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Prognosis of -7/del(7q) in Ph- cells and underlying MDS
leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the conse- quent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia- negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal.
Introduction
Concurrently with the BCR-ABL1 fusion gene resulting from t(9;22)(q34;q11) in Philadelphia-positive (Ph+) cells, clonal chromosome abnormalities (CCA) can be present at the time of diagnosis of chronic myeloid leukemia (CML) or emerge during therapy. CCA in Ph+ cells (CCA/Ph+) are well known; they are associated with clonal cytogenetic evolu- tion and failure of tyrosine kinase inhibitor (TKI) therapy.1 However, CCA may also occur in Philadelphia-negative cells (CCA/Ph-). According to reported series, CCA/Ph- could be present in 2% to 17% of CML patients treated with TKI. These differences in frequencies could be partly explained by taking into account (or not) the loss of chro- mosome Y and transitory abnormalities.2–7 While the fre- quency of CCA/Ph- varies greatly from study to study, other characteristics seem more reproducible, such as the median age at onset (between 49 and 58 years), the median time of the first appearance during TKI therapy (between 10 and 17 months) and the type of CCA/Ph- which is, according to their frequencies: trisomy 8 (+8), monosomy 7/deletion 7q [-7/del(7q)], loss of the Y chromosome (-Y), deletion 20q (20q) and others. Despite very limited infor- mation on the occurrence of this phenomenon among patients treated with second-generation TKI, the incidence and type of abnormalities after nilotinib or dasatinib treat- ment seem to be similar to those reported in patients after imatinib therapy.3,7,8
Controversies still exist regarding the emergence of CCA/Ph-, not only on the time of appearance (before or after treatment), but also on the potential impact of the type of TKI or high doses of TKI. For Kovitz et al.9 the appear- ance of CCA was not observed in the Ph- cells prior to ther- apy with interferon or imatinib. This pleads for a support- ing action of the treatment or a selective pressure on pro- genitor cells. Conversely, HUMARA-polymerase chain reaction and deep mutational screening of Ph- cells could argue for the existence of clonal Ph- hematopoiesis, either before or after CML therapy.10,11 It could then be speculated that a clonal Ph- state could precede the acquisition of BCR- ABL1, as evidence of a two-step model of CML. Another hypothesis is that Ph+ or Ph- concomitant clones arise from genetically unstable progenitors, with the Ph- clone revealed at the time of TKI-induced remission of CML.
Most CCA/Ph- are similar to those commonly associated with myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (AML), raising many questions about their association with myelodysplasia and the risk of transformation to MDS or AML. In 2013, the European LeukemiaNet (ELN) recommendations,1 -7/del(7q) abnor- malities are considered as a “warning” compared to other
CCA/Ph-. This is an innovation compared to the 2009 ELN recommendations. This singling out of -7/del(7q) abnormal- ities was based on some case reports indicating MDS fea- tures and an increased risk of AML development among patients with such abnormalities, not present with other CCA/Ph- in the absence of dysplasia.2,9,12–14 Indeed Deninger et al. reported 17 patients treated with imatinib after failure of interferon therapy who had CCA/Ph- and developed MDS; eight of them had -7.2 In a meta-analysis, Groves et al. found that 32% of 16 CCA/Ph- patients with -7 had transformation to MDS/AML.12 However, the prognostic impact of CCA/Ph-, and specifically those of chromosome 7, on clinical outcomes is unclear as only limited studies have had a sufficiently long follow up.4 We, therefore, con- ducted a large, retrospective French multicenter study of CCA/Ph- CML patients with a prolonged follow up to: (i) evaluate the frequency of abnormalities of chromosome 7 among CCA/Ph-, especially in the era of second-generation TKI; (ii) determine their impact on clinical outcomes; and (iii) assess the existence of an underlying associated high- risk MDS by systematic bone marrow morphological review and next-generation sequencing (NGS) using a MDS/AML panel.
Methods
Patients
The databases of French institutions were screened, leading to the identification of 102 CML patients with a CCA/Ph- at diagno- sis or during the course of treatment with one or more lines of TKI, and 11 MDS patients without a history of CML who had an abnormal karyotype who formed the control group. Among these patients, a chromosome 7 abnormality [-7/del(7q)] was detected in 26 CML cases and in four MDS cases. Patients in blast phase CML at diagnosis were excluded.
The patients’ clinical and biological data were obtained from medical records. The study was performed in accordance with the Declaration of Helsinki, and was approved by a local investigation- al review board (CPP DC 2015/133).
Procedures
Cytogenetic response was determined using standard proce- dures. Clonality was defined by two or more metaphases present- ing the same abnormality, or three metaphases presenting the same monosomy except for -Y because the rate of this monosomy could be age-related. The potential involvement of -Y in the leukemic process was only established for patients with more than 75% –Y metaphases. All karyotypes were reviewed by Groupe Francophone de Cytogénétique Hématologique members and then clas- sified according to the 2016 International System for Human
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