Alkhateeb, Hassan B.

Abstract Background Cytogenetic abnormalities have significant prognostic role in AML at the time of diagnosis. Several prognostic groupings have been recommended including the NCCN and European LeukemiaNet classification. It is still unknown whether cytogenetic abnormalities have any prognostic role at the time of relapse for predicting clinical outcome. In addition, clonal evolution (CE) has been seen in many AML cases, but its prognostic value remains to be identified. Aim To study cytogenetic abnormalities and clonal evolution impact on clinical outcome for patients diagnosed with rAML Method A retrospective, single institution study through chart review of all cases diagnosed with rAML at Mayo Clinic Rochester between 2003 to 2011 was performed. Pts who achieved complete remission and relapsed at our institution were included. Pts with PML-RARA and BCR-ABL rearrangements were excluded from this study. Pts with available cytogenetics data, both at presentation and relapse, were included. Response to treatment was defined as per international working group (IWG) criteria (Cheson JCO 2003). Appropriate IRB approval was obtained in accordance with Helsinki declaration. Comparison between groups’ medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier curves using JMP V9. Results Out of 192 pts, 74 pts matched our inclusion criteria. The median age at diagnosis is 60 years (range 18-81), 53% were males. At relapse, median white blood cell (WBC) was 3.2 x109, hemoglobin 10.4 g/dL, platelet 59 x109, peripheral blood (PB) blast 2% (range, 0-96), bone marrow (BM) blasts 23% (range, 1-95) and cellularity 60%. Relapse site was mainly in the BM (95%). Flt3 mutation was found in 12/43 (28%), while NPM1 mutation in 2/7 (29%). Upon treatment with salvage therapy, 27 (36%) pts achieved complete remission (CR) and 16 (22%) pts partial remission (PR) for a total overall response (OR) of 58%. Twenty one (28%) pts were able to proceed to allogeneic stem cell transplant (SCT) after achieving remission. Median overall survival (mOS) was 198 days. Pts had a longer mOS if they proceeded to SCT (386 days vs 121 days, p =0.0003). Cytogenetic analysis (CG) were diploid in 32 (43%) of 74 pts at relapse. Five pts had favorable cytogenetics (3 pts with t(8,21) and 2 pts with inv (16)). CG was divided into favorable, intermediate and poor prognosis as per NCCN classification in 5 (7%), 45 (61%), 24 (32%), respectively. As per European LeukemiaNet, there were 4 CG groups divided into: favorable, Intermediate-1, intermediate-2, and adverse in 5 (7%), 33 (45%), 12 (16%), 24 (32%), respectively. Upon comparison of CG at diagnosis and relapse; clonal evolution (a change in CG due to gain or loss of chromosomal abnormalities) was found in 42/74 (57%) of pts. CG reverted back to diploid in 8/42 (19%) or gained additional CG abnormalities at relapse in 32 (76%) pts. CR2 was achieved in 80% of favorable CG (NCCN grouping), 40% (intermediate), and 21% in poor risk (p=0.01). Using NCCN CG grouping mOS was: 435 days (favorable), 266 (intermediate), and 104 (poor) (p value = 0.01). However, using European LeukemiaNet grouping mOS was: 435 days (favorable), 174 (intermeidtae-1), 363 (intermediate-2), and 104 (poor) (p=0.004). CE did not affect mOS (p =0.7). On multivariate analysis, response to salvage therapy (p<0.0001), NCCN CG grouping (p =0.03), wbc (p=0.045), and PB blasts (p=0.01) were significant but not age, BM blast, platelet and CE. Conclusion CG were diploid in 43% of relapsed pts. CE (gain or loss of cytogenetic abnormalities) was seen in 57% of CG at relapse compared to diagnosis but did not affect mOS. NCCN (and not European LeukemiaNet) cytogenetic grouping did affect clinical outcome through both achieving second CR and mOS (both on univariate and multivariate analysis). Our results confirm the prognostic value of CG on relapse, and need to be confirmed by larger studies. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Myelodysplastic syndromes (MDS) are clonal hematological diseases which present with cytopenias. Hematopoietic cell transplantation is usually limited to fit patients with higher risk MDS and donor availability. Hypomethylating agents (azacitidine and decitabine) have been the mainstay option for the management of MDS with different clinical efficacy in low versus high risk MDS trials. No trials have compared the two agents. Aim: To conduct a systematic review and network analysis comparing the efficacy of azacitidine to decitabine. Methods: The protocol of the systematic review was developed a priori. A comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus) was conducted from each database's earliest inception through November 20th, 2014 without language restrictions. Trials enrolling adults diagnosed with MDS who received hypomethylating agents (azacitidine or decitabine) therapy were included. Studies were screened by two independent reviewers and differences were resolved by consensus. The Cochrane Risk of bias tool was used to appraise the trials. Random effects model was used to pool relative risks (RR) of outcomes (overall survival, overall response rate, hematologic improvement and grade 3 or 4 toxicity). Adjusted indirect comparisons were used to estimate RR for indirect comparisons (Glenny AM, et al. Health Technol Assess. 2005). All statistical analyses were conducted using STATA, version 13 (StataCorp LP, College Station, TX). Results: Only four trials met the eligibility criteria (Figure 1). Two trials compared Azacitidine (75mg/m²/day SC x 7 days) to the best suppurative care (BSC) and included 549 patients (278 azacitidine and 271 BSC, age average: 69; range: 31-92), and the other 2 compared decitabine (15 mg/m² IV q 8 hours x9) to BSC and included 403 patients (208 Decitabine and 195 BSC, age average: 69.7; range: 60-90) (Table 1). The proportion of patients with intermediate-2 and high-risk myelodysplastic syndrome (based on International Prognostic Scoring System (IPSS)) in trials comparing decitabine to BSC was 82.21% and 83.08%; respectively, and in trials comparing azacitidine to BSC was 62.59% and 61.26%; respectively. The risk of bias was moderate overall. Compared to BSC, azacitidine was significantly associated with lower risk of death (RR=0.83, 95% CI: 0.74-0.94, p=0.002) whereas the effect of decitabine did not reach statistical significance (RR=0.88, 95% CI: 0.77-1.001, p=0.053). Both drugs were superior to BSC in terms of partial and complete response. Head to head comparisons were not statistically significant (except for the outcome of complete response where low certainty evidence suggested that azacitidine treated patients were less likely to have complete response compared to decitabine (RR=0.11, 95% CI= 0.01, 0.86, p=0.04). (Table 2). Conclusion: Azacitidine and decitabine are both superior to BSC. The available indirect evidence comparing the two agents warrants low certainty and cannot reliably confirm superiority of either agent. Head-to-head trials are needed. In the meantime, the choice of agent should be driven by patients' preferences, drug availability and cost. Table 2. Results of meta-analysis Outcome Azacitidine VS. Decitabine Azacitidine VS. BSC Decitabine VS. BSC RR LCI HCI P value RR LCI HCI P value RR LCI HCI P value Death 0.95 0.79 1.13 0.54 0.83 0.74 0.94 0.002 0.88 0.77 1.001 0.05 Complete response 0.11 0.01 0.86 0.04* 2.56 1.44 4.58 0.001 23.46 3.22 170.84 0.002 Partial response 0.35 0.04 3.03 0.34 4.91 2.27 10.63 <0.0001 14.02 1.87 105.08 0.01 Major erythroid improvement 0.47 0.03 8.37 0.60 6.37 3.93 10.33 <0.0001 13.67 0.79 235.57 0.07 Major platelet improvement 1.51 0.30 7.56 0.62 4.80 2.98 7.70 <0.0001 3.19 0.68 14.89 0.14 Major neutrophil improvement 2.89 0.56 14.82 0.20 2.63 1.68 4.12 <0.0001 0.91 0.19 4.38 0.907 Hematologic improvement 0.25 0.06 1.09 0.07 2.18 1.67 2.85 <0.0001 8.62 2.05 36.32 0.003 Anemia 1.18 0.53 2.63 0.69 0.89 0.75 1.06 0.198 0.76 0.35 1.66 0.49 Neutropenia 0.99 0.75 1.30 0.92 1.87 1.63 2.14 <0.0001 1.90 1.49 2.42 <0.0001 Thrombocytopenia 0.87 0.64 1.18 0.37 1.63 1.43 1.86 <0.0001 1.87 1.43 2.45 <0.0001 Infection 1.13 0.52 2.43 0.76 1.25 0.60 2.60 0.55 1.11 0.87 1.42 0.41 *These results warrant low certainty due to imprecision (very small number of events) and are driven by 14 patients achieving complete response in BSC arm in one trial. Disclosures Al-Kali: Celgene: Research Funding.

