ALBERT

Description: TRM, drug toxicities, life-threatening infections, poor quality of life, and graft versus host disease (GVHD) are significant risks of hematopoietic cell transplantation (HCT). In addition to the risks of HCT, existence of pre-transplant comorbidities can have significant impact on transplant outcomes. A comparison of CCI and the HCT-CI revealed that HCT-CI was prognostic and better at predicting TRM and overall survival (OS). However, the HCT-CI and CCI results have been inconsistent in predicting the TRM and OS in validation studies. In subgroup analyses of a large retrospective trial, HCT-CI did not predict TRM or OS for UCB recipients. Patient heterogeneity in age, disease, disease-risk, comorbidities, and conditioning regimens may have limited validation in these UCB recipients. The design of this research was to explore whether or not the HCT-CI and/or CCI can accurately predict post-transplant outcomes in young patients with high risk hematologic malignancies undergoing uniform RIC UCB transplantation. A retrospective chart review was performed on 52 consecutive young (age 〈 55) UCB transplant recipients receiving the RIC regimen fludarabine, cyclophosphamide, ATG, and 200 cGy TBI. All patients had received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Information on pre-transplant comorbidities was obtained from the CIBMTR pre-TED form for each patient and retrospective chart reviews. Demographic information, ECOG performance status (PS), identification of comorbidities, and post-transplant outcomes were obtained. Between 2005 and 2011, 52 patients age 19 – 54 (median 38) years, 30 males (58%) and 22 females (42%), underwent RIC UCB transplantation with the above regimen. Most patients had advanced stage or high risk hematologic malignancies; 28 patients had MDS/AML (54%), 8 patients had ALL (15%), while 16 patients had other hematologic malignancies. 39 patients had a PS = 0, while 13 had a PS = 1. Half of the patients were in CR 〉 2, with the same number receiving more than 2 prior therapies. 8 patients had received a prior autologous HCT, 8 a prior allo-HCT, and one patient had failed a previous UCD transplantation. 11 patients did not achieve engraftment. Median time to neutrophil engraftment was 26 days (95% CI: 24 – 28 d) and median time to platelets engraftment was 38 days (95% CI: 31 – 45 d). No patient developed grade 4 acute GVHD. Grade 3 acute GVHD was seen in 12 / 52 patients (23%). Chronic GVHD was seen in likewise seen in 12 patients (23%). To date 16 patients (30%) have relapsed. OS was 42% and PS was 37% at one year. Median PFS and median OS were 5 months and 7 months, respectively (PFS 95% CI: 1 – 11 months, OS 95% CI: 1 – 13 months). Neither CCI, nor HCT-CI were significant predictors of OS and PFS, however the ECOG PS was significantly associated with an improved OS and PFS (Table).OSPFSN1 yr2 yrs4 yrsp1 yr2 yrs4 yrspECOG PS03946%36%21%0.02644%36%21%0.0311331%0015%00CCI≤ 23944%26%10%0.2238%26%10%0.2〉 21338%31%31%38%31%31%HCT-CI02236%31%5%0.3632%32%5%0.3211443%14%14%29%14%14%≥21643%31%31%44%31%31%TRM occurred in 18 patients (35%). Neither comorbidity indices, nor the performance status were correlated to TRM (p 〉 0.05). For ECOG PS, OR 1.6 p = 0.49, CI 0.42 - 5.93; CCI OR = 2.4, p = 0.09, CI 0.86 - 6.59, HCT-CI OR = 0.6, p = 0.46, CI 0.19 - 2.08. In a previous presentation our group concluded that CCI performs better than HCT-CI in elderly patients undergoing UCB transplant. When tested in a population younger than 55 years old though, we were unable to validate the generally accepted prognostic indices. It is unclear whether this is due to a selection bias: it appears most of the patients were essentially health from a non-hematological stand-point, and as such the “classic” cardiac or pulmonary risk factors were underrepresented. The excess TRM is likely due to the severity of their underlying disease, and the majority were in CR ≥ 2 and had received multiple previous courses of antineoplastic chemotherapy. As umbilical cord transplants become more utilized, a new prognostic index needs to be developed, more fitting to the patients 〈 55 years old. Disclosures: No relevant conflicts of interest to declare.

