Begna, Kebede H.

Abstract Abstract 3795 Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (IL-2R, IL-8, IL-12, IL-15 and CXCL10) and large cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). In order to examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex ELISA to measure 30 plasma cytokines in 78 patients with primary MDS. Compared to normal controls (n =35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (p<0.01), IL-7 (p=0.02) and IL-6 (p=0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the international prognostic scoring system (IPSS), age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (p<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (p=0.01). Comparison of plasma cytokines between MDS (n =78) and primary myelofibrosis (n =127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically-relevant plasma cytokine signatures in hematologic malignancies.Figure:Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002).Figure:. Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002). Disclosures: No relevant conflicts of interest to declare.

Abstract Background BMS-911543 is an oral, selective small-molecule inhibitor of JAK2 (IC50=1.1nM) with potent anti-proliferative and pharmacodynamic effects in cell lines and in vivo models dependent upon JAK2 signaling. In vitro, BMS-911543 demonstrates high selectivity within the JAK family (JAK1 [IC50=356nM], JAK3 [IC50=73nM] or TYK2 [IC50=66nM]) and across a large kinase panel (at 1 µM concentration of BMS-911543, only 8 of 451 kinases were markedly inhibited [≥67%]) It also has little activity in cells dependent on other JAK family pathways. Anti-proliferative responses were observed with BMS-911543 in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive polycythemia vera (PV) (Leukemia 2012;26:280). Methods In a multicenter phase 1/2a study, BMS-911543 was administered orally using a BID dosing schedule, in patients with high-, intermediate-2 or intermediate-1 risk symptomatic primary or secondary MF (JAK2 WT or mutant) with platelet counts ≥50,000/mm3. Patients were not required to have palpable splenomegaly. The aim of the study is to determine safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of BMS-911543. Safety was assessed using NCI-CTCAE version 4.0. Treatment effect was assessed using the International Working Group (IWG) response criteria, MF-SAF, BFI, physical examination, spleen and liver volume assessment by MRI, bone marrow morphology, karyotype, V617F mutant allele burden, plasma cytokine analysis, circulating CD34+ cells and other molecular parameters. Current status To date, 84 patients have been treated (dose escalation [n=42]; dose expansion [n=42]) and the maximum tolerated dose (MTD) was defined as 200mg BID. The summary below represents an interim data analysis of 36 patients from the dose escalation phase dosed at 5, 10, 20, 40, 80, 120, 160, and 200mg BID. Fifteen of 36 (42%) patients had received prior Jak inhibitors (Jaki) including 3 who had received ≥2 Jak inhibitors. PK, PD, Safety, Tolerability and Efficacy After repeat dosing, greater than dose-proportional increase in the Cmax and AUC, and drug accumulation was observed at doses ≥40mg BID. PD analysis indicated inhibition of JAK/STAT pathway signaling activity in peripheral blood mononuclear cells, and modulation of several soluble peripheral blood proteins including IL-6, EPO and Leptin. Eleven patients (31%) had drug-related AEs. The nine hematological AEs included 3 anemia (1 grade 3 and 2 grade 2); 3 neutropenia (grade 4); and single leukopenia (grade 4), thrombocytopenia (grade 4), and reduction in platelet count (grade 2). Nine non-hematological AEs included 3 nausea (grade1/2); amylase increased (grade 3) and lipase increased (grade 3) one each; and grade 1 fatigue, muscle spasms, insomnia, erectile dysfunction one each. Ten patients (28%) discontinued treatment: 4 were attributed to disease progression, 2 to lack of efficacy, 2 at patient’s request, 1 to poor compliance, and 1 to unrelated AE. Spleen volume reductions (SVR) by MRI were observed in Jaki failure and in Jaki naive patients. Of 11 patients treated at 160 and 200mg, 8 patients (73%) had SVR greater than 35% at 3 months. In contrast, 1 of 4 patients treated at 120mg and none treated below 120mg had SVR greater than 35%. Of the patients treated at 160mg and 200mg, more than 50% had MF-SAF reductions > 50%. Overall, 3 patients (8.3%; 2 treated at 10mg BID and 1 at 200mg BID) had an increase in hemoglobin of ≥2g/dL;. Other signs of clinical activity included reductions in V617F mutant allele burden, leukocytosis, leukoerythroblastosis, circulating CD34+ cells, and LDH. Conclusion BMS-911543 was generally well tolerated and has an acceptable safety and efficacy profile. BMS-911543 induced rapid control of constitutional symptoms, and splenomegaly in patients with symptomatic MF, including those previously treated with one or more Jak inhibitors. Updated data from all 84 patients who have been treated in the dose escalation and ongoing expansion phases, including MRI assessments of spleen and liver volume, V617F mutant allele burden and levels of select plasma cytokines, will be presented.