Citations

Abstract Introduction: MPN-related pain, including abdominal discomfort (53.2%), and bone pain (48.5%), is a prevalent complaint within the disorder and is associated with impaired patient quality of life, reduction in most functional domains and overall poor prognosis. Non-targeted treatments for MPN disorders have been previously shown to provide little symptomatic relief for MPN pain. To date, little is known about patient viewpoints on MPN pain, its relationship to other chronic pain syndromes and the impact of pharmacologic and non-pharmacologic pain therapies. In this study, we performed an international survey of MPN patients to better understand the prevalence and management of MPN pain. Methods: This study was performed by the MPN Quality of Life Study Group. A survey was designed by a team of MPN investigators experienced with MPN symptomatology. Survey content included the Barriers Questionnaire II (BQII), a 27-item survey validated to assess patient belief barriers to optimal management of cancer pain measured on a 0 (do not agree at all) to 5 (agree very much) scale (Pain. 2002 Oct;99(3):385-96.). Patients also completed the MPN-10, a 10-item survey of MPN symptoms completed on a 0 (absent) to 10 (worst imaginable) scale (Blood. 2011 Jul 14;118(2):401-8). The survey was posted on high-traffic MPN-related webpages focused on patient education and advocacy (MPN Forum, MPN Net, MPN Research Foundation, MPN Voice) for a total of 28 days. Survey questions evaluated patient demographics, pain histories, current and prior treatment strategies, as well as satisfaction with and barriers to available treatment options. Results: Demographics A total of 502 MPN patients (MF 26.9%, PV 44.2%, ET 28.9%) completed the survey. Patients were of expected mean age (60.5 years) and primarily female (74.9%). Most were from the United States (66.7%) and primarily English speaking (92.2%). Patients described being diagnosed with their MPN 3 to 10 years (35.4%) or >10 years ago (30.8%). Splenic enlargement was vocalized by 36.5% of patients and few patients had had a known history of blood clots (25.4%), severe bleeding (13.3%), conversion to acute leukemia (0.4%) or prior bone marrow transplant (1.4%). Patients described a treatment history of a variety of MPN therapies including aspirin (82.7%), hydroxyurea (60.6%), phlebotomy (40.6%), ruxolitinib (25.9%), interferon (18.5%), anagrelide (17.3%), active clinical trial (5.0%) and radiation treatment (0.4%). Pain Severity, Prevalence and Treatments Among surveyed patients, the MPN-10 mean was 28.3. Mean individual symptom scores and prevalence were 3.1 and 65.6% for abdominal discomfort and 3.0 and 60.4% for bone pain, respectively indicating a low to moderate symptom burden. Most patients had no prior history of chronic pain prior to their MPN diagnosis (47.1%), with chronic abdominal pain and chronic bone/muscle pain noted prior to MPN development in 5.6% and 20.8% of patients, respectively. Most patients felt that their chronic pain has either stayed the same (26.2%), worsened (28.3%) or significantly worsened (14.5%) since their MPN diagnosis. Many patients found pharmacologic and non-pharmacological therapies efficacious for individual pain symptoms, and 42.1% described regularly taking medication to control their pain (Table 1). Barriers to Pain Management Overall, 42.3% of MPN patients reported being unsatisfied with their current pain management plan. Despite this, only 43.5% of patients stated that their MPN providers discussed pain during office visits. Palliative Care (3.1%) and Pain Management (7.3%) were infrequently engaged. On the BQII, patients described being confident that cancer can cause pain (mean 4.2, SD 1.1) but did not necessarily expect to have pain following their MPN diagnosis (mean 2.2, SD 1.8). Conclusion Chronic pain (abdominal, bone) is a prevalent and undermanaged feature of MPN disorders. Chronic non-MPN pain is further complicated by the development of the disorder. Many MPN patients lack understanding on its prevalence and furthermore feel ill-equipped to manage it. Patients have, however, found symptomatic benefit from various pharmacological and non-pharmacological treatment modalities that require further exploration. Results from this study suggest MPN patients should be assessed regularly for pain and offered early referral to specialized services for evaluation, source identification and treatment. Table 1. Table 1. Disclosures Scherber: Incyte: Consultancy; Orphan Pharmaceuticals: Honoraria. Mesa:Ariad: Consultancy; Galena: Consultancy; CTI: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Novartis: Consultancy; Celgene: Research Funding. Dueck:Bayer: Employment; Pfizer: Honoraria; Phytogine: Employment. Palmer:Novartis: Research Funding.

