Litzow, Mark R.

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 Abstract 2850 Myelofibrosis (MF), both primary myelofibrosis (PMF) and post essential thrombocytosis/polycythemia vera myelofibrosis (post ET/PV-MF), are chronic myeloproliferative neoplasms characterized by a progressive clinical course that leads to shortened survival. The heterogeneous nature of MF lends itself to a variable clinical course that commonly includes hepatosplenomegaly, constitutional symptoms, and progressive cytopenias. Medical therapy for myelofibrosis has been effective in palliation of common symptoms related to anemia, splenomegaly but allogeneic stem cell transplantation (ASCT) remains the only potentially curative therapeutic modality. The timing of ASCT, choice of conditioning regimen, patient selection and the impact of co-morbidities are critical to optimal use of this modality. We have retrospectively analyzed our experience for patients undergoing ASCT for primary and post ET/PV myelofibrosis at Mayo Clinic across all 3 sites: Scottsdale Arizona; Rochester, Minnesota; and Jacksonville, Florida. Methods: We conducted a retrospective review of all patients from 1992 to 2012 with PMF or post ET/PV-MF who underwent an ASCT at Mayo Clinic. This retrospective review included a waiver of informed consent and was approved by the Mayo Clinic Institutional Review Board. Patients that transformed to the MPN blast phase and individuals who underwent a second transplant for either relapse or graft failure were also included. Overall survival was estimated using Kaplan-Meier. Associations between prognostic factors and overall survival were assessed using Cox regression. Results: Baseline Patient Characteristics: Forty-eight patients (29 male) with a median age of 57 yrs (range 31–73) underwent ASCT. DIPSS-plus risk score was low in 2, intermediate 1 in 2, intermediate 2 in 9 and high in 35 patients. Disease type was PMF in 24, PV-MF in 10, ET-MF in 10, and MPN/MDS overlap in 4 pts. Eight patients evolved to the MPN-blast phase prior to transplant. JAK-2 mutation was positive in 27 patients and negative in 12 patients with JAK-2 status unknown in 9 patients. The median time from PV/ET to MF was 136 months (83–189 months) and from MF diagnosis to transplant was 59 months (3–144 months). All but 2 patients were red cell transfusion dependent prior to transplant (96%). Eight patients underwent splenectomy prior to transplant. Transplantation Characteristics: Patients who underwent ASCT received either myeloablative (MA, 13 pts) or reduced-intensity conditioning (RIC, 35 pts) regimen. The graft was from an unrelated donor in 22 pts and related donor in 26 pts with 44 being matched and 4 being mismatched. The myeloablative regimens included Bu/Cy, TBI/Cy, and Bu/Flu. The RIC regimens included flu/mel, Bu/Flu, FBM, and TBI/Flu. GVHD prophylaxis was with tacrolimus/MTX, CSA/MTX, and tacrolimus/MMF. Nineteen patients received ATG. Infectious disease prophylaxis, CMV monitoring, and additional supportive care measures were according to institutional guidelines. A majority of patients received peripheral blood stem cells with only 1 patient receiving bone marrow as the source of stem cells. Outcomes: The median time to neutrophil engraftment was 17.2 days. Two patients received a second transplant for relapsed disease. The incidence of graft failure was 10%. Graft versus host disease both acute and chronic occurred in 33 patients and 15 patients respectively. Day 100 overall survival was 92% and 2 year survival was 62% (95% CI 45–75%). There were no statistically significant associations between individual prognostic factors (DIPSS-plus classification, age, and HLA match) and survival. Conclusions: The Mayo Clinic national experience of ASCT for MF across our geographically diverse Cancer Center is encouraging. Our centers have transplanted 48 patients over the past 10 years with very favorable outcomes. Our results from a multi center practice are consistent with regards to survival, graft versus host disease, and types of transplants being performed compared to currently available published data from large single location transplant centers. This data helps confirm the prevailing knowledge that ASCT is a useful treatment. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract Background Acute promyelocytic leukemia (APL) is commonly complicated by complex coagulopathy. The early use of all-trans retinoic acid (ATRA) appears to have reduced induction mortality; however, with modern regimens the risk of early hemorrhagic death remains at about 5-10% in clinical trials and up to 30% in population-based studies. Previously identified as markers of bleeding risk in this setting are: white blood cell count (WBC), peripheral blood blast count, platelet count, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT) and creatinine. Nonetheless, uncertainty remains as to which ones are independent predictors. Materials and Methods The database for study was from APL patients enrolled on three large clinical trials that used ATRA for induction: APML3 (single arm of ATRA + idarubicin ± prednisone), APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone) and ECOG 2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA). Known determinants of bleeding were assessed at baseline and considered as potential predictors of hemorrhagic death in the first 30 days of induction. In univariate analysis, using Wilcoxon Rank Sum and Fisher’s exact test, we looked at the association of the parameters mentioned above with hemorrhagic death within 30 days of induction. Results A total of 619 patients were enrolled: ECOG 2491 (intergroup I0129) - 394, APML3 - 101, and APML4 -124. Among these, thirty (4.8%) deaths from bleeding during the first 30 days (early deaths, ED) following induction were recorded. Baseline characteristics of the patients are shown in Table 1 and Table 2. Initial coagulation parameters (PT, aPTT and fibrinogen) were not available for the ECOG trial. Parameters with significant differences between the ED cases and the remaining of the cohort included WBC (median: 7.4 vs 2.4 /Kmcl respectively, p<0.001), peripheral blood blast count (median: 1.0 vs 0.2 /Kmcl respectively, p=0.049) and platelet count (median: 20 vs 33 /Kmcl respectively, p=0.002). Conclusions In this large cohort of approximately 600 APL patients enrolled on 3 large clinical trials, higher WBC, peripheral blast count and lower platelet count emerged as univariate predictors of early hemorrhagic death. Surprisingly, age, PT, aPTT, fibrinogen and creatinine clearance did not differ between the patients who died from bleeding and the remaining of the cohort. Multivariate analysis will clarify the relative strength of the significant predictors in assessing ED, and will be available, along with coagulation parameters for ECOG, at the time of presentation. These data hopefully will allow us to build a clinical prediction rule to identify patients at the highest risk of early hemorrhagic death. Such a stratification tool could prove useful in future trials testing novel approaches to treat the coagulopathy associated with APL. : Abstract 948. Table 1 Baseline Characteristics of Patients, Continuous Variables Variable Total Death from Bleeding within 30 days No Yes N Median (IQR) N Median (IQR) N Median (IQR) p-value Age (years) 619 40.0 (26.0 - 54.0) 589 40.0 (26.0 - 54.0) 30 47.0 (26.0 - 63.0) 0.15 White Blood Cell Count (K/mcL) 611 2.5 (1.2 - 8.2) 582 2.4 (1.1 - 7.6) 29 7.4 (3.1 - 20.7) <0.001 Peripheral blood blast count (K/mcL) 581 0.2 (0.0 - 2.2) 552 0.2 (0.0 - 1.9) 29 1.0 (0.1 - 5.7) 0.049 Hemoglobin (g/dL) 615 9.3 (8.0 - 10.5) 585 9.3 (7.9 - 10.5) 30 9.4 (8.2 - 10.7) 0.75 Platelets (K/mcL) 615 31.0 (17.0 - 56.0) 585 33.0 (17.0 - 57.0) 30 20.0 (13.0 - 34.0) 0.002 Prothrombin time (s) 184 16.0 (13.3 - 18.2) 179 16.0 (13.3 - 18.1) 5 16.7 (16.5 - 144.3) 0.15 Activated partial thromboplastin time (s) 225 29.0 (26.0 - 32.0) 216 29.0 (26.0 - 32.0) 9 31.2 (29.0 - 38.0) 0.07 Fibrinogen (mg/dL) 217 1.8 (1.3 - 2.6) 208 1.8 (1.3 - 2.6) 9 2.3 (2.0 - 2.5) 0.36 Creatinine Clearance (mg/dL)* 225 389 (261.2 - 511.6) 216 392 (264.9 - 512.4) 9 262 (219.2 - 432.0) 0.15 *calculated using the Jelliffe formula : Table 2 Baseline Characteristics of Patients, Categorical Variables. Variable Total Death from Bleeding within 30 days No Yes N % N % N % p-value ECOG Performance Status 579 93.54 552 93.72 27 90.00 0.50 Good(0-2) Poor(3-4) 36 5.82 33 5.60 3 10.00 Missing 4 0.65 4 0.68 0 0 FAB Classification 248 40.06 239 40.58 9 30.00 >0.95 M3 M3v 67 10.82 65 11.04 2 6.67 Missing 304 49.11 285 48.39 19 63.33 Disclosures No relevant conflicts of interest to declare.

