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Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia.

ABSTRACT: Drug-resistant acute lymphoblastic leukemia (ALL) patients do not respond to standard chemotherapy, and an urgent need exists to develop new treatment strategies. Our study exploited the presence of B-cell activating factor receptor (BAFF-R) on the surface of drug-resistant B-ALL cells as a therapeutic target. We used anti-BAFF-R (VAY736), optimized for natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), to kill drug-resistant ALL cells. VAY736 antibody and NK cell treatments significantly decreased ALL disease burden and provided survival benefit in vivo However, if the disease was advanced, the ADCC efficacy of NK cells was inhibited by microenvironmental transforming growth factor-beta (TGF?). Inhibiting TGF? signaling in NK cells using the TGF? receptor 1 (R1) inhibitor (EW-7197) significantly enhanced VAY736-induced NK cell-mediated ALL killing. Our results highlight the potential of using a combination of VAY736 antibody with EW-7197 to treat advance-stage, drug-resistant B-ALL patients.

SUBMITTER: Vicioso Y

PROVIDER: S-EPMC6606383 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia.

Vicioso Yorleny Y Gram Hermann H Beck Rose R Asthana Abhishek A Zhang Keman K Wong Derek P DP Letterio John J Parameswaran Reshmi R

Cancer immunology research 20190528 7

Drug-resistant acute lymphoblastic leukemia (ALL) patients do not respond to standard chemotherapy, and an urgent need exists to develop new treatment strategies. Our study exploited the presence of B-cell activating factor receptor (BAFF-R) on the surface of drug-resistant B-ALL cells as a therapeutic target. We used anti-BAFF-R (VAY736), optimized for natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), to kill drug-resistant ALL cells. VAY736 antibody and NK cell ...[more]

PMID: 31138521

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Project description:BackgroundProphylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse.MethodsWe conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it.ResultsThe 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection.ConclusionsWith effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.)

Project description:BackgroundBlinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects.MethodsIn this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival.ResultsOf the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group.ConclusionsTreatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).

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Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia.

Publications

Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia.

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