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Desmopressin (DDAVP), a synthetic analog of vasopressin, has been used in patients with von Willebrand disease (VWD), mild hemophilia A, and platelet dysfunction to reduce the risk of bleeding associated with surgical and interventional procedures. We report the case of a patient with VWD presenting with a bulging disc and radicular pain that underwent transforaminal epidural steroid injections. Her course was complicated with the interval development of headaches and dizziness symptomatic of moderate hyponatremia, likely due to excessive fluid intake. This report highlights a relatively rare side effect of DDAVP when used for prophylaxis in patients with VWD and reinforces the need for vigilance in these patients.

Desmopressin (DDAVP), a synthetic analog of vasopressin, has been used in patients with von Willebrand disease (VWD), mild hemophilia A, and platelet dysfunction to reduce the risk of bleeding associated with surgical and interventional procedures. We report the case of a patient with VWD presenting with a bulging disc and radicular pain that underwent transforaminal epidural steroid injections. Her course was complicated with the interval development of headaches and dizziness symptomatic of moderate hyponatremia, likely due to excessive fluid intake. This report highlights a relatively rare side effect of DDAVP when used for prophylaxis in patients with VWD and reinforces the need for vigilance in these patients.

Primary myelofibrosis (PMF) commonly results in extramedullary hematopoiesis (EMH) in the spleen and liver as well as a variety of other organs. We present a first report of a unique presentation of PMF in a liver transplant recipient patient as EMH in the transplanted liver graft. A 76-year-old man with history of cryptogenic cirrhosis received cadaveric liver transplantation in 1996. He maintained a normal graft function and stable hematologic parameters until 2013 when he presented with anemia and progressive fatigue. Extensive work-up did not identify the etiology of the recent decline in his hemoglobin; thus a liver biopsy was done which showed findings of EMH within the sinusoids with increased megakaryocytes, some with atypical morphology. A BM biopsy revealed a hypercellular marrow, moderately increased reticulin fibrosis, and features consistent with primary myelofibrosis. Abdominal imaging showed a normal-size spleen and did not identify any sites of EMH outside of the liver. The diagnosis of myelofibrosis was thus made, and this case demonstrated predominant tropism to a transplanted liver graft with absence of EMH elsewhere. We would thus like to emphasize that findings of EMH in subjects with no preexisting hematologic neoplasm should warrant close follow-up and assessment.

Various translocations involving the PDGFRB gene are identified in myeloid neoplasms. However, the PRKG2/PDGFRB fusion gene associated with t(4;5)(q21;q33) has previously been reported in only 3 patients. We present the case of a 26-year-old woman with microcytic anemia, basophilia, thrombocytosis, and massive splenomegaly, who was found to have systemic mastocytosis and associated clonal hematological non-mast cell lineage disease (SM-AHNMD), with myeloid neoplasm with PRKG2/PDGFRB rearrangement. Initial findings included basophilia (37%, 4.1 k/μL), hypercellular marrow with eosinophilia, and increased and atypical megakaryocytes, suggestive of myeloproliferative neoplasm. Additional studies revealed large clusters of CD25 positive mast cells, fulfilling the criteria for the diagnosis of systemic mastocytosis. Consistent with prior reports of this translocation, our patient has responded well to imatinib. This case, in conjunction with others in the literature, suggests a possible connection between t(4;5)(q21;q33) PRKG2/PDGFRB and systemic mastocytosis and highlights their favorable response to imatinib.