Abstract Background Chronic myelomonocytic leukemia (CMML) is a clonal hematologic disorder that was classified by the World Health Organization (WHO) as a myelodysplastic/ myeloproliferative overlap disease. Cytogenetic abnormalities have a significant prognostic role in many hematologic neoplasms, but their prognostic value in CMML has been debatable. Recently, monosomal karyotype (MK) has been reported to be a marker of poor prognosis in patients with myelodysplastic syndromes (MDS) and primary myelofibrosis, but its value in CMML is unknown. Aim To study MK effect on clinical outcome for patients diagnosed with CMML Method A retrospective study of all cases diagnosed with CMML at Mayo Clinic Rochester between 1994 to 2011 was performed. Only pts with complete cytogenetic analysis at presentation to our institution were included. MK was defined as the presence of ≥ 2 autosomal monosomies or one autosomal monosomy with at least one structural abnormality (Breems et al, JCO 2008). CK was defined as the presence of at least 3 chromosomal abnormalities. Appropriate IRB approval was obtained in accordance with Helsinki declaration. Comparison between groups’ medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier curves using JMP V9. Results A total of 262 pts diagnosed with CMML had available cytogenetic data at diagnosis. Median age was 72 years, 176 (67%) were male. Median hemoglobin 10.5 g/dL, white blood cells (wbc) 12 x109/L, platelet 89 x109/L, peripheral blood (PB) blast 0, and bone marrow (BM) blast 4%. CMML2 was seen in 9% while 47% were proliferative (wbc >13). Leukemic transformation was documented in 34 pts (13%). Median overall survival was 513 days. Cytogenetic (CG) analysis was diploid in 167 pts (64%). Trisomy 8 was the most frequent cytogenetic abnormality at 8% (22), followed by complex karyotype (CK) 5% (14), then -7 at 4% (10) and MK 3% (7, six of which were also CK). Comparing pts with diploid CG to other categories indicates: to abnormal CG pts had lower wbc (0.001), PB blasts (p<0.0001), and BM blasts (p=0.0001); to CK pts had lower PB blasts (p=0.003) and higher platelets (p=0.03); to -7 pts had lower wbc (p=0.005), PB blast (p=0.0004), BM blasts (p=0.03) and higher platelets (p=0.03); to +8 pts had lower PB blast (p=0.02) and BM blasts (p= 0.01); no difference was noted when compared to MK. Median OS was statistically significantly worse in MK+ vs MK- (24 vs 527 days, p= 0.002), but not in other comparisons: -7 vs others (250 vs 527 days, p=0.2), CK+ vs CK- (256 vs 527 days, p=0.05), diploid vs others (570 vs 365 days, p=0.1), +8 vs others (312 vs 527 days, p=0.1). Pts with MK+ only or MK+CK+ did worse than CK+ only or other groups (4, 63, 304, 527 days, respectively, p<0.0001). On a multivariate analysis, MK+ (in addition to platelet, BM blast, hemoglobin, and wbc) did have an impact on OS (p=0.0004), while CK+, -7, +8, diploid CG, age, PB blast did not. Conclusion Cytogenetic abnormalities were not frequent findings in pts diagnosed with CMML (36%), but did affect wbc, PB and BM blasts. The most common cytogenetic abnormality was +8 while MK was present at 3% (less than published data in MDS). Only MK predicted statistically significant shorter mOS between all other cytogenetic categories on both univariate and multivariate analysis. This finding needs to be validated by larger cohorts of pts due to its rare occurrence in CMML. Disclosures: No relevant conflicts of interest to declare.

