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A. Bidet et al.
was 2.3 (range, 0.66-10.5) years for -7/del(7q) CCA/Ph- patients versus 3.55 (range, 0.5-11.77) years for patients with other CCA/Ph- (P=NS, exact Mann-Whitney test) (Figure 2A). However, landmark analysis after 3 years of therapy revealed the adverse effect of -7/del(7q) CCA/Ph- (P=0.04) (Figure 2B) on the cumulative incidence of MR4.5. The type of CCA/Ph- did not have an impact on overall survival (P=0.717; data not shown). The overall rates of progression- free survival at 3, 5 and 10 years were 94.74% [95% confi- dence interval (95% CI): 90.35-99.35], 86.28% (95% CI: 78.94-94.30), and 78.60% (95% CI: 69.12-89.39), respec- tively. The overall rates of event-free survival at 3, 5 and 10 years were 67.36% (95% CI: 58.63-77.39), 56.32% (95% CI: 46.72-67.90), and 43.61% (95% CI: 33.34-57.06), respectively (data not shown). Landmark analyses at 3 years after starting first TKI therapy revealed a strong negative impact of -7/del(7q) CCA/Ph- on both event-free and pro- gression-free survival (P=0.015 and P=0.022, respectively, log-rank test), as shown in Figure 3.
Discussion
To our knowledge, this is the largest study of CML patients with CCA/Ph-, with 26 (25.4%) out of 102 patients having -7/del(7q) abnormalities in a consistent, long follow up [median 6.47 (range, 1-11) years]. Our cohort required particular care as 37% of them needed at least two switches of TKI prior to achieving their optimal response. Patients who developed -7/del(7q) CCA/Ph- were significantly younger (means 48 years old) and mostly benefited from second- and/or third-generation TKI, with a significantly lower cumulative incidence of MR4.5 at the landmark analysis 3 years after starting TKI therapy (P=0.04) than other patients. Almost half of the patients (46%) with - 7/del(7q) CCA/Ph- were in complete cytogenetic remission at the time of detection of the CCA/Ph-. Because the quality of cytogenetic responses significantly affects the prognosis, the high proportion of good cytogenetic responders in this group strengthens the involvement of chromosome 7 abnormalities in our prognostic results. Furthermore, addi- tional cytogenetic abnormalities in Ph+ cells (which are con- sidered as clonal evolution with greater risk of transforma- tion) cannot be suspected to be involved in prognosis in our study because only one out of 102 patients had an atypical t(7;14)(p21;q12) translocation in Ph+ cells at diagnosis.
Associated dysplastic features, identified by morphologi- cal analysis of bone marrow, seemed to be a more frequent event in the -7/del(7q) group, and had a significant negative impact on quality of response and outcomes as compared to that in other types of CCA/Ph- cases. In addition, irre- spectively of the type of CCA/Ph-, patients with morpho- logical MDS signs had significantly lower rates of major molecular response (P<0.0001). Likewise, 78% of the patients who did not have a complete cytogenetic response were those who had morphological features of MDS. This is in accordance with the findings of a preceding study by Deininger et al.2 who reported that patients with isolated CCA/Ph- without morphological evidence of dysplasia do not require special management. In a study by Terré et al., CCA/Ph- were not associated with myelodysplasia and did not impair the cytogenetic response to imatinib.6 However, although this was the largest published series of CCA/Ph- cases to date, only two out of 28 evaluated patients had dysgranulopoiesis, the median follow up was short (only 24
A
B
Figure 3. Landmark survival analyses according to the type of clonal chromo- some abnormalities in Philadelphia chromosome-negative cells 36 months after initiation of the first line of tyrosine kinase inhibitor therapy. (A) Event- free survival. (B) Progression-free survival. TKI: tyrosine kinase inhibitor.
months after imatinib initiation), and the majority of patients in this study had been previously treated.
Even though the overall survival rates were not statistical- ly significantly different between the two groups, landmark analyses of the impact of -7/del(7q) CCA/Ph- after 3 years of starting TKI treatment revealed lower event-free and pro- gression-free survival rates (P=0.015 and P=0.022, respec- tively). Recently, Issa et al.4 reported the prognostic rele- vance of CCA/Ph- in 58 patients with a median follow-up of 7.6 years. Among them, only four patients had -7/del(7q) type abnormalities. The disease progressed in three of these four patients, transforming to either MDS or CML blast cri- sis, without an obvious link with MDS signs in this small cohort. Excluding –Y CCA/Ph-, a decreased survival was observed for patients with CCA/Ph- and seemed to be relat- ed to MDS or CML transformation. A specific -7/del(7q)- associated risk could not be determined in their study. In another recent study, Wasilewska et al. found that -7 and +8 CCA/Ph- did not have an impact on the long-term outcome of CML patients, but survival was not investigated in this study and the series was limited to five observations.17
The occurrence of Ph+ and CCA/Ph- in the same patient could suggest the presence of two concurrent, distinct hematologic disorders: CML and MDS. To investigate the biological features of such underlying diseases, we screened for mutations in frequently altered genes in MDS or AML by NGS at the time of best response to therapy. Mutations were detected more frequently in our MDS control group of patients than in the CML group, and were also mostly found
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