Myelofibrosis evolving during imatinib treatment of a chronic myeloproliferative disease with coexisting BCR-ABL translocation and JAK2^V617F mutation

Among the more than 100 published cases of Philadelphia chromosome–positive chronic myelogenous leukemia (Ph⁺ CML) investigated for the 1849G > T mutation of the Janus kinase 2 (JAK2^V617F),¹ no mutated cases have been found so far.^2,3  Selected patients with Ph⁺ CML with marked thrombocytosis also proved to be negative for the JAK2^V617F mutation.³  We report for the first time a case of coexisting JAK2^V617F mutation in Ph⁺ CML evolving to myelofibrosis during imatinib treatment.

The 55-year-old white man presented with splenomegaly, leukocytosis (white blood cell [WBC] count of 163 × 10⁹/L), a low hemoglobin (Hb) level (115 g/L), and an elevated lactate dehydrogenase (LDH) level (1337 U/L). A total of 14% blast cells in peripheral blood indicated acceleration. Peripheral blood smears revealed typical features of a CML, and molecular analysis showed a rare variant of bcr-abl fusion gene (e19a2). Imatinib therapy induced normalization of the patient's blood parameters within 11 months (WBC count, 5 × 10⁹/L; Hb, 138 g/L; LDH, 232 U/L; and 0% blast cells), including cytogenetic and molecular remission, with no detectable BCR-ABL fusion transcripts in the bone marrow. Furthermore, splenomegaly was no longer present. Follow-up biopsies of the bone marrow 11, 14, and 23 months after initial diagnosis and onset of treatment revealed an increasing accumulation of megakaryoctes and focal deposition of argyrophilic fibers (Figure 1). Whereas histomorphology suggested persistence or relapse of the Ph⁺ CML clone, no BCR-ABL fusion transcripts could be detected in the bone marrow. Consequently, a JAK2^V617F mutation was analyzed with a highly sensitive pyrosequencer assay,^2,4  and in the initial biopsy, 5% mutated alleles were found, which increased to 15% and 23% after 14 and 23 months, respectively (Figure 1). During the first 23 months of follow-up red blood cell counts, Hb, platelets, and WBC counts remained stable and within normal range. When the initial pretherapeutic trephine was re-evaluated, minor focal fibrosis was obvious, but besides a BCR-ABL fusion, there was evidence for a small JAK2^V617F-mutated clone encompassing 5% of alleles. In rare cases, JAK2^V617F can occur simultaneously with the recently discovered thrombopoietin receptor point mutation in the oncogene of myeloproliferative leukemia (MPL 1544G > T/W515L),^5,6  but pyrosequencing and direct sequencing revealed a MPL wild-type status in all biopsies.

This case demonstrates for the first time that BCR-ABL translocation and JAK2 mutation may be concomitantly detectable in hematopoietic cells of a single patient. The suppression of the Ph⁺ CML clone beyond the level of detection by imatinib therapy while the JAK2^V617F-mutated alleles steadily increased argues in favor of 2 independently growing aberrant stem cell clones in this patient. The clinical and histopathologic diversity of Ph⁻ chronic myeloproliferative disease (CMPD), encompassing polycythemia vera, essential thrombocythemia, and chronic idiopathic myelofibrosis, all of which share the JAK2^V617F mutation, is still unexplained. Recently, it has been hypothesized by Kralovics et al⁷  that a varying combination of different molecular defects in 1 pathologic stem cell might be responsible for the phenotypic heterogeneity,⁷  but this case indicates that at least in a subfraction of patients, heterogeneity might also be caused by independently coexisting abnormal hematopoietic stem cell clones. Furthermore, persistent anemia or evolving myelofibrosis during imatinib treatment of Ph⁺ CML despite molecular suppression might be caused by a coexisting Ph⁻ CMPD clone.

Correspondence: Hans Kreipe, Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; e-mail: kreipe.hans@mh-hannover.de.

Supported by Deutsche Krebshilfe, Dr Mildred Scheel Stiftung 10-2191 (O.B., H.K.) and Deutsche Forschungsgemeinschaft—DFG BO 1954/1-1 (O.B., H.K.)