Citations

Abstract Introduction: Disease relapse remains one of the major causes of treatment failure in hematopoietic stem cell transplant (HSCT) following reduced-intensity conditioning (RIC) regimens. Donor chimerism assessment early after HSCT may help identify patients at risk for relapse who may benefit from additional therapeutic interventions but its precise role in this setting is unclear. In addition, the differential impact of conditioning regimen is not well studied. Aim: 1. Study the impact of early full T-lymphocyte chimerism (T-lymphocyte chimerism ≥ 90% on day 30 to 60) on relapse incidence (RI) and acute graft versus host disease (aGVHD) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) following RIC-HSCT. 2. Looking at the tempo of achievement of complete donor T-lymphocyte chimerism based on the two most common RIC regimens, Fludarabine/Melphalan (FM) and Fludarabine/Busulfan (FB). Method: After IRB approval, patients with AML or MDS who underwent RIC-HSCT with FB or FM between 2008 and 2014 at our institution were identified. Post-transplantation CD3 (lymphocyte) and CD33 (myeloid) donor chimerism were measured per protocol using PCR-based analysis of short tandem repeats. Categorical and continuous variables were analyzed using Pearson's chi-squared and Wilcoxon / Kruskal-Wallis, respectively. Survival estimates were calculated using the Kaplan-Meier and log-rank test. RI was estimated accounting NRM on a competing event analysis using Grey's model. Cox proportional regression was used to compute hazard ratios (HR). Results: Baseline characteristics: Out of 134 patients who received FM or FB, 75 patients had evaluable early sorted chimerism data. 42 and 33 patients received FB and FM, respectively. Patient, disease and transplant variables were balanced in both FM and FB (Table 1). The median follow up of the cohort was 37 months (2.4-43) and at last follow up 29.1% of patients relapsed and 59% died. All patients achieved early complete myeloid chimerism whereas T-lymphocyte chimerism was complete in 50 patients and mixed in 25 patients. Characteristics of early lymphocyte chimerism by status are shown in table 1. Notably, likelihood of achieving complete T-lymphocyte chimerism ≥ 90% at 60 days was 100% versus 47% in FM and FB respectively (p <0.0001). Acute graft versus host disease: There was no significant difference in incidence of grade II-IV aGVHD between patients with full early donor T-lymphocyte chimerism in comparison to those with early mixed donor chimerism (46% vs. 48%, p =0.87). Impact of full chimerism and conditioning regimen on RI and overall survival (OS): Among the entire cohort, patients achieving early full T-lymphocyte chimerism had a significantly lower RI compared to those with mixed chimerism with a HR of 0.38 (CI 0.14-0.97; p=0.044) but OS was not significantly different with HR 0.69 (CI 0.33-1.51; p=0.34). In patients conditioned with FB, there was no difference in 2-year RI between complete or mixed early T-lymphocyte chimerism at 38.2% and 40.7% respectively (p = 0.9). After FM conditioning, all patients achieved early T-lymphocyte chimerism and the 2-year RI was 6.9%. Achievement of early complete lymphocyte chimerism post FB in comparison to FM was associated with significantly higher risk of relapse (HR 8.6 CI 2.07-57, p=0.0025). Furthermore, there was a trend towards worse OS with FB vs. FM with a median of 23 vs. 44 months, respectively (p = 0.058). Conclusion: Similar to prior reports, we observed that full T-lymphocyte chimerism is associated with decreased relapse risk without an increase in aGVHD. Our findings also suggest that RIC with FM yields a higher incidence of early complete T-lymphocyte chimerism and is significantly associated with decreased risk of relapse compared to FB. There was a greater risk of relapse in the FB group, even among those achieving early complete donor lymphoid chimerism. This needs further validation given the small sample size. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background The impact of cytomegalovirus (CMV) infection on the risk of relapse after Hematopoietic Cell Transplantation (HCT) remains controversial, with some studies demonstrating lower risk (Green et al, Blood 2013), while others demonstrating no impact (Schmidt-Hieber et al, Blood 2013), or lower relapse risk only in myeloablative (MA) (Manjappa et al, BBMT, 2014) or in reduced intensity conditioning (RIC) (Cichocki et al, ASH 2014) HCT. Furthermore, the majority of studies have used antigenemia for CMV monitoring, while there is limited data with the use of Quantitative Nucleic Acid Testing (QNAT). Aim To determine the impact of CMV infection, as detected by QNAT, on transplant-related outcomes for patients with acute myeloid leukemia (AML), stratified by MA or RIC HCT. Methods After IRB approval, consecutive adults with AML who underwent allogenic HCT from HLA-matched peripheral blood (PB) grafts at our institution between 2006 and 2014 were retrospectively reviewed. All grafts were T-cell replete. Early CMV infection was defined as any positive CMV result by PCR assay during the first 100 days post HCT. Relapse incidence (RI), non-relapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) were compared between patients with and without CMV infection, and stratified according to MA or RIC. DFS and OS were estimated using the Kaplan-Meier method, and compared with log-rank test. Cumulative incidence of relapse and NRM were analyzed as competing events, using Gray's test. Multivariable analyses adjusting for patient's age, disease status at transplant, cytogenetic risk, and ABO incompatibility were performed using Cox's proportional hazards regression, and the Fine and Gray approach. Results A total of 190 consecutive patients, including 94 (49%) MA and 96 (51%) RIC HCT were analyzed. Patients, disease, and transplant characteristics are shown in table 1. Of the 94 MA HCT (median age 45 y, 50% male), 66 (70%) received total body irradiation. After a median follow up of 18 m, 36 (38%) CMV infection, 16 (17%) relapses, 22 (23%) NRM and 35 (37%) deaths occurred in the MA group. Median time to CMV infection and to relapse in this group was 38 (range 8-241) and 140 (29-1690) days, respectively. Among the recipients of MA HCT, patients with early CMV infection showed no difference in the RI (figure 1), but had a significant trend towards higher NRM and significantly lower DFS and OS in both univariate and multivariable analysis (figure 2) (P values shown in table 2). Among 96 RIC HCT (median age 59 y, 56% male), fludarabine plus melphalan was used in 62 (65%) and fludarabine plus busulfan in 34 (35%) patients. In this group, early CMV infection occurred in 33 (34%), relapse in 25 (26%), NRM in 25 (26%), and deaths in 46 (48%) patients after a median follow up of 21 m (1-91 m). Among the recipients of RIC HCT, median time to CMV infection and to relapse was 40 (17-175) and 291 (19-1971) days, respectively. In the RIC group, early CMV infection was associated with a significant trend towards lower RI (figure 1) and higher NRM in both univariable and multivariable analysis, but no difference in DFS and OS (figure 2). Conclusion Our study of a large homogenous group of AML patients who underwent a uniform HLA-matched PB HCT demonstrates a significantly lower risk of relapse associated with early CMV infection detected by QNAT following RIC, but not MA HCT. Early CMV infection in MA HCT is associated with higher NRM and therefore inferior survival, whereas in the RIC HCT, there is no impact on survival as the benefit of lower relapse is offset by the higher NRM. Table 1. Patients, disease and transplant characteristics according to CMV infection All Patients Patients with CMV Viremia Patients without CMV Viremia P value Patients, no (%) 190 (100) 69 (36) 121 (64) - Median age, y (range) 54 (18-72) 54 (26-70) 54 (18-72) 0.75 Male Patients, no (%) 104 (55) 30 (43) 74 (61) 0.02 D/R CMV Serostatus, no (%) <0.0001 -/- 29 (15) 1 (1) 28 (23) +/+ 64 (34) 35 (51) 29 (24) +/- 13 (7) 1 (1) 12 (10) -/+ 84 (44) 32 (47) 52 (43) Conditioning 0.65 MA 96 (51) 33 (48) 63 (52) RIC 94 (49) 36 (52) 58 (48) Disease status at Transplant 0.96 CR1 129 (68) 46 (67) 83 (69) CR2 34 (18) 13 (19) 21 (17) Other 27 (14) 10 (14) 17 (14) Cytogenetic 0.65 Favorable 8 (4) 2 (3) 6 (5) Intermediate 130 (68) 46 (67) 84 (69) Unfavorable 52 (28) 21 (30) 31 (26) Disclosures Al-Kali: Novartis: Research Funding.