</abstract> Disclosures: Pardanani: JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other; PharmaMar: Clinical trial support, Clinical trial support Other; Sanofi: Clinical trial support, Publication support services, Clinical trial support, Publication support services Other; Bristol Myers Squibb: Clinical trial support Other. Off Label Use: Use of BMS-911543, Ruxolitinib, Momelotinib, Fedratinib and Pomalidomide for treatment of Myelofibrosis in Clinical Trial setting. Roberts:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment. Seymour:Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Verstovsek:Incyte Corporation: Research Funding. Yoshitsugu:Bristol-Myers Squibb: Employment, Equity Ownership. Gestone:Bristol-Myers Squibb: Employment, Equity Ownership. Phillips:Bristol-Myers Squibb: Employment, Equity Ownership. Xing:Bristol-Myers Squibb: Employment, Equity Ownership. Peltz:Bristol-Myers Squibb: Employment, Equity Ownership. Lorenzi:Bristol-Myers Squibb: Equity Ownership, Former employment Other. Alland:Bristol-Myers Squibb: Employment, Equity Ownership. Woolfson:Bristol-Myers Squibb: Equity Ownership, Former employment Other.

Abstract Background JAK inhibitors, including ruxolitinib, are to date incapable of inducing complete (CR) or partial (PR) remissions, reversal of bone marrow (BM) fibrosis or molecular responses in myelofibrosis (MF). This is consistent with the fact that JAK2 mutations are neither specific nor pathogenetically essential for the disease. Other currently available drugs in MF are equally ineffective in terms of disease-modifying activity. Methods In an investigator-sponsored single-center study (ClinicalTrials.gov Identifier: NCT01731951), imetelstat, a lipid-conjugated oligonucleotide inhibitor of human telomerase, was administered to patients with high or intermediate-2 risk MF (JCO 2011). Adverse events were monitored by common terminology criteria (Version 4.03) and responses by the International Working Group criteria (Blood 2013). Eligibility criteria included platelets ≥50 x 10(9)/L. Study drug and funding were provided by Geron Corporation (Menlo Park, CA, USA). Imetelstat was administered by a 2-hour intravenous infusion (9.4 mg/kg) every three weeks (cohort A) or weekly x 3 followed by every three weeks (cohort B). Mutations with prognostic (ASXL1 and SRSF2) or phenotypic (SF3B1 and U2AF1) relevance were screened by DNA sequencing. Quantitative PCR was used to measure JAK2V617F burden (assay sensitivity 0.01%). Laboratory correlative studies included analyses of granulocyte telomere length, mononuclear cell telomerase activity and human telomerase reverse transcriptase (hTERT) isoforms. Results Thirty-three patients were accrued; the first 18 patients enrolled and followed for a minimum of 3 months or discontinued are presented in this abstract: 11 cohort A and 7 cohort B; 44% PMF, 33% post-PV MF and 22% post-ET MF. Median age was 68 years and baseline risk was high in 56% and intermediate-2 in 44%. Seven patients were transfusion-dependent. Median spleen size was 13 cm and 11 patients had constitutional symptoms. Karyotype was abnormal in 7 patients and 89% were JAK2-mutated. Fifteen (83%) patients were previously treated including 7 with a JAK inhibitor and 3 with pomalidomide. i) Toxicity At a median f/u of 3.2 months, 16 (89%) patients remain on treatment; the two discontinuations were from unrelated death and disease progression. In cohort A, there were no grade-4 treatment-related adverse events; grade-3 events were limited to thrombocytopenia in 27% and anemia in 9%. In cohort B, two (29%) patients experienced grade-4 thrombocytopenia; grade-3 events were limited to thrombocytopenia, neutropenia and anemia in one patient each. Dose reduction was necessary in only two (11%) patients because of grade 3 or 4 myelosuppression. ii) Efficacy Overall response rate was 44%. This included five (28%) patients who met the BM and peripheral blood morphologic criteria for CR (n=4) or PR (n=1) and 3 patients with clinical improvement, pending validation of response duration and resolution of drug-induced grade-1 thrombocytopenia. The four (22%) CR patients experienced reversal of BM fibrosis and recovery of normal megakaryocyte morphology. Two CR patients were transfusion-dependent