Abstract Introduction: Donor T cell chimerism is tested frequently early after allogeneic hematopoietic cell transplantation (HCT). However, the predictive ability of testing this early after HCT, i.e. at day +30 or day +60, has not been well described, outside of smaller single center studies. Herein, we evaluate the correlation of early donor T cell chimerism with clinical outcomes of overall survival (OS) and relapse in patients undergoing HCT for various hematological malignancies. Methods: We identified patients who received HCT with 8/8 matched unrelated donors at our center between 2007 and 2016 and obtained the clinical data retrospectively. Chimerism studies were included for patients who had testing done at day+30 and/ or day +60. Chimerism is tested using PCR based technique. Due to limited variability in chimerism levels <100% donor chimerism, a cut-off of 100% was used for analysis. Hence, patients were divided into those who achieved full donor chimerism in CD3 fraction (100%) and those in whom CD3 donor chimerism was < 100% at the respective time points. Clinical outcomes evaluate for this abstract were OS and time to relapse. Univariate and multivariate Cox proportional hazard regression models were used using variables of interest, the later adjusted for age at HCT, use of ATG, conditioning regimen and disease risk index (DRI). Results: Baseline patient and HCT data: There were 209 patients who met the selection criteria of which 4 died within 30 days from HCT and hence, were not included in the analysis. Among the 205, 87 (42%) were women and median age at HCT was 55 (range, 18 - 74) years. The hematological malignancy diagnosis was acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS) in 112 (55%), acute lymphoblastic leukemia (ALL) in 35 (17%), chronic leukemias in 13 (6%), lymphomas in 13 (6%) and myeloproliferative neoplasm in 20 (10%); with DRI being very high in 9 (5%), high in 53 (27%), intermediate in 120 (60%) and low in 17 (9%) patients. Myeloablative conditioning was used in 81 (40%) and reduced intensity conditioning in 124 (60%). Graft versus host disease prophylaxis used was calcineurin inhibitor with methotrexate of mycophenolate in all patients while anti-thymocyte globulin was used in 125 (61%) patients. All patients received a peripheral blood graft. Outcomes: Median follow-up for all included patients was 615 (range, 30 - 3147) days. At day +30, 138 patients had achieved 100% donor CD3 chimerism of 189 patients in whom this data was available (73%) while at day +60, 131 (76%) out of 173 had 100% donor CD3 chimerism. In the univariate model, CD3 donor chimerism level at day +30 as well as day +60, was not predictive of OS (HR 1.5, 95% CI 0.82 - 2.9; p = 0.18 for day +30, HR 1.8, 95% CI 0.81 - 4.0, p = 0.15 for day +60). As for time to relapse, CD3 chimerism did not significantly affect the risk of relapse at these time points (HR 0.43, 95% CI 0.17 - 1.1, p = 0.08 for day +30; HR 0.55, 95% CI 0.18 - 1.6, p = 0.28 for day +60). In the multivariate model also, after adjustment as described above, CD3 at day +30 or at day +60 was not significantly associated with the risk of OS or time to relapse (Figure 1). Kaplan Meier curves for OS for CD3 chimerism at day +30 and day +60 are shown in Figure 2. Conclusions: In this study, T cell chimerism as early as day +30 or day +60 does not seem to predict OS or relapse in patients undergoing HCT for various hematological malignancies. Given the limitations of a smaller retrospective design, this must be validated in a larger study, possibly using registry data. If these findings are indeed confirmed, then the practice of testing chimerism early and frequently, that adds additional expense to the overall cost of HCT, must be reconsidered. Disclosures Palmer: Novartis: Research Funding.