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.

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 Background:The 2008 World Health Organization (WHO) developed a new classification system for Myelodysplastic Syndrome (MDS). The well-defined categories are refractory anaemia with excess blasts (type 1 or 2 based on the marrow blast count being below or above 10%), refractory anaemia with or without ringed sideroblasts, refractory cytopenias with multilineage dysplasia and myelodysplastic syndromes with isolated deleted 5q. MDS cases that do not meet the diagnostic criteria of the above categories are classified myelodysplastic syndrome (MDS-U). However, few reports in the literature exist in terms of natural progression and clinical outcome of patients with MDS-U. Aim: To study the clinical outcome of patients with MDS-U. Method: A retrospective, IRB-approved, single-institution study through chart review of cases with MDS at Mayo Clinic Rochester between 1993 and 2014 was performed. Patients diagnosed with MDS based on WHO classification were included. MDS classification was based on routine Mayo Clinic pathology reports. Central independent hematopathology review for bone marrow biopsy was performed for cases diagnosed with MDS-U or simply generic MDS. Comparison between groups’ medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier curves using JMP V10. Result: A total of 802 patients, who met WHO criteria for MDS, were studied. Median age was 71 years (range, 18-99), 69% were males. Median white blood cell (WBC) 3.6 x109, hemoglobin (Hbg) 9.6 g/dl, platelets (PLT) 105 x109, peripheral blood (PB) blasts 0% and bone marrow (BM) blasts 2%. Median overall survival (OS) was 28 months. One hundred nine (14%) cases transformed to AML. Out of the 802 patients, 90 (11%) patients were initially classified as MDS-U according to 2008 WHO criteria, 69% were males with median age 71 years. Upon pathology review, only 42/90 cases (47%) were confirmed to be MDS-U (group 1). Among 47 cases not meeting MDS-U, 40% were best classified as RARS, 17% refractory anemia, and 9% as 5Q del Syndrome, while 2 cases did not have any myeloid neoplasm. Group 1 had median WBC 3 x109, Hbg 9.9g/dL, PLT 71 x109, PB blasts 0% and BM blasts 0%. IPSS grouping was low, intermediate-1, intermediate-2 and high in 27%, 52%, 21% and 0%, respectively. R-IPSS grouping was very low, low, intermediate, high and very high in 15%, 42%, 15%, 21% and 6%, respectively. Median OS in group 1 was 68, 37, 13 and 0 months per IPSS (p=0.04), and 101, 44, 14, 11, 13 months per IPSS-R (p=0.005), respectively. Of the 43 patients with MDS-U, 39 had follow-up; 21 patients (54%) of which progressed. MDS-U became 42% RAEB, 24% RCMD, 14% CMML, 5% RARS, 10% MDS/MPN, and 5% atypical. Group 2 (MDS other than MDS-U) 759 patients had median age 71 years, 69% were males. They had WBC 3.6 x109, Hbg 9.6g/dL, PLT 107 x109(p=0.01), PB blasts 0% and BM blasts 0%. IPSS grouping was low, intermediate-1, intermediate-2 and high in 29%, 44%, 22% and 5% respectively. R-IPSS grouping was very low, low, intermediate, high and very high in 17%, 32%, 20%, 17% and 14% respectively. On comparison between Group 1 vs 2, mOS was 27 vs 29 months (p=0.7), and percentage transformed to AML 14% in both groups. On multivariate analysis for mOS only age, IPSS-R and IPSS but not MDS-U nor gender were statistically significant. Conclusion: MDS-Uis a small subset of MDS. With independent pathology review, half of the MDS-U cases were subclassified into other MDS groups. In follow-up more than half of the cases were subclassified into other MDS groups and some were non-MDS. IPSS and IPSS-R are helpful tools for survival assessment in MDS-U. High risk MDS was infrequent in MDS-U per IPSS. We found no significant difference in mOS nor AML transformation when comparing MDS-U to other groups. Disclosures No relevant conflicts of interest to declare.