at baseline and became transfusion-independent. Complete molecular responses were documented in 2 CR patients: one had U2AF1Q157P and 10% JAK2V617F and the other SF3B1K666E and 50% JAK2V617F. A third CR patient had a >50% reduction in U2AF1 469_insAGTATG mutation. Among 13 patients with leukocytosis, 10 (77%) normalized their count or had >50% reduction. Eleven (61%) patients had complete or partial resolution of leukoerythroblastosis. iii) Laboratory correlative studies Three (50%) of 6 spliceosome-mutated vs. 1 (8%) of 12 unmutated (p=0.045) achieved CR. Spliceosome-mutated patients were also more likely to experience grade-3/4 myelosuppression (67% vs. 25% ; p=0.09). Treatment was associated with suppression of telomerase activity, shortening of telomere length and alteration of hTERT isoform pattern. Conclusions The current study signifies the potential value of telomerase-based treatment strategies in MF and identifies imetelstat as an active drug in that regard. The observed morphologic and molecular remissions confirm selective anti-clonal activity, which has thus far eluded other drugs in MF, including JAK inhibitors. The association between response and spliceosome mutations suggests a broader application for the drug in myeloid malignancies.</abstract> Disclosures: Stuart: Geron: Consultancy.

Abstract Abstract 630 Introduction: Medical treatment options for myelofibrosis (MF) are palliative in nature. Short of allogeneic stem cell transplantation, no therapies are available that are curative or confer a survival benefit. Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor that belongs to a structurally novel cinnamic hydroxamic acid class of compounds. Preclinical studies demonstrated that treatment with PAN alone depletes the levels of JAK2V617F (JAK2) and signaling downstream through STAT3 and 5, AKT, and c-RAF/MAPK in human MPN progenitor cells, including those from patients (pts) with MF (Blood 2009; 114:5024). In a prior phase IA/II study of PAN in pts with advanced hematologic malignancies, among 12 pts with MF evaluable for response, 4 pts demonstrated durable clinical improvement. Methods: In this phase II trial, approximately 50 adult pts with primary MF, post essential thrombocythemia, or post polycythemia vera MF who have an International Prognostic Scoring System -MF score of 2 or 3 along with either symptomatic splenomegaly (>10 cm below the costal margin [BCM]) or anemia, enrolled. Initial PAN dose is 40 mg three times a week until disease progression or unacceptable toxicity with dose adjustments as required. Response is assessed using the International Working Group criteria. Peripheral blood samples are collected for correlative science studies at 7 time points during treatment; pre-dose on the first day of the study, 6 and 24 hours after the first dose, pre-dose on the first day of cycles 2, 4 and 6, and at the end of the study. The correlative studies include the determination of JAK2V617F allelic burden, immunoblot analyses of the protein expression of p-STAT3, p-STAT5, p-AKT, p-ERK1/2, p-PIM, as well as of their un-phosphorylated counterparts. Also, protein levels of HSP70 and acetylated (Ac)-α-tubulin, as well as the mRNA expression of JAK2 and PRV-1 genes were determined. Results: As of August 12, 2010, 31 pts (24 JAK2 mutated, 7 JAK2 wild type) have been enrolled in the trial. The majority of pts required dose reduction. Adverse events observed are consistent with the known safety profile of PAN. Correlative studies have been performed on MPN cells from19 patients. As compared to the pre-treatment levels, treatment with PAN (for 6 and/or 24 hours) resulted in varying levels of depletion of p-STAT3, p-STAT5, p-AKT, p-ERK1/2 and p-PIM protein. A decline in JAK2 and PRV1 mRNA levels (20 to 80%) was also observed. Conversely, PAN treatment induced Ac-α-tubulin and HSP70 levels, consistent with HDAC6 and HSP90 inhibition. This was associated with decline in the protein levels of AKT, PIM1 and STAT3. PAN treatment also reduced MCL-1 and Bcl-xL, while inducing BIML levels. Notably, of the 10 patients in whom it has been determined, PAN treatment depleted the allelic burden of JAK2V617F by an amount ranging between 10 to 90%. Conclusions: Consistent with its role as a pan-deacetylase inhibitor, PAN exerts in vivo anti-MPN cell activity, as was highlighted by the decrease in the allelic burden of JAK2V617F. Further patient enrollment is ensuing, and more mature clinical toxicity and efficacy data will be presented. Disclosures: DeAngelo: Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. Paley:Novartis: Employment. Snyder:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees. Ondovik:Novartis: Employment. Rine:Novartis: Employment.