Abstract Background: Hypomethylating agents (HMA) such as 5-Azacitidine (Aza) have overall responses rate of ~35-50% in acute myeloid Leukemia (AML) and higher risk myelodysplastic syndrome (MDS) patients (pts). However, eventually all pts develop resistance on therapy. To improve upfront response rates and to address HMA failure, we performed genome-scale RNAi screens targeting genes on chromosomes 5 and 7, recurrent cytogenetic abnormalities in AML/MDS. These screens identified Hedgehog pathway (Hh) genes as potentially targetable vulnerabilities with Aza. Combination experiments with smoothened (SMO) inhibitors (SMO is a central activating gene within the Hh pathway) showed pre-clinical synergy. These and additional published data support the Hh pathway as a targetable vulnerability in AML, and provide a rational for a trial. Methods: A phase I/Ib protocol of the oral SMO inhibitor LDE225 (Sonidegib) in combination with Aza in untreated and relapsed/refractory (rel/ref) AML, chronic myelomonocytic leukemia (CMML), MDS, or MDS/myeloproliferative neoplasm overlap pts. Objectives of the phase I part are to determine safety, toxicity and MTD and for the phase Ib part to assess the preliminary overall efficacy. Sonidegib was started at dose level (DL) 0 at 400mg oral daily continuously and Aza at the approved doses (75mg/m2 x 7 days or days 5-2-2) with dose adjustment per label. A classical 3+3 design was used and DLT (CTCAE v4.0) defined as > grade 3 CPK elevation or hepatic or non-hematologic adverse events (AEs) lasting > 7 days or any grade 4 event, except for hematologic toxicities. DLT was assessed after 42 days when steady-state concentrations of Sonidegib were reached. Pharmacokinetic assessments were not performed for this study. Results: Patients and Dose Levels : Between 5/22/2014 and the data cut-off date (7/20/2015), 36 pts were enrolled. Median age was 72 y (range 52-85 y) and 64% were male. Most AML pts (23 of 24) had intermediate or unfavorable cytogenetics and most MDS/CMML pts were in the int.- to high-/very high-risk group (IPSS-R). Six pts were treated at DL-0 of Sonidegib 400mg/day and one DLT of CPK elevation was observed. Another patient had grade 4 neutropenia (which at the time was included in the DLT definition, later removed). Due to overall tolerance of the combination at DL 0 and investigator assessment, despite only 1/6 pts having a formal DLT, DL -1 at Sonidegib 200mg was explored at which 0/3 pts (1 pt non-evaluable) had DLT and the phase Ib portion was opened at DL -1. To date a total of 24 AML (13 newly dx, 11 rel/ref), 11 MDS/CMML (5 newly dx, 6 rel/ref ) and 1 myelofibrosis pt have been enrolled. Safety and Tolerability: An initial safety and efficacy assessment for 25 of the 29 pts treated on the phase Ib (n=26) + the MTD cohort of 200 mg (n=3) and for who at least 2 cycles of treatment follow up was available, showed that all pts experienced at least one grade-3 or 4 hematologic AE with a lower rate in the untreated vs. treated cohort. Other, non-hematologic grade-3 and 4 AEs respectively were seen in 24 and 28% of patients-most commonly hyponatremia and fatigue, known AEs for this drug class. Treatment delays occurred in 28% of pts and Aza or Sonidegib dose reductions in 16%. 23 (79%) pts are alive and 6 have died (21%), with one death while pt was actively treated but was deemed unrelated; 11 pts remain on study, with the remainder showing disease progression (n=3) or taken-off study for other reasons (n=3 each for AEs and did not want further treatment; n=4 other). Efficacy : As of 7/20/15 with a median treatment duration of 2 cycles, 2/5 untreated MDS/CMML pts achieved CR/CRi; 1 HMA rel/ref AML had CR; 1 untreated AML pt each had PR and MLFS. 90% of pts have not progressed. Updated results will be presented at the ASH 2015 meeting; by then all 29 pts will have completed a minimum of 4-6 cycles on study and full efficacy and AE result on all pts will be reported. To date the OS at 6 mo is 77% (95% CI: 44-97%) with a median PFS of 4 mo (range: 2-NR). Many pts in the untreated cohorts have just enrolled. Conclusion: Hh pathway inhibition with the clinically well tolerated SMO inhibitor Sonidegib in combination with Aza in MDS and AML pts is well tolerated with mostly hematologic AEs as expected with early signs of clinical activity in untreated and HMA-failure pts. Full efficacy results of 29 pts and updated safety data will be reported for this first combination trial of a SMO inhibitor in combination with a HMA in MDS and AML pts. Disclosures Mesa: Gilead: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding. Al-Kali:Novartis: Research Funding.

