Clofarabine, cytarabine, and mitoxantrone in refractory/relapsed acute myeloid leukemia: High response rates and effective bridge to allogeneic hematopoietic stem cell transplantation

Harinder Gill, Rita Yim, Herbert H Pang, Paul Lee, Thomas S Y Chan, Yu-Yan Hwang, Garret M K Leung, Ho-Wan Ip, Rock Y Y Leung, Sze-Fai Yip, Bonnie Kho, Harold K K Lee, Vivien Mak, Chi-Chung Chan, June S M Lau, Chi-Kuen Lau, Shek-Yin Lin, Raymond S M Wong, Wa Li, Edmond S K Ma, Jun Li, Gianni Panagiotou, Joycelyn P Y Sim, Albert K W Lie, Yok-Lam Kwong, Harinder Gill, Rita Yim, Herbert H Pang, Paul Lee, Thomas S Y Chan, Yu-Yan Hwang, Garret M K Leung, Ho-Wan Ip, Rock Y Y Leung, Sze-Fai Yip, Bonnie Kho, Harold K K Lee, Vivien Mak, Chi-Chung Chan, June S M Lau, Chi-Kuen Lau, Shek-Yin Lin, Raymond S M Wong, Wa Li, Edmond S K Ma, Jun Li, Gianni Panagiotou, Joycelyn P Y Sim, Albert K W Lie, Yok-Lam Kwong

Abstract

Clofarabine is active in refractory/relapsed acute myeloid leukemia (AML). In this phase 2 study, we treated 18- to 65-year-old AML patients refractory to first-line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high-dose cytarabine consolidation, with clofarabine (30 mg/m2 /d, Days 1-5), cytarabine (750 mg/m2 /d, Days 1-5), and mitoxantrone (12 mg/m2 /d, Days 3-5) (CLAM). Patients achieving remission received up to two consolidation cycles of 50% CLAM, with eligible cases bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mutational profile of a 69-gene panel was evaluated. Twenty-six men and 26 women at a median age of 46 (22-65) years were treated. The overall response rate after the first cycle of CLAM was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematologic recovery, CRi: 21.2%). Twenty-two CR/CRi patients underwent allo-HSCT. The 2-year overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were 65.8%, 45.7%, and 40.2%, respectively. Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allo-HSCT (P = .005), and superior RFS and EFS were associated with allo-HSCT (P < .001). Remarkably, CR after CLAM and allo-HSCT resulted in 2-year OS of 84.3% and 90%, respectively. Karyotypic aberrations and genetic mutations did not influence responses or survivals. Grade 3/4 neutropenia/thrombocytopenia and grade 3 febrile neutropenia occurred in all cases. Other nonhematologic toxicities were mild and uncommon. There was no treatment-related mortality and the performance of allo-HSCT was not compromised. Clofarabine, cytarabine, and mitoxantrone was highly effective and safe in refractory/relapsed AML. This study was registered at ClinicalTrials.gov (NCT02686593).

Keywords: acute myeloid leukemia; adult; clofarabine; cytarabine; mitoxantrone; refractory; relapsed.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Heatmap shows gene mutations at diagnosis in various functional groups in 52 patients with relapsed/refractory acute myeloid leukemia treated with CLAM. Each small square denotes 1 patient. Karyotype: 0 = normal; 1 = core‐binding factor AML; 2 = t(9;11)(p21.2;q23.3); 3 = inv(3)(q21.3q26.2) or t(3;3)(q21.2;q23.3); 4 = t(v;11q23.3) or del(11)(q23); 5 = complex; 6 = others. AML, acute myeloid leukemia; CLAM, clofarabine, cytarabine, and mitoxantrone
Figure 2
Figure 2
Swimmer plot illustrating the outcome of 52 patients treated with CLAM. A, Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) after initially achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) with CLAM. B, Patients who did not undergo allogeneic HSCT after initially achieving CR/CRi with CLAM. C, Patients with nonremission (NR) to CLAM. CLAM, clofarabine, cytarabine, and mitoxantrone
Figure 3
Figure 3
Survivals and prognostic factors for survivals in 52 patients with refractory/relapsed acute myeloid leukemia treated with CLAM. A‐C, overall survival (OS); D and E, relapse‐free survival (RFS); F and G, event‐free survival (EFS). CLAM, clofarabine, cytarabine, and mitoxantrone

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