Sequential Development of JAK2(V617F) Mutation and BCR-ABL1 Fusion in Individual Patients With Myeloproliferative Neoplasms A Linear Clonal Evolution or Parallel Clonal Competition?

Context.-Concomitant BCR-ABL1 and JAK2(V617F) in myeloproliferative neoplasms (MPNs) is rare, and its pathogenesis and clinical significance are unclear. Objective.-To investigate the clonal relationship between the 2 genomic alterations, as well as the clinico-pathologic impact. Design.-Retrospective analysis of MPNs with sequential development of BCR-ABL1 and JAK2(V617F). Results.-Of 6 cases, 5 had JAK2(V617F)-positive MPN diagnosed before acquiring BCR-ABL1 years later, and 1 had BCR-ABL1(+) chronic myeloid leukemia before JAK2(V617F)-positive myelofibrosis completely replaced the BCR-ABL1(+) clone 1 year after tyrosine kinase inhibitor therapy. Among the former group, treatment for the initial MPN involved hydroxyurea, ruxolitinib, and/or supportive care, and the latency to the development of JAK2(V617F) ranged from 4 to 13 years (median of 9 years). Four cases showed retention of JAK2(V617F), whereas BCR-ABL1 emerged as the major clone, including 2 cases that exhibited parallel increases in JAK2(V617F) and BCR-ABL1 burdens, with both genomic markers exceeding 50%. Three patients received stem cell transplants and demonstrated sustained engraftment, with the genomic markers below detectable levels. Conclusions.-Most MPNs with concomitant JAK2(V617F) and BCR-ABL1 are actually composite MPNs with a "second hit" residing on a different clone. Rare cases demonstrate a subclone harboring a "double-hit" in a background of a JAK2(V617F)-positive stem line clone. The probability of a "double-hit" with a BCR-ABL1(+) stem line clone is probably reduced by effective tyrosine kinase inhibitor treatment. The treatment often involves combined kinase inhibitors and/or hydroxyurea, but the outcome is unpredictable; hematopoietic stem cell transplantation may be the ultimate therapeutic option for this complicated disease.