Peginterferon alfa-2a (PEG-IFN alfa-2a) is commonly used to treat hepatitis C virus infection and is also being used increasingly to treat myeloproliferative neoplasms including polycythemia vera. Sarcoidosis associated with IFN therapy for treatment of hepatitis C is well described, with hypercalcemia occurring as a rare manifestation. We describe a 25-year-old man with polycythemia vera who became resistant to hydroxyurea after 6 years of treatment, requiring therapeutic phlebotomy procedures with increasing frequency for elevated hemoglobin and hematocrit levels. PEG-IFN alfa-2a was then initiated at 90 μg subcutaneously once/week and was progressively increased to 180 μg/week over the next 11 months, with normalization of his hemoglobin and hematocrit. The patient then developed hypercalcemia with low parathyroid hormone, parathyroid hormone-related protein, and 25-hydroxyvitamin D levels, and high 1,25-dihydroxyvitamin D and angiotensin-converting enzyme levels, without other evidence of sarcoidosis. PEG-IFN alfa-2a was discontinued, treatment with intravenous fluids and zoledronic acid was initiated, and the hypercalcemia resolved 10 weeks later. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 7) between the patient's development of hypercalcemia and PEG-IFN alfa-2a therapy; the relationship could not be considered as definite because the patient was not rechallenged with the drug. To our knowledge, this is the first case report of IFN-induced hypercalcemia without other manifestations of sarcoidosis. Practitioners should be aware of hypercalcemia as a potential complication of PEG-IFN alfa-2a therapy, as well as its protracted time course, in patients with myeloproliferative neoplasms.

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6615 Background: ATRA administration in suspected APL patients (sAPL) is thought to impact early death rate (EDR) (Tallman and Manji, Blood Cells Mol Dis. 2011). Delay in ATRA therapy at specialized centers was associated with EDR (Altman et al Blood 2011). EDR within this study was significantly lower compared to the SEER database (12% vs 17.3%) and hence may not reflect overall delay in ATRA therapy. We determined time to ATRA therapy in sAPL, and fraction of sAPL that did not have disease. Methods: Retrospective analysis of patients that received ATRA for newly diagnosed s APL between 01/01/98-12/31/11 at Albany Medical Center. Time to hematologist evaluation, ATRA ordered and administered, and mortality data was collected from cancer registry, medical record, and chemo-pharmacy database. Results: A total of 39 patients with newly diagnosed sAPL were administered ATRA (46% male, mean age 50y). APL diagnosis: 29/39 (75%) true APL (APL); 9/10 ATRA-treated non-APL (A-nAPL); and one patient for whom cytogenetic data unavailable. EDR amongst APL was 5/29 (17%) compared to 2/9 (22%) within A-nAPL. Time variables were compared between APL patients that died early (<30d) to those that survived 30 days, and included: time to hematologist response (0.9d vs. 0.4d); time to ATRA ordered (2.9d vs. 2.0d); time to ATRA administered (3.4d v. 2.2d); and time elapsed between hematologist response to ATRA administered (2.5d v. 1.9d), respectively. Cryoprecipitate was administered to 1/5 (20%) patients who expired within 30d compared to 10/23 (43%) who survived. Overall mortality for APL was 9/29 (31%) compared to 4/9 (44%) for A-nAPL group. Compared to recent reports, time to ATRA administration in our institution was later (2.0d vs. 2.4d). Conclusions: Our data indicate that APL patients who survived 30d received ATRA early. EDR at our institution is comparable to that reported by SEER database and may be attributed to delay in ATRA administration. Higher fraction of patients that survived 30d received cryoprecipitate. Hence aggressive blood product support may contribute to improved survival. Timing at which these products were administered is currently being evaluated.

Purpose: Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations of the fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase has a poor prognosis, with short disease-free survival following both chemotherapy and allogeneic hematopoietic stem cell transplantation. FLT3 inhibitors are active, but their activity is limited and transient. New treatments and approaches are needed. The novel retinamide (NR) VNLG-152, targets translation by promoting degradation of MAPK-interacting kinases (Mnks), thereby inhibiting phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a downstream target of FLT3-ITD. eIF4E aids in translation by recruiting ribosomes to mRNA, a process that is upregulated in AML with FLT3-ITD. The association of the eIF4E protein complex is the rate- limiting step in translation initiation. We characterized the effects of VNLG-152 in AML cell lines and patient samples with FLT3-ITD and with wild-type FLT3. Methods: Cell lines studied included human MV4-11 and MOLM-14, with endogenous FLT3-ITD expression, HL60 and U937, with wild-type FLT3, and Ba/F3-ITD and Ba/F3-WT, which are murine Ba/F3 cells transfected with human FLT3-ITD and wild-type FLT3, respectively. Cytotoxicity was measured in a WST-1 colorimetric assay, proliferation by carboxyfluorescein diacetate succinimidyl ester (CFSE) staining, and apoptosis by Annexin V-FITC and propidium iodide labeling, measured by flow cytometry. AML patient samples obtained on an IRB-approved protocol were studied in cytotoxicity assays. Results: VNLG-152 was cytotoxic to the human FLT3-ITD AML cell lines MV4-11 and MOLM-14 with low micromolar IC50 concentrations, while IC50 concentrations were greater than 10 μM in the wild-type FLT3 AML cell lines HL60 and U937. IC50s in Ba/F3-ITD and Ba/F3-WT cells were 3.6 μM (95% CI, 3.0-3.9 μM) and 5.7 μM (95% CI, 5.0-6.4 μM), respectively. The cellular effects of VNLG-152 were evaluated further in Ba/F3-ITD cells. Concentration-dependent slowing of proliferation was seen at low micromolar concentrations, while concentration-dependent pro-apoptotic effects occurred at higher concentrations. VNLG-152 was also cytotoxic to blasts isolated from FLT3-ITD AML patient samples at IC50 concentrations &lt;1 μM, whereas its IC50 concentrations in blasts from AML patient samples with wild-type FLT3 were &gt; 5 μM. Conclusion: We conclude that the novel Mnk degrading agent VNLG-152 is active in AML with FLT3-ITD. Subsequent work will examine combinations with FLT3 inhibitors and with chemotherapy drugs in this prognostically unfavorable AML subtype. Citation Format: Sheetal Karne, Karthika Natarajan, Senthilmurugan Ramalingam, Lalji K. Gediya, Vincent C.O. Njar, Maria R. Baer. The novel retinamide VNLG-152, which targets translation by promoting degradation of MAPK-interacting kinases, has preferential activity in acute myeloid leukemia with FLT3-ITD. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5408. doi:10.1158/1538-7445.AM2015-5408