Abstract Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown. Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%. Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA). Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. Table Table. Figure Figure. Disclosures Sekeres: Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

Background: Hematopoietic stem cell transplantation (HCT) remains the most effective postremission therapy for high-risk acute myeloid leukemia (AML). FMS-like tyrosine kinase3 (FLT3) mutations occur in about 30% of patients with cytogenetically normal AML. FLT3-ITD (internal tandem duplications) mutations are associated with short-lived remissions and poor outcomes. These adverse effects can be offset by allogeneic HCT in first complete remission (CR1). We carried out this study to get a real world perspective on feasibility of allogeneic HCT in CR1 for FLT3-ITD mutant AML patients. Methods: The Mayo Clinic AML database was queried for all patients that had tested positive for the FLT3 ITD, from January 2003 to December 2014. 75 patients were identified, of which 28 (37%) underwent allogeneic HCT in CR1. 12 were excluded as they were transplant ineligible from an age standpoint, 6 patients actually had MDS and 2 were excluded for primary induction failure. Clinical and outcomes data were abstracted retrospectively. Results: 29 patients were included in the final analysis, with a median age of 57 years (range 21-68), 38% males. Median time from diagnosis to last follow up was 339 days. 24(83%) had normal cytogenetics. 26(90%) received treatment with anthracycline + cytarabine based therapy, 3(10%) were enrolled on a clinical trial. 25(87%) patients went on to receive consolidation therapy. 22 (75%) of the patients relapsed after achieving a CR1, with a median time to relapse of 134 days (range 27-1710 days). Only 8 (26%) of the 22 patients were able to achieve a CR2 with salvage chemotherapy, of which 6 (75 %) successfully underwent allogeneic HCT.2 (25%) out of 8 patients received FLT3 inhibitor in 1st relapse. We then assessed the reasons why relapsed patients did not undergo HCT in CR1. The most common being; relapse during evaluation/work up for HCT in 8(27%) patients, 5 (17%) had comorbidities that precluded HCT, 3 (10%) were never referred for HCT due to personal preferences. At last follow up 19(65%) patients were dead. Conclusion: While allogeneic HCT is an effective consolidative strategy for FLT3 ITD mutant AML patients, in the real world, a large number are not transplanted in CR1 due to delays in donor search and transplant scheduling strategies resulting in disease relapse. Effective strategies to avoid delays in scheduling, rapid donor searches and the use of alternative donor sources are much needed for these patients. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Acute graft versus host disease (aGVHD) is the leading cause of morbidity and mortality following allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first line treatment although <50% of patients with severe aGVHD (grades III-IV) achieve durable remissions. Monoclonal antibodies (mAb) are often used as second line agents for steroid refractory aGVHD (SR-aGVHD) (Patriarca et. al.; 2004). However, data regarding their tolerability and efficacy is retrospective and limited. We carried out this study to assess the clinical outcomes related to mAb therapy (Infliximab and Tocilizumab) for SR-aGVHD. Methods: Patients with SR-aGVHD that received therapy with either Infliximab or Tocilizumab between January 2003 