Abstract Background: The myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) can be characterized by heterogeneous symptoms, disease features, and prognosis. Timely monitoring of blood counts and if needed, referral for discussion of stem cell transplant (SCT), are critical to optimizing survival and quality of life. In connection with the MPN SCT Transplantation Timing Taskforce's (MS3T's) work in developing the DIPPS-based Stem Cell Spectrum Timing Tool, the survey was deployed to explore factors contributing to delayed entry to SCT. National Comprehensive Cancer Network (NCCN) guidelines for MPNs strongly recommend referral to specialized centers with expertise in the management of MPNs (Mesa et. al. 2017). To date, efforts to assess the timing and quality of MPN patient care from the patient's perspective have been minimal. Methods: Patients were recruited from MPN-related Facebook pages, subscribers of MPNforum Magazine and E-mail support groups including the MPN-NET, MPDchat, and the MPN Research Foundation. Hematologists, MPN patients, and advocates constructed the 11-item survey questions and content. The survey was available for patient response between July 4-11th2018. Patients were queried on MPN type, time of diagnosis, and details regarding knowledge of their MPN disease features and care. Data: Demographics.Overall 2382 MPN patients responded to the online survey. Of these, 901 (38%) patients had ET, 865 (36%) had PV, 561 (24%) had MF, 41 (2%) had MPN-unclassifiable or MPN/MDS overlap and 15 (1%) did not respond. Among MF patients, 56% reported having primary MF, 42% secondary MF, 1% prefibrotic MF, and 1% reported having already undergone SCT (1% did not specify type of MF or transplant). The majority of patients were diagnosed with their MPN by a hematology/oncology (77.8%) or family practice (15 %) physician. MPN Care provider and monitoring: Out of all respondents, 35% reported being cared for by an MPN specialist, 36% were not cared for by an MPN specialist and 27% were unsure if their provider was an MPN specialist. Overall less than half (42%) of patients reported having sought a second opinion from an MPN specialist. The majority (87%) of participants knew their mutational status relating to the highly publicized and widely tested JAK2 V617F mutation (73.8%) and CALR (10.2%). However, a statistically insignificant number of patients had any idea of other driving and secondary mutations including MPL, EZH2, SRSF2, IDH1/2 or ASLX-1. Blood counts were reviewed by a hematologist for the majority of patients (93% responded "yes", 4% responded "sometimes", 3% responded "no"). SCT Referral: Among ET and PV, <1% of patients reported being referred to SCT. For MF, 34% of participants reported having been referred for SCT discussion (30% for primary MF and 28% for secondary MF). Conclusions: MPN patients often report receiving care outside of the care of an MPN specialist. Additionally, despite the poor outcomes and higher likelihood of progression to AML, less than a third of patients with secondary MF report being referred for SCT discussion. Independent validation of patient responses, particularly in regards to MPN specialized care and timing of transplant discussion should be investigated further. However, these patient responses suggest many patients may be receiving less than optimal MPN care. These results demonstrate the importance of community hematology/oncology physician and patient education regarding optimal MPN care. Disclosures Mesa: UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; Novartis: Consultancy; Incyte Corporation: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding; Genentech: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding. Palmer:Novartis: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Scherber:Gilead: Honoraria.

Abstract Background: Myelofibrosis (MF) is a clonal bone marrow disorder characterized by a constitutional symptoms, splenomegaly, anemia, elevated WBC and bone marrow fibrosis. Ruxolitinib is a JAK2 inhibitor approved for patients with Intermediate-2 (INT-2) or high risk disease based on dynamic international prognostic scoring system (DIPSS)), however, there are limited options for patients with early disease. Interferon alpha (IFNa) is a cytokine therapy that has been used in treatment of chronic myelogenous leukemia and polycythemia vera (PV). In these diseases, there can be a reduction in the clonal burden in addition to a hematologic response. Therefore, we sought to use this therapy in patients with MF. Methods: Patients who had MF were enrolled on an IRB approved clinical protocol in a single arm, single institution study. Patients were stratified to either an early disease arm (characterized by intermediate 1 (INT-1) risk or advanced disease (Int-2 or high risk disease based on DIPSS). Patients were started on Ropeginterferon alfa 2b (P1101) at 50 ug every two weeks, and the dose was titrated up to either 300 ug every other week, or unacceptable toxicity. Patients were monitored for response based on international working group criteria. Results: Demographics: Eight patients with MF have been enrolled on the study to date (Early: 2, Int/High: 6). Median age was 69.5 (45 - 88), five patients were female. Five patients had primary MF (PMF) and 3 had post-essential thrombocythemia or post PV MF. Three patients had previous treatment for their disease. Four patients continue to receive active treatment (2 early disease, and 2 advanced disease), and for those who remain on treatment, they range from 7 - 29 cycles. Efficacy: Three patients experienced a clinical improvement (1 based on MPN-SAF total symptom score, and 2 based on reduction of spleen size). Both early stage patients have had a CI based on spleen responses as their best response and currently remain on treatment. The remaining 2 who are on therapy had stable disease. Those who remain on therapy have been receiving treatment for 7-29 cycles with continued response. Toxicity: A grade 3 adverse event (AE) potentially attributable to the treatment occurred in 4 patients (50%), 3 (37.5%) patients had anemia, and 2 (25.0%) patients had lymphopenia. Only one patient discontinued therapy due to AEs (dizziness, atrial fibrillation). Reasons for stopping include disease progression (1), toxicity (1) and lack of benefit (2). The median number of cycles for those who ended treatment was 8 (4-10). No deaths have occurred. Discussion: P1101 appears to be a well-tolerated therapy that has shown a durable clinical improvement in 37.5% in a small study. These results, along with historic data suggesting possible reduction in clonal burden, suggest that ongoing studies are warranted to further understand the clinical benefit of P1101 in MF. Disclosures Palmer: Novartis: Research Funding. Zimmerman:PharmaEssentia: Employment. Zagrijtschuk:PharmaEssentia: Employment. Mesa:Gilead: Research Funding; CTI: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Promedior: Research Funding; Incyte: Research Funding; Galena: Consultancy; Novartis: Consultancy.