Abstract Introduction: Hypocellular myelodysplastic syndrome (h-MDS) represents only a small portion of MDS, of which, the clinical significance and outcomes are not well understood. Both laboratory and clinical evidence suggests that h-MDS shares immune-mediated pathogenic mechanisms similar to acquired aplastic anemia. As a result, immunosuppressive therapy (IST) has been the mainstay treatment. Since h-MDS is poorly understood and reported response rates to IST vary, we retrospectively reviewed the outcome of our patients with hypocellular MDS and identified the effectiveness of alternative therapy using hypomethylating agents (HMA). Methods: AllMDS patients over a 13-year period (June 1997 to May 2010) were captured after an IRB approval was obtained. Patients' demographics, labs, bone marrow aspirates and biopsies as well as cytogenetic data were collected. We used the currently accepted age-adjusted criteria to define hypocellularity as ≤ 30% in patients <70 years old, and ≤20% in >70 years old. Only patients with available response data were included in the final analysis. Survival estimates were calculated using Kaplan-Meier curves. Results: We identified 65 (8%) h-MDS patients from a cohort of 827 adult MDS. Median age was 68 years (range, 20-90), with 69% males. The largest group of patients were RAEB-1 at 9 (14%) and RAEB-2 at 14 (22%) along with RCMD at 18 (28%) and 15 (23%) MDS-U, 2 (3%) MDS 5q, 4 (6%) RARS and 2 (3%) were considered atypical. Cytogenetic analysis was normal in 17 (26%) with 7 (11%) having trisomy 8, and 11 (16%) and 14 (22%) having abnormalities of chromosome 7 and 5, respectively. IPSS-R were very low, low, intermediate, high, and very high in 4%, 30%, 28%, 21% and 17%, respectively. Leukemic transformation (LT) occurred in 6 (9%). The 4 year overall survival and progression free survival was 35% and 34%, respectively. Median overall survival and progression free survival was 30.2 and 29.7 months, respectively. Nine out 65 h-MDS patients were treated with a HMA, azacitidine (4) or decitabine (5). The median age of patients was 71 years (range, 66-85) with 6 (66%) being males. The median cellularity of the diagnostic bone marrow was 15% with the majority of patients presenting with RAEB-1 (11%) and RAEB-2 (55%) classification and 2 (22%) cases of RCMD as well as 1 (11%) case of MDS with isolated 5q. Cytogenetic analysis was normal in 3 (33%). IPSS-R were low in 1 (11%), intermediate in 4 (44%), high in 1 (11%) and very high risk in 3 (33%). The median time to initiation of a HMA from diagnosis was 5 months with response assessed at a median of 4.2 months. Two patients had received prior therapy including lenalidomide (for MDS 5q) and one had 1 cycle of trial therapy. Two patients (22%) achieved a marrow complete remission at a median time of 2.95 months; with one case of relapse at 9.8 months using HMA. Three patients (33%) had LT at a median time of 7.9 months post initiation of HMA. Median overall survival of patients with LT was 20 days. A total of 4 (44%) patients remain alive with a leukemia free survival of 67% at 2 years. In comparing to h-MDS patients without HMA treatment versus HMA treated, median OS was 28.2 vs 50.9 months (p=0.41) and PFS was 28.1 vs 40.6 months (p=0.69), respectively. Conclusions: The results from our clinical experience confirm that hypocellular MDS is a rare variant and that it is distinct from normocellular/hypercellular MDS. Two thirds of h-MDS received HMA for the treatment of higher risk disease (RAEB1-2). HMA has some efficacy in h-MDS. Further studies are warranted to better understand the clinical significance and outcomes of hypocellular MDS. Disclosures Binder: American Society of Hematology: Research Funding. Al-Kali:Celgene: Research Funding.

