syndrome (TLS) in the other.

Cytokine release syndrome (CRS) occurred in 17 patients, though only two cases reached grade 3. Neurologic adverse events were seen in nine patients, of which five were grade 3 or 4.

SOURCE: Siddiqi T et al. ASH 2019, Abstract 503.

ORLANDO – Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated manageable toxicity and promising clinical activity in the phase 1 portion of a trial enrolling heavily pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, according to an investigator.

Andrew D. Bowser/MDedge News

The overall response rate exceeded 80%, and most patients in response at 6 months had maintained that response at the 9-month mark, said Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif.

“Clinical responses were rapid, improved with time, and were deep and durable,” Dr. Siddiqi said at the annual meeting of the American Society of Hematology.

These findings have provided justification for conducting the phase 2 portion of the study, which is currently enrolling at the higher of two dose levels evaluated in phase 1, she added.

Dr. Siddiqi reported on a total of 23 patients enrolled in the study, known as TRANSCEND CLL 004. All patients had relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and had received at least two prior therapies, including ibrutinib, while about one-third had failed venetoclax as well.

The median patient age was 66 years, and 83% had high-risk features, according to Dr. Siddiqi, who said patients had received a median of five prior lines of therapy.

Nine patients were treated at dose level 1, or 50 x 10⁶ CAR+ T cells, while 14 were treated at dose level 2, or 100 x 10⁶ CAR+ T cells. Two patients experienced grade 3 or 4 dose-limiting toxicities at the second level, including hypertension in one patient, and encephalopathy, muscle weakness, and tumor lysis syndrome (TLS) in the other.

Cytokine release syndrome (CRS) occurred in 17 patients, though only two cases reached grade 3. Neurologic adverse events were seen in nine patients, of which five were grade 3 or 4.

SOURCE: Siddiqi T et al. ASH 2019, Abstract 503.

ORLANDO – Zanubrutinib has produced a high overall response rate in one the largest cohorts of patients with treatment-naive 17p-deletion chronic lymphocytic leukemia (CLL) studied to date.

Andrew D. Bowser/MDedge News

An overall response rate of nearly 93% was seen in this 109-patient, high-risk cohort, enrolled as part of the phase 3 SEQUOIA study (BGB-3111-304), said Constantine S. Tam, MBBS, MD, of St. Vincent’s Hospital and Peter MacCallum Cancer Centre in Melbourne.

Tolerability of zanubrutinib was essentially consistent with previous reports of the agent as used in other B-cell malignancies, Dr. Tam said in an oral presentation of the results at the annual meeting of the American Society of Hematology.

Deletion of chromosome 17p13.1, or del(17p), is a marker of poor prognosis and poor response to chemotherapy in patients with CLL or small lymphocytic lymphoma (SLL). For patients with del(17p) CLL, the first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib has become a standard of care, Dr. Tam said.

Zanubrutinib, a next-generation BTK inhibitor, was developed to improve BTK occupancy and minimize off-target inhibition of TEC and epidermal growth factor receptor kinases. “What this effectively means is that we are able to dose this drug at levels much higher than that achievable with ibrutinib, and not get intolerable side effects,” Dr. Tam said.

Zanubrutinib has been approved in the United States for previously treated mantle cell lymphoma, and generated durable responses among CLL/SLL patients with or without del(17p) in a phase 1/2 study, according to Dr. Tam.

In the present study, which exclusively enrolled patients with del(17p) CLL/SLL, patients received 160 mg twice daily of zanubrutinib, Dr. Tam said. Out of 109 patients enrolled, 10 (9.2%) had SLL. All patients were aged at least 65 years or were deemed unsuitable for treatment with the combination of fludarabine, cyclophosphamide, and rituximab.

Of 109 patients enrolled, 104 received on-study treatment. The median age was 70 years, Dr. Tam reported, and a number of patients had other high-risk markers beyond del(17p), including unmutated IgVH status in 61.5% of patients.

With a median follow-up of 10 months, the overall response rate was 92.7%, including 1.9% complete responses and 78.9% partial responses. “Only one patient had primary progressive disease after starting this drug,” Dr. Tam said.

Time to response was rapid, according to the investigator, at about 2.8 months; after 6 months, 95% of responders remained in response.

Further analysis showed that the response rate was consistent across subgroups. “There was not a single group that did not respond with a high response rate, including poor prognostic groups,” Dr. Tam said.