Abstract Introduction: Primary refractory and early relapsed acute myeloid leukemia (RR-AML) continue to pose a therapeutic challenge. Salvage therapy treatment regimens for refractory and relapsed disease are not standardized but include the commonly-used mitoxantrone, etoposide, and cytarabine (MEC) and cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M). Previous studies have suggested a potential benefit of CLAG-M, and therefore we performed an analysis of consecutive patients selected to receive either CLAG-M or MEC as salvage therapy for RR-AML. Methods: The study included 150 consecutive patients with RR-AML who received either CLAG-M or MEC between 09/01/2009 and 12/31/2017. Patients were identified through a pharmacy database based on use of mitoxantrone. Baseline disease and patient-related characteristics and clinical outcomes including allogeneic transplantation (ASCT) were obtained by systematic review of EMR. Overall survival (OS) and progression free survival (PFS) were estimated according to the Kaplan Meier method and log-rank test was used to compare outcomes between patients who received either of the two regimens. Results: There were 150 consecutive treated patients with RR-AML included in this analysis, 34 patients received CLAG-M and 116 patients received MEC. The median age was 57 years (18-76), and, and 52% were male. Forty-seven (31%) were treated for early relapsed disease (<6 months after successful induction), 17% (>6 months after induction), and the remainder had primary refractory disease (mean number of induction regimens was 1.8, range 1-6). AML risk was defined by cytogenetic criteria. There were a predominance of intermediate-risk subtypes at 47% (71/150) and followed by high-risk at 37% (55/150). Overall CR/CRi rates for CLAG-M and MEC were 74% (23/31) and 58% (63/108) in patients eligible for analysis (p=0.18). The median follow-up from relapse was 23.5 months (1-76). The median OS was 9.5 months for CLAG-M and 10.0 months for MEC (HR=0.88, 95%CI=0.54-1.41, p=0.59). In total, 76 patients (51%) were able to proceed to ASCT following salvage therapy with either CLAG-M or MEC. Among transplant recipients 56% (19/34) and 49% (57/116) were treated with CLAG-M and MEC, respectively. Median OS after ASCT was 13.0 months for CLAG-M and 31.0 months for MEC (HR=1.76, 95%CI=0.87-3.56, p=0.12). The median OS for refractory AML was 13.0 and 66.0 months for CLAG-M and MEC recipients, respectively (HR=0.92, 95%CI=0.46-1.84, p=0.24). Median OS for those with early relapse was 12.0 months for CLAG-M and 10.0 months for MEC (HR=0.69, 95%CI=0.22-2.11, p=0.51). Lastly, among those who had late relapse, median OS was 9.0 and 48.0 months for CLAG-M and MEC, respectively (HR=17.6, 95%CI=1.57-198, p<0.001). A univariate analysis was performed to investigate the impact of factors associated with OS, including treatment, age, gender, whether they proceeded to ASCT, cytogenetic risk type, and donor source. ASCT was associated with significant improvement in both PFS (HR=0.24, 95%CI=0.16- 0.37, p<0.001) and OS (HR=0.26, 95%CI=0.17-0.40, p<0.001) in this cohort. Age greater than 65 was associated with worse PFS (HR=1.02, 95%CI=1.00-1.03, p=0.04) but not OS (HR=1.01, 95%CI=1.00-1.03, p=0.06) after controlling for other variables including the impact of ASCT. Discussion: Despite a lower 30-day induction mortality we did not identify significant differences in outcomes among patients selected to receive CLAG-M vs. MEC. There was a statistically significant improvement in survival in patients who had late relapses and were treated with MEC, and a trend towards improvement in OS of those treated with MEC who proceeded to ASCT. As expected, ASCT was associated with significant improvement in OS in this cohort, and our results strongly support the use of ASCT as consolidation of remission after relapse for AML. Our data suggests that MEC may be a superior regimen, in particular including those with late relapse. Figure. Figure. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Al-Kali:Novartis: Research Funding. Palmer:Novartis: Research Funding.