Heat shock factor 1 (HSF1) is a stress-activated transcription factor, that up-regulates the transcription of heat shock proteins (Hsps) and a growing list of tumor-promoting genes. HSF1-induced genes promote protein folding and maturation (through Hsps and associated co-chaperones) as well as orchestrate the transcription of tumor-promoting genes (for e.g., VEFGR, HIF1-alpha, GLUT-1, etc). In this study we propose to evaluate the efficacy of inhibiting HSF1 in Chronic Lymphocytic Leukemia (CLL), a disease that invariably relapses after patients show complete or partial response to first line chemotherapy. Consistent with the established tumor-promoting roles of HSF1, we report that CD19+ B cells isolated from relapsed/refractory CLL patients show high levels of immunofluorescent, nuclear HSF1 staining compared to normal CD19+ B cells, where it is weakly expressed and pre-dominantly cytosolic. CD19+ B primary CLL cells also show enhanced expression of HSF1 as assessed by immunoblot analysis compared to normal CD19+ cells. Treatment of cultured and primary CLL CD19+ B cells with the HSF1 inhibitor triptolide causes a dose-dependent increase in apoptosis, while relatively sparing normal CD19+ B cells. Treatment with triptolide results in the reduced expression of Hsp40, Hsp70 and Hsp27 proteins and a concomitant increase in the PARP cleavage and Caspase 3 cleavage in cultured and primary CLL cells. Lentiviral shRNA-mediated knockdown of HSF1 or triptolide treatment decreased the levels of Bcl-XL and pro-survival signaling molecules, phosphorylated STAT3 (Y-705) and AKT (S473). Based on the established role of Hsps in cytoprotection and resistance to chemotherapy, we hypothesized that inhibition of HSF1 would sensitize CLL cells to agents that promote the accumulation of misfolded proteins (for e.g. Hsp90 inhibitors) or inhibit their disposal (for e.g. treatment with autophagy inhibitors) by inducing proteotoxicity. Consistent with this hypothesis, knockdown of HSF1 or co-treatment with triptolide and the autophagy inhibitor chloroquine resulted in superior anti-CLL activity compared to treatment with either agent alone. Similarly, knockdown of HSF1 or its inhibition with triptolide also sensitized CLL cells to the Hsp90 inhibitor, 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). These pre-clinical studies provide a strong rationale to test the in vitro and in vivo activity of HSF1 inhibitors in combination with agents that promote proteotoxic stress against CLL. Citation Format: Rekha M. Rao, Yacoub Abdulraheem, Suman Kambhampati, Siddhartha Ganguly. Therapeutic targeting of Heat shock factor 1 in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-109. doi:10.1158/1538-7445.AM2014-LB-109

7058 Background: PAC is a novel JAK2/IRAK1 inhibitor that has shown significant activity in pts with MF, including those with platelet (plt) counts 9/L. Recently, JAK inhibitors have come under increased scrutiny due to specific, emerging toxicities with drugs in this class. This safety analysis focuses on these toxicities of interest for pts treated with PAC 200 mg BID and best available therapy (BAT), including ruxolitinib (RUX), on the Phase 3 PERSIST-2 and Phase 2 PAC203 studies. Data are presented as risk-adjusted incidences to account for differential time at risk for adverse events (AEs) between arms due to cross-over. Methods: Pts treated with PAC 200 mg BID on PERSIST-2 and PAC203, and those treated with BAT on PERSIST-2, were included. Risk-adjusted AEs, representing event rate per 100 patient-years (pt-yrs), were calculated for overall and fatal AEs, bleeding AEs (determined by Standardized Medical Dictionary for Regulatory Activities Query [SMQ]), cardiac AEs (by SMQ), major cardiac events (per major adverse cardiovascular events [MACE] classification), infections, thromboses, and secondary malignancies. Results: A total of 160 pts were analyzed as the pooled PAC group (n=106 in PERSIST-2; n=54 in PAC203) and 98 pts in the BAT group (44 on RUX). At baseline, median plt count was 57×109/L; 61% had prior JAK2 inhibitor therapy. The rate of AEs was higher on PAC versus BAT, while the rate of fatal AEs was lower (Table). Both bleeding and cardiac events occurred at slightly lower rates on PAC compared to BAT. There were no MACE events on PAC, whereas there were on BAT. Malignant neoplasms occurred at similar rates on PAC and BAT, though rate of non-melanoma skin cancers was lower in pooled PAC (3/100 pt-yrs) versus BAT (7/100 pt-yrs), including RUX (11/100 pt-yrs). Infection occurred more frequently on PAC, though fungal and viral infections occurred less frequently, as did herpes zoster reactivation (pooled PAC: 0/100 pt-yrs vs BAT: 2.4/100 pt-yrs, including RUX: 5.5/100 pt-yrs). Thrombosis occurred at similar rates on PAC and BAT. Conclusions: Risk-adjusted analysis demonstrates that the safety profile of PAC 200 mg BID is comparable or superior to BAT, including RUX. PAC 200 mg BID may represent a full-dose therapeutic option for pts with MF, including those with thrombocytopenia. Clinical trial information: NCT02055781; NCT04884191. [Table: see text]