Most adverse events were grade 1-2 in severity, and the most common events included confusion and upper respiratory tract infection. The only common grade 3 event, according to Dr. Tam, was neutropenia. Rates of grade 3 major bleeding were low, he said, and the rate of grade 3 atrial fibrillation was 0.9%. One patient died due to pneumonia.

The ongoing SEQUOIA study, designed to compare zanubrutinib to the combination of bendamustine and rituximab in patients with previously untreated CLL or SLL, is sponsored by BeiGene. Dr. Tam reported disclosures related to Novartis, Pharmacyclics, AbbVie, BeiGene, Janssen, and Roche.

SOURCE: Tam C et al. ASH 2019, Abstract 499.

ORLANDO – Zanubrutinib has produced a high overall response rate in one the largest cohorts of patients with treatment-naive 17p-deletion chronic lymphocytic leukemia (CLL) studied to date.

Andrew D. Bowser/MDedge News

An overall response rate of nearly 93% was seen in this 109-patient, high-risk cohort, enrolled as part of the phase 3 SEQUOIA study (BGB-3111-304), said Constantine S. Tam, MBBS, MD, of St. Vincent’s Hospital and Peter MacCallum Cancer Centre in Melbourne.

Tolerability of zanubrutinib was essentially consistent with previous reports of the agent as used in other B-cell malignancies, Dr. Tam said in an oral presentation of the results at the annual meeting of the American Society of Hematology.

Deletion of chromosome 17p13.1, or del(17p), is a marker of poor prognosis and poor response to chemotherapy in patients with CLL or small lymphocytic lymphoma (SLL). For patients with del(17p) CLL, the first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib has become a standard of care, Dr. Tam said.

Zanubrutinib, a next-generation BTK inhibitor, was developed to improve BTK occupancy and minimize off-target inhibition of TEC and epidermal growth factor receptor kinases. “What this effectively means is that we are able to dose this drug at levels much higher than that achievable with ibrutinib, and not get intolerable side effects,” Dr. Tam said.

Zanubrutinib has been approved in the United States for previously treated mantle cell lymphoma, and generated durable responses among CLL/SLL patients with or without del(17p) in a phase 1/2 study, according to Dr. Tam.

In the present study, which exclusively enrolled patients with del(17p) CLL/SLL, patients received 160 mg twice daily of zanubrutinib, Dr. Tam said. Out of 109 patients enrolled, 10 (9.2%) had SLL. All patients were aged at least 65 years or were deemed unsuitable for treatment with the combination of fludarabine, cyclophosphamide, and rituximab.

Of 109 patients enrolled, 104 received on-study treatment. The median age was 70 years, Dr. Tam reported, and a number of patients had other high-risk markers beyond del(17p), including unmutated IgVH status in 61.5% of patients.

With a median follow-up of 10 months, the overall response rate was 92.7%, including 1.9% complete responses and 78.9% partial responses. “Only one patient had primary progressive disease after starting this drug,” Dr. Tam said.

Time to response was rapid, according to the investigator, at about 2.8 months; after 6 months, 95% of responders remained in response.

Further analysis showed that the response rate was consistent across subgroups. “There was not a single group that did not respond with a high response rate, including poor prognostic groups,” Dr. Tam said.

Most adverse events were grade 1-2 in severity, and the most common events included confusion and upper respiratory tract infection. The only common grade 3 event, according to Dr. Tam, was neutropenia. Rates of grade 3 major bleeding were low, he said, and the rate of grade 3 atrial fibrillation was 0.9%. One patient died due to pneumonia.

The ongoing SEQUOIA study, designed to compare zanubrutinib to the combination of bendamustine and rituximab in patients with previously untreated CLL or SLL, is sponsored by BeiGene. Dr. Tam reported disclosures related to Novartis, Pharmacyclics, AbbVie, BeiGene, Janssen, and Roche.

SOURCE: Tam C et al. ASH 2019, Abstract 499.

ORLANDO – Zanubrutinib has produced a high overall response rate in one the largest cohorts of patients with treatment-naive 17p-deletion chronic lymphocytic leukemia (CLL) studied to date.

Andrew D. Bowser/MDedge News

An overall response rate of nearly 93% was seen in this 109-patient, high-risk cohort, enrolled as part of the phase 3 SEQUOIA study (BGB-3111-304), said Constantine S. Tam, MBBS, MD, of St. Vincent’s Hospital and Peter MacCallum Cancer Centre in Melbourne.