Abstract Introduction: PRM-151, a recombinant human pentraxin-2 molecule, has been shown to prevent and reverse fibrosis in animal models of myelofibrosis (MF) by postulated targeting differentiation of fibrocytes (essential cells in fibrotic process) from monocytes. In the first stage of a two-stage trial, 27 patients (pts) with primary myelofibrosis (PMF), post-essential thrombocythemia/polycythemia vera (post-ET/PV) MF, and Grade 2 or 3 bone marrow fibrosis (BMF) received PRM-151 10 mg/kg IV ± ruxolitinib (RUX) for 6 cycles (24 weeks). A reduction in BMF, decrease in symptoms (MPN-SAF Total Symptom Score [TSS]), and a reduction of palpable splenomegaly were observed, along with a favorable safety profile. Pts experiencing clinical benefit were allowed to continue beyond 24 weeks in an open label extension (OLE) study. Here, we report interim efficacy and safety data for 18 pts enrolled in the OLE, who had been treated for up to 35 cycles (140 weeks). Methods: All pts in the OLE received a monthly infusion of PRM-151 10 mg/kg IV. Pts receiving PRM-151 alone or in combination with RUX in the main study continued with their respective drugs. Safety and hematology parameters were assessed monthly, and MPN-SAF TSS Q3 months. BM biopsies were obtained at baseline, end of main study, and at physician discretion in the OLE. These were evaluated centrally by two independent, blinded hematopathologists for the degree of reticulin and collagen fibrosis. Immunostaining for fibrocytes was performed on available biopsies. The primary objective of the OLE was to assess safety and efficacy of long-term administration of PRM-151. Results: Of the 18 pts enrolled in the OLE, 9 received PRM-151 as single agent, and 9 in conjunction with RUX. Baseline characteristics included median age of 66 years (51-78); 8 pts were DIPSS Int-1, 9 Int-2, and 1 high-risk; 6 (33%) had Hgb < 100 g/L, 12 (67%) had PLT < 100 x 109/L; 7 (39%) had PLT <50 x 109/L; 8 pts had PMF, 10 had post-ET/PV MF; 13 pts (72%) had a palpable spleen, and 9 (50%) had Grade 3 BMF. Median time on study for these 18 pts was 30.9 months (15.9-47.2 months). All pts experienced at least 1 adverse event (AE), with 8 pts (44%) reporting a possible study drug-related AE. No unexpected AEs were observed, and no deaths were reported during the study period. The mean best percent change (by palpation) in spleen size from baseline was −37%, with a median percent reduction of −26.1% (Figure). The mean best percent improvement in MPN-SAF TSS was −54%, with a median percent reduction of TSS of −64%. Pts in the PRM-151 monotherapy group showed similar improvements in MPN-SAF TSS and splenomegaly as those receiving PRM-151 + RUX (Figure). Complete data on hematology parameters will be available at the time of presentation. Improvement in BM reticulin grade was observed in 5 of 7 pts (71%) with Grade 2 BMF at baseline, and in 4 of 9 pts (44%) with Grade 3 BMF at baseline. Of the pts with Grade 3 BMF at baseline, 2 of 9 pts (22%) had a 2-grade reduction (Table). In addition, 5 of 6 pts (83%) with Grade 2 collagen fibrosis at baseline had a 1-grade reduction, with 2 of 6 pts (33%) improving to Grade 0. Also, 2 of 7 pts (28%) with Grade 3 collagen fibrosis had a reduction of 1-grade with 1 of 7 (14%) improving to Grade 0 (Table). Eight of 18 pts had BM fibrocyte immunostaining done: mean fibrocyte count in the hematopoietic BM decreased from 378.0 ± 255.3 per mm2 (11.2 ± 7.7% of total cells) at study baseline to 81.3 ± 86.5 per mm2 (2.0 ± 2.1% of total cells; 7 of 8 pts evaluable) at cycle 25, with continuous reduction in fibrocyte numbers observed at interim. Over the same period, improvement in BM reticulin grade was detected in 4 of 7 pts (57%), and collagen fibrosis grade was decreased in 3 of 7 pts (43%). Conclusions: This long-term follow-up study of 18 pts with MF who received PRM-151 for a median of 31 months showed the drug to be well tolerated. An overall improvement in BM reticulin and collagen fibrosis grade, as well as reductions in MPN-SAF TSS and splenomegaly were observed. In a subset of pts for whom bone marrow fibrocyte immunostaining data were available, a mean reduction in fibrocyte counts was observed, as well as improved bone marrow reticulin and collagen fibrosis grade. These data warrant confirmation in a larger controlled study. Figure. Figure. Disclosures Verstovsek: Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees. Pozdnyakova:Promedior, Inc.: Consultancy. Mesa:Promedior: Research Funding; Incyte: Research Funding; Ariad: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Galena: Consultancy; Gilead: Research Funding; CTI: Research Funding. Foltz:Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Roche: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding. Ritchie:Astellas Pharma: Research Funding; NS Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Palmer:Novartis: Research Funding. Kremyanskaya:Incyte: Research Funding. van den Blink:Promedior, Inc.: Employment. Gupta:Promedior, Inc.: Employment. Gotlib:Deciphera: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Kartos: Consultancy; Promedior: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Abstract Background: Myelofibrosis (MF) is a bone marrow disorder characterized by anemia, splenomegaly and constitutional symptoms. There has been substantial work documenting quality of life (QoL) in patients with MF, however, very little data about patients following allogeneic stem cell transplant (alloSCT) for MF. Many patients decline alloSCT due to concerns secondary to QoL. Methods: Medical facts and patient reported outcomes (PRO) measures were collected within a month prior to transplant, at day 30, 100 and 1 year post alloSCT. PRO measures include Brief Fatigue Inventory, Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), global assessment of change and the Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF). The group was measured as a whole, and the patients in the upper quartile of MPN-TSS (the aggregate score of the 10 core items of the MPN-SAF) were also considered. Results: Fifty patients were enrolled on this study, 47 who proceeded with transplant. The median age of the patients was 63, ranging from 35-74. The majority of the patients were male (29, 66%), and Caucasian (43 (96%)). Most patients had primary MF (26, 59%), 9 patients had post-PV MF, and 9 patients had post-ET MF. Twenty patients had DIPSS Intermediate 2 risk disease, and 16 had DIPSS high risk disease. Twenty-six (51%) had a matched unrelated donor, 12 (30%) had a matched related donor and 5 (12%) had a mismatched unrelated donor. The majority of the patients had RIC regimens (35, 88%). At baseline the mean MPN-TSS was 27.7 (out of possible 100), and at day 30, day 100 and 1 year it was 24.6, 32.0, and 25.0, which reflected no significant change between the time points. Interestingly, all the MPN specific symptoms (including fevers, night sweats, pruritis, abdominal pain) had a significant improvement at least one time point following alloSCT. Patients in the highest quartile based on baseline TSS score (12 patients with scores at baseline greater than or equal to 37), had significant improvement in TSS score at day 100, headache at day 30, insomnia at day 100, night sweats at day 100, itching at day 100 and overall QOL at day 100. With regards to the FACT BMT, as would be expected, there was a significant decline in the FACT BMT total score, as well as trial outcome index (TOI) at day 30, but a return to close to baseline by one year. In the global assessment of change, on day 30, 11 (27.5%) of patients reported feeling a little/moderately/very much better overall quality of life since their transplant and 27 (67.5%) felt a little/moderately/very much worse quality of life. At day 100, 11 (31.4%) reported better quality of life and 20 (57%) reported worsening since transplant. By one year, 17 (60.7%) reported feeling better and 7 (25%) reported worsening. These findings did not appear to have a correlation with presence or absence of graft versus host disease. We were unable to assess the impact of conditioning as the majority of the patients had RIC conditioning. Discussion/ Conclusions: Our study evaluated the quality of life in patients with myelofibrosis who have undergone bone marrow transplantation. We have shown that there is very little change in symptom burden over the first year following transplant in general; however, significant improvement was observed in MF specific symptoms, and in patients who had a high symptom burden at baseline. By one year 61% felt that their QoL was better than it was prior to transplant. Our findings suggest that many of the patients do not experience a significant decline in QoL at 1 year after alloSCT, and actually report that their QoL improves. Further investigation is required to validate these findings. Figure. Figure. Disclosures Palmer: Novartis: Research Funding. Dueck:Phytogine: Employment; Pfizer: Honoraria; Bayer: Employment. Mesa:Novartis: Consultancy; NS Pharma: Research Funding; Incyte Corporation: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Pfizer: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Genentech: Research Funding.