Abstract Abstract 3833 Background: Survival in primary myelofibrosis (PMF) is assessed by the Dynamic International Prognostic Scoring System (DIPSS) (Blood 2010;115:1703) and DIPSS-plus (JCO 2011;29:392). The latter is based on eight risk factors including age>65 years, constitutional symptoms, hemoglobin <10 g/dL, red blood cell transfusion need, leukocyte count >25 × 109/L, platelet count <100 × 109/L, peripheral blood (PB) blasts ≥1% and unfavorable karyotype. Recent studies have highlighted the prognostic significance of monosomal karyotype (MK) (Blood 2011;117:5612), unfavorable karyotype (Leukemia 2011;25:82) and platelet count <100 × 109/L ((JCO 2011;29:392), for leukemic transformation (LT) in PMF. Methods: A combination of multivariable and receiver operating characteristic (ROC) analyses were applied to a Mayo Clinic database of 884 karyotypically-annotated patients with PMF, in order to define karyotype-dependent and karyotype-independent risk models for LT. The karyotype-independent model was further validated in a separate cohort of 525 PMF patients from an international database (Blood 2010;115:1703). Patients in the Mayo cohort were evaluated at time of referral and those of the international database at time of initial diagnosis. Results I: Sixty cases of LT were documented. Karyotype (categorized into MK, inv(3)/i(17q) abnormalities, other unfavorable, and favorable), PB blast percentage (as a continuous variable), and platelet count (as a continuous variable) were the most reliable (p<0.01) in predicting leukemia-free survival (LFS). The best discriminant levels for inferior LFS were MK (HR 6.2, 95% CI 2.2–17.1), inv(3)/i(17q) abnormalities (HR 7.6, 95% CI 1.8–33.3), PB blast ≥2% (HR 2.4, 95% CI 1.4–4.2) and platelet count ≤41 × 109/L (HR 2.6, 95% CI 1.3–5.1). MK and inv(3)/i(17q) abnormalities were subsequently consolidated into one “very high risk” cytogenetic category (n =27), with a corresponding HR of 6.6 (95% CI 2.7–16.0). HR-based risk scores were assigned to “very high risk” karyotype (2 points), PB blast ≥2% (one point) and platelet count ≤50 × 109/L (one point) to classify patients into low (no adverse points; n =522), intermediate (one adverse point; n =290) and high risk (two or more adverse points; n =72) groups; the corresponding 3-year LT rates were 3%, 10% (HR 2.6; 95% CI 1.4–4.6) and 35% (HR 9.4, 95% CI 4.7–18.7) (Figure 1). Results II: The karyotype-independent model was based on PB blast percentage and platelet count only; low-risk (no adverse points; n =525), intermediate-risk (one adverse point; n =311) and high-risk (two adverse points; n =48); the corresponding 3-year LT rates were 3%, 12% (HR 3.1, 95% CI 1.8–5.4; p<0.0001) and 25% (HR 6.0, 95% CI 2.6–14.1). The karyotype-independent model was validated in a separate cohort of 525 PMF patients with 70 documented cases of LT, from an international database (Blood 2010;115:1703). Conclusions: The current leukemia risk models are applicable at diagnosis or during follow-up, in the presence or absence of cytogenetic information, and complement DIPSS-plus in the comprehensive prognostication of patients with PMF. Disclosures: Vannucchi: Novartis: Honoraria.

