Allogeneic stem cell transplantation (allo-SCT) for de novo Ph+ AML: a study from the French Society of Bone Marrow Transplantation and Cell Therapy
Philadelphia chromosome incidence in primary AML (Ph+ AML) is 0.5–3%. The reality of Ph+ AML remains controversial and to date is not described in the 2008 revision of the WHO (World Health Organization) classification as a separate entity. CML in myeloid blast crisis (MBC-CML) and mixed phenotype acute leukemia (MPAL) with t(9;22)(q34;q11) are differential diagnoses. Unlike CML, cases of Ph+ AML do not have a history of abnormal hemograms, lack an argument for a previous chronic phase of CML and lack basophilia or splenomegaly. In addition, cytogenetic and molecular abnormalities may be useful to distinguish CML from Ph+ AML as much as trisomy 8, trisomy 19 or isochromosome 17q, besides t(9;22) and ABL1 mutations are common additional abnormalities in MBC-CML, while Ph+ AML generally exhibits gene mutations suppressing cell differentiation (Core Binding Factor AML, NPM1) or mutations increasing cell proliferation (FLT3, RAS). Primary Ph+ AML has recently been described as a distinct AML subtype with a specific genome signature compared with CML. Although allogeneic stem cell transplantation (Allo-SCT) is often proposed as the curative option, the outcome of Ph+ AML treated with Allo-SCT remains unknown in the literature. The objective of the study was to compared primary Ph+ AML with others Ph+ acute leukemia (MPAL and MBC-CML). Here we wanted to present the result of a retrospective, multi-center study assessing the results of allo-HSCT in Ph+ acute leukemia patients that reported to the SFGM-TC registry between 2000 and 2012 (though ProMISe, a Project Manager Internet Server). Nineteen patients with Ph+ AML were identified in France and compared with 21 patients with Ph+ MPAL and 52 patients with MBC-CML. For AML, MPAL and MBC-CML patients, the median age per group was, respectively, 46 (range: 18–67), 36 (range: 18–52) and 36 (range: 18–63) years. Ph+ de novo AML was defined in patients with AML who do not have a history of abnormal hemograms, lack evidence of a previous chronic phase of CML and lack basophilia or splenomegaly. MBC-CML was defined by CML history or AML with CML features such as splenomegaly, basophilia or cytogenetic additional abnormality known to be associated with CML-MBC (as trisomy 8, trisomy 19 or isochromosome 17q). MPAL was defined by bone marrow aspiration and immunophenotyping results. Median follow-up was 24 months (range: 0.36–155). Additional cytogenetic abnormality was not different between the three groups. p210 BCR-ABL expression was 63% in Ph+ AML, 24% in MPAL and 100% in CML. p190 BCR-ABL expression was 21% in Ph+ AML, 57% in MPAL and 0% in CML-MBC (8% missing data). Complete remission rate before transplant was 90% for Ph+ AML, 85% for MPAL and 42% for CML-MBC (Po0.0001). However tyrosine–kinase inhibitor (TKI) exposure during induction was similar in each arm (47, 52 and 52% in Ph+ AML, MPAL and CML-MBC, respectively) and was not associated with a higher remission rate (Supplementary data). No difference was observed between the three groups, regarding myeloablative conditioning rate, graft source and use of antithymocyte globulin. Acute GvHD with a grade⩾ 2 was observed, respectively, in 37, 19 and 32% of the Ph+ AML, MPAL and MBC-CML groups and chronic GvHD incidence was 42, 24 and 27% in the three groups. Survival was not influenced by TKI use in induction in each group (data not shown). Relapse incidence was 28, 29 and 49% in the three groups. Two-year overall survival probability for Ph+ AML, MPAL and MBC-CML was 68.0% (42.1–84.2), 61.9% (38.1–78.8) and 43.3% (95% CI: 29.5–56.3), respectively (P= 0.016, log-rank test, Figure 1a). Two-year relapse free survival probability for Ph+ AML, MPAL and MBC-CML was 64.3% (39.2–85.5), 55.4% (31.7–73.8) and 34.9% (21.9–48.3), respectively (P= 0.008; Figure 1b). Two-year cumulative incidence of non-relapse mortality was 21.0% (0.08–0.46) for Ph+ AML, 24.1 % (0.11–0.49) for Ph+ MPAL and 31.6% (0.19–0.48) for the MBC-CML group (P=ns, Figure 1c). In univariate analysis, remission status and type of disease (Ph+ AML) were predictive factors for a better survival rate (Table 1). In multivariate analysis, remission status was the sole prognostic factor for better overall survival (Table 1). Figure 1 also describes the overall survival in each subgroup according to the remission status (Figures 1d and e). The onset of chronic GvHD was also predictive of a better overall survival (hazard ratio 0.43 (0.23–0.78), P= 0.006). To date, this study reported survival of the larger cohort of Ph+ AML treated with allo-HSCT. Very limited data have been published on primary Ph+ AML and the prognosis of this rare subgroup of AML was unknown. This study provided survival results of primary Ph+ AML in comparison with a diagnosis of Ph+ leukemia other than primary AML: the prognosis of primary Ph+ AML was significantly better than MBC-CML group. There is now clinical evidence, in addition to biological genome signature, that primary Ph+ AML is different from MBC-CML. In the present study, the Ph+ AML prognosis may be also better than MBC-CML because patients have never been exposed to TKI before induction chemotherapy. Moreover, the study started in 2000 and most MBC-CML did not received second generation TKI. Imatinib mesylate may be sufficient in naive primary Ph+ AML patients but certainly not in a cohort of MBC-CML. That point may explain the lower remission rate and worse outcome in the MBC-CML group in comparison with the two other groups. As previously described in AML, patients in this study developing a chronic graft versus host disease (GvHD) have both improved overall survival and better relapse free survival. However, the present study has some limits. The retrospective nature of the study may have induced selection biases. On the other hand, it is possible to criticize the other two groups (MBCCML and MPAL) taken for comparison. Indeed, these two groups must be differentiated from Ph+ AML in terms of treatment choice and/or response to chemotherapy. The majority of MPAL patients received lymphoblastic like therapy in contrast to patients with Ph+ AML or MBC-CML. Nevertheless, whatever the comparator arms, the present study has the merit to describe the survival of Ph+ AML patients treated with allo-SCT, which has never been done. In conclusion, our study enriches the knowledge of primary Ph+ AML, describing a promising 68% 2-years overall survival. 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