Abstract Introduction Myelofibrosis (MF), both primary myelofibrosis (PMF) and post essential thrombocytosis/polycythemia vera myelofibrosis (post ET/PV-MF), are chronic myeloproliferative neoplasms that are incurable with standard medical therapy. The only potential curative therapeutic modality remains allogeneic stem cell transplant (ASCT), but the optimum conditioning regimen has yet to be defined and may vary due to pre-ASCT factors such as age, donor source, and comorbidities. In the past, traditional myeloablative (MA) regimens have proven toxic. Reduced intensity conditioning (RIC) regimens have generally become the accepted standard of care for patients with PMF or Post PV/ET MF in need of ASCT, but with the potential for increase in relapse especially for high risk disease. The optimal conditioning regimen has yet to be defined. The regimen of Fludarabine, BCNU, and melphalan (FBM) is considered a reduced toxicity regimen that may afford the benefit of reduction in relapse without increase in toxicity and may “bridge the gap” between MA and RIC especially in older patients. Patients with MF have high inflammatory cytokine levels which may act as mediators of MF symptom burden and may further aggravate mediators of acute GVHD, which is one of the most frequent and severe complications of ASCT. Selection of conditioning regimen and GVHD prophylaxis are keys to MF transplant outcomes. We report here the results of 16 patients who received conditioning with FBM with rATG (FBM-A) with PMF and post PV/ET MF. Methods We conducted a retrospective review of all patients from October 2009 to November 2012 with PMF or post ET/PV-MF who underwent an ASCT with FBM-A. Patient demographic and transplant data were analyzed from a comprehensive database. The use of such data for reporting purpose was approved by the Mayo Clinic Arizona Institutional Review Board. Overall survival was estimated using Kaplan-Meier. Results There were 16 patients analyzed who had PMF or post PV/ET MF or overlap syndromes. The median follow-up of surviving patients is 20.4 months (range 8 months – 46 months). The median age was 60 (range 47-68 yrs) with 56% of patients being ≥ 60yrs. There were 8 males and 8 females. The JAK2 V617F mutation was present in 64% of patients. 86% were high risk according to the DIPSS system with 14% being intermediate-2 risk. None of the patients underwent splenectomy prior to transplant. The median HCT-CI score was 1.5 with 6 (38%) of the patients having an HCT-CMI ≥3. Donors were related in 10 patients (8 matched, 2 mismatched at 1 antigen) and unrelated in 6 (matched, n=3, 1-antigen mismatch, n=3). GVHD prophylaxis consisted of tacrolimus, MMF, and ATG 2.5 – 5.0 mg/kg. The cumulative incidence of acute GVHD grades III-IV was 15.3% at 6 months, and the cumulative incidence of NIH-defined moderate-to-severe chronic GVHD was 25% at 2 years. No patient has relapsed, and no patient has developed graft failure. There have been 4 deaths, 3 from GVHD, and 1 from infection. Among the 3 patients who died from GVHD, all were unrelated donor transplants, and 2 were mismatched unrelated transplants. The 2-year Kaplan-Meier estimate of overall survival (OS) is 72% (95% CI, 45 – 91%). The cumulative incidence of TRM was 12.6% (95% CI 3.9%-34%) at 1 year. Conclusion The reduced-toxicity regimen of FBM-A in PMF, Post ET/PV MF and overlap syndromes appear to provide the benefit of an ablative regimen with the tolerance of a RIC. The 2-year overall survival of 72% in our series is encouraging in an older population of predominantly high-risk patients. Treatment failure was related predominately to GVHD, which continues to be a significant obstacle to better long-term outcomes, especially in unrelated and mismatched patients. Reduced toxicity ASCT conditioning regimens in the setting of MF warrant further investigation. Disclosures: Reeder: Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

Abstract Background: Acute myeloid leukemia (AML) is an aggressive blood cancer with a wide range of response and relapse rates using standard chemotherapy combining anthracycline plus cytarabine (7+3). The stem cell receptor tyrosine kinase KIT is expressed on more than 10% of blasts in 95% of relapsed AML cases and mediates leukemic proliferation and has anti-apoptotic effects (Domen and Weissman 2000). AML with high KIT expression is associated with poorer outcome (Del Poeta, Venditti et al 2003). Goals: To study the efficacy and safety of combination 7+3 and nilotinib in patients (pts) with AML and KIT expression. Primary goal is to determine the complete response (CR) rate; while secondary goals include 2-year overall survival (OS) and disease free survival (DFS) in addition to safety. Methods: A single arm, Phase II study, enrolled pts at Mayo Clinic (MN and AZ). Appropriate IRB was obtained and study was registered (NCT 01806571). Pts were enrolled if they were newly diagnosed with AML with KIT (CD117) expression of ≥ 20% on myeloblasts by flow cytometry. KIT mutations were allowed. Nilotinib 300 mg twice daily was given on days 4-14 of induction and consolidation; and continuous daily maintenance therapy for up to 2 years. Cytarabine 100 mg/m2/day continuous IV x7 days plus daunorubicin 60 mg/m2 IV daily x3 days were used