Abstract Introduction Steroid refractory chronic graft-versus-host-disease (SR-cGVHD) is the leading cause of late morbidity and mortality in allogeneic transplant patients. Safety of extracorporeal photophoresis (ECP) has led to multiple studies evaluating its role in SR-cGVHD. Overall and organ specific response rates (RR) of SR-cGVHD have varied significantly between studies. We conducted a systemic review and meta-analysis to assess the efficacy of ECP in SR-cGVHD. Methods A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central register of Controlled Trials,, Scopus) for articles published in any language between 1984-2012 was conducted. Unpublished studies using electronic databases from the annual meetings abstracts of hematology/transplant societies were searched. Experts in the field were also contacted for selection of studies and missing data from selected trials. End points included complete response rate (CR), overall RR (ORR), and organ-specific RR's. Results Initial search generated 312 studies, out of which 18 studies (4 prospective) met selection criteria (N=595). Random effects model was used for pooled rates. Pooled CR rate (11 studies) was 29% (CI 19%-42%). Pooled ORR (16 studies) was 64% (CI 65-82%). 1 year overall survival was 49% (CI 29-70%). There was significant heterogeneity between studies (I²=72) likely due to differences in ECP schedules utilized, and a variety of scales used to measure outcomes. Pooled RR's for SR-cGVHD of skin was 74% (CI 60-85%), liver was 68% (CI 57-77%), ocular was 60% (CI 40-78%), oral was 72% (CI 51-86%), lung was 48% (CI 33-63%), gastrointestinal (GI) was 53% (CI 21-83%), and musculoskeletal (MSK) was 64% (CI 18-94%). No significant differences in responses to ECP for pediatric and adult populations were found. Sensitivity analysis could not be done due to limited number of prospective studies. Conclusions ECP is an effective therapy for oral, skin & liver SR-cGVHD, with modest activity in lung and GI SR-cGVHD. Further studies must report standardized outcomes with a uniform schedule of ECP. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Patient (Pt) outcomes have improved significantly in multiple myeloma (MM) due to widespread use of novel therapeutic agents and stem cell transplant (SCT) butoutcome disparities among racial/ethnic groups exist. Differences in access to and utilization of novel therapeutics are likely contributing factors. We performed an analysis of the SEER-Medicare database to explore such differences. Methods: Pts with a confirmed MM diagnosis between 2007-2009 and continuous Medicare coverage from 1 year prior to diagnosis through end of 2012 were included. Medicare Part D data (oral medications) is not available prior to 2007 so utilization analysis of lenalidomide (LEN), thalidomide (THAL) and bortezomib (BORT) was performed from 2007-2009. Demographic/survival data (PEDSAF files) and drug/SCT utilization (NCH, OUTSAF, PDESAF files) were obtained (HCPCS/NCH codes). Categorical and continuous variables were compared using /Fisher tests and Wilcoxon tests, respectively. Gender, age, and year-adjusted p-values were calculated using logistic regression. A proportional odds model was used to detect time-dependent trends in drug usage within 12 months of MM diagnosis across year of diagnosis by race. Separate multivariate models were fit for each drug adjusting for gender, age, drug use and race. Associations between drug use and overall survival (OS) were examined using a time dependent proportional hazards model. Results: A total of 5358 MM pts were included (any Medicare claims) with 2733 (51%) males. Mutually exclusive race categories were White (W; 67%), African-American (AA; 18%), Hispanic (H; 10%) and Asian (A; 5%). Median follow up was 2.4 yrs. Baseline pt characteristics were significantly different for age with AA being the youngest at diagnosis (p<0.001) and for gender (p<0.001) with W having the largest (53.4%) and AA the smallest (45.2%) proportion of males. Medicare claims capture only pts without any supplemental insurance and so drug utilization in this database was much lower than expected for all subgroups. Year-wise comparison showed that LEN use within the first year of MM diagnosis increased from 2007 to 2009 (16.5% to 27.7%; p<0.001) and there was a significant decrease in median days to first dose (p=0.002). Over the same period, use of THAL decreased (26.6% to 14.6%; p<0.001) while use of BORT (7.8% to 15.4%; p<0.001), SCT (3.3% to 6.2%; p<0.001) and more than 1 novel agent (2.5% to 5.7%; p<0.001) increased significantly. Utilization patterns within first year of MM diagnosis were significantly different among racial subgroups for LEN, THAL, BORT, SCT and >1 novel agent use. (Figure 1) No significant difference was seen for days to first dose of LEN/THAL for any race but for BORT, H got first dose in median 117 days after diagnosis as compared to median 46-51 days for other races (p=0.025). During the first year after diagnosis, W and AA had higher BORT only usage while H and A had a higher LEN/THAL only usage (p<0.001). For drug use by year and race, a significant increase in LEN use was seen from 2007 to 2009 in W (p<0.001), AA (p=0.001) and A (p<0.001) but not H (p=0.26) while THAL use decreased significantly for all races. BORT use increased significantly for all except A (p=0.602) and SCT use increased significantly for all except AA (p=0.068). Inferior OS was significantly associated with older age (p<0.001) and males (p<0.001). LEN/THAL use within the first year of diagnosis did not affect OS while BORT use within the first year of diagnosis increased mortality risk (HR 1.18, p=0.021). SCT use improved OS (HR 0.52, p<0.001). Conclusions: In this comprehensive analysis of MM therapeutics utilization, we noted significant variability among different racial groups. The use of LEN, BORT and SCT has increased while THAL has decreased over time but disparities exist in utilization among different races, with lower use of LEN in AA, lower use of BORT in A and significantly delayed use of BORT in H, which are all notable since racial/ethnic minorities are fast growing in the US population mix and seem to have inequitable utilization and/or access. Inferior survival with early BORT use may represent selection bias of pts with more advanced/aggressive disease. These trends need to be examined in larger sample sizes especially from commercial payers to eliminate drug access and utilization disparities and achieve equitable benefit of therapeutic advances across all racial subgroups. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: The incidence for acute myelogenous leukemia (AML) is on the rise in the United States (US). Roughly 20,000 new AML patients are expected to occur in 2016 in the US (data from Surveillance Epidemiology and End Results Program). It is mainly a disease of older individuals with median age of 67 years. Unfortunately, most patients are not cured. Recent data suggest that early referral for hematopoietic stem cell transplant (HSCT) leads to more favorable outcomes, particularly those with non-good risk cytogenetics compared to alternate therapies. The objective of our study was to assess the use of upfront HSCT among AML patients with a focus on patients with non-good risk cytogenetics and determine disparity in its access based on sociodemographic and regional considerations. Methods: We analyzed data obtained from National Cancer Data Base (NCDB) Participant User Files for patients diagnosed with AML between 2004 and 2013 using the International Classification of Diseases for Oncology version 3 (ICD-O-3) codes 9840-9861, 9865-9874, 9891-9931. The data is collected prospectively by joint program of Commission on Cancer (CoC) and American Cancer Society. It covers nationwide oncology outcome from more than 1,500 CoC-accredited hospitals. Over 70% of all newly diagnosed cancer cases in the US are captured by NCDB. Since unique ICD-O-3 codes exist for the good-risk but not for intermediate- or poor-risk AML, we categorized the AML subtypes as good risk or non-good risk for analytic purposes. We considered patients with t(15;17), inv(16) and t(8;21) with corresponding ICD-O codes of 9871, 9896, and 9866, as good-risk patients. All others were considered non-good risk. Proportion of HSCT usage was estimated in various subgroups with 95% confidence intervals calculated using robust estimates of standard error. Results: We identified 80,087 patients who were diagnosed with AML between 2004 and 2013. Majority of these patients were Whites (85.9%), males (53.8%) and between the ages of 40 and 79 years (71.5%). The overall use of upfront HSCT increased consistently over time. This occurred predominantly among the non-good risk AML from a rate of 6.5% in 2004 to 12.5% in 2013 (Figure). Non-good risk patients who were Black, had Medicare insurance, with lower annual household income, and treated at facilities located in the East, South and Central parts of US ( AL, KY, MS, TN) had less access to HSCT (Table). Conclusion: The use of upfront HSCT in AML has almost doubled in the past decade, predominantly among those with non-good risk cytogenetics. Nevertheless, we found substantial disparity among sociodemographic and geographic subgroups. Future studies should try to understand and address how to bridge this gap. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Acute myeloid leukemia (AML) is an aggressive form of blood cancers with a wide range of response and relapse rates using standard chemotherapy regimen (commonly known as 7+3). Several genes (FLT3, IDH1, RAS) have been targeted using small molecule tyrosine kinase inhibitors with encouraging results. The stem cell receptor tyrosine kinase KIT is expressed more than 10% in the 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 of DATA regimen. 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% or higher on myeloblasts by flow cytometry. KIT mutations were allowed if present. 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. If 11 or fewer pts achieve complete remission, the regimen will be considered ineffective. Results: Eighteen pts have been enrolled between July 2013 and July 2015, 17 of which have baseline data. Median age was 58 years (range 24-65) with 76.5% being male. Median laboratory findings include hemoglobin of 9.3 gm/dL, platelets of 52 x109, and white blood count of 7.0 (0.5-125). Cytogenetics were normal in 41% of the pts. Favorable cytogenetics were seen in 2 pts (inv 16). FLT3 testing was done on 15 pts and was positive in 27%. KIT gene sequencing (exon 8, 9, 10, 11, 17) revealed no pathogenic mutation. Median number of cycles was 3 (range 1-7). Six pts had treatment delays, with 2/13 (15%) delays being due to non-hematologic toxicities. No delays or missed doses affected cytarabine and daunorubicin administration. Out of 15 pts evaluable for response, 12 (80%) achieved CR (or CR with incomplete platelet recovery). Six of the 12 pts (50%) who achieved remission