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  • br Results and discussion br Authorship

    2019-05-21


    Results and discussion
    Authorship contributions
    Conflict of interest
    Acknowledgments This work is supported by grants from the United States National Institutes of Health/National Cancer Institute: R01 CA098472 and R01 CA170334. We thank Dr. Dan Zhang and Andy Awwad for technical assistance. We gratefully acknowledge the helpful expertise of David E. Hamm, M.Sc., (Adaptive Biotechnologies Corp) for assistance with ImmunoSEQ analyses along with Jennifer Berman, Ph.D. and Bo Song, Ph.D. (BioRad) for assistance with ddPCR assay design.
    Introduction Essential thrombocythemia (ET) is a clonal disorder of the hematopoietic stem cell that is closely related to two other myeloproliferative neoplasms (MPNs) polycythemia vera (PV) and primary myelofibrosis (PMF). The Janus-Associated-Kinase 2 (JAK2) V617F mutation is present in the vast majority of PV patients and in 50% of patients with ET and PMF [1]. JAK2 V617F produces constitutive activation of the thrombopoietin and erythropoietin signaling pathways, driving ET and PV respectively. Over time, ET and PV can both progress to myelofibrosis [1]. Further, all three conditions can transform into acute myelogenous leukemia (AML), although this occurs most frequently in PMF [2]. Transformation carries a dismal prognosis [2] and is often associated with complex genetic changes. Transformation of ET, PV or PMF into acute promyelocytic leukemia (APL), a favorable risk leukemia characterized by the t(15;17) translocation, is exceedingly rare with only eight documented cases in the literature [3–9]. Of these, only two prior cases have been reported of ET transforming into APL with molecular documentation of t(15;17) [3,4]. We report an 83-year-old woman with a history of ET and progression to myelofibrosis, who then transformed to APL. To our knowledge, this is the first case to demonstrate co-expression of PML-RARα and JAK2 V617F by leukemic blasts. Clinically she also developed severe differentiation syndrome during induction with ATRA plus arsenic trioxide (ATO), suggesting that JAK2 signaling may augment differentiation syndrome.
    Case study The patient was diagnosed with ET in 1995 and began treatment with hydroxyurea and aspirin. In 2011 she noted worsening fatigue and left lower quadrant abdominal pain. She underwent a bone marrow biopsy that revealed myelofibrosis with a JAK2 V617F allelic burden of 92% and was found to have splenomegaly. Treatment with the JAK1/2 inhibitor ruxolitinib was initiated, which resulted in a significant improvement in buy AMG-900 and appetite. She did well until May of 2013 when she was noted to be pancytopenic with a WBC of 2.0 ×103/mm3, hemoglobin of 8.5mg/dL and platelets of 96×103/mm3. Concerned that her cytopenias were the result of ruxolitinib, it was discontinued; however, she remained persistently pancytopenic. A bone marrow biopsy revealed a hypercellular marrow with 70% blasts, megakaryocytic hyperplasia and grade 3/3 fibrosis. Fluorescence in-situ hybridization (FISH) confirmed the t(15;17) in 90% of cells and diagnosis of APL. A GeneTrails AML/MDS next-generation sequencing panel (Supplementary Table 1, Knight Diagnostics Lab, Portland, OR) was performed on marrow aspirate and was significant for a JAK2 V617F allelic burden of ~90%, indicating that the APL cells also contained the JAK2 V617F mutation. A FLT3 D835 mutation was also found with this panel. Given her advanced age she was started on ATRA+arsenic trioxide (ATO) induction [10]. After two days of ATRA her WBC count began to increase rapidly and despite escalating doses of hydroxyurea her WBC count continued to rise, reaching 67.4×103/mm3 on day 6 of ATRA (Fig. 1A,B). During this time she was started on treatment-dose dexamethasone for differentiation syndrome. She developed severe abdominal pain and ultrasound demonstrated splenomegaly (15.8×6.8×13.7cm). Despite dexamethasone, her symptoms were felt to be secondary to severe differentiation syndrome and she was given a single dose of idarubicin (12mg/m2) for rapid cytoreduction. Her WBC count peaked on day 7 at 95.9×103/mm3. At this time she developed increasing oxygen requirements with a chest X-ray demonstrating evolving bilateral patchy opacities (Fig. 1C). Given her clinical deterioration, ATRA was held for two days but by day 9 her WBC had decreased to 27.5×103/mm3. ATRA was restarted, hydroxyurea was tapered, and on day 10 ATO (0.15mg/kg/day) was initiated. However, despite her declining WBC count, her oxygen requirement again increased to 10L on day 12 and she was aggressively diuresed in addition to continued dexamethasone. By day 17 she showed dramatic clinical improvement and was successfully weaned from oxygen. A repeat ultrasound at this time demonstrated a greater than 50% reduction in splenic volume (11.2×10.8×5.5cm), suggesting that extramedullary APL cells were abundant in the spleen and the bone marrow. A bone marrow biopsy performed on day 34 revealed a morphologic complete remission and she was discharged to a rehab facility to recover. On day 47 after initiation of therapy, her peripheral blood had counts recovered with a WBC count of 29.9×103/mm3, hemoglobin of 11.0mg/dL and platelets of 603×103/mm3, consistent with her previous ET, so she was restarted on 10 mg twice daily ruxolitinib and 81mg aspirin. She then received four cycles of consolidation therapy with ATRA plus ATO [10]. Ruxolitinib was well tolerated during consolidation and dose reduced only when her platelet count decreased with ATO. A bone marrow biopsy after completion of consolidation revealed complete molecular remission and a return to her underlying myeloproliferative disease with grade 2/3 myelofibrosis.