Coexistence of a JAK2 Mutated Clone May Cause Hematologic Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Abstract

Coexistence of JAK2 mutation and BCR-ABL has been rarely described. We report 3 cases with the presence of 2 different clones, 1 Philadelphia chromosome positive and the other JAK2 mutated, becoming prevalent after treatment with tyrosine kinase inhibitors (TKIs). The presence of a JAK2-positive clone may cause hematologic resistance to TKIs.

Full Abstract

Introduction

In myeloproliferative neoplasms, coexistence of the JAK2 mutation and BCR-ABL rearrangement has been rarely described in patients. We report 3 such cases.

Case 1

Patient 1 was diagnosed as chronic myeloid leukemia (CML) following the discovery of thrombocytosis. She took imatinib with no platelet control, and hydroxyurea (HU) was added. She started nilotinib for leukocytosis, thrombocytosis, and 100% Philadelphia chromosome (Ph) positivity. In 6 months she obtained a complete cytogenetic response (CCyR), but the hematologic improvement was transient. We thus researched the JAK2 mutation that was positive. Interestingly, the JAK2^V617F was present since nilotinib start, but its expression achieved the maximum with CCyR.

Case 2

Patient 2 was diagnosed as primary myelofibrosis with leukocytosis, thrombocytopenia, splenomegaly, and fibrosis in the bone marrow (BM). Karyotype was normal. After 2 years with no treatment, BM showed 15% myeloblasts with 100% Ph positivity. The patient started imatinib. After an initial improvement, a new increase of leukocytes and platelets followed, with normal karyotype. HU was added, but hematologic control remained unsatisfactory and imatinib was stopped. The patient stayed on CCyR with insufficient hematologic response for more than one year, until he developed a Ph-negative myeloblast crisis with homozygosis for JAK2^V617F. We found that before imatinib the patient had a 50% JAK2-mutated phenotype, and after 3 months of therapy, more than 70%.

Case 3

Patient 3 was diagnosed as having essential thrombocytopenia with a normal karyotype. Good control of the thrombocytosis was obtained with HU, which continued for 10 years, and then the patient refused therapy for the next 3 years of stable disease, until he developed bone pain, leukocytosis, and enlarged spleen. Conventional cytogenetics was normal, but fluorescence in situ hybridization disclosed a 47% Ph positivity. The patient started imatinib with a rapid decrease of leukocytes; however, the platelets increased, and HU was added. After 3 months, the BM showed 7.4% Ph-positive cells. JAK2 was found mutated from imatinib start. This report suggests the presence of 2 different clones, one Ph-positive and the other JAK2 mutated and the prevalence of the latter when the former was inhibited by a tyrosine kinase inhibitor (TKI). The presence of a JAK2-positive clone may be a rare cause of hematologic resistance to TKIs.