Ruxolitinib Treatment Outcome In a Patient With Secondary Chronic Myelomonocytic Leukemia

Chronic myelomonocytic leukemia ( CMML) is a de novo myelodysplastic/myeloproliferative disease with an unfavorable prognosis. Secondary CMML cases are rare and sporadically reported. Published data have shown that development of monocytosis in patients during the course of PMF or MDS is associated with poor prognosis (M.A. Elliott, Leukemia Research, 31 (2007).

Essential thrombocythemia (ET) is an indolent myeloproliferative disorder characterized by long symptom-free intervals. Uncommonly, few patients with ET may develop bone marrow (BM) fibrosis which to be distinguished from cases with early PMF accompanied by thrombocytosis. Progression to acute leukemia or myelodysplastic syndrome (MDS) occurs in < 5% of patients and is likely related to previous cytotoxic therapy.

We report here a rare case of a patient with ET who developed BM fibrosis and rapidly progressed to a secondary myelomonocytic leukemia.

A 54 years old  female patient, diagnosed with ET in 2003,  as she presented a persistent isolated high platelet count of 700 G/L, with normal white blood cells (WBCs): 8 G/L, hemoglobin (hb): 15 g/dl,  monocytes: 0.5 G/L and no splenomegaly.  She was treated with Anagrelide 1.5 -2 mg daily due to intolerance to hydroxyurea. No major event has been declared during the last 10 years and a median platelet count of 450 G/L.

In January 2013, a routine check-up showed leukocytosis (WBCs: 25 G/L), slight anemia (hb: 11.6 g/dl), with relative thrombocytopenia, 266 G/L, monocytosis:  2 G/L with 3% circulating blasts and a palpable spleen.  The bone marrow biopsy revealed BM fibrosis grade III and 7% of blasts.  Progression to secondary myelofibrosis was declared and treatment with hydroxyurea was initiated to control peripheral blood counts prior to transplantation.  Treatment with ruxolitinib started in May, at a dose of 20 mg bid due to failure of blood count reduction with hydroyurea. A rapid decline in WBCs count to 3 G/L was achieved but with sustained median monocytosis of 1.4 G/L.  The patient developed marked anemia (7.5 g/dl) as well as thrombocytopenia (13 G/L) and ruxolitinib was interrupted by the end of June 2013.

Within 15 days, the patient showed rapid progression, her WBCs count attained 105 G/L, anemia and thrombocytopenia persisted. The absolute monocyte count increased up to 66 G/L with marked dysplastic features and morphological shifting to aspects compatible with overt secondary myelomonocytic leukemia in both blood and bone marrow smears, 3% circulating and 8% bone marrow blastes  (WHO criteria for CMML diagnosis). Molecular studies showed the presence of JAK2 V617F allele burden at 66% and absence of BCR/ABL transcript. Only two mitosis, with an unidentified additional marker were obtained on chromosome analysis. Unfortunately, the patient died 2 weeks later.

This observation shows the adverse prognostic development of monocytosis in ET which is similar to that published in PMF in 10 patients (Leonardo Boiocchi, Modern pathology, 2013), thus requiring particular attention in the treatment of these patients. As chromosomal analysis was unavailable at diagnosis, we weren’t able to prove the presence of clonal heterogeneity, a concept developed recently to explain the mechanism of development of two different diseases.

Ruxolitinib is an inhibitor of JAK1 and JAK2 resulting in a dramatic decrease in cytokines and growth factors that are important for hematopoiesis and growth function.  Of note, in this case, ruxolitinib which was administrated for the treatment of 2ry myelofibrosis, inhibited as well the increase in monocytosis and controlled the progression of CMML evidenced by the remarkable increase in dysplastic monocytes after its interruption. To our knowledge a clinical trial is actually on going to assess if its administration can improve the outcome of patients with CMML and the optimal dose to be administrated.