Tolerability of zanubrutinib was essentially consistent with previous reports of the agent as used in other B-cell malignancies, Dr. Tam said in an oral presentation of the results at the annual meeting of the American Society of Hematology.

Deletion of chromosome 17p13.1, or del(17p), is a marker of poor prognosis and poor response to chemotherapy in patients with CLL or small lymphocytic lymphoma (SLL). For patients with del(17p) CLL, the first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib has become a standard of care, Dr. Tam said.

Zanubrutinib, a next-generation BTK inhibitor, was developed to improve BTK occupancy and minimize off-target inhibition of TEC and epidermal growth factor receptor kinases. “What this effectively means is that we are able to dose this drug at levels much higher than that achievable with ibrutinib, and not get intolerable side effects,” Dr. Tam said.

Zanubrutinib has been approved in the United States for previously treated mantle cell lymphoma, and generated durable responses among CLL/SLL patients with or without del(17p) in a phase 1/2 study, according to Dr. Tam.

In the present study, which exclusively enrolled patients with del(17p) CLL/SLL, patients received 160 mg twice daily of zanubrutinib, Dr. Tam said. Out of 109 patients enrolled, 10 (9.2%) had SLL. All patients were aged at least 65 years or were deemed unsuitable for treatment with the combination of fludarabine, cyclophosphamide, and rituximab.

Of 109 patients enrolled, 104 received on-study treatment. The median age was 70 years, Dr. Tam reported, and a number of patients had other high-risk markers beyond del(17p), including unmutated IgVH status in 61.5% of patients.

With a median follow-up of 10 months, the overall response rate was 92.7%, including 1.9% complete responses and 78.9% partial responses. “Only one patient had primary progressive disease after starting this drug,” Dr. Tam said.

Time to response was rapid, according to the investigator, at about 2.8 months; after 6 months, 95% of responders remained in response.

Further analysis showed that the response rate was consistent across subgroups. “There was not a single group that did not respond with a high response rate, including poor prognostic groups,” Dr. Tam said.

Most adverse events were grade 1-2 in severity, and the most common events included confusion and upper respiratory tract infection. The only common grade 3 event, according to Dr. Tam, was neutropenia. Rates of grade 3 major bleeding were low, he said, and the rate of grade 3 atrial fibrillation was 0.9%. One patient died due to pneumonia.

The ongoing SEQUOIA study, designed to compare zanubrutinib to the combination of bendamustine and rituximab in patients with previously untreated CLL or SLL, is sponsored by BeiGene. Dr. Tam reported disclosures related to Novartis, Pharmacyclics, AbbVie, BeiGene, Janssen, and Roche.

SOURCE: Tam C et al. ASH 2019, Abstract 499.

ORLANDO – In young patients who experience relapse after chemotherapy for B-cell acute lymphoblastic leukemia (B-ALL), the novel agent blinatumomab (Blincyto, Amgen) can be used instead of intensive chemotherapy to try to achieve a second remission, experts say.

In fact, blinatumomab should be the new standard of care in these patients because it yielded better overall survival, was less toxic, and allowed more patients to proceed to transplant, said Robert A. Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins University, Baltimore.

Dr. Brodsky was commenting on new data presented in a late-breaking abstract (LBA1) at the annual meeting of the American Society of Hematology, for which he holds the role of secretary.

These results are “truly practice changing,” he told journalists at a press briefing.

Cure rates for B-ALL in children and adolescents and young adults (AYAs) are high, but for the small group of patients who experience relapse (about 15%), the prognosis is poor.

When relapse occurs in these patients, “it’s a real problem,” Dr. Brodsky explained. “At that point, the major emphasis is trying to get them back into full remission and get them to a transplant,” he continued, “but it’s very hard to get these patients back into remission.”

The standard treatment approach for these patients includes intensive chemotherapy. In the new study, this was compared to monotherapy with blinatumomab, which is described as a bispecific T-cell engager antibody.

The results were presented by Patrick A. Brown, MD, from the division of pediatric oncology at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University.

The Children’s Oncology Group Study AALL1331 trial was conducted in 208 children and AYA patients with B-ALL after a first relapse. Median follow-up was 1.4 years.

Blinatumomab was superior in achieving both disease-free survival (59.3 plus or minus 5.4% at 2 years vs. 41% plus or minus 6.2% at 2 years with chemo; P = .05) and overall survival (79.4 plus or minus 4.5% at 2 years vs. 59.2 plus or minus 6% at 2 years with chemo; P = .05).