needed a second induction on protocol. Two out of 15 did not respond (did not get re-induction on protocol). One pt died before disease assessment due to liver failure (G5, had only one dose of nilotinib and toxicity was attributed to daunorubicin). Of the 14 pts having at least 1 bone marrow biopsy, the overall CR rate was 86%. Five (33%) pts proceeded to allogeneic stem cell transplant, all are alive and none were able to initiate protocol nilotinib maintenance therapy. Only 2 out of 12 (17%) pts relapsed after achieving CR, one was secondary AML from myelodysplastic syndrome with complex karyotype and the other was therapy-related AML with t(9;11). Only 2 (11%) pts died at time of report. Thirteen pts were evaluated for adverse events (AE). Six pts had G4 non-hematological AEs. Five of 12 G4 AEs were related to infection, 2 were electrolyte imbalances, and 2 were heart failures. Most common G3 non-hematological AEs were febrile neutropenia (53%), hypophosphatemia (23%), hyperglycemia (23%), and hypertension (23%). In agreement with the favorable outcomes, the molecular target validation revealed that nilotinib treatment down-regulates the expression of KIT, Sp1, DNA methyltransferase (DNMT) 1, DNMT3a and DNMT3b. Conclusion: Combination daunorubicin and cytarabine with nilotinib (DATA) appears to be safe and effective. Interim results show an acceptable safety profile in the first 12 evaluable pts with most common AE being infection as expected. Thirty day mortality is acceptable (7%). DATA regimen has encouraging CR rates of 80% (intent to treat) and 86% in assessed pts, with half of the pts who achieved remission requiring 2 cycles of induction. Relapse rate seems to be low at 17%. We will continue accrual until all pts accrued for final results. Disclosures Al-Kali: Celgene: Research Funding. Off Label Use: This is a Phase II study of combination nilotinib to standard chemotherapy in patients diagnosed with AML.. Tibes:TetraLogic Pharmaceuticals: Research Funding.

Abstract BACKGROUND: While hematologic cancers comprise only 10% of all malignancies, they are divided into >100 distinct World Health Organization subtypes. It is known that higher volume of care is generally associated with better clinical outcomes. However, such a volume-outcome relationship in the medical management of hematologic cancers has not been rigorously explored. The American Society of Clinical Oncology (ASCO) National Census of Oncology Practices shows that the majority of hematologist-oncologists in the United States (US) have a combined hematology-oncology practice (J Oncol Pract 2013). In this study, we estimated the annual number of new and established patients with major hematologic cancers seen on average by a hematologist-oncologist in the US. METHODS: We estimated the number of hematologist-oncologists working in the US using the ASCO workforce information system data from 2011. We utilized statistics from the Surveillance Epidemiology and End Results (SEER) Program to determine the incidence and 37-year limited prevalence of hematologic cancers in 2011. We used 'first malignant tumor per site' statistics as the tumor inclusion method. For potentially curable hematologic cancers (acute lymphocytic leukemia, acute myeloid leukemia, Burkitt lymphoma, diffuse large b-cell lymphoma, Hodgkin lymphoma, and marginal zone lymphoma), we used the estimated 1-5 year survival rates from SEER and excluded patients who survived >5 years, since relapses are rare afterwards. Because prevalence estimates of chronic myelomonocytic leukemia, myelodysplastic syndromes, and certain subtypes of non-Hodgkin lymphoma are unavailable, we were unable to calculate the number of annual established cases. For myeloproliferative neoplasms, we obtained the prevalence estimate from Mehta J, et al (Leuk Lymphoma 2014). We derived the distribution of major non-Hodgkin lymphoma subtypes from the National Cancer Data Base (NCDB) Participant User File. RESULTS: The ASCO workforce information reported a total of 13,084 hematologist-oncologists working in the US in 2011. The Table summarizes the average number of specific hematologic cancer cases seen per hematologist-oncologist in 2011. CONCLUSION: Hematologic cancers are relatively rare but complex. In the US, a hematologist-oncologist on average cares for only 1-2 new patients of any subtype of hematologic cancers annually. The number of established patients is correspondingly low. These numbers are expected to vary by practice setting and disease specialization. As the diagnosis and management of hematologic cancers becomes more sophisticated, future research should explore the potential of a volume to clinical outcome relationship for these providers. Table. Hematologic Cancer Average Annual Number of Cases per Hematologist-Oncologist in the US New Cases Established Cases All Cases Acute lymphocytic leukemia 0.4 1.4 1.8 Acute myeloid leukemia 1 1.5 2.5 Chronic lymphocytic leukemia 1.1 10.7 11.8 Chronic myeloid leukemia 0.4 2.7 3.1 Chronic myelomonocytic leukemia 0.1 - - Hodgkin lymphoma 0.7 2.7 3.4 Multiple myeloma 1.6 6.3 7.9 Myelodysplastic syndromes 1.2 - - Myeloproliferative neoplasms 0.6 22.2 22.8 Non-Hodgkin lymphoma 5.1 - - Anaplastic large cell 0.1 - - Burkitt 0.1 0.3 0.4 Diffuse large B-cell 2 6 8 Follicular 1.1 - - Hairy cell leukemia 0.1 - - Lymphoplasmacytic 0.1 - - Mantle-cell 0.3 - - Marginal zone 0.5 2.1 2.6 Peripheral T-cell, not otherwise specified 0.1 - - Disclosures No relevant conflicts of interest to declare.