for induction, while consolidation used standard cytarabine 3 gm/m2 twice daily days 1, 3, 5 for a total of 4 cycles. This is a Simon 1-stage design with a safety analysis after enrolling 12 pts, and an interim analysis after enrolling 18 out of 43 pts (Al-Kali, ASH 2015) recommended to continue study accrual. Results: i)- Demographics: Thirty four pts were enrolled from July 2013 to June 2017. Median age was 59 years (range 24-69) with 71% being male. Median laboratory findings include hemoglobin of 8.8 gm/dL, platelets of 56 x109/L, white blood count of 3.3 x109/L (0.4-125), and peripheral blood blasts 17 %(0-94%). Cytogenetics were normal in 43% of the pts and favorable cytogenetics were seen in 6%(inv 16). FLT3 gene testing was done on 26 pts and was positive in 13%. KIT gene sequencing (exon 8, 9, 10, 11, 17) revealed pathogenic mutation in 1/28 cases (4%). ii)- Clinical outcome Out of all 34 pts enrolled on the study, 18 (53%) achieved CR (or CR with incomplete platelet recovery) with a median CR duration of 21.8 months. Of 26 evaluable pts, the overall CR rate was 69%. 4 of the 18 pts (22%) who achieved remission needed a second induction. One pt died due to liver failure (had only one dose of nilotinib and toxicity was attributed to daunorubicin). 13 (38%) pts proceeded to allogeneic stem cell transplant (HSCT), 12 of whom are alive and none were able to initiate nilotinib maintenance. Only 6 (1 had HSCT) out of 34 (18%) pts relapsed after achieving CR. Median DFS was 45.8 months, while median OS was 42.4 months. 2-year DFS and OS were 58% and 72%, respectively. iii)- Safety Thirty four pts were evaluated for adverse events (AE). Fourteen pts had G4 non-hematological AEs, including fourteen G4 AEs related to infection, 2 with electrolyte imbalances, 1 heart failure, 1 elevated bilirubin, 1 elevated lipase, and 1 jejunal hemorrhage. One patient had G5 liver failure. Most common (>20%) G3 non-hematological AEs were febrile neutropenia (56%), hypophosphatemia (21%), elevated ALT (21%) and hypertension (21%). Conclusion: Combination daunorubicin and cytarabine with nilotinib (DATA) appears to be safe and effective. Final results show an acceptable safety profile with most common AE being infection. Thirty day mortality was low (3%). DATA regimen has comparable CR rates of 53% (intent to treat) and 69% in evaluable pts. Relapse rates were very low at 18% with durable responses and encouraging survival rates. Figure. Figure. Disclosures Al-Kali: Novartis: Research Funding. Tibes:Novartis: Research Funding. Palmer:Novartis: Research Funding.

Abstract Abstract 467 Background: While donor-recipient disparity at HLA loci is associated with greater risk for severe acute graft vs. host disease (GVHD) and inferior survival after unrelated donor allogeneic hematopoietic cell transplantation (HCT), the impact of amino acid substitution (AAS) at peptide binding pockets of the HLA molecule is incompletely understood. Methods: Adult and pediatric patients who received myeloablative or reduced intensity/non-myeloablative first unrelated bone marrow or peripheral blood stem cell transplantation for AML, ALL, CML or MDS between 1988 and 2009 were included. Donors and patients were fully high resolution matched for HLA-A, B, C, and DRB1 (8/8) or had single mismatch (7/8) at one HLA class I locus. Among 7/8 donor-recipient pairs, cases were categorized based on the presence or absence of the AAS of interest at positions 9, 77, 99, 116, or 156 of the class I molecule. In multivariable analysis accounting for patient, disease, and transplantation variables, we studied the independent impact of AAS at these residues on risk for grade III-IV acute GVHD, chronic GVHD, treatment-related mortality, primary malignancy relapse, and overall survival. We compared 7/8 donor-recipient pairs with AAS of interest to 7/8 pairs without these AAS in the primary analyses. Additionally, we performed this analysis restricted to each HLA class I locus. Results: Donor-recipient pairs were 8/8 matched (n=5282), 7/8 with AAS of interest (n=1713), or 7/8 without AAS of interest (n=318). In multivariable analysis, AAS at position 116 was associated with increased risk for grade III-IV acute GVHD (HR 1.21, 1.04–1.42, p=0.0165). No other significant association was detected between AAS studied and clinical outcomes. In multivariable analysis restricted to each class I HLA locus, we detected the following: Among 7/8 matched pairs with mismatch at HLA-C, AAS at position 116 was associated with increased risk for severe acute GVHD (HR 1.42, 1.13–1.79, p=0.0031) and inferior OS (HR 1.2, 1.01–1.41, p=0.0343). AAS at position 99 was associated with increased TRM (HR 1.37, 1.11–1.69, p=0.0037). Of 7/8 pairs with mismatch at HLA-B, AAS at position 9 was associated with increased chronic GVHD (HR 2.19, 1.31–3.66, p=0.0029). Specific amino acid substitution pairs with frequency > 30 were tested for association with HCT outcomes. None met the significance level of 0.00125, pre-specified for multiple comparisons. Conclusions: These results support the concept that AAS at key peptide-binding residues in the HLA class I molecule are associated with increased risk for severe acute GVHD and lower survival. Disclosures: No relevant conflicts of interest to declare.