In addition, more patients who received blinatumomab subsequently underwent transplant (79% vs. 45% with chemo; P less than .0001).

The drug was also better tolerated than chemotherapy, causing fewer and less severe toxicities, including fewer cases of grade 3+ infection, sepsis, and mucositis.

Dr. Brown concluded that, for children and AYA patients with high- or intermediate-risk first relapse of B-ALL, blinatumomab is superior to standard chemotherapy as postreinduction consolidation prior to transplant, resulting in fewer and less severe toxicities, higher rates of minimum residual disease response, greater likelihood of proceeding to hematopoietic stem cell transplant, and improved disease-free and overall survival.

Dr. Brown noted that blinatumomab already has conditional approval from the Food and Drug Administration for use in relapsed ALL in both adults and children, but that approval was based on clinical trial data in adults. This is now the definitive trial in children and AYAs, and it should support full approval for this indication, he said.

Dr. Brown has relationships with Novartis, Servier, and Jazz. Many coauthors also have relationships with pharmaceutical companies. Dr. Brodsky has relationships with Achillion, Alexion, and UpToDate.
 

A version of this story originally appeared on Medscape.com.

ORLANDO – In young patients who experience relapse after chemotherapy for B-cell acute lymphoblastic leukemia (B-ALL), the novel agent blinatumomab (Blincyto, Amgen) can be used instead of intensive chemotherapy to try to achieve a second remission, experts say.

In fact, blinatumomab should be the new standard of care in these patients because it yielded better overall survival, was less toxic, and allowed more patients to proceed to transplant, said Robert A. Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins University, Baltimore.

Dr. Brodsky was commenting on new data presented in a late-breaking abstract (LBA1) at the annual meeting of the American Society of Hematology, for which he holds the role of secretary.

These results are “truly practice changing,” he told journalists at a press briefing.

Cure rates for B-ALL in children and adolescents and young adults (AYAs) are high, but for the small group of patients who experience relapse (about 15%), the prognosis is poor.

When relapse occurs in these patients, “it’s a real problem,” Dr. Brodsky explained. “At that point, the major emphasis is trying to get them back into full remission and get them to a transplant,” he continued, “but it’s very hard to get these patients back into remission.”

The standard treatment approach for these patients includes intensive chemotherapy. In the new study, this was compared to monotherapy with blinatumomab, which is described as a bispecific T-cell engager antibody.

The results were presented by Patrick A. Brown, MD, from the division of pediatric oncology at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University.

The Children’s Oncology Group Study AALL1331 trial was conducted in 208 children and AYA patients with B-ALL after a first relapse. Median follow-up was 1.4 years.

Blinatumomab was superior in achieving both disease-free survival (59.3 plus or minus 5.4% at 2 years vs. 41% plus or minus 6.2% at 2 years with chemo; P = .05) and overall survival (79.4 plus or minus 4.5% at 2 years vs. 59.2 plus or minus 6% at 2 years with chemo; P = .05).

In addition, more patients who received blinatumomab subsequently underwent transplant (79% vs. 45% with chemo; P less than .0001).

The drug was also better tolerated than chemotherapy, causing fewer and less severe toxicities, including fewer cases of grade 3+ infection, sepsis, and mucositis.

Dr. Brown concluded that, for children and AYA patients with high- or intermediate-risk first relapse of B-ALL, blinatumomab is superior to standard chemotherapy as postreinduction consolidation prior to transplant, resulting in fewer and less severe toxicities, higher rates of minimum residual disease response, greater likelihood of proceeding to hematopoietic stem cell transplant, and improved disease-free and overall survival.

Dr. Brown noted that blinatumomab already has conditional approval from the Food and Drug Administration for use in relapsed ALL in both adults and children, but that approval was based on clinical trial data in adults. This is now the definitive trial in children and AYAs, and it should support full approval for this indication, he said.

Dr. Brown has relationships with Novartis, Servier, and Jazz. Many coauthors also have relationships with pharmaceutical companies. Dr. Brodsky has relationships with Achillion, Alexion, and UpToDate.
 

A version of this story originally appeared on Medscape.com.

ORLANDO – In young patients who experience relapse after chemotherapy for B-cell acute lymphoblastic leukemia (B-ALL), the novel agent blinatumomab (Blincyto, Amgen) can be used instead of intensive chemotherapy to try to achieve a second remission, experts say.

