First-Line Second Generation Tyrosine Kinase Inhibitors in Newly Diagnosed Accelerated Phase Chronic Myeloid Leukemia Patients.
Authors: Balsat Marie , Alcazer Vincent , Etienne Gabriel , Fossard Gaelle , Huguet Francoise , Berger Marc G. , Cayssials Emilie , Charbonnier Aude , Escoffre-Barbe Martine , Johnson-Ansah Hyacinthe , Dubruille Viviane , Legros Laurence , Roy Lydia , Delmer Alain Jacques , Ianotto Jean-Christophe , Gardembas Martine , Larosa Fabrice , Courby Stephane , Ame Shanti , Morisset Stephane , Mahon Francois-Xavier , Rea Delphine , Nicolini Franck Emmanuel 
Published: October 2019

Abstract
Introduction
Up to 10% of patients (pts) with chronic myeloid leukemia (CML) are already in accelerated phase (AP) at diagnosis and despite treatment advances in the field of tyrosine kinase inhibitors (TKIs), management of these pts is challenging. This study aims to examine the benefit of second generation BCR-ABL tyrosine kinase inhibitors (TKI2) as first-line treatment for newly diagnosed AP-CML.
Methods
Pts meeting criteria for AP-CML at diagnosis and treated with first-line TKI2 (i. e. Nilotinib or Dasatinib) were included in this retrospective multicenter observational national study. AP-CML were defined according to the ELN (Baccarani, Blood 2013) as hematological acceleration (HEM-AP, any of the following features: blasts in PB or marrow 15-29%, or blasts+promyelocytes in PB or marrow >30% with blasts <30%, basophils in PB ≥20%, or persistent thrombocytopenia <100×109/L (unrelated to therapy) and/or chromosomal abnormalities in addition to the Ph at diagnosis (ACA-AP). Pts initiated nilotinib at 6-800 mg BID or dasatinib at 100-140 mg QD with further dose adaptations according to toxicities or response. Overall survival (OS), progression-free survival (PFS) and failure-free survival [FFS= progression to blast crisis, death, loss of any previous response (CHR, CCyR, or MMR) discontinuation of TKI2 for toxicity], were analysed since TKI2 initiation in intention-to-treat.
Results
Sixty-six pts were analysed: 45 males (68%) and 21 females (32%) with a median age at diagnosis of 49 (15-78.5) years. The median follow-up of the cohort was 43.5 (1.7-117) months. We segregated the pts in HEM-AP (n=33) and ACA-AP (n=33) for further analyses. Nine pts with HEM-AP harboured ACA and were analysed in the HEM-AP group. Fusion transcripts were of the Major BCR in 57 pts, 6 pts had atypical BCR-ABL transcripts (2 e19a2, and 1 e1a2 in the HEM-AP group and 2 e19a2 and 1 Ma3 in the ACA-AP group), and 3 transcripts unknown. Not surprisingly, spleen enlargement was significantly greater in the HEM-AP group [10 (5-14.75) vs. 3 (0-10)cm, p=0.014]. PB basophils [median 10 (6-16) vs. 3 (2-5)%, p <0.001], PB blasts [median: 12.05 (7.5-15) vs. 1.5 (0-4)%, p<.001], as well as PB blasts+promyelocytes [median 14 (11-20) vs. 4 (1-7)%, p<.001]. Hemoglobin levels were significantly lower in the HEM-AP group [median 93 (6-113.5) vs 120 (100-134) g/L, p<0.001]. Neither WBC counts, platelets counts, nor BCR-ABL/ABL load differed significantly between the 2 groups. In the ACA-AP group, 10 (30%) pts harbored major route ACA and 23 (70%) pts harbored minor route ACA of whom 3 pts with i(17q) and 1 with 7q abnormalities. In the ACA-AP group, Sokal score was low in 42%, intermediate in 32% and high in 26% of pts (2 pts unknown). Dasatinib was initiated in 19/33 pts (57.5%) in the HEM-AP group and in 8/33 pts (24%) in the ACA-AP group.
Treatment responses did not significantly differ between ACA-AP and HEM-AP group, regardless of the TKI2 administered, with 33/33 (100%) vs 31/33 (94%) pts achieving a CHR, 2/33 (6%) pts vs 0/33 (0%) pts achieving a MCyR, 5/33 (15%) pts vs 5/33 (15%) pts achieving CCyR, 9/33 (27%) pts vs 4/33 (12%) pts achieving a MMR respectively. However, 11/33 (33%) HEM-AP vs 22/33 (66%) ACA-AP pts achieved a deep molecular response (p=0.013, Fisher test). Median times to CHR and MMR were not significantly different between ACA-AP group and HEM-AP group with 1.05 vs 1.25 months (p=0.088) for CHR and 6 vs 7 months (p=0.156) for MMR, respectively.
Overall, the estimated 7-yr FFS rate was 56.92% (95%CI: 40-81), 7-yr PFS was 83.42% (95% CI: 69.6-100%) and 7-yr OS was 87.14% (95%CI: 73.5-100%) (Figure 1.) with no significant differences between ACA-AP vs HEM-AP pts [7-yr FFS: 57.7 vs. 62%, p=0.739; 7-yr PFS: 84.7% vs. 84%, p=0.185; 7-yr OS: 88.9% vs 86.6%, p=0.132] respectively.
There was also no difference in FFS, PFS and OS according to the type of TKI2. The only factors influencing negatively OS were the % of BM blasts (HR=1.17, 95%CI: 1.1-1.28, p<0.001) and the % of BM blasts+promyelocytes (HR=1.14, 95%CI: 1.06-1.22, p<0.001). We identified too few significant factors in univariate analysis to perform a multivariate analysis.
Conclusion
The initiation of a TKI2 in newly diagnosed AP-CML pts induces excellent response and survival rates, probably superior to that of Imatinib first-line, and counterbalances the negative impact of this advanced disease, particularly in HEM AP subgroup.

Disclosures
Etienne: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau. Berger:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau. Rea:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Pfizer: Honoraria. Nicolini:BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau; Sun Pharma Ltd: Consultancy.