Coincidence of bcr/abl-Positive Chronic Myeloid Leukemia and bcr/abl-Negative Chronic Myeloproliferative Disorder and Its Relevance to the Course of Disease.
Authors: Buesche Guntram , Bock Oliver , Hussein Kais , von Neuhoff Nils , Schlegelberger Brigitte , Kreipe Hans H. 
Published: October 2019

Recently, several case reports have been published reporting the occurrence of a JAK2-V617F-mutated clone in the bone marrow from patients with bcr/abl-positive chronic myeloid leukemia (CML) treated with imatinib mesylate. Representative data on the probability and prognostic significance of the coincidence of CML and bcr/abl-negative chronic myeloproliferative disorder (CMPD) do not exist as yet. The bone marrow biopsies from a total of 600 patients with CML treated with interferon-alpha (n = 200) or imatinib mesylate (n = 400) and a total of 1600 patients with CMPD were evaluated for the coincidence of bcr/abl-positive CML and bcr/abl-negative CMPD, and in all suspect cases, the bone marrow cells were analyzed for the JAK2-V617F-mutation. During a median follow-up period of three years, a total of six patients evolved morphologic features of CML as well as of bcr/abl-negative CMPD: One of 200 CML patients treated with interferon-alpha (.5%), four of 400 CML patients treated with imatinib (1.0%), and one of 1600 patients with CMPD (.06%). All patients were bcr/abl-positive with a bcr/abl-negative JAK2-V617F-mutated clone besides the bcr/abl-positive clone. In one patient, bcr/abl-positive CML occurred 15 years after diagnosis of polycythemia vera. Four patients showed morphologic features of bcr/abl-positive CML and bcr/abl-negative CMPD in the diagnostic bone marrow biopsy. One patient evolved features of bcr/abl-negative CMPD two years after imatinib treatment. However, in the diagnostic bone marrow biopsy of this patient, 5% JAK2-V617F-mutated cells were detected besides the bcr/abl-positive clone. During treatment with imatinib (n = 4) or interferon-alpha (n = 1), the proportion of JAK2-V617F-mutated alleles increased to 21 – 90% (median: 23%); in one patient, the follow-up was too short for a statistical analysis. One of five patients evolved essential thrombocythemia, one showed a relapse of polycythemia vera, and three patients suffered from chronic idiopathic myelofibrosis. The patient with essential thrombocythemia did not show a progression of disease. The patient with polycythemia vera died from JAK2-V617F-positive myeloid blast crisis, and all three patients with chronic idiopathic myelofibrosis suffered from full-blown marrow fibrosis one to four years after detection of JAK2-V617F-mutated CMPD. Conclusion: In a minority of patients with CML, a JAK2-V617F-mutated clone exists besides the bcr/abl-positive clone, and rarely, bcr/abl-positive CML may evolve during the course of a bcr/abl-negative JAK2-V617F-mutated CMPD. Without cytoreductive treatment, the bcr/abl-positive clone overgrows the bcr/abl-negative JAK2-V617F-mutated clone. However, in the case of a significant remission of bcr/abl-positive CML during treatment with imatinib or interferon-alpha, the bcr/abl-negative clone gets the chance to expand within bone marrow with development of morphologic and clinical signs of bcr/abl-negative CMPD. Depending on the type of CMPD, these patients show a significantly increased risk of imatinib-resistant marrow fibrosis or blast crisis.