Abstract Abstract 3849 Background: CYT387 is a potent JAK-1/2 inhibitor. The maximum tolerated dose (MTD) and preliminary safety and efficacy of once daily dosing of CYT387 were determined in a single center Phase I/II study. Previously reported results from the first 60 subjects enrolled in this study determined a MTD of 300 mg QD and demonstrated improvements in splenomegaly and constitutional symptoms as well as in RBC transfusion requirements. The study was expanded into a multicenter study with planned accrual of 165 subjects at 6 study sites and a twice daily dosing arm was added. The preliminary safety and efficacy results from this expanded multicenter study will be presented. Methods: Subjects with high or intermediate-risk primary myelofibrosis (PMF) and post-polycythemia vera (post-PV) or post-essential thrombocythemia (ET) myelofibrosis were enrolled. In the core expansion study, oral CYT387 was administered either once daily at 150 mg or 300 mg or twice daily at 150 mg for 9 months. Patients who maintained at least stable disease were permitted to continue CYT387 treatment beyond 9 months in an extension phase of the study. Responses were assessed by International Working Group (IWG) Criteria. Results: At present, 163 subjects have been enrolled across the 6 study sites. The diagnoses of enrolled subjects include 64% PMF, 14% post-ET MF and 22% post-PV MF; 67% of the patients were JAK2V617F positive. Starting doses of CYT387 in the dose escalation, confirmation and expansion phases of the study are shown in Table 1. The median duration (range) of treatment was 6.6 months (0.25 to 20.4 months). Patient characteristics were as follows: median age 68 years, 58% male, 87% were spleen evaluable at baseline per IWG criteria (median spleen length was 18 cm by palpation). Sixty three percent (63%) of subjects were anemia evaluable at baseline per IWG criteria; 46% were transfusion dependent. Previous JAK inhibitor and IMiD therapy was reported for 11% and 8% of enrolled subjects, respectively. Reductions in spleen size, improvements in constitutional symptoms and the achievement of transfusion independence were observed in subjects in the expanded multicenter study. CYT387 was well tolerated. Based on currently available data, 73% of subjects reported treatment-related adverse events, with the majority reported as Grade 1. The most common Grade 3–4 treatment related adverse events included thrombocytopenia (16%), and hyperlipasemia (3%). New onset treatment-related Grade 3–4 anemia remains rare (<1%). Grade 1 toxicities included peripheral sensory neuropathy whose incidence and natural history is currently being studied. Twenty-five of 163 subjects (15%) have discontinued from the 9 month core study giving a retention rate of 85%. Conclusions: When examined in an expanded, multicenter study, CYT387 continues to show substantial clinical activity in myelofibrosis, with improvements in splenomegaly, constitutional symptoms and anemia. It appears to be well tolerated when administered in either a once or twice daily dosing regimen. CYT387 continues to demonstrate an ability to induce durable anemia responses in a subset of subjects. Detailed analyses of safety and efficacy will be available at the time of the meeting. Disclosures: Gupta: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Smith:YM Biosciences: Employment, Equity Ownership. Bavisotto:YM Biosciences: Consultancy. Kowalski:YM Biosciences: Employment, Equity Ownership.

