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CSF3R truncation mutations in a patient with B-cell acute lymphoblastic leukemia and a favorable response to chemotherapy plus dasatinib.

ABSTRACT: Activating mutations in the gene encoding for receptor of colony stimulating factor 3 (CSF3R) are drivers of pathogenesis in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). We describe a patient with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and three unique CSF3R truncating mutations which are predicted to be activating. After a slow early response to induction chemotherapy, dasatinib was added based on data from in vitro experiments demonstrating that dasatinib effectively targets key downstream kinases in CSF3R-mutated CNL/aCML. The patient subsequently achieved complete remission with minimal residual disease negativity that has been durable.

SUBMITTER: Schwartz MS

PROVIDER: S-EPMC7305335 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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CSF3R truncation mutations in a patient with B-cell acute lymphoblastic leukemia and a favorable response to chemotherapy plus dasatinib.

Schwartz Marc S MS Wieduwilt Matthew J MJ

Leukemia research reports 20200608

Activating mutations in the gene encoding for receptor of colony stimulating factor 3 (CSF3R) are drivers of pathogenesis in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). We describe a patient with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and three unique CSF3R truncating mutations which are predicted to be activating. After a slow early response to induction chemotherapy, dasatinib was added based on data from <i>in vitro</i> experiments demo ...[more]

PMID: 32577374

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Project description:Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.

Dataset Information

CSF3R truncation mutations in a patient with B-cell acute lymphoblastic leukemia and a favorable response to chemotherapy plus dasatinib.

Publications

CSF3R truncation mutations in a patient with B-cell acute lymphoblastic leukemia and a favorable response to chemotherapy plus dasatinib.

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