In fact, blinatumomab should be the new standard of care in these patients because it yielded better overall survival, was less toxic, and allowed more patients to proceed to transplant, said Robert A. Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins University, Baltimore.

Dr. Brodsky was commenting on new data presented in a late-breaking abstract (LBA1) at the annual meeting of the American Society of Hematology, for which he holds the role of secretary.

These results are “truly practice changing,” he told journalists at a press briefing.

Cure rates for B-ALL in children and adolescents and young adults (AYAs) are high, but for the small group of patients who experience relapse (about 15%), the prognosis is poor.

When relapse occurs in these patients, “it’s a real problem,” Dr. Brodsky explained. “At that point, the major emphasis is trying to get them back into full remission and get them to a transplant,” he continued, “but it’s very hard to get these patients back into remission.”

The standard treatment approach for these patients includes intensive chemotherapy. In the new study, this was compared to monotherapy with blinatumomab, which is described as a bispecific T-cell engager antibody.

The results were presented by Patrick A. Brown, MD, from the division of pediatric oncology at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University.

The Children’s Oncology Group Study AALL1331 trial was conducted in 208 children and AYA patients with B-ALL after a first relapse. Median follow-up was 1.4 years.

Blinatumomab was superior in achieving both disease-free survival (59.3 plus or minus 5.4% at 2 years vs. 41% plus or minus 6.2% at 2 years with chemo; P = .05) and overall survival (79.4 plus or minus 4.5% at 2 years vs. 59.2 plus or minus 6% at 2 years with chemo; P = .05).

In addition, more patients who received blinatumomab subsequently underwent transplant (79% vs. 45% with chemo; P less than .0001).

The drug was also better tolerated than chemotherapy, causing fewer and less severe toxicities, including fewer cases of grade 3+ infection, sepsis, and mucositis.

Dr. Brown concluded that, for children and AYA patients with high- or intermediate-risk first relapse of B-ALL, blinatumomab is superior to standard chemotherapy as postreinduction consolidation prior to transplant, resulting in fewer and less severe toxicities, higher rates of minimum residual disease response, greater likelihood of proceeding to hematopoietic stem cell transplant, and improved disease-free and overall survival.

Dr. Brown noted that blinatumomab already has conditional approval from the Food and Drug Administration for use in relapsed ALL in both adults and children, but that approval was based on clinical trial data in adults. This is now the definitive trial in children and AYAs, and it should support full approval for this indication, he said.

Dr. Brown has relationships with Novartis, Servier, and Jazz. Many coauthors also have relationships with pharmaceutical companies. Dr. Brodsky has relationships with Achillion, Alexion, and UpToDate.
 

A version of this story originally appeared on Medscape.com.

ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.

“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”

Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.

However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
 

Experts predict new standard of care

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.

“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.

Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.

“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.

“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.

“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
 

Study details

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

• 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
• 79% achieved CR and 21% achieved CRi after induction therapy
• 78% received at least one cycle of consolidation therapy
• 43% of patients had minimal residual disease (MRD)–positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).

Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).

Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.

But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
 

Awaiting longer follow-up

Both experts said that longer-term follow-up is needed.

“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.

“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.

At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”

The study was funded by Celgene.

Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
 

A version of this story originally appeared on Medscape.com.

ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.

“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”

Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.

However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
 

Experts predict new standard of care

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.

“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.

Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.

“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.

“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.

“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
 

Study details

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

• 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
• 79% achieved CR and 21% achieved CRi after induction therapy
• 78% received at least one cycle of consolidation therapy
• 43% of patients had minimal residual disease (MRD)–positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).

Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).

Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.

But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
 

Awaiting longer follow-up

Both experts said that longer-term follow-up is needed.

“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.

“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.

At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”

The study was funded by Celgene.

Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
 

A version of this story originally appeared on Medscape.com.

ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.

“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”

Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.

However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
 

Experts predict new standard of care

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.

“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.

Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.

“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.

“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.

“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
 

Study details

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

• 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
• 79% achieved CR and 21% achieved CRi after induction therapy
• 78% received at least one cycle of consolidation therapy
• 43% of patients had minimal residual disease (MRD)–positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).

Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).

Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.

But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
 

Awaiting longer follow-up

Both experts said that longer-term follow-up is needed.

“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.

“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.

At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”

The study was funded by Celgene.

Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
 

A version of this story originally appeared on Medscape.com.