Abstract Abstract 1759 Background: Pomalidomide is a second generation IMiDsÒ immunomodulatory drug that has been shown to be active in the treatment of myelofibrosis (MF)-associated anemia (J Clin Oncol 2009; 27: 4563; Leukemia 2011;25: 301). In the current sponsor-independent analysis, we report long-term follow up data on patients from the Mayo Clinic who had participated in three consecutive clinical trials using single agent pomalidomide for MF. Methods: From May 2007 to January 2010, 94 patients with MF (including primary and post-polycythemia/essential thrombocythemia) were enrolled in three consecutive phase I and II clinical trials involving pomalidomide with or without prednisone. Eight two patients who received only single agent pomalidomide constitute the study population for the current study. Follow up information was updated in July, 2011. Results: Among the 82 study patients, 19 were included in a phase I dose escalation study (2.5-3.5 mg/day), 58 in a phase II low-dose single agent pomalidomide study (0.5 mg/day), and 5 in a phase II randomized study (2 mg/day). Median age was 67 years and 63 (77 %) patients were red blood cell transfusion dependent at study entry. Forty-five (55%), 24 (29%), 7 (9%), and 2 (2%) patients remained on pomalidomide therapy for at least 6, 12, 24, and 36 months, respectively (Table 1). The overall anemia response rate per IWG-MRT criteria was 27% (22/82). Response occurred in the first 6 months in 21 (96%) of the 22 responders. The median time for response was 2.3 months (range, 1–10). The median response duration was 16.5 months (2–40). The anemia response rate in patients with spleen size palpable at less than 10 cm below the costal margin was 44 % (17/39) vs. 10 % (4/39) in those whose spleen was palpable at or above 10 cm (p=0.002). The anemia response rate was twice as likely in JAK2 mutated versus non-mutated cases (30% vs 15% p=0.2). Anemia response rate was also higher in patients with at least 50% increase in absolute basophil count during the first month of therapy: 39% (19/49) vs 6% (2/32) p=0.001). The anemia response rate was not significantly affected by karyotype, transfusion need or leukocyte count. Among the anemia responders (n=22), 3 (14%) relapsed in the first 12 months; relapse was more likely in the presence of baseline leukocytosis (p=0.006). Among the 24 patients who took pomalidomide for at lease 12 months, grade 1 sensory neuropathy developed in 4 (16%) patients. Conclusion: Anemia response to pomalidomide therapy in myelofibrosis often occurs in the first 6 months of treatment and is more likely to occur in the presence of JAK2V617F and absence of marked splenomegaly. Long-term treatment with pomalidomide might be associated with sensory peripheral neuropathy in a subset of treated patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: The cytoreductive treatment options for myeloproliferative neoplasms, in those who have indications, may be limited to hydroxyurea and interferon. Busulfan has been reported to have some activity, but used less frequently in the management of BCR/ABL negative MPNs (Haanen CM et al Br J Cancer 1981; Brodsky American J of clinical oncology 1998). One study has shown significant JAK2V617F allele burden reduction with busulfan (Kuriakose ET et al; Haematologica 2013). Ruxolitinib was approved by the FDA for intermediate and high risk myelofibrosis; and as second line therapy for polycythemia vera in those who are intolerant or develop side effect to hydroxyurea. Objective: To assess the utility of busulfan, an old drug, in patients with myeloproliferative neoplasms who are intolerant to other forms of therapy. Methods: The mayo clinic data base from 1970 to 2014 was interrogated using the terms myeloproliferative disorder, polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF) and busulfan. Patients' follow up information was collected till July 2015. Results : Seventy five patients with full demographic, diagnostic and therapeutic information were identified, and those included 37 patients with ET, 22 with PV, 12 with MF, and 4 with myeloproliferative neoplasms unclassifiable. The median age was 64 (range 31-91) years. After a median follow up of 17 years, 40 patients (53 %) died, and leukemic transformation was documented in 4 (5%). The median time for leukemic transformation was 86 months (12-229). 