and May 2016 were retrospectively identified. Clinical grading of aGVHD was per the Glucksberg criteria (Glucksberg et. al.; 1974). SR-aGVHD was defined as any grade progression within 3 days or failure to achieve at least one grade improvement within 7 days of initiation of systemic steroids. Infliximab and Tocilizumab were administered intravenously at 10mg/kg and 8mg/kg weekly for a total of 4 doses, respectively. Clinical response was evaluated at 4 weeks and 12 weeks post mAb treatment. Complete response (CR) was defined as sustained resolution of all clinical signs of aGVHD; partial response (PR) was defined as overall improvement of 1 or more grades; no response (NR) was defined as neither improvement nor worsening of the overall aGVHD grade. Overall response (OR) was defined as either CR or PR. Overall survival (OS) was calculated from the first day of mAb treatment until death or last available follow up. Results: Forty-three patients (median age 54, range 29-74 years; male 67%) with severe SR- aGVHD were included in the study. Of these, 35 (81%) received Infliximab for a median of 4 (range 1-6) cycles and 8 (19%) received Tocilizumab for a median of 3 (range 1-4) cycles. Both groups were comparable with regards to age, gender, conditioning regimen, graft source, degree of HLA match, ABO blood group, CMV incompatibility, and GVHD prophylaxis regimens. Only differences seen were a higher proportion of unrelated donor (p = 0.004) and cord blood HCT (p = 0.031) in the Tocilizumab group. Twenty (57%) of 35 patients treated with Infliximab and 6 (75%) of 8 patients treated with Tocilizumab had an overall aGVHD grade of IV prior to initiation of mAb therapy (p = 0.44). Organ specific distribution and severity of aGVHD are described in table 1. At 4 weeks post mAb therapy, 17 (40%) patients had an OR, 7 (16%) had no response, and 19 (44%) had died. Twenty-six (60%) patients died at 12 weeks, with OR and no response observed in 9 (21%) and 8 (19%) patients, respectively (table 2). Overall response for Tocilizumab versus Infliximab was comparable at 4 weeks (38% vs. 40%; p = 1.0) and at 12 weeks (38% vs. 17%; p = 0.33). Outcomes per aGVHD grade and gastrointestinal-specific stage at 4 weeks and 12 weeks are shown in figures 1-A and 1-B, with organ specific responses shown in figures 1-C and 1-D, respectively. The estimated median OS was 41 (range 4-3837) days for patients treated with Infliximab and 60 (range 10-756) days for those treated with Tocilizumab (p = 0.48). Disease relapse occurred in 5 (11%) patients treated with Infliximab and in none (0%) treated with Tocilizumab (p = 0.56). Thirty-four (79%) patients had infectious complications during and up to one month after mAb therapy. These included 31 (72%) patients with bacterial blood stream infection and 10 (23%) with invasive fungal infections. Overall, infectious complications were comparable (Infliximab - 83% vs. Tocilizumab - 63%; p = 0.33). CMV reactivation occurred in 11 (31%) and in 2 (25%) patients who were treated with Infliximab and Tocilizumab, respectively (p = 1.0). Given the retrospective nature of the study and the concomitant presence of aGVHD, it was difficult to attribute and grade gastrointestinal and hepatobiliary side effects. Conclusions: The use of anti-inflammatory monoclonal antibody therapy in patients with steroid refractory acute GVHD is associated with significant infectious complications (~80%) and poor response rates (~20% at 12 weeks). Current data, limited by a small sample size, does not show any advantages of using Tocilizumab over Infliximab or vice versa. Prospective clinical trials addressing this question are needed. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: APL, while highly curable in the modern era, remains a therapeutic challenge in the high-risk subset, with high rates of early mortality and relapse compared to non-high-risk APL. Recent evidence has confirmed excellent outcomes in non- high-risk APL with the combination of ATO and ATRA, and a previous pilot study had indicated the efficacy of a combination of ATO + ATRA + GO in high-risk APL. The North American Leukemia Intergroup designed a larger phase 2 study to confirm the efficacy and safety of this combination in high-risk APL. Primary Objectives: 1) assessment of 3-year event-free survival (EFS); 2) assessment of early (6 week) death rate. Methods: Adult patients with newly diagnosed high-risk APL (WBC ≥10k/uL) were eligible. Induction therapy consisted of: ATRA (45 mg/m2/day), beginning on day 1; ATO 0.15 mg/kg/day, beginning on day 10; GO 9 mg/m2on day 1. ATRA and ATO were continued until remission achieved. Patients in remission went on to receive consolidation with ATO x 2 cycles, followed by ATRA + daunorubicin x 2 cycles, followed by GO x 2 cycles. Subsequent maintenance therapy consisted of ATRA + 6-mercaptupurine + methotrexate for up to 1 year. Results: Between 2008 and 2013, 73 registered patients began protocol treatment. Median age was 46.5 years, with 52% females and 48% males. Sixty-two (85%) patients completed induction therapy as planned, and 50 patients (68%) completed all planned consolidation. Sixty-two patients (85%) achieved a documented complete response (CR). Non-responses were attributable to lack of response assessment (n=10), most commonly related to death. One patient had resistant disease. With a median follow-up of 3.3 years, the Kaplan Meier 3-year EFS estimate was 79% (95% CI 68% - 87%), which was significantly improved compared to the protocol-defined historical rate of 50% (p<0.001). The 3-year overall survival estimate was 88% (95% CI 78% to 93%). The 3-year relapse-free survival estimate was 93% (95% CI 82% to 97%). At data cut-off, there was 1 documented death during remission and no reported cases of relapse. Eight of 73 patients (11%) died within 6 weeks of treatment initiation (95% confidence interval 5-20%), at a median time of 11 days (range 3-31), which was significantly lower than the protocol defined null rate of 30% (p<0.001). The most common treatment-emergent grade 3-4 adverse events during induction included: febrile neutropenia (34%), AST/ALT elevation (12%), hypoxia/differentiation syndrome (11%), hyperglycemia (11%), headache (11%), prolonged QTc (11%). Summary: the combination of ATO + ATRA + GO was safe and effective in patients with high-risk APL, producing highly durable responses, low rates of early mortality, and comparing favorably with chemotherapy-based induction regimens in this setting. Although GO is not currently commercially available in the US, this regimen should be considered as a therapeutic option for patients with high-risk APL in the future. Support: NIH/NCI grants CA180888, CA180819, CA180820, CA180821, and in part by Wyeth Pharmaceuticals (Pfizer, Inc.) Figure Figure. Disclosures Komrokji: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy. Coutre:Gilead Sciences: Consultancy, Research Funding. DeAngelo:Amgen: Consultancy; Ariad: Consultancy; Baxter: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Celgene: Consultancy. Othus:Glycomimetics: Consultancy; Celgene: Consultancy.

