Impact of frontline treatment approach on outcomes of myeloid blast phase CML

Kapil Saxena,Jorge E Cortes,Abhishek Maiti,Marina Konopleva,Ghayas Issa,Naval Daver,Musa Yilmaz,Hagop Kantarjian,Elias Jabbour,Tapan Kadia,Kelly Chien,Koji Sasaki,Farhad Ravandi,Courtney D Dinardo,Sherry Pierce,Nicholas J Short

doi:10.1186/s13045-021-01106-1

Abstract

BackgroundThe natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcomes of blast phase CML remain poor with no consensus frontline treatment approach.MethodsWe retrospectively analyzed the response rates and survival outcomes of 104 consecutive patients with myeloid blast phase CML (CML-MBP) treated from 2000 to 2019 based on 4 different frontline treatment approaches: intensive chemotherapy (IC) + TKI (n = 20), hypomethylating agent (HMA) + TKI (n = 20), TKI alone (n = 56), or IC alone (n = 8). We also evaluated the impact of TKI selection and subsequent allogeneic stem cell transplant (ASCT) on patient outcomes.ResultsResponse rates were similar between patients treated with IC + TKI and HMA + TKI. Compared to treatment with TKI alone, treatment with IC/HMA + TKI resulted in a higher rate of complete remission (CR) or CR with incomplete count recovery (CRi) (57.5% vs 33.9%, p < 0.05), a higher complete cytogenetic response rate (45% vs 10.7%, p < 0.001), and more patients proceeding to ASCT (32.5% vs 10.7%, p < 0.01). With a median follow-up of 6.7 years, long-term outcomes were similar between the IC + TKI and HMA + TKI groups. Combination therapy with IC/HMA + TKI was superior to therapy with TKI alone, including when analysis was limited to those treated with a 2nd/3rd-generation TKI. When using a 2nd/3rd-generation TKI, IC/HMA + TKI led to lower 5-year cumulative incidence of relapse (CIR; 44% vs 86%, p < 0.05) and superior 5-year event-free survival (EFS; 28% vs 0%, p < 0.05) and overall survival (OS; 34% vs 8%, p = 0.23) compared to TKI alone. Among patients who received IC/HMA + TKI, EFS and OS was superior for patients who received a 2nd/3rd generation TKI compared to those who received imatinib-based therapy. In a landmark analysis, 5-year OS was higher for patients who proceeded to ASCT (58% vs 22%, p = 0.12).ConclusionsCompared to patients treated with TKI alone for CML-MBP, treatment with IC + TKI or HMA + TKI led to improved response rates, CIR, EFS, and OS, particularly for patients who received a 2nd/3rd-generation TKI. Combination therapy with IC + TKI or HMA + TKI, rather than a TKI alone, should be considered the optimal treatment strategy for patients with CML-MBP.

Highlights

Chronic myeloid leukemia (CML), which is characterized by the presence of the Philadelphia chromosome (Ph +) and the resultant BCR-ABL1 fusion, occurs in different phases dependent on the absence or presence of certainSaxena et al J Hematol Oncol (2021) 14:94 clinical features, including cytogenetic clonal evolution, basophilia, and elevated blast percentage [1]
BCR-ABL1 tyrosine kinase inhibitors (TKIs) have remarkably altered the prognosis of chronic myeloid leukemia (CML), with patients in chronic phase (CP) having a normal lifespan compared to their age-matched peers and the prospect of a cure within reach for those who enter a durable treatment-free remission (TFR) [6, 7]
Twenty patients were treated with intensive chemotherapy (IC) + TKI, 20 with hypomethylating agent (HMA) + TKI, 56 with TKI alone, and 8 with IC alone

Summary

Introduction

Chronic myeloid leukemia (CML), which is characterized by the presence of the Philadelphia chromosome (Ph +) and the resultant BCR-ABL1 fusion, occurs in different phases dependent on the absence or presence of certainSaxena et al J Hematol Oncol (2021) 14:94 clinical features, including cytogenetic clonal evolution, basophilia, and elevated blast percentage [1]. CML presents in a chronic phase (CP) in about 95% of patients [2]. 5% of patients present with an advanced phase of disease, either in an accelerated (AP) or blast phase (BP) [2]. In the pivotal phase III IRIS study comparing imatinib to chemoimmunotherapy (cytarabine + IFNα), the 10-year rate of progression to an advanced phase was reduced from 12.8% with chemoimmunotherapy to 6.9% with imatinib [8]. The natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcomes of blast phase CML remain poor with no consensus frontline treatment approach

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