Concomitant occurrence of BCR-ABL and JAK2V617F mutation

To the editor:

In a recent issue of the journal, Makishima et al¹  reported on the occurrence of mutations typically associated with Philadelphia-chromosome (Ph¹) negative myeloproliferative (MPN)/ myelodysplastic neoplasms in 54 patients with typical chronic myelogenous leukemia (CML) in chronic (CP), accelerated (AP) and blast (BP) phase. Mutations in TET2, CBL, ASXL1 or IDH1 were observed in 14% of AP and 40% of BP patients. No CP patient harbored mutation additional to BCR/ABL, including the most common JAK2V617F mutation. However, several isolated cases of concomitant JAK2V617F mutation and BCR-ABL rearrangement have been reported in the literature.² 

To evaluate the frequency of this double mutated phenotype, we performed a large screening of JAK2V617F mutation in 314 patients with typical BCR-ABL positive CML; 304 (97%) were in CP, 6 (2%) in AP and 4 (1%) in BP. This was an unselected series of patients receiving tyrosine-kinase inhibitor (TKI) treatment who referred to 3 centers (Florence, Bari, Torino) for routine BCR-ABL quantification assessment over a 6-month period. Methods for quantitative assessment of BCR-ABL³  and JAK2V617F mutation⁴  were as described; all JAK2 mutations were confirmed independently by direct sequencing. Informed consent was obtained under an IRB-approved protocol.

We found 8 subjects who were both BCR-ABL rearranged and JAK2V617F mutated accounting for 2.55%; main clinical characteristics are reported in Table 1. Patient 1 had a previous diagnosis of Polycythemia Vera (PV), treated with pipobroman and hydroxyurea for approximately 10 years. Because of progressive leukocytosis under hydroxyurea, a suspicion of CML was supported by demonstration of BCR-ABL rearrangement. At that time, JAK2V617F allele burden was at detection limit, approximately 1%–2%; nevertheless, after 9 months of Imatinib therapy, that produced a hematologic response only, the JAK2V617F allele burden increased up to 61%. Patient 4 was diagnosed with Ph-positive CML and treated with interferon-α, obtaining hematologic and cytogenetic response. He discontinued for poor tolerance and loss of CCyR. He achieved MMR under Imatinib, but thrombocytosis persisted; JAK2V617F mutation was discovered (allele burden, 15%). This led us to hypothesize a phenomenon of proliferative competition between the JAK2 positive clone and the BCR-ABL rearranged one, the latter partially controlled by imatinib. This behavior is consistent with a previous report by Bocchia et al.⁵  However, none of the additional 6 double mutated patients presented specific clinical features of a Ph¹ -negative MPN, with the possible exception of patient 6 who had extensive thrombocytosis. We also did not observe a particular behavior in patients' response to TKI, since all of them, except for patient 1 with a previous PV diagnosis, achieved at least CCyR.

In summary, in this larger cohort of CML patients compared with that studied by Makishima et al,¹  we found 2.55% of cases presenting concomitant BCR/ABL rearrangement and JAK2V617F mutation, indicating that the simultaneous occurrence of these mutations is rare event but it is not a phoenix; however, while the pathophysiologic significance of this double mutated phenotype remains to be clarified, it seems clear that the predominant clinical phenotype is, in most cases, that of a typical BCR-ABL rearranged CML.