Abstract Abstract 1476 Background: Monosomal Karyotype (MK) is defined as the presence of two or more autosomal monosomies or one autosomal monosomy and one structural abnormality. MK has been found to be an independent poor prognostic factor in myeloid diseases (Patnaik et al, Leukemia 2011, Haferlach et al, Blood 2012) even in the setting of allogeneic stem cell transplantation (Fang et al, Blood 2011). The prognostic relevance of MK in Acute Lymphoblastic Leukemia (ALL) is unknown. Absolute lymphocyte count (ALC) at diagnosis, on the other hand, has been shown to be prognostic in a variety of lymphoproliferative disorders (Porrata et al, Leukemia 2010). However, the prognosis of ALC at diagnosis in ALL is undetermined Methods: This is a retrospective analysis of the Mayo Clinic leukemia database (1998–2010). The study was approved by the Institutional Review Board. Outcomes analyzed included overall survival (OS), leukemia free survival (LFS) and relapse rate. Clinical characteristics, cytogenetics, therapy and outcomes of patients with Philadelphia negative ALL (Ph-negative ALL) were analyzed. Cytogenetics were classified as follows: standard risk [hyperdiploidy], intermediate risk [Normal, del(11q)-not MLL, del(6q), del(17p), del(9p), del(12p), del(13q), t(14q32), t(10;14), low hyperdiploidy, others], high risk [-7, del(7p), +8, MLL translocations, t(1;19), t(17;19), t(5;14)], and very high [t(4;11), t(8;14), complex (≥5 abnormalities), hypodiploidy, triploidy] (Pullarkat et, Blood 2008). Multivariate analysis was performed using Cox Regression Model. Results: Between 1998 and 2010, a total of 175 consecutive patients with ALL were identified. Of these, 112 (64%) had Ph-negative ALL. The median age was 39.5 (16–88) years and 74 were male (66%). The majority of cases were B-ALL (78 patients, 69%). At presentation, the median hemoglobin was 10 (4.1–18.5) g/dL, platelet count was 61 (3–523) ×10(9)/L, WBC was 7.2 (0.8–377) ×10(9)/L and ALC was 1.9 (0–69.0) ×10(9)/L. The ALC was > 1000 in 75 (71%) patients. Cytogenetics risk categories were as follows: standard risk in 5 (4.4%), intermediate risk in 70 (62.5%), high risk in 8 (7.1%) and very high risk in 29 (25.9%) patients. Twenty-two patients (20.9%) presented with extranodal disease (CNS disease in 13 patients, 11.6%). Six patients (5.4%) had prior exposure to chemotherapy. Treatment involved allogeneic stem cell transplantation (SCT) in 34 (30.4%) patients. The median OS for the whole cohort was 24 (0–206) months and LFS was 18 (0–193) months. Forty four patients (39.3%) relapsed after achieving initial remission with a median time to relapse of 15 (2–73) months In a univariate analysis, low platelet count at diagnosis, poor ECOG performance status (PS), and high or very high risk cytogenetics risk categories were associated with inferior OS. ALC at diagnosis did not impact OS or LFS. On a multivariate analysis, high/very high risk cytogenetics, low platelet counts and poor ECOG PS were independent predictors of inferior outcomes. Nineteen patients (16.9%) had a MK. Of these, 16 (84.2%) fell in the very high risk cytogenetics category regardless of MK status. Three patients (1.6%) presented with extramedullary disease and six (3.2%) underwent SCT. The median OS of these 19 patients was 15 (1–73) months. While MK was associated with inferior LFS and a trend towards worse OS, this was not significant on a multivariate model that included cytogenetic risk categories, thrombocytopenia and the ECOG PS. Conclusions: Our study demonstrates that cytogenetics risk stratification, thrombocytopenia and ECOG performance status are independent prognostic factors in ALL. MK and ALC at diagnosis had no prognostic significance. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Retrospective analyses have demonstrated significantly improved survival for AYA ALL patients (pts) aged 16-21 years (yrs) when treated on pediatric versus adult U.S. NCI Cooperative group regimens where 2-yr event-free survivals (EFS) have been only 35-40%. The purpose of C10403, a large prospective US intergroup trial, was to evaluate the feasibility and effectiveness [with EFS as a primary endpoint), of treating AYA ALL pts (ages 16-39 yrs) using the standard arm of the successful Children's Oncology Group regimen (COG AALL0232) . Methods: Newly diagnosed AYA patients with B-precursor (B-ALL) or T-precursor (T-ALL) ALL were eligible to enroll on C10403. Burkitt type and Ph+ ALL were excluded. The regimen was identical to the Capizzi methotrexate arm of COG AALL0232 (Larsen E. JCO 2011; 29 suppl:3) and consisted of four intensive courses: remission induction, remission consolidation, interim maintenance, delayed intensification, and prolonged maintenance therapy. Pts with M2 marrow response (>5% but < 25% lymphoblasts) after remission induction received an extended remission induction course of therapy. Events were defined as induction failure (M3 [³25% blasts] day 29 of induction or M2 day 43 of extended induction), death, relapse, or second malignancy. Key correlative science studies in a subset of the total accrued population included assessment of Minimal Residual Disease (MRD) using quantitative real-time PCR of clonal IgH or TCR gene rearrangements as well as Low Density Microarray (LDA) assays designed to detect a previously validated gene expression profile (Harvey, R; ASH 2013, abstract 826) which can prospectively identify ALL pts with Ph-like (BCR-ABL1-like) ALL. Results: 318 pts were enrolled on C10403 from 11/2007 to 8/2012; 22 withdrew prior to therapy. Of 296 evaluable pts, the median age at diagnosis was 24 yrs (range: 17 to 39): 25% were 17-20 yrs, 53% were 21-29 yrs, and 22% were 30-39 yrs. The majority had B-ALL (76%) and were male ( 61%). Approximately 25% were non-Caucasian and 15% were Hispanic or Latino. 32% of pts were obese (BMI³30). There were 5 (2%) treatment-related deaths during protocol therapy: liver failure (n=2, both during induction), infection (1 in induction, 1 in consolidation), and ventricular arrhythmia (1 in induction). Overall, treatment toxicities were similar to those reported in the standard arm of COG AALL0232, with an increased thrombosis and early hyperbilirubinemia for C10403 pts, as reported previously (Advani A, ASH 2013, abstract 303). To date, 70 deaths have been reported and 87 pts remain on protocol therapy. With a median follow-up of 28 months for surviving pts, 105 events have been observed. The median EFS overall is 59.4 months (95% CI: 38.4 to NR) and the 2-yr EFS rate overall is 66% (95% CI: 60 – 72%) [Fig 1a] with similar 2-yr EFS rates for B and T- ALL pts (65%, and 68%). The 2-yr OS rate is 78% (95% CI: 72 – 83%)[Fig 1b], which is similar for B (78%, 95% CI: 72 – 84%) and T-ALL, (80%, 95% CI: 70 – 91%). These results allow rejection of the null hypothesis of this Phase II trial that the true median EFS is, at most, 32 months. In multivariable analysis of presenting clinical features, age > 20 years and initial WBC count ³ 30k/microliter were significantly associated with worse EFS and OS. Presence of MRD at day 28 following initiation of induction therapy and presence of a Ph-like gene expression signature were significantly associated with both worse EFS and OS. Notably, absence of detectable MRD noted in 22/58 [38%] evaluable pts at day 28 of induction was associated with 100% EFS (p=0.0006). The Ph-like like signature was detected in 28% of pts tested on C10403 and the 2 yr EFS for these patients was only 52%, compared to 81% for those without Ph-like disease (p = 0.04). Conclusions: This large prospective US adult intergroup trial (C10403) for pts 16-39 years old employing an intensive pediatric regimen demonstrates a significant improvement (compared to historical controls) in AYA EFS and OS and validates this approach for treatment of AYA with ALL by adult hematologists. The improved clinical outcomes and the predictive value of the correlative studies in this trial lay the foundation for the design of future trials, where incorporation of novel agents to eradicate MRD, and/or use of tyrosine kinase inhibitors to target the frequently detected Ph-like ALL in AYA pts may further improve survival for young adults with ALL. Figure 1a Figure 1a. Figure 1b Figure 1b. Disclosures Stock: Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Sigma Tau: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Liedtke:Onyx: Membership on an entity's Board of Directors or advisory committees. Larson:Novartis: Consultancy, Research Funding.