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 Background: Adult T-cell acute lymphoblastic leukemia / lymphoma (T-ALL) is a rare and aggressive hematological malignancy. Unlike B-cell ALL, apart from age and presenting WBC, additional prognostic factors remain largely unknown. Additionally, the prognostic impact of a monosomal karyotype, which has a negative impact on survival in myeloid neoplasms, remains to be determined in T-ALL (Kenderian et al, BCJ 2013) Aim: To study predictors of survival including the role of a monosomal karyotype in T-ALL. Methods: After due IRB approval, adults diagnosed with T-ALL from 1990-2014 at Mayo Clinic Rochester were identified. All clinical and pathologic data including FISH studies and cytogenetics were retrospectively reviewed. Chi-square test was used to compare variables. Survival was estimated and compared using the Kaplan-Meier Method and log-rank test. Univariate and multivariate analysis was performed using the Cox regression model. Results: Between 1990 and 2014, a total of 92 consecutive patients (pts) with T-ALL were identified, 41 had acute lymphoblastic lymphoma (LBL), and 51 (55%) acute lymphoblastic leukemia (ALL). Median age at diagnosis was 33 years (range; 18-88 years) with 72%males. Median follow up of our cohort was 25 months (range; 0.9-260 months) during which time 42 deaths (45%) were documented. A. Baseline characteristics: Fifty six (67%) had constitutional symptoms, and 63 (77%) had lymphadenopathy at diagnosis. Mediastinal mass was identified in 49 (55%) pts with palpable splenomegaly in 16 (20%) pts. Fifty one (58%) pts had extranodal disease, and 17 (19%) pts had CNS involvement. Pleural and pericardial effusion were evident in 16 (19%), and 6 (7%) pts, respectively. Median laboratory values included; LDH 288 U/L (115-6590), hemoglobin (Hb) 12.8 g/dl (4.5-18.2), WBC 8.65 x109 (1.4-406), platelets 169 x109 (8-485), bone marrow blasts 29% (0-99). B. Treatments: Induction therapies were variable and included; 11 (12%) CHOP like regimens, 7 (8%) modified NHL regimens (Asparginase+CHOP), 54 (58%) ALL like regimens (CALGB 9111, E2993, or HyperCVAD), 13 (14%) Pediatric regimens (ALL 10403, CCG 1961, BFM, Augmented BFM, GRAALL 2003, or Hoelzer regimen), with 7 (8%) patients' receiving palliative care only. Seventy-one (77%) pts achieved complete remission (CR1) during induction therapy while eight pts had refractory disease (8%). Thirty-three (35%) pts underwent stem cell transplant; 7 (21%) autologous and 26 (79%) allogeneic. Forty one (44%) pts had disease relapse and median time to relapse was 10.8 months (range; 8.2-16 months) C. Predictors of survival: In univariate analysis, that included age > 60 years, leukocyte count Hb, Plt, Blast percentage, mediastinal mass, LDH and CNS involvement, only age >60 and CNS involvement were predictors of inferior survival and both retained significance in the multivariable analysis with HR 3.9 (CI 1.5 - 9; p=0.0055) and 2.8 (1.3 - 5.7; p =0.0085), respectively (Figure 1 and 2). In this cohort age >60 was a better stratification that the conventionally used age above 40 (p = 0.1). Among 56 pts with evaluable cytogenetics data, 7 (13%) pts had MK which did not have an impact on survival with HR 1.9 (CI 0.4-5.6; p=0.33). Conclusion: In this large cohort of adult T-ALL patients, we observed that age >60 years and CNS involvement were independent predictors of inferior survival. MK was infrequent, but unlike in myeloid neoplasms, does not seem to impact overall survival. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding. Witzig:Novartis: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Spectrum: Research Funding; Valeant Pharma: Equity Ownership.