Description: Venous thromboembolic events (VTE) are common after the diagnosis of lymphoma. Although various risk factors have been associated with VTE in cancer patients, there is no specific VTE risk prediction score for diffuse large B cell lymphoma (DLBCL) patients. The Khorana score is a prediction-model of VTE in cancer patients receiving chemotherapy that incorporates clinical and laboratory parameters. We evaluated the risk factors for VTE, the effect of VTE on the outcomes of DLBCL patients and the utility of the Khorana score in DLBCL patients. Methods: We searched the Hematologic Malignancies Database of University Hospitals Seidman Cancer Center for newly diagnosed DLBCL patients between 2002 and 2014. Data on patient characteristics including risk factors, disease characteristics, treatment, outcomes and VTE was collected. The Khorana score was calculated using clinical (disease type, body mass index) and laboratory (hemoglobin level, platelet and leukocyte count) parameters. Risk factors identified as having statistical significance on univariate Cox proportional hazards analysis (p 12g/dL), increased white cell count (〉11,000/mcl), hemoglobin (800/mcl) and chromosomal translocations involving MYC presented statistically significant increases in hazard of VTE (Table 2). On multivariate analysis only bone involvement (p=0.017) and anemia (p=0.035) retained statistical significance as risk factors for VTE. Three-year OS for patients presenting with VTE within 1 year of DLBCL diagnosis was 46.7 % (95% CI 30-63.3) vs. 72.3% (95% CI 67.4-77.3) in subjects without early VTE (p=0.05) (Figure 2). Presence of VTE at any time after DLBCL diagnosis was also associated with worse OS rates, with estimated 3-year OS of 52.2 % (95 % CI 39.8-64.7) for subjects experiencing VTE and 74 % (95 % CI 69-79) for those without VTE after DLBCL diagnosis (p

Description: Background: Patients (pts) diagnosed with non-Hodgkin lymphoma (NHL) have increased risk of venous thromboembolic event (VTE). Retrospective studies have observed the risk of VTE is not the same across lymphoma subtypes, with aggressive subtypes having higher risk than indolent lymphomas. Current VTE prediction models such as the Khorana score (K-Score) consider all lymphomas as having equal risk of VTE. We conducted retrospective time - based analyses to develop a VTE prediction model that includes lymphoma subtype as a risk factor. Methods: We accessed the Hematologic Malignancies Database at University Hospitals Seidman Cancer Center and collected records of pts diagnosed with diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) between 2000 and 2016. Pts with CNS involvement or active anticoagulation were excluded. FL grade 3B pts were included in the DLBCL cohort. Information retrieved included demographic characteristics, baseline disease and laboratory parameters, as well as comorbidities and diagnosis of VTE, including radiographic confirmation. Time to VTE was measured from the date of NHL diagnosis to the date of VTE incidence or censored at the date of last follow-up for those without VTE. Cumulative incidence of VTE was estimated using Kaplan-Meier method and its difference among groups was examined by log-rank test. Cumulative incidence of VTE was also calculated considering death as competing risk and comparisons done using the Gray test. Cox proportional hazards model was used to evaluate the effect of continuous and categorical covariates on cumulative incidence of VTE and to identify prognostic factors of VTE. Fifty percent of the study participants were randomly assigned to training cohort or reserved as an independent validation cohort. Performance of multivariate models was evaluated using the Akaike Information Criterion (AIC) and Concordance Index (C-Index). The final models built using the training dataset were further validated using the validation cohort. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Results: We identified 627 pts with DLBCL (n=421) or FL (n=206) with available baseline characteristics, (Table 1). After a median follow up of 48 months (range 1-191), 77 pts experienced a VTE after NHL diagnosis. The cumulative incidence of VTE at 4 years for the whole cohort was 10.5% (95% CI 8.3-13.2). DLBCL pts had a significantly higher 4 - year cumulative incidence of VTE: 13.7% (95% CI 10.8-17.5) vs. 4.0% (95% CI 2.0 - 7.9) in FL pts (p

Description: Abstract 2019 High-dose chemotherapy (HDC) followed by autologous hematopoietic cell transplantation (AHCT) has been shown to result in better outcomes than conventional salvage chemotherapy for treatment of relapsed Hodgkin (Lancet 2002;359:2065–71) and non – Hodgkin lymphoma patients (N Engl J Med 1995;333:1540–5). The relative efficacy of different conditioning regimens is still uncertain. Our center has had extensive experience with BEP, consisting of BCNU (600mg/m2), etoposide (2400mg/m2) and cisplatin (200mg/m2) (Lazarus HM, J Clin Oncol 1992;10:1682–9) with more than 150 patients transplanted using this conditioning regimen. We have observed it to be efficacious and associated with a low incidence of transplant-related mortality (Biol Blood Marrow Transplant 2005;11:13–22). The purpose of this analysis is to compare the outcomes of patients transplanted with BEP with a contemporaneous cohort of patients transplanted with BEAM (BCNU 300mg/m2, etoposide 800mg/m2, cytarabine 1600mg/m2, melphalan 140 mg/m2). We performed a retrospective analysis of 55 consecutive relapsed lymphoma patients who had either BEAM or BEP preparative therapy for AHCT between 2005 and 2010 at our institution. Given the potential for nephrotoxicity and ototoxicity of cisplatin, patients were selected to receive BEAM if they had previous renal dysfunction (any elevation of serum creatinine) or had previous hearing loss. All patients received corticosteroids for prophylaxis of BCNU – induced pneumonitis. The Mann – Whitney test was used for analysis of continuous variables, Fisher's exact test for categorical data, while survival analysis was performed with the Kaplan – Meier method. Twenty-four patients received BEAM and 31 received BEP. The median age was higher in BEAM-treated patients (51 vs. 43 years, p = 0.0392). Other baseline characteristics were comparable between both cohorts: gender (male 54 vs. 58%, p = 0.791); diagnosis (NHL 75 vs. 77.4%, p = 1.000); status of disease at transplant (partial remission or worse 33.3 vs. 35.5%, p = 1.000); median number of previous therapies (2 in both groups, p = 0.51). The rate of non-renal comorbidities was higher in the BEAM cohort, but the difference was not statistically significant (45.8 vs. 32.3%, p = 0.403). The median CD34 cell dose was similar in both groups (6.252 x106 vs. 6.475 x106 CD34 cells/μL, p = 0.842). The rate of complications, including bacteremia, other infections, mucositis, diarrhea and renal dysfunction were not statistically different (Table 1). The small sample size may have prevented us from observing a statistical difference in cardiac toxicity.Table 1.Complications observed after BEAM or BEP conditioning for Autologous Hematopoietic CellBEAM (%)BEP (%)Bacteremia45.835.5p = 0.580Non – bacteremic infections37.541.9p = 0.787Mucositis54.258.1p = 0.791Diarrhea79.164.5p = 0.370Increase in serum creatinine 〉 50%12.516.1p = 1.000Cardiac complications16.73.2p = 0.153BCNU pneumonitis4.26.4p = 1.000 The median follow up time for the whole cohort was 31 months (28 vs. 34 months, p 0.267). Relapse free survival (RFS) after 36 months was 81.1% and 82.9% for BEAM and BEP, respectively (p = 0.693) (Figure 1). Overall survival at 24 months was 89.6% for BEAM and 90.8% for BEP (p = 0.371) (Figure 2). Among patients transplanted in partial response or worse, the median RFS was 57 months after BEAM and 66 months after BEP (p = 0.3173). There were no deaths in the first 100 days after transplant for both cohorts. There were no differences in the median number of days from hematopoietic cell infusion to discharge (12.5 vs. 12.0 days, p = 0.600) or achievement of ANC 〉500/μL (10 days for both cohorts, p = 0.415). In conclusion, BEP conditioning achieved comparable engraftment, toxicity and survival outcomes to those achieved by BEAM for treatment of relapsed lymphoma patients. BEP is therefore a valid alternative for treatment of this patient population. The BCNU dose in BEP is twice that in BEAM, but we continue to observe limited rates of BCNU – induced pneumonitis. BEP may be preferable over BEAM in patients with underlying cardiac comorbidity. Longer follow up and prospective trials will help in identifying variables that aid in the selection of patients for the most appropriate conditioning regimen. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Autologous hematopoietic cell transplant (HCT) is frequently used to treat plasma cell dyscrasias. High-dose melphalan is the most commonly utilized preparative regimen. Frequently seen non-hematologic adverse effects include oropharyngeal mucositis and GI toxicity. Reported incidence rate of overall and severe (grade 3-4) mucositis is 60-90% and 30-40%, respectively. Amifostine is a thiol derivative, which has been used for protection of normal tissues in radiation and chemotherapy. Amifostine has a relatively safe profile with hypotension, nausea, vomiting and diarrhea (N/V/D) as main side effects. We explored the efficacy of amifostine to reduce overall incidence and severity of mucositis after high-dose melphalan therapy. Methods: We conducted a retrospective study of 126 autologous HCT (110 patients) with high-dose melphalan performed from January 2007 to July 2014 at our center for plasma cell myeloma. Twelve patients underwent tandem transplants and four had second autologous transplants after relapsed disease and were excluded from survival analysis. Patients' characteristics (n=110) as listed in Table 1. All but one patient received two doses of Amifostine given as 740 mg/m2 IV bolus on days T-2 and T-1. Melphalan was administered as IV bolus on T-1 at the dose of 200 mg/m2, except for 4 patients who received 140 mg/m2 due to impaired renal function. All patients received ice chips peri-melphalan infusion. All patients received cryopreserved autologous hematopoietic cell infusion on T-0. We graded mucositis and GI toxicities as per CTCAE v4.0 and recorded patient controlled analgesia (PCA), total parenteral nutrition (TPN), transplant and disease outcomes. Results: Severe (grade 3-4) mucositis and diarrhea rates were 14% and 12%, respectively (Table 2). PCA was used in 10% of transplants at a mean duration of 0.9 days and TPN was utilized in 5% of transplants for a mean duration of 0.45 days. Median length of stay for transplant was 15 days (range 3-44 days). Median time to neutrophil and platelet engraftment was 10 and 19 days, respectively (Table 3). Three patients died within 100 days after transplant (2 due to infections and 1 due to renal amyloidosis). At a median follow up of 39 months, median PFS is 25 months and OS is greater than six years. All patients were able to receive amifostine at prescribed doses except for one patient who received only one dose due to intractable N/V/D. Conclusion: Amifostine is effective in reducing high-dose melphalan-induced severe mucositis. Our data would suggest a decrease in severe mucositis and GI toxicity rates when compared to historically reported incidences. In addition, amifostine does not appear to have a deleterious effect on engraftment and/or survival and response rates (Table 3). Table 1. Patients characteristics Median Age (years) 59 (36-71) Gender (%) Male 54Female 46 Performance status (ECOG) 1 (0-2) Median time to transplant from diagnosis (years) 0.97 Median number of treatment regimens prior to transplant 2 (1-6) Response prior to transplant (%) Partial remission (PR)Very good partial remission (VGPR)Complete remission (CR)Stable disease (SD) 60%21%18%0.8% Table 2. Toxicity Overall (grade 1-4) Severe (grade 3-4) Median grade Median Duration (days) Mucositis 55% 14% 2 2 Diarrhea 92% 12% 2 7 Nausea 89% 4% 1 8 Vomiting 67% 3% 1 2 Table 3. Engraftment and post-HCT disease response Engraftment Median (days) Range (days) Neutrophils 10 6-21 Platelets 19 8-71 Post-HCT disease responses (%) Stringent complete response (sCR) 13% Complete response (CR) 32% Very good partial response (VGPR) 24% Partial response (PR) 25% Not evaluated 6% Disclosures Off Label Use: Amifostine use to prevent mucositis.

Description: Background: Bendamustine plus rituximab (BR) is an effective front-line treatment for chronic lymphocytic leukemia (CLL). Immunosuppression induced from disease- and/or treatment-related factors can frequently result in infectious complications, including varicella zoster virus (VZV) reactivation. Antiviral prophylaxis is not universally prescribed for these patients and the duration of treatment is not well defined. We therefore retrospectively reviewed the incidence of VZV reactivation and the impact of antiviral prophylaxis on this complication in CLL patients treated with front-line BR. Methods: We reviewed charts of 82 consecutive CLL patients with adequate clinical follow-up who were treated a median of 5 cycles with front-line BR at the Cleveland Clinic and University Hospitals of Cleveland from December 2005 to February 2015. Patients were grouped as having received antiviral prophylaxis or not. Baseline characteristics were compared between groups using the Chi-square test or Wilcoxon rank sum test. VZV reactivation from the start of front-line therapy was estimated using the cumulative incidence method and compared using the Gray test. Univariable prognostic factors for VZV reactivation were identified with Fine and Gray regression. The number of patients who reactivated was too small for multivariable analysis. All analyses were done using SAS software (SAS Institute Inc., Cary, NC, USA). All statistical tests were two-sided and P 〈 0.05 was used to indicate statistical significance. Results: The median age of patients at the time of BR treatment was 69 years (range 44-93 years). 71% were male. Median follow-up was 1.5 years. 23 patients (28%) received antiviral prophylaxis, 20 acyclovir and 3 valacyclovir. The median duration of antiviral prophylaxis was 8.8 months. Patients who received antiviral prophylaxis were more likely to have had a history of VZV than those who did not receive prophylaxis (17% vs. 0%, P = 0.001). Additionally, patients who received antiviral prophylaxis were more likely to have received prior Zostavax compared to those who did not receive prophylaxis (22% vs. 5%, P = 0.022). All other baseline demographics including age, gender, ECOG PS, Rai stage, and cytogenetics were similar between the groups. 7 patients (8.5%) reactivated VZV following front-line BR therapy. Of the 7, 4 received antiviral prophylaxis with acyclovir and 3 did not receive prophylaxis (P = 0.20). Only one patient who reactivated VZV did so after receiving second line therapy. None of the patients who reactivated had a prior history of zoster activation. Notably, patients who received antiviral prophylaxis and reactivated VZV did so more than 6 months from the time of BR initiation, with reactivation occurring greater than 3 years after the start of front-line BR. [Figure 1] Conclusions: CLL patients who receive front-line BR are at risk for VZV reactivation regardless of antiviral prophylaxis. History of VZV did not predict the likelihood of viral reactivation. Patients who received prophylaxis and experienced VZV reactivation did so more than 6 months from treatment initiation. These data suggest that when given to CLL patients receiving front-line BR, a standard 6-8 month regimen of VZV prophylaxis is insufficient. Rather, prolonged prophylaxis extending years after treatment completion may be more appropriate to prevent VZV reactivation. Further prospective studies are required to further explore this benefit. Figure 1. Incidence of VZV reactivation over time in CLL patients treated with front-line BR who received antiviral prophylaxis. Figure 1. Incidence of VZV reactivation over time in CLL patients treated with front-line BR who received antiviral prophylaxis. Disclosures Smith: celegene, spectrum, genentech: Honoraria. Hill:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Proteasome inhibitors (PIs) capitalize on the constitutive activation of NF-KB in AML cells and increase chemosensitivity to anthracyclines and cytarabine. We combined the second generation PI, ixazomib, with the standard AML salvage regimen of MEC (mitoxantrone, etoposide, cytarabine). The primary objectives of this study were to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and phase 2 dose of ixazomib in combination with MEC in relapsed/ refractory (R/R) AML. Secondary objectives included evaluating the efficacy of this combination and correlating response to the gene expression profile and CD74 expression, which may identify a subset of leukemias in which NF-KB is operative with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446-54). Methods: Patients (pts) were treated at Cleveland Clinic and University Hospitals of Cleveland from Oct 2014 to present. An IND was approved by the FDA, and the protocol was approved by each institutional review board. Eligibility: age 18-70 yrs, R/R AML, and cardiac ejection fraction ≥ 45%. The fraction of blasts positive for CD74 was assessed by flow cytometry. Samples were stored for gene expression profiling pre- and post-treatment (at the time of response assessment). Pts received MEC: mitoxantrone (8 mg/ m2), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) intravenous (IV) Days 1-6. Ixazomib, provided by Takeda, was given orally on Days 1, 4, 8, and 11 and was dose escalated using a standard 3x3 design. Dose levels (DLs): 1 (1.0 mg), 2 (2.0 mg), 3 (3.0 mg), 4 (3.7 mg). An additional 18 pts were to be treated at the MTD. One cycle of treatment was administered. Response was assessed by bone marrow aspirate/ biopsy by Day 45 and complete remission (CR) was defined by IWG criteria (Cheson 2006). Toxicities were graded according to NCI CTCAE v 4.03. Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLTs included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting/ alopecia and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy and not related to leukemia; (4) any Grade 4 NHT 〉 grade 2 by 45 days beyond the start of chemotherapy. Grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5-〈 10x upper limits of normal (ULN), 10-20 x ULN, and 〉 20 x ULN. Results: Of 23 pts enrolled, 22 are evaluable. The median age was 58 yrs (range 31-70), 12 (52%) were male and the median baseline WBC was 2.56 K/ uL (range 0.1-62.9). The median time from initial diagnosis to registration was 7.1 months (range 1.4-36.8) and 7 pts (30%) had a history of an antecedent hematologic disorder. Thirteen pts were in 1st relapse and 10 pts were refractory to their last therapy. One pt had received a prior allogeneic hematopoietic cell transplant (AHCT), 7 pts had FLT3 ITD mutations and 7/ 21 pts (33%) had adverse cytogenetics per CALGB 8461 criteria at the time of relapse. At DL1, 1 DLT occurred (grade 4 thrombocytopenia), so this DL was expanded to 6 pts. At DL2, 2 pts developed Grade 4 thrombocytopenia; therefore, the MTD of ixazomib was 1.0 mg. The most common grade 3-5 NHTs in the dose escalation phase were febrile neutropenia (100%), hypoalbuminemia (25%), hypokalemia (42%), hypotension (33%), and respiratory failure (33%). No adverse events in the dose escalation phase were attributed to ixazomib alone. The overall response rate was 55% [CR/ CR with incomplete count recovery (CRi)], and 9 pts proceeded to AHCT. Five of these 9 pts remain alive with a median follow-up of 12.8 months. Five pts had CD74 expression performed. Two pts had high levels of CD74 expression (〉 80%); and both achieved CRi. Myeloid mutation panel data was available in 14 pts. Previous data has demonstrated the number of mutations in DNTMT3A, TP53, ASXL1, and NRAS (0, 1, 〉1) is associated with a worse response to salvage therapy (Advani et al, abstract 3825, ASH 2015). Seven pts had at least one of these mutations and 6 of the 7 achieved CR/ CRi. Conclusions: The combination of MEC and ixazomib was well-tolerated and produced an overall response rate of 55% in patients with relapsed/ refractory AML irrespective of molecular mutation status. The combination is safe with a similar toxicity profile to MEC alone. CD74 expression may represent a biomarker for response to this therapy. Results from gene expression profiling will be complete by the time of the meeting and will be presented. Disclosures Mukherjee: Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Caimi:Genentech: Speakers Bureau; Gilead: Consultancy; Roche: Research Funding; Novartis: Consultancy. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Description: Lithium (Li) is a GSK3 inhibitor that induces differentiation and anti-proliferation of AML cells in vitro. Pre-clinical studies demonstrated GSK3 inhibition leads to increased expression of the receptor of tretinoin, the retinoic acid receptor. We conducted a phase I trial of Li in combination with tretinoin for non-promyelocytic AML based on pre-clinical studies demonstrating synergistic AML cell differentiation using the two-drug combination. We report laboratory correlative data demonstrating AML cell differentiation using the combination of Li and tretinoin. Methods. 12 relapsed or refractory AML patients were enrolled. Li was administered at 300mg three times daily (twice daily in patients age ≥60) continuously and adjusted to meet the target Li plasma concentration of 0.6-1mEq/L; tretinoin doses were 22.5 mg/m2/day (dose level 1) and 45 mg/m2/day (dose level 2) administered on days 1-7 and 15-21 of a 28-day cycle. Li was given for a 3-day lead-in period prior to cycle 1. 7 patients were evaluable for laboratory correlative studies. Blood and/or bone marrow samples were collected at baseline, day 1 and day 8 of cycles 1 and 2 and at the end of the study period. Specimens were processed only if ≥5% leukemic cells were available for analysis. Immunophenotyping was performed by multi-parameter flow cytometry using fluorochrome-labeled antibodies to CD11b, CD14 and CD15 as markers for monocytic and/or granulocytic differentiation. Cells were concurrently stained for CD34, CD117 and CD38 for identification of the leukemic blast and stem cell population (CD34+CD38-). After fixation and permeabilization using a formaldehyde-based solution, intracellular staining was performed for phosphorylated Serine-9 GSK3β (pGSK3β) as a marker for GSK3 inhibition. Li directly binds GSK3 and causes reversible enzyme inhibition by Ser9 phosphorylation. Results. The target serum concentration of Li was achieved in all patients and found to inhibit GSK3 in leukemic cells. pGSK3β measured by mean fluorescence intensity (MFI) increased by a median of 1067 (168-1738) by day 30 in 4 patients with samples available for analysis; the earliest increase in pGSK3β MFI occurred at day 1 after the Li lead-in period. Six subjects (86%) demonstrated differentiation as defined by ≥10% increase in a cell population expressing at least one of the surface markers associated with monocytic or granulocytic differentiation, with median increase 27.4% (range 10.0-59.2%). Maximum increase occurred at median day 30 (range 8-60) of the study period. Three patients (50%) exhibited differentiation in both the CD34+ or CD117+ blast population and in non-blast cells. Two subjects (33%) had increased differentiation in the non-blast population only, and 1 (17%) had increased differentiation in the blast population only. Three patients had clinically stable disease (defined as no increase in blasts for ≥4 weeks from study start) and showed a median increase in differentiated cells of 27.4% (17.2-37.6%) compared to a 14.8% (10.0-19.6%) increase in the 3 patients with progressive disease (p=0.44). Four patients had day 60 bone marrow available for analysis; in 3 patients, there was a median of 29.3% (range 12-32%) increase in cells expressing at least one differentiation surface marker in the CD34+ or CD117+ blast population. In 6 subjects with evaluable sample, a median relative reduction of 67% (37-98%) of the AML stem cell population (CD34+ CD38-) was seen in the blood at day 8 to 60. Conclusions. The combination of lithium and tretinoin induces differentiation in leukemic cells. Unlike most cytotoxic AML therapies which target rapidly dividing cells, this strategy may be effective in targeting the AML stem cell population. Response to differentiation therapy was variable, suggestive of the heterogeneity of the disease. Li induced a modest effect on GSK3 inhibition at clinically achievable plasma concentrations. Though this study demonstrated the ability to inhibit GSK3 in leukemic blasts and induce differentiation, higher levels of GSK3 inhibition are likely necessary for greater clinical efficacy. As Li concentrations cannot be increased significantly due to drug toxicity, future studies investigating the use of more potent GSK3 inhibitors in AML are needed to further investigate this strategy. Disclosures Wald: Invenio Therapeutics: Equity Ownership.

Description: Introduction: Extra-nodal Natural Killer/T-Cell Lymphoma, Nasal Type (ENKL) is an aggressive, rare variant of non-Hodgkin lymphoma most frequently found in Asia, with 5-year survival estimates of 30-45%. The utility of stem cell transplant (HSCT) has been evaluated in a number of primarily small retrospective studies, almost exclusively from Asia, in which outcomes appear to be improved with HSCT by 10-20%. We conducted this study with the aim to determine the outcomes of autologous (AUTO) and allogeneic (ALLO) HSCT in patients with ENKL. Methods: This multi-center study was conducted in collaboration with 4 different centers, 3 in the United States, and 1 in Singapore. All patients with a diagnosis of ENKL who received either AUTO or ALLO HSCT after January 1, 2000 were eligible. Univariate probabilities of overall survival (OS) and progression-free survival (PFS) were estimated utilizing the Kaplan-Meier method using IBM SPSS version 22.0. Probabilities of non-relapse mortality (NRM) and relapse mortality (RM) were calculated by the cumulative incidence (CI) procedure to accommodate for competing risks utilizing EZR software. The log-rank test was used to assess for differences between groups in regard to OS and PFS, and the Fine-Gray analysis was performed to compare outcomes with competing risks. Results: Twenty-seven patients, with median age of 48 years (range 22-68), and a median of 2 prior chemotherapy lines (range 1-5) received HSCT for ENKL; 14 AUTO and 13 ALLO, of which 70% were performed at MD Anderson. Sixty-seven percent were male, 30% were not in complete remission (CR) at transplant, and 40% had an NK-IPI risk group of 3-4. Seventy-four percent of patients received myeloablative (MAC) conditioning, with the most common regimen being BEAM in 55% of ALLO and 65% of AUTO. All patients received peripheral blood as the stem cell source except one who received cord blood. With a median follow-up time of 11 years, OS and PFS for the entire group were 51% and 50%. The CI NRM was 19% at 1 and 2 years and the CI RM was 16% at 1 year, 26% at 2 years, and 40% at 11 years (Figure 1). Amongst ALLO recipients, there were 2 cases of grade II-IV acute GVHD (14% of ALLO) and 5 cases of chronic GVHD (1 limited, 4 extensive, 36% of ALLO). PFS was significantly better for patients in CR versus those not in remission at transplant (67% vs 13%, p=0.002). There was no impact of MAC vs non-MAC conditioning, disease stage at diagnosis (I-II vs III-IV), prior number of chemotherapy lines, comorbidity index, NK-IPI risk group 1-2 vs 3-4, age 〉50, sex, or race on PFS or OS. We did an exploratory analysis of transplant outcomes between the AUTO versus ALLO groups. More patients in the ALLO group (46% vs 17%, p=0.082) were not in CR at transplant, though other characteristics were balanced. PFS for AUTO versus ALLO was 67% vs 31% at 1 and 3 years (p=0.032), (Figure 2). OS for AUTO vs ALLO was 75% vs 54% at 1 year, and 64% vs 39% at 3 years, (p=0.146). One patient received an ALLO with progressive disease and survived. Additionally, 3 of 4 patients who received ALLO after prior AUTO survived, though one died of a second malignancy 11 years post-transplant. One of these patients received a prior AUTO but developed graft failure and subsequently received an ALLO and was counted in the ALLO group. CI NRM was higher in the ALLO vs AUTO group at 1 year (39% vs 0%, p=0.013). CI of RM was higher in the first year in the AUTO vs ALLO group at 1 year (26% vs 8%), though by 3-years this difference was not significant (36% vs 23%, p=0.472). Conclusion: Here we present the results of a multi-center study of patients who received a HSCT for ENKL. Our results are similar to those seen in Asian studies, with long-term PFS and OS of 50%, demonstrating that HSCT is an effective therapy for patients with ENKL. Patients in CR at transplant had better OS and PFS than those not in CR; therefore, complete remission should be the goal prior to HSCT for ENKL. ALLO is an effective treatment option for relapse post-AUTO or for progressive disease at transplant, with less relapse than AUTO, particularly within the first year. This is particularly interesting given that 46% of patients who received ALLO were not in remission at transplant, indicating a strong graft-versus-lymphoma effect. However, these results are limited by an increased NRM. Strong consideration for AUTO should be given to patients who are in CR at the time of transplant, and ALLO should primarily be reserved for refractory disease or relapse post-AUTO. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Brammer: Celgene: Research Funding. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Maziarz:Novartis: Consultancy; Athersys: Consultancy, Patents & Royalties, Research Funding.