Nadiminti, Kalyan

Introduction: Patients who develop therapy-related myeloid neoplasms (t-MN) have dismal outcomes. Previous studies reported the incidence and risk factors associated with t-MN development. Lenalidomide, in the setting of oral, but not intravenous, melphalan is associated with a higher risk of t-MN (Palumbo et. al, Lancet Oncology, 2014). We carried out this study to evaluate the clinical and pathologic features of t-MN, therapies employed, and factors that predict long-term survival after diagnosis. Patients and methods: We identified patients who received the first ASCT 1998-2016 at our institution. t-MN was defined per the WHO 2016 classification. Median overall survival (OS) was calculated from the time of t-MN diagnosis to last follow-up or death. Statistical analyses were performed using SAS (JMP v14.1) or GraphPad Prism (v7). Results: Out of 2115 patients that underwent at least one ASCT, 53 (2.5%) developed t-MN. Thirty-five of 53 (66%) patients who developed t-MN had received lenalidomide. Among 2062 patients that did not develop t-MN, 916 (44.4%) patients received lenalidomide. Lenalidomide exposure was associated with development of t-MN (χ2 with Yate's correction 8.9, p=0.003). Ten patients were excluded from further analyses due to lack of follow up. Clinical characteristics are shown in Table 1a (N=43). Median age at t-MN diagnosis was 70 years (range 44-79). Median time from ASCT to t-MN was 5 years (range 1-15). After a median follow-up of 70 months (95% CI, 38-134), the median OS was 12 months (95% CI, 9-17, Figure). Primary causes of death were t-MN (71%), MM (12%), both (6%), and other including infection, GVHD, and unknown (12%). Seven (16%) had t-AML and 36(84%) had t-MDS. Three (42%) of 7 patients with t-AML had pure erythroid phenotype. At the time of last follow-up, 9 (21%) were alive. Seven (17%) underwent two ASCT, 16 (36%) received more than 2 years cumulative dose of lenalidomide. Median number of cycles of alkylator therapy including high-dose melphalan (HDM) used for ASCT was 2 (range 1-6). On univariate analysis, factors predicting OS from t-MN diagnosis were ≥ 2 alkylator vs. < 2 cycles (11 vs. 27 months, p=0.02), ≥10% vs. <10% blast at the time of t-MN diagnosis (5.5 vs. 17 months, p=0.01), and the presence of complex karyotype (CK) vs. not (11 vs. 17 months, p=0.03). There was no difference in survival among t-MDS patients who transformed to t-AML vs. those who did not, those who received 1 vs. 2 ASCT, and those with lenalidomide duration ≥ 2 vs. <2 years. On multivariate analysis, the number of alkylator therapies and CK, but not % blasts predicted OS from t-MN diagnosis (Figure). Eight (19%) patients proceeded to receive an autologous (n=4) or allogeneic (n=4) transplant for t-MN (Table 1b). There was no survival advantage for patients who underwent SCT for t-MN, compared to those who did not (17 vs. 10 months, p=0.3). Similarly, there was no survival advantage for patients who received allo SCT compared to auto SCT (21 vs. 16 months, p=0.7). Survival for t-MDS and t-AML was also not different (15 vs. 6 months, p=0.2). There is only one long-term survivor in the transplant group (s/p allogeneic SCT). Four of seven (57%) patients died of progressive t-MN, 1 died of progressive MM, progressive MM and t-MN, and TRM each. Conclusions: Lenalidomide, in the setting of HDM, is associated with an increased risk of t-MN. Increased exposure to alkylators, a higher tumor burden, and the presence of CK predict poor survival in t-MN. As HDM/ASCT followed by lenalidomide maintenance remains the standard of care for eligible patients, minimizing exposure to other alkylator regimens may be prudent. While considered the standard, only a minority undergo transplant; and post-transplant outcomes remain poor. Studies to identify prognostic genetic and epigenetic risk factors are ongoing. Disclosures Al-Kali: Astex Pharmaceuticals, Inc.: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Introduction: Allogeneic hematopoietic stem cell transplant is curative in several benign and malignant hematological disorders with predominant complications of graft versus host disease (GVHD) and infections. Antithymocyte globulin (ATG) has been shown in a number of prospective trials to be effective in decreasing acute and chronic GVHD. Recently, it has been suggested that recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration interacts with the dose of ATG administered and predicts transplantation outcomes. This interaction may depend on the preparative regimen and the dose of ATG used. We sought to determine if ALC at time of administration of ATG could impact clinical outcomes in a population treated with busulfan fludarabine myeloablative regimen and a fixed dose of 4mg/kg of ATG. Methods: Seventy consecutive pts who underwent a matched unrelated donor transplant with ATG at the University of Iowa were retrospectively analyzed. All pts received rabbit ATG (Thymoglobulin®) at 0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2 mg/kg on day -3 in addition to tacrolimus and methotrexate. All received a myeloablative preparative regimen with busulfan (130 mg/m2 days -6 to -3) and fludarabine (40 mg/m2 daily for 4 days). All but one pt received peripheral blood as graft source. The effect of patient, disease, and transplant characteristics on 2-year outcomes was evaluated using Cox and Fine and Gray regression models. For relapse, GVHD, and infections, death was considered a competing risk. Estimated effects of predictors are reported as hazard ratios (HR) along with 95% confidence intervals. Results: Median age was 59 years (range 20-68). Underlying diagnoses were AML (n=47), MDS (n=20) and CML (n=3). Disease Risk index showed 25 high risk, 24 intermediate risk and 21 low risk patients in this study. The median peripheral blood ALC on day -3 was 100 × 102/µL (range 0-1144 × 102/µL). Univariate analysis showed no significant impact of ALC (100+ vs <100) on 2-year risk of developing GVHD (HR 1.49, 95%CI: 0.77 - 2.86), 2-year overall infection risk (HR 0.86, 95%CI: 0.51-1.46), 2-year bacterial (HR 0.78, 95%CI: 0.43-1.42), viral (HR 0.81, 95%CI: 0.41-1.60) and fungal (HR 0.63, 95% CI: 0.17-2.33) infections. Univariate analysis also showed no significant influence on 2-year relapse-free survival (HR 0.67, 95%CI: 0.21-2.14) and overall survival (HR 0.84, 95%CI: 0.34-2.06). Significantly worse survival is seen in MDS in comparison to leukemic pts, and high disease risk in comparison to low disease risk. Conclusion: Our single center experience using busulfan and fludarabine myeloablative regimen and rabbit ATG dosed at 4 mg/kg showed no interaction between the recipient peripheral blood ALC and ATG to predict GVHD, infections, overall and relapse free survival. Disclosures Farooq: Celgene: Honoraria; Kite Pharma: Research Funding.