1. Essential Thrombocytopenia (n=37): Twenty nine (79%) were females, and the median (range) age was 67 (33-90) years. At diagnosis the median (range) hemoglobin (Hgb) (gm/dL), white blood cell count (WBC) (X109/L), and platelet count (X109/L) were 13.6 (9.8-16.9), 10.2 (5-231), 1113 (593-2062) respectively. After a median follow up time of 230 months, 15 patients (41%) died, and leukemic transformation was documented in 1 patient who was also treated with radioactive phosphorous (P32). Leukemic transformation was documented 230 months from date of diagnosis. Follow up complete blood count was available in 20 patients and the median (range) Hgb, WBC and platelet count was 12 (9.9-16), 7.4 (3.1-25), and 267 (126-573) respectively. 2. Polycythemia Vera (n=22): Fourteen (61%) were females, and the median (range) age was 64 (46-91) years. At diagnosis the median (range) Hgb, WBC, and platelet count were 17.5 (15.1-20.8), 11.5 (1.2-26.6), and 669 (185-2370) respectively. After a median follow up time of 188 months 13 (57%) patients died, and leukemic transformation was documented in 2 patients and one of them was given P32. Follow up complete blood count was available in 21 patients and their median (range) Hgb, WBC and platelet count was 12.9 (10-15.2), 7.2 (2.8-20), and 303 (124-833) respectively. 3. Myelofibrosis (Primary and Post-PV and Post-ET myelofibrosis) (n=12) : The median age was 52 (31-75) and 5 were females. The median Hgb, WBC, and platelet count were 13.6, 14.5, and 472. Six (50 %) patients did have splenomegaly (and 5 of them have splenic size reduction after busulfan), 3 underwent splenectomy, and 3 have no palpable spleen. At a median follow up of 208 months, and 39 months (range 78-401) from the start of busulfan, 10 (84%) patients died and no leukemic transformation was documented. Conclusion: Busulfan should be considered as alternative therapy in myeloproliferative neoplasms especially in ET and PV that are intolerant to other forms of cytoreductive therapy. Busulfan may be given as pulse therapy in controlling cell counts. Disclosures Off Label Use: Busulfan as alternative therapy in myeloproliferative neoplasms.

Abstract Background: Myeloid sarcoma is a tumor mass consisting of myeloid blasts occurring at anatomical site other than the bone marrow (Arber et al. Blood 2016;127(20):2391-2405). It is a subgroup of acute myeloid leukemia, which can be localized or disseminated and may involve multiple organs. It can present with or without a positive bone marrow. It may precede or follow bone marrow involvement. It may be identified at diagnosis or relapse, and is not uncommon after stem cell transplantation (Koc et al. Cancer 1999;85(3):608-615; Yoshihara et al. Biol. Blood Marrow Transplant 2012;18(12):1800-1807). Objective: To describe the clinical characteristics, cytogenetics, prognosis and outcome of patients with myeloid sarcoma with or without bone marrow involvement. Methods: The Mayo Clinic database was interrogated using the ICD-9 codes 205.0, 205.2, 205.3, as well as terms "myeloid sarcoma," "chloroma," and "extramedullary sarcoma" in clinical notes and pathology reports. Patients' follow up information was collected until July 2016. Results: Ninety six patients with a diagnosis myeloid sarcoma were identified. The diagnosis was based on biopsy results and in some cases imaging studies in addition to bone marrow biopsy. The median age was 53 (range 17-83) years, and 64 (67%) patients were males. Myeloid sarcoma with de novo (primary) and secondary acute myeloid leukemia (with antecedent hematologic malignancy and therapy related) accounted for 64% (61) and 36% of the cases respectively. The sites involved based on their frequency of occurrence included integumentary system (skin and soft tissues) in 37 (38%), lymphatic system in 17 (18%), the gastrointestinal and genitourinary system in 14 (15%), the nervous system in 9 (9%), the breast in 3 (3%) and multiple and other single sites in 16 (17 %). Bone marrow cytogenetics findings were documented in 74 (77%) patients; favorable, intermediate, and poor cytogenetic abnormalities account for 7 (9%), 45 (61%), and 22 (30%) cases respectively. After a median follow up of 135 weeks, 57 (59%) patients died. The median survival of primary and secondary acute myeloid leukemia with myeloid sarcoma was 52 and 11.5 months (P<0.0001); and that of favorable, intermediate and unfavorable cytogenetics abnormalities was 169, 52 and 17.5 months (P=0.04) respectively. Twenty six (27%) patients had no bone marrow involvement; and 18 (69%) of them were primary myeloid sarcoma (without antecedent malignancy or therapy). The median (range) age of those with and without bone marrow involvement was 53 (17-83) and 56 (17-81) years (P=0.6). At diagnosis patients with and without bone marrow involvement have a median (range) hemoglobin (gm/dL) (10.3 (6.2-15.4) vs 13.1 (9.9-15.2) P=0.0002), white blood cell count (X109/L) (21.4 (1.1-182.5) vs 5.8 (2.4-23.2) P<0.0001), and platelet count (X109/L) (71 (8-437) vs 250 (17-561) respectively. Aggressive chemotherapy therapy was given to 58 (83%) and 20 (77%) of patients with and without bone marrow involvement (P=0.6). The median survival was 17 and 20 months with and without bone marrow involvement (P=0.4). Of those with bone marrow involvement, 49 (70%) achieved complete remission, and 26 (53%) of those individuals subsequently relapsed. Conclusion: The treatment outcome of patients with myeloid sarcoma with or without bone marrow involvement seems the same. The conventional risk factors, antecedent hematological neoplasms and cytogenetic findings, have significant impact on survival. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Abstract Abstract 1752 Background: Patients with primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF) myelofibrosis often harbor a JAK2 mutation and also display abnormally increased inflammatory cytokines (J Clin Oncol. 2011;29:1356). Therefore, JAK-STAT is an appealing drug target in such patients. Ruxolitinib (INCB018424) is a small molecule ATP mimetic that inhibits both JAK1 and JAK2 and has been evaluated for its therapeutic activity in MF, in the setting of phases 1, 2, and 3 clinical trials. Methods: The first phase-1/2 MF study using ruxolitinib was conducted at the MD Anderson Cancer Center and Mayo Clinic. A total of 153 patients were included in the study whose first line results were published in September, 2010 (NEJM 2010;363:1117). The current report constitutes a sponsor-independent analysis of long-term outcome in the 51 Mayo Clinic patients who participated in the particular clinical trial. Results I: Baseline characteristics: The 51 patients (37 males) from the Mayo Clinic were enrolled between October, 2007 and February 2009. The median time from treatment initiation is now 3.5 years. MF subtype distributions were PMF 60%, post-PV MF 32% and post-ET MF 10%. Median (range) values were age 61 years (39–79), hemoglobin 10.6 g/dL (7.4-15.3), leukocyte count 15.8 (2.0–136), and palpable spleen size 19 cm (0–32). The proportion of patients with red cell transfusion dependency was 24%, hemoglobin <10 g/dL 38%, unfavorable karyotype 18%, pruritus 24%, night sweats 26%, and JAK2V617F 84%. DIPSS-plus risk distributions were high 18%, intermediate-2 48%, intermediate-1 22% and low 14%. Results II: Response and treatment duration: According to the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria, spleen response rate was 29% and anemia response rate 21%. Responses were also seen in constitutional symptoms (63%) and pruritus (92%). To date, treatment has been discontinued in 47 (92%) patients. The treatment discontinuation rates at 1, 2 and 3 years were 51%, 72% and 89%, respectively. For the 47 patients who were taken off study, median duration of treatment was 9.2 months (range 1.3–42 months). Reasons for treatment discontinuation included loss or lack of response/disease progression (∼40%), toxicity with and without lack of response/disease progression (∼34%), patient/physician choice often associated with lack of response (13%), and death on study (∼4%). Results III: Toxicity: Grade ≥2 thrombocytopenia and anemia occurred in 26% and 33% of patients and persisted in the majority of afflicted patients after drug discontinuation. To date, 18 deaths (36%) and 5 (10%) leukemic transformations have been recorded. Serious adverse events occurred upon drug discontinuation in 6 cases (13%) and were characterized by immediate relapse of symptoms, rapid and painful enlargement of spleen sometimes associated to splenic infarct, and acute hemodynamic decompensation occasionally leading to a septic shock-like syndrome. Results IV: Survival: There was no significant difference in the survival of the 51 ruxolitinib-treated patients compared to that of a cohort of 410 cases of PMF seen at the Mayo Clinic in the most recent 10-year period: unadjusted (Figure 1; p=0.43) and adjusted for DIPSS-plus (Figure 2; p=0.58). Conclusions: Ruxolitinib is effective in alleviating constitutional symptoms in the majority of patients with MF. Its activity in reducing spleen size is modest and not always durable. It is imperative that patients be alerted about important drug adverse events including potentially irreversible thrombocytopenia, worsening of anemia, and potentially catastrophic withdrawal symptoms. Ruxolitinib therapy does not appear to affect survival in MF. Disclosures: No relevant conflicts of interest to declare.