Abstract Background: 'Myelodysplastic syndrome (MDS) with isolated del(5q),' as defined by the World Health Organization (WHO) criteria (SwederlowSH, et al, 2008) is a unique pathological entity with favorable outcomes. The 2016 revision to the classification expands this entity to include cases that have an additional cytogenetic abnormality, with the exception of monosomy 7 or del(7q) (Arber DA, et al, Blood 2016). The objective of our study was to evaluate the prognostic impact of an additional cytogenetic abnormality, other than monosomy 7 or del(7q), in patients with 'MDS with isolated del(5q)'. Methods: After due IRB approval, the Mayo Clinic MDS database (n=1067) was utilized for this study. All patients had bone marrow (BM) biopsies and cytogenetic studies performed at diagnosis. The International Society for Cytogenetic Nomenclature guidelines were used for cytogenetic nomenclature, while the 2008 and 2016 WHO criteria were used for morphological diagnosis. Results: Patient Characteristics: 72 patients (7.2%) met the 2016 WHO criteria for 'MDS with isolated del(5q)' of which 60% were female and median age was 74 years (28-90). In 61 (85%) cases del(5q) was the only cytogenetic abnormality, while in 11 (15%), del(5q) was present with an 'additional cytogenetic abnormality' (ACA). One additional case within the database had del(5q) accompanied with monosomy 7, which was not included in the analysis. Risk stratification by IPSS-R was as follows; 24 (29%) 'very low', 44 (64%) 'low' and 4 (6%) 'Intermediate' risk, with no patient classified as 'high' or 'very high' risk. At a median follow up of 43 months, 55 (76%) deaths and 5 (7%) leukemic transformations were documented. del(5q) versus del(5q) with an additional cytogenetic abnormality- phenotypic correlates: In the 'del(5q) with ACA' group, the additional abnormalities included trisomy 8 (n=4), del(20q) (n=3), der(9;18) (n=1), inv(3)(p25,q21)(n=1), -Y (n=1), and i(Xp) (n=1) (Table 1). There was no significant difference between the 'del(5q)' and 'del(5q) with ACA' groups in terms of age, gender, hemoglobin, platelet count, white cell count, absolute neutrophil count, bone marrow blast percentage or transfusion requirement. A greater proportion of the 'del(5q) with ACA' group (27%) had IPSS-R risk in the 'intermediate' category compared to the 'del(5q)' group (2%) (p=0.01). 18 of 42 cases diagnosed after 2004 (43%) were treated with lenalidomide, with no difference in the proportions treated between the two groups (p=1.00). del(5q) versus del(5q) with an additional cytogenetic abnormality- impact on overall survival (OS) and leukemia-free survival (LFS): The median survival of the cohort was 54 months. Survival was not significantly different between the 'del(5q)' group (median 55 months) and the 'del(5q) with ACA' group (median 38 months) (p=.75, Figure 1). This finding was consistent when analysis was restricted to patients in both groups treated with lenalidomide (p=0.29). The incidence of leukemic transformation in the del(5q) group was 5%, compared with 18% for the 'del(5q) with ACA' group (p=0.16), however there was no significant difference in LFS between the two groups (p=0.57). Conclusion : In our cohort of primary MDS patients meeting the 2016 WHO definition of 'MDS with isolated del(5q)', we confirm no significant survival difference between cases with del(5q) as the sole cytogenetic abnormality versus cases where del(5q) was accompanied by an additional cytogenetic abnormality. Table 1 Additional Cytogenetic Abnormalities with del(5q): Table 1. Additional Cytogenetic Abnormalities with del(5q): Figure 1 del(5q) vs del(5q) with an additional abnormality (ACA): Overall Survival Figure 1. del(5q) vs del(5q) with an additional abnormality (ACA): Overall Survival Disclosures Al-Kali: Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding.