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48 First-Line Second Generation Tyrosine Kinase Inhibitors in Newly Diagnosed Accelerated Phase Chronic Myeloid Leukemia Patients.

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Therapy: Epidemiology, Prognosis, and Real Life Care
Hematology Disease Topics & Pathways:
Diseases, CML, Therapies, Non-Biological, Myeloid Malignancies
Saturday, December 1, 2018: 8:45 AM
Seaport Ballroom A (Manchester Grand Hyatt San Diego)

Marie Balsat, MD1,2*, Vincent Alcazer, MD3*, Gabriel Etienne, MD, PhD2,4*, Gaelle Fossard, MD1*, Francoise Huguet, MD2,5*, Marc G. Berger, MD, PhD2,6*, Emilie Cayssials, MD2,7*, Aude Charbonnier, MD2,8*, Martine Escoffre-Barbe, MD2,9*, Hyacinthe Johnson-Ansah, MD2,10*, Viviane Dubruille, MD2,11*, Laurence Legros, MD, PhD2,12*, Lydia Roy, MD2,13*, Alain Jacques Delmer, MD2,14, Jean-Christophe Ianotto, MD, PhD2,15*, Martine Gardembas, MD2,16*, Fabrice Larosa2,17*, Stephane Courby, MD2,18*, Shanti Ame, MD2,19*, Stephane Morisset, Stat3*, Francois-Xavier Mahon, MD, PhD2,20, Delphine Rea, MD2,21 and Franck Emmanuel Nicolini, MD, PhD2,3,22

1Hematology, Centre Hospitalier Lyon Sud, Pierre Benite, France
2French group of CML (Fi-LMC), Pessac, France
3Hematology, Centre Leon Berard, Lyon, France
4Hematology Department, Institut Bergonié, Bordeaux, France
5Hematology Department, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
6Hématologie Biologique and EA 7453 CHELTER, CHU Estaing and Université Clermont Auvergne, Clermont-Ferrand, France
7CHU POITIERS, POITIERS, FRA
8Hematology department, Institut Paoli Calmettes, Marseille, France
9Service d'Hématologie Adulte, CHU de Rennes, Rennes, France
10Hematology department, CHU Caen, Caen, France
11Clinical Hematology, Nantes University Hospital, Nantes, France
12Department of Hematology, Centre Hospitalier Universitaire de Nice, Nice, France
13Hematology department, Hopital Henri Mondor, Creteil, France
14Hopital Robert Debre CHU de Reims, Reims, Cedex, France
15Institute of Oncology and Hematology, Brest, France
16Hematology department, University Hospital Angers, Angers, France
17HOPITAL JEAN MINJOZ, BESANCON CEDEX, FRA
18Hematology department, CHU Grenoble, Grenoble, France
19Hematology department, Hopital Civil , CHU Strasbourg, Strasbourg, France
20Hematology Department, Institut Bergonie, Bordeaux, France
21Adult Hematology department, Hôpital Saint-Louis, Paris, France
22INSERM U590, CRCL, Lyon, France

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.

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