Variant Philadelphia-Positive Chronic Myeloid Leukemia, der(9) Deletions and Response to Imatinib Mesylate: A Retrospective Multicentric Analysis from the French Fi-LMC Group.
Authors: Corm S. , Nicolini Franck , Richebourg S. , Huguet F. , Rea D. , Tigaud I. , Dastugue N. , Raynaud S. , Legros L. , van den Akker J. , Mahon F.X. , Maloisel F. , Roche-Lestienne C. , Guerci A. , Preudhomme C. , Eclache V. 
Published: October 2019

Abstract
Purpose: Major initial prognostic factors predicting chronic myeloid leukaemia (CML) response to imatinib mesylate (IM) therapy are represented by hema-tological status, Sokal score and duration of disease before IM. Before the era of IM, CML patients harbouring der(9) deletion classically had a worse outcome when compared to non deleted pts, but some preliminary studies suggest that this adverse factor might be reversed by IM. Additionally der(9) deletion seems to be more frequent in Variant Ph chromosome (vPh) patients (up to 30%) whereas its frequency is about 10% in classical Ph pts. We evaluated in this retrospective multicentric study the response to IM in vPh population and the possible impact of der(9) deletion on this response. 92 vPh patients treated by IM were selected from 11 hematology departments within the country. vPh chromosome was assessed by conventional karyotyping analysis and der(9) deletion by FISH. IM resistant patients were screened for ABL kinase site mutation by direct sequencing. Statistical analysis of survival and descriptive parameters were performed according to Kaplan Meyer method, log-rank test, Chi-2 and non parametric Kruskal Wallis tests.
Results: among the vPh population 75% pts had a simple translocation and 25% had a more complex one (chromosomes 9, 22 and at least two other break-points). Initially 95% pts were in chronic phase (CP), 2.5% in accelerated phase (AP) and 2.5% in blastic crisis (BC).19 pts (33.3%) were scored in each Sokal score category (low, intermediate and high). At IM initiation: 83% were in CP (>35% Ph+ ), 8% were in major cytogenetic response (after interferon) and 9% were either in AP or in BC. 74 pts were screened for der(9) deletion, which was present in 16.2% of them. IM response and survival data were available for 53 pts with CP (with > 35% Ph+ ) at IM initiation. Median age of this CP population at diagnosis was 50.8 (19.5–79.4), median disease duration before IM initiation : 2 Mo (0–92.4), median follow-up after IM initiation : 24.8 Mo (6.1–69.9). 71.7% achieved RcyM including 67.9% in RcyC. 19 pts presented IM failure or suboptimal response (European LeukemiaNet consensus). 1 pt stopped IM for liver intolerance. We observed 9 (16.9%) primary resistance and 10 (18.9%) loss of response. 12% pts progressed towards AP/BC. 12 resistant pts were screened for ABL kinase site mutations : 3 of them harboured mutations. We found no difference for the overall survival between the populations with (n=9) and without (n=33) der(9q) deletions (median of survival not reached ). Respectively 1 pt (11%) and 3 pts (9%) died in these two cohorts. We found a trend for an increased rate of resistance in the der(9) deletion cohort (55.6% vs 30.3%) but the difference was not significative (p=0.16). We only found significant differences in the repartition of the Sokal score between these two cohorts with more frequent high scores for vPh patients (p=0.03). Resistance in vPh IM treated pts is high (35.8%) but the disease duration before IM was heterogenous. Der(9) deletions slightly increases the rate of IM resistance but we found no difference of survival between the two cohorts.