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  • br Discussion ATRA and arsenic are both known

    2019-06-12


    Discussion ATRA and arsenic are both known to induce differentiation syndrome but this case was notable for its severity. Previous studies of differentiation syndrome have demonstrated that APL sphingosine 1-phosphate receptor modulator treated with ATRA secrete the chemokines CCL2 and IL-8, which in combination with chemokine production from alveolar epithelial cells, are thought to initiate a hyperinflammatory cascade in the lung [11]. While dexamethasone does not directly affect the production of CCL2 or IL-8 from APL cells, it does reduce their production in the lung and thus attenuates the clinical development of differentiation syndrome [11]. Since inflammatory cytokine signaling plays a significant role both in the pathogenesis of JAK2 V617F MPNs as well as in the development of differentiation syndrome, we postulated that robust differentiation syndrome experienced by this patient was the result of excessive inflammatory response related to her underlying JAK2 V617F mutation. To test whether JAK2 inhibition has any direct effects on the production of cytokines by APL cells, we used ATRA to differentiate the NB-4 APL cell line in the presence or absence of ruxolitinib. Cytokine release into the media was measured over three days of ATRA-induced differentiation. There was a substantial increase in both CCL2 and IL-8 with ATRA treatment, although this was not abrogated by JAK inhibition (Fig. 2). In fact, ruxolitinib had very little effect overall on cytokine production of NB-4 cells. Therefore, CCL2 and IL-8 production by APL cells is unaffected by JAK inhibition, similar to what has been shown for dexamethasone [11]. However, there is substantial evidence that signaling downstream of cytokines is through activation of JAK2 [1]. Indeed, it is possible that the presence of JAK2 V617F in APL and non-leukemic cells enhances CCR2 and IL-8 signaling during differentiation syndrome, accelerating leukocyte extravasation and inflammatory amplification within the lungs and other organs. This suggests that JAK inhibitors may have clinical utility in attenuating the inflammatory amplification step in differentiation syndrome in a manner similar to glucocorticoids. Further studies with in vivo models of differentiation syndrome are needed to evaluate this possibility.
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    Case Report The general physical examination revealed an obese man with a heart rate of 140/minute but was otherwise unremarkable. The cardiac exam revealed an irregular rhythm. The abdominal exam revealed no tenderness or hepatosplenomegaly. A complete blood count (CBC) was performed and the results of the CBC are outlined in Table 1. Evaluation of the peripheral blood smear revealed a mild basophilia (2%) and myelocytes (1%) and meta myelocytes (1%). A hematology consultation was requested for evaluation. A bone marrow aspiration and biopsy was performed in October 2013. Examination of the marrow revealed a slightly hypercellular marrow with a granulocytic hyperplasia [Fig. 2]. Rare monolobated megakaryocytes were present. Karyotype analysis revealed 46, XY, t(9;22) (q34;q11.2) in 20 cells analyzed and was the sole abnormality observed. FISH performed with the ABL1/BCR probe identified the fusion of the ABL on chromosome 9 with the BCR gene on chromosome 22 in 90.5% of the metaphases. Quantitative Reverse Transcriptase-Polymerase Chain Reaction analysis revealed the presence of the BCR-ABL transcript (p210 form) in 162/200 (81.0%) cells scored. The patient was diagnosed with chronic phase CML. The initial hematology opinion recommended initiating tyrosine kinase inhibitor therapy, and the patient sought a second opinion. Considering his asymptomatic presentation and stable blood counts, the treating physicians supported a plan of active surveillance with periodic CBCs and differential and LDH. He was last seen in August 2014. He remains asymptomatic with essentially stable blood counts [Table 2].