Abstract Background:Morphologic complete remission (CR) is the gold standard for assessing response in acute myelogenous leukemia (AML). CR with incomplete count recovery (CRi) and CR with incomplete platelet recovery (CRp) are associated with inferior overall survival post induction therapy (Walter et al, JCO 2010 and Chen et al, JCO 2015). Furthermore, residual cytogenetic disease is associated with a higher relapse compared with patients with cytogenetic CR (CCR; Chen et al, JCO 2011). There is a paucity of literature regarding the impact of CRi, CRp and CCR prior to allogeneic transplantation. Aim:To study the impact of CRi, CRp and CCR and their impact on relapse incidence (RI), non-relapse mortality (NRM) and overall survival (OS) in reduced intensity allogeneic stem cell transplantation (RIC-SCT). Methods:After due IRB approval, patients (pts) with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who received RIC-SCT at our institution between 2008-2014 were identified. All clinical and pathologic data were retrospectively extracted. CR, CRi, CRp and CCR were defined in accordance to the international working group definition. Categorical and continuous variables were analyzed using Pearson's chi-squared and Wilcoxon/Kruskal-Wallis, respectively. Survival estimates were calculated using the kaplan-meier and log-rank test. RI was estimated on a competing event analysis using Grey's model. Cox proportional regression was used to compute hazard ratios (HR). Results: A. Baseline characteristics: A total of 134 patients were identified. A total of 70 (52%) were in CR, 40 (30%) in CRi and 24 (18%) in CRp. 129 patients had evaluable cytogenetic data pre-SCT; 81 (63%) were in CCR and 48 (37%) had persistent cytogenetic disease. Baseline patient, disease and transplant characteristics stratified by peripheral count recovery pre-SCT are shown (Table 1). Significantly more patients in CR had higher KPS, higher proportion AML diagnosis, more likely to be in first complete remission (CR1), higher rate of cytogenetic CR and a higher proportion of minor ABO mismatched donor. No other significant variables were identified between the three cohorts. B. Transplant outcomes: Median follow up of the entire cohort was 41.9 months and the 2-yr OS, RI and NRM were 61.7%, 25.7% and 21.9%. Patients in CR, CRi and CRp had a similar 2-year rates of RI (26.3%, 18.4% and 28.9%, respectively; p = 0.66), 2-year NRM (20.5%, 38.8% and 22.1%, respectively; p = 0.18) and 2-year OS (61.8%, 55.1% and 58.6%, respectively; p = 0.82). RI was significantly lower for patients in CCR pre-SCT with HR 0.25 (95% CI 0.11-0.51 p = 0.0001) without a difference in overall survival HR 0.68 (0.41-1.15; p = 0.14). However, we observed a similar RI in CR, CRi and CRp patients who had persistent cytogenetic disease pre-SCT (p = 0.55). The outcome remained similar between strata after excluding MDS patients (data not shown). Conclusion: We observed equivalent post-transplant outcomes between CR, CRi and CRp despite the presence of persistent cytogenetic disease. This suggests that RIC SCT had a role in mitigating the negative prognosis associated incomplete hematologic recovery. These findings have implications as physicians may not need to postpone SCT to await count recovery. This important question should be further validated in a larger cohort of patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding.