ALBERT

Description: Key Points Anti-CD45 RIT may replace TBI and simplify BMT-preparative regimens. Anti-CD45 RIT and haploidentical BMT, without TBI, prolongs survival in a murine leukemia model.

Description: Abstract 2622 Background: Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS with 10–19% blasts) are associated with higher mortality in the elderly population. This poor outcome is in part attributed to therapy resistance and therefore, using combinations of agents with different mechanisms of action may improve outcomes. The nitrogen mustard Bendamustine combines unique alkylating characteristics with putative anti-metabolite activity while Idarubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs. In this single-arm adaptive phase I/II dose-escalation trial, we assessed increasing doses of Bendamustine in combination with a uniform dose of Idarubicin. We used a Bayesian approach to determine whether there was a dose of Bendamustine which, together with Idarubicin can provide a complete response (CR) rate of at least 40%, with minimal ( 50. Methods: Eligible patients were age 350 with untreated AML or high-risk MDS, had an ECOG performance status 40% was also

Description: Background Treatment outcomes for older patients with newly diagnosed AML remain poor. TST is an oral aminopeptidase inhibitor that has anti-neoplastic activity in a variety of malignancies, including AML. Phase I/II monotherapy studies in patients with relapsed AML and MDS have shown TST to have adequate safety and promising efficacy. Pre-clinical AML blast proliferation assays have demonstrated synergy between TST and both cytarabine and hypomethylating agents. For this reason, we performed a randomized, open-label Phase II trial using TST in combination with intermediate-dose cytarabine or decitabine in patients with untreated AML or high-risk MDS (i.e. RAEB-2). Methods Patients ≥60 years old with untreated AML or high risk MDS were randomized to receive TST 120 mg daily by mouth days 1-21 with 5 days of either cytarabine 1 g/m2/day IV or decitabine 20 mg/m2/day IV delivered every 35 days. Patients received up to three 35-day cycles if they had at least stable disease with an acceptable toxicity profile following the initial course. Patients who did not achieve a complete remission (CR) or CR with incomplete blood count recovery (CRi) after 3 cycles of therapy were taken off study; patients who obtained CR/CRi were eligible to receive up to 2 additional cycles (maximum of 5). The primary objective was to determine the rates of CR and 4 month survival using TST in combination with either cytarabine or decitabine for older patients with untreated AML or high-risk MDS. Results A total of 26 patients have been treated, with 14 receiving TST/cytarabine and 12 receiving TST/decitabine. The median age was 69 (range, 60-83), and 22 patients (85%) presented with an ECOG performance status of 1. Nineteen patients (73%) had AML and 7 (27%) had MDS RAEB-2. Nineteen patients (73%) had intermediate-risk and 7 (27%) had adverse-risk disease by European Leukemia Net criteria. Fourteen patients (54%) had secondary AML/MDS or antecedent hematologic disorder. The median duration of treatment was 3 months. The overall CR/CRi rate was 54%, with 10 patients (39%) achieving a CR and 4 patients (15%) achieving a CRi. Five patients required 3 cycles, four patients required 2 cycles and five patients required 1 cycle of therapy to achieve maximal disease response. CR/CRi was attained in 3 patients with adverse cytogenetics and 4 additional patients with FLT3 mutations. Of the 14 patients who achieved a CR/CRi (54%), 7 were treated on each of two study arms. Nine of the 14 patients who achieved a CR/CRi were referred for allogeneic hematopoietic cell transplantation (HCT), 3 patients deferred HCT, and 1 patient died of sepsis in CRi 133 days after starting induction. Ten patients were taken off study after a median of 2 cycles due to lack of response or disease progression. With a median follow-up of 5.7 months (range, 0.5-13.4), 21 patients (81%) lived longer than 4 months. Five (19%) of the 26 patients died within 4 months of starting therapy. Of these five patients, three died of sepsis on subsequent salvage protocols, one with a history of myeloproliferative disorder died of splenic infarct within 15 days of starting therapy and a fifth patient died at age 83 during cycle 2 of unknown cause. Eight patients (31%) were treated completely as outpatients without requiring hospitalization, and 15 patients (58%) were hospitalized at some point during treatment for febrile neutropenia. There were no Grade 3-4 non-hematologic toxicities requiring withdrawal from the study. Conclusions These results demonstrate that TST at 120 mg daily in combination with cytarabine or decitabine resulted in a 54% CR/CRi rate in 26 older patients with untreated AML or high-risk MDS. This approach was well tolerated as predominantly outpatient therapy and may warrant further study in a controlled trial. Disclosures: Wang: Cell Therapeutics, Inc.: Employment. Myint:Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment, Equity Ownership.

Description: Background: Chemoimmunotherapy regimens remain the preferred first-line treatment for most of patients with CLL/SLL. Recent studies have demonstrated the efficacy of maintenance regimens by improving progression-free survival (PFS). We studied safety and efficacy of a treatment protocol that included induction and maintenance components using vorinostat, a histone deacetylase inhibitor, in combination with FCR for induction and with rituximab for the maintenance. Methods: Previously untreated CLL/SLL patients with indication for treatment were eligible. Primary objective of the Phase I part was the maximum tolerated dose (MTD) of vorinostat that could be combined with FCR and PFS was the primary endpoint for phase II. In the induction phase, FCR (fludarabine 25 mg/m2 days 1-3, cyclophosphamide 250 mg/m2 days 1-3 and rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of subsequent cycles) was given every 28 days for 6 cycles. In addition to FCR, patients received vorinostat orally on days 1-5 and days 8-12 of each treatment cycle. In the dose finding phase, vorinostat was given at 3 dose levels: 200 mg, 300 mg and 400 mg PO daily. There was no dose limiting toxicity and 400 mg was chosen as the MTD for phase II. Patients who received at least 4 cycles of induction were eligible to receive maintenance beginning within 3 months of the last cycle of FCR. In the maintenance phase, given every 3 months for 8 cycles, rituximab was given at dose of 500 mg/m2 on day 1 and vorinostat was given at 400 mg PO daily on days 1-14 of each cycle. Results: 40 patients (CLL 32, SLL 8) were treated. Median age was 58 years (36-72). Median time from diagnosis to treatment was 27 months (0 -102). Rai stage at the time of treatment was I/II in 23 (60%) and III/IV in 17 (40%) patients. Cytogenetic (CG) abnormalities included del17p in 2 (5%), del11q in 2 (5%), trisomy 12 in 4 (10%), del13q in 3 (7.5%), normal CG in 14 (35%) and other abnormalities in 6 (15%) patients. Median number of induction cycles was 6 (1-6) and 33 patients (83%) patients finished at least 4 cycles of induction and were eligible for maintenance. Reasons for delivery of less than 4 induction cycles were patient preference (2), GI toxicity (1), thrombocytopenia (1), pulmonary emboli (1), progressive disease (1) and sepsis (1). Twenty-six patients (65%) received at least 1 cycle of maintenance treatment (median 8; range, 1-8) and 15 patients (40%) finished all 8 planned maintenance cycles. Eleven patients started maintenance treatment but did not receive all 8 maintenance courses due to neutropenia (3), patient preference (3), infections (1), insurance issues (1) or other reasons (3). Six patients (15%) were eligible for maintenance but did not receive it because of hematologic toxicities (3), infection (1) or patient preference (2). Overall response rate after induction was 91% with CR in 26 (74%), PR in 4 (11%), nPR in 2 (6%) and stable disease (SD) in 1 (3%). One patient (3%) had progressive disease during the induction and 1 (3%) was not evaluable. Twenty-one of 23 (88%) patients who achieved CR after induction, were tested for minimal residual disease (MRD) by flow cytometry and cytogenetics and 21 (91%) had negative MRD status. One of 2 CR patients who was MRD positive after induction converted to MRD negative after maintenance. After median follow-up of 42 months, 5-year estimate of overall survival was 90% (95% CI 75%-96%) and 5-year estimate of PFS was 72% (95% CI 51%-85%). None of the patients who achieved CR after induction (n=26; 74%) had disease progression after median 46 months of follow-up while 3 of 6 patients with PR or nPR had disease progression which occurred median of 40 months (29-51). Most common grade 3-4 toxicities were hematologic (36%), electrolyte abnormalities (9%), gastrointestinal (8%) and cardiovascular (6%). 4 patients (10%) died during the follow-up because of disease progression (1), sepsis (1), fungal infection (1) and suicide (1). Median time to death was 9.5 months (5 -20). Conclusion: Combination of vorinostat with FCR for induction and with rituximab for maintenance was feasible and effective with a high ORR and long OS and PFS with no relapses observed among patients who achieved CR after induction. Cytopenias and infections were main reasons for treatment discontinuation especially during the maintenance phase. Combination of novel agents with conventional induction and maintenance regimens is a promising strategy for treatment of CLL/SLL. Disclosures Shadman: Gilead: Honoraria, Research Funding; Emergent: Research Funding; Acerta: Research Funding; Pharmacyclics: Honoraria, Research Funding. Gopal:Paid Consultancy- Gilead, Janssen, Seattle Genetics, Spectrum, Research funding- Gilead, Janssen, Pfizer, BMS, Merck, Teva, Takeda, Spectrum, Seattle Genetics: Consultancy, Honoraria, Research Funding. Press:Roche / Genentech: Consultancy, Research Funding. Maloney:Juno Therapeutics: Research Funding; Genentech/Roche: Consultancy, Honoraria.

Description: Background Despite the initial response to combination chemotherapy in CLL/SLL patients, disease relapse and minimal residual disease (MRD) remain major issues in treatment of these diseases. Therefore, developing more effective treatments for CLL/SLL patients is a necessity. One strategy is to eliminate persistent disease using radioimmunotherapy (RIT), such as 131I-tositumomab (Bexxar®), as consolidation after an objective complete (CR) or partial response (PR) after an induction regimen. In this study we investigated the tolerability and efficacy of standard non-myeloablative doses of 131I-tositumomab following primary induction chemotherapy in CLL/SLL patients in first remission. Patients and Methods Patients older than 18 with CLL/SLL with indication for treatment were included if they were in first CR or PR from prior treatments and had

Description: Introduction: Patients with Diffuse large B-cell lymphoma (DLBCL) may experience excellent long-term outcomes after initial anthracycline containing therapy. However, patients with relapsed or refractory (R/R) DLBCL often have poor outcomes. Select R/R DLBCL patients may be treated with additional chemoimmunotherapy (CIT) followed by hematopoietic stem cell transplant (HSCT). However, as many as 50% of R/R DLBCL patients are unable to undergo HSCT due to lack of response to CIT or comorbidities (Gisselbrecht C, et al JCO 2010). Recent data reported in the SCHOLAR-1 study suggest a median overall survival (OS) of 6.3 months for these patients, with only 20% of patients alive at 2 years (Crump M, et al Blood 2017). Chimeric antigen receptor T-cell (CAR-T) therapy, a novel form of immunotherapy, offers improved outcomes for such patients with complete response rates of approximately 40% and 50% OS at 12 months or greater (Neelapu SS et al. NEJM 2017; Borchmann P et al, EHA 2018). Delivery of CAR-T therapy is specialized and remains limited to a small number of centers at present. The broad applicability of CAR-T therapy in a real world population of R/R DLBCL patients remains unknown. This retrospective study aimed to identify the characteristics and outcomes of a cohort of R/R DLBCL patients who would have been eligible for CAR-T cell therapy if available over a 4 year period at Swedish Cancer Institute (SCI). The SCI is a specialty cancer research center, based in a non-profit, non-university affiliated medical center. Methods: All patients with recorded diagnosis of DLBCL (ICD9/10) seen for an outpatient encounter in a SCI facility between the dates of 01/01/2014 and 01/01/2018 were identified from an electronic medical record database. Patients who had received anthracycline-based chemotherapy only at SCI as initial therapy and then subsequently received 2nd line or beyond therapy at SCI between January 2014 and January 2018 were included. This population was defined as the study cohort of R/R DLBCL patients and was then evaluated for would-be eligibility for CAR-T therapy by application of the defined Kite Zuma-1 clinical trial Inclusion/Exclusion (I/E) criteria. Patient characteristics for the CAR-T eligible population were obtained by retrospective medical record review. Overall survival of the potential CAR-T eligible population was assessed including stratification by receipt of HSCT at any time during the study period. Results: 486 patients with a diagnosis of DLBCL were seen during outpatient SCI encounters between Jan 2014 and Jan 2018. Of these, 60 patients received prior 1st line anthracycline therapy exclusively at SCI and then received 2nd line or beyond therapy at SCI between 2014 and 2018 for R/R DLBCL. The majority of patients, 82% (n=49), met all Zuma-1 I/E criteria for CAR-T therapy. Characteristics of these patients are identified in Table 1. Among all CAR-T eligible patients, OS was 37.1% at 24 months (Figure 1). Patients received a variety of 2nd line or beyond therapies, including 47% (n=23) who received HSCT. OS at 24 months for CAR-T eligible patients was significantly better for those receiving HSCT in 2nd line or beyond versus those who did not receive HSCT (61.6% vs 12.0%, respectively; p

Description: Background: Blasts and leukemic stem cells of acute myeloid leukemia (AML) as well as several other hematologic malignancies express CD123, potentially providing a target for novel therapies. XmAb14045 (also known as SQZ622) is a potent bispecific antibody targeting both CD123 and CD3 that stimulates targeted T cell-mediated killing of CD123-expressing cells, regardless of T cell antigen specificity. It is a full-length immunoglobulin molecule designed to be dosed intermittently, in contrast to smaller constructs that are referred to as "DART" or "BiTE" bispecific antibodies that require a continuous infusion. Methods: Patients with relapsed or refractory AML, B cell acute lymphoblastic leukemia (B-ALL), blast phase chronic myelogenous leukemia, or blastic plasmacytoid dendritic cell neoplasm were eligible to enroll on this first-in-human, multicenter, open-label phase 1 dose-escalation study (XmAb14045-01) with standard 3+3 design. The primary objective was to estimate the maximum tolerated dose (MTD) or recommended dose and schedule of XmAb14045. Secondary objectives included safety, preliminary antileukemic activity, and pharmacokinetics/pharmacodynamics of XmAb14045. Treatment was administered weekly in 28 day cycles, using a weight-based dose with a single dose level in Part A and, in Part B, an initial priming dose on Day 1 followed by an escalated dose on subsequent weeks. Premedication to prevent cytokine release syndrome (CRS) was instituted as needed and included a steroid, acetaminophen, and diphenhydramine. Patients were premedicated at all XmAb14045 doses ≥0.075 µg/kg. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the 2017 European LeukemiaNet (ELN) criteria after Cycle 1 and after each odd-numbered cycle. CRS was graded using the CRS revised grading system (Lee et al., Blood, 2014). Results: At data cut-off, 64 patients have been treated to date, 63 with relapsed/refractory AML and 1 with B-ALL. Patients had a median age of 61 years and were heavily pretreated (median of 3 prior therapies [range 1-8], including 19 [30%] who had undergone prior allogeneic stem cell transplantation). The recommended dose for Part A was 1.3 µg/kg after a single dose-limiting toxicity of Grade 4 CRS at 2.3 µg/kg; no MTD has been identified. CRS or its component symptoms was the most common treatment-emergent adverse event (TEAE). CRS episodes began within approximately 1-4 hours of the start of drug infusion and occurred in 49 of 64 patients (77%). Seven patients (11%) developed Grade ≥3 CRS, the majority of these on the first dose. There were no CRS-related deaths. Excluding CRS-related events, additional TEAEs occurring in 〉10% of patients included fatigue (31%), febrile neutropenia (30%), peripheral edema (30%), cough (23%), elevated hepatic transaminases (19%; all recovered without sequelae), pneumonia (17%), stomatitis (14%), hyperglycemia (13%), and sepsis (11%). No myelosuppression requiring dose modification or evidence of tumor lysis syndrome was seen. In Part A, single agent antileukemic activity was documented with a best response of CR (2) or CRi (1) in 3/13 AML patients (CR/CRi rate 23%) treated at the two highest dose levels studied to date (1.3 and 2.3 µg/kg weekly); no CR, CRi, or morphologic leukemia-free state (MLFS) responses were seen at lower doses. Antileukemic activity occurred quickly; all responders had achieved at least an MLFS response after 4 doses (1 cycle). Two responders were bridged to stem cell transplantation, and the third was ineligible for medical reasons but remains in remission at 14+ weeks after initiating therapy. Conclusions: XmAb14045 demonstrated evidence of antileukemic activity in heavily pretreated patients with relapsed/refractory AML treated in Part A at the 1.3 and 2.3 µg/kg doses administered once weekly, with a 23% CR/CRi rate. CRS was the most common toxicity but was generally manageable with premedications. The study is ongoing with further optimization of dose, schedule, and premedication regimen for CRS anticipated during accrual to dose escalation cohorts in Part B. ClinicalTrials.gov Identifier: NCT02730312 Disclosures Ravandi: Xencor: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding. Foran:Xencor, Inc.: Research Funding; Agios: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Mawad:Swedish Cancer Institute: Employment. Blum:Astellas: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Research Funding; Forma: Research Funding; Xencor: Research Funding; Tolero: Research Funding. Saville:Xencor, Inc.: Employment, Equity Ownership. Johnson:Xencor, Inc.: Employment, Equity Ownership. Vanasse:Novartis: Employment, Equity Ownership. Ly:Xencor, Inc.: Employment, Equity Ownership. Mims:Novartis: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Description: Background The limitations of current CLL/SLL treatments include suboptimal response rates, variable remission durations, toxicities, and few cures. Vorinostat is a histone deacetylase inhibitor that regulates gene transcription and possibly CD20 expression, leading to its investigative use in the treatment of B-cell malignancies. For this reason, we studied the addition of vorinostat to fludarabine, cyclophosphamide and rituximab (FCR+V) followed by maintenance therapy with rituximab and vorinostat. Methods Patients over age 18 with previously untreated Rai stage I-IV CLL or SLL and ECOG 0-2 were eligible. They received 4-6 cycles of FCR+V followed by up to eight cycles of maintenance with rituximab and vorinostat. Each cycle of FCR used cyclophosphamide 250 mg/m2 IV on days 1-3 and fludarabine 25 mg/m2 IV days 1-3 of each cycle given every 28 days; with rituximab 375 mg/m2 IV once with cycle 1 followed by 500 mg/m2IV once per cycle for cycles 2-6. Rituximab 500 mg/m2 IV was given day 1 of each 3 month cycle of maintenance for up to 8 cycles. Vorinostat was given on days 1-5 and 8-12 of each treatment cycle and days 1-14 of each 3-month maintenance cycle. The Phase I vorinostat starting dose was 200 mg/day and escalated by 100 mg/day to a maximum pre-determined dose of 400 mg/day in a 3 x 3 design. Since no dose limiting toxicity was seen during Phase I, the previously designated maximum dose of 400 mg/day vorinostat was chosen for the Phase II portion of the trial. Results Ten patients were treated on the Phase I portion of the study, and 26 patients have been enrolled in the Phase II portion at the maximum vorinostat dose of 400 mg/day combined with FCR and rituximab maintenance. The median age of patients on study was 58 (range, 36-72); with 6 patients enrolled with Stage I, 15 with Stage II, 5 with Stage III and 10 with Stage IV disease. Nine patients (25%) had 〉30% CD38 expression, 13 patients (36%) had 〉20% ZAP70 expression, and 4 patients (11%) had 17p deletions detected by FISH of marrow samples. Median follow-up on study is 15 months (range, 0.9-38.6). Of the 36 patients enrolled, 22 patients are evaluable after completing 4-6 cycles of FCR+V, 1 patient progressed after cycle 2 (del17p), 9 patients are currently receiving FCR+V and 4 patients are unevaluable. Of these 4 patients, one withdrew voluntarily, one was taken off study due to non-compliance, one went off study after cycle 3 due to cytopenias, and one patient with multiple co-morbidities died of sepsis after cycle 5. Of the 22 patients who have completed 4-6 cycles of FCR+V, 16 (73%) obtained a complete response (CR), 5 (22.5%) obtained a partial response (PR), and 1 (4.5%) has stable disease. Of these 22 patients, 4 (18%) have completed 8 cycles of maintenance with rituximab and vorinostat, 5 (23%) were taken off study due to cytopenias, 1 (4.5%) went off study due to insurance issues, 1 (4.5%) went off study due to recurrent infections, 2 (9%) voluntarily withdrew from study, and 9 (41%) are still receiving maintenance therapy. The most common grade 3-4 non-hematologic toxicities during FCR+V were gastrointestinal symptoms in 10 patients and fatigue in 3 patients. However, there were no grade 3-4 non-hematologic toxicities that resulted in patient withdrawal from study during treatment with FCR+V. No grade 3-4 non-hematologic toxicities have been observed in patients who have completed or are undergoing maintenance with rituximab and vorinostat. Conclusion Treatment of CLL/SLL with fludarabine, cyclophosphamide, rituximab and 400mg/day vorinostat (FCR +V) followed by maintenance with rituximab and vorinostat appears feasible and tolerable, and may warrant further study. Disclosures: Gopal: Merck: Research Funding. Press:Roche/Genentech: Consultancy.

Description: Background: Tosedostat is an oral aminopeptidase inhibitor that has anti-neoplastic activity in a variety of malignancies. Pre-clinical assays have demonstrated synergy between tosedostat and both cytarabine and hypomethylating agents. We performed a randomized, open-label Phase II trial to determine the rates of complete remission (CR) and 4 month overall survival using tosedostat in combination with intermediate-dose cytarabine or decitabine in patients with untreated AML or high-risk MDS. Methods: Patients ≥60 years old were randomized in a 1:1 fashion to receive tosedostat 120 mg daily by mouth days 1-21 with either 5 days of intravenous cytarabine 1 g/m2/day or decitabine 20 mg/m2/day delivered every 35 days for up to three cycles. Eight patients received 180 mg tosedostat daily continuously. Patients who obtained a CR or CR with incomplete blood count recovery (CRi) after 3 cycles of therapy were eligible to receive up to 2 additional cycles (maximum of 5). Results: Thirty-four patients with a median age of 70 (range, 60-83) years were treated, with 17 each receiving either tosedostat/cytarabine or tosedostat/decitabine. Twenty-nine patients (85%) had AML and 5 (15%) had MDS RAEB-2. Nineteen patients (56%) had cytogenetics with intermediate-risk, 14 (41%) adverse-risk, and 1 (3%) favorable-risk by European Leukemia Net criteria. Seven patients had FLT3/ITD mutations with normal cytogenetics. Fifteen patients (44%) had secondary AML/MDS or antecedent hematologic disorder. The median duration of treatment was 3 months. The overall CR/CRi rate was 53% (9 in each arm), with 14 patients (41%) achieving a CR and 4 patients (12%) a CRi. CR/CRi was attained in 6 patients with adverse cytogenetics and 4 additional patients with FLT3 mutations. Fourteen patients (41%) were taken off study after a median of 2 cycles due to lack of response or disease progression. With a median follow-up of 11.2 months (range, 0.5-22.3 months), the median overall survival was 11.5 months (95% CI, 5.2-16.7). Twenty-three patients (67.6%) were treated as outpatients and 10 of these patients (44%) required hospitalization during treatment for febrile neutropenia. There were no Grade 3-4 non-hematologic toxicities requiring withdrawal from the study. Conclusions: Tosedostat in combination with cytarabine or decitabine likely provides a CR/CRi rate of 〉50% with acceptable toxicity in older patients with untreated AML/ MDS. This approach delivered predominantly as outpatient therapy suggests that further study in a larger, controlled trial may be warranted. Disclosures Off Label Use: Pravastatin is not FDA approved for treatment of AML. Wang:CTI Biopharma: Employment. Singer:CTI BioPharma, Corp: Employment, Equity Ownership.

Description: Introduction Central nervous system (CNS) recurrence after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. Our goal was to investigate the post-HSCT outcome of ALL patients and identify patient groups who may benefit from post-HSCT CNS prophylaxis. Methods In this two-center retrospective study, we studied all adult (age≥18) ALL patients who underwent HSCT at MD Anderson Cancer Center or Fred Hutchinson Cancer Research Center between 1997 and 2011. We included all adult ALL patients who were transplanted in the first or second complete remission (CR) and who received any prophylactic or therapeutic CNS therapy before HSCT. We assessed the cumulative incidence of systemic and CNS relapses in a competing risks framework with a competing risk of non-relapse death. Since data from second and subsequent relapses were not available, patients whose first relapse did not include CNS involvement were censored at the time of relapse. To analyze the association between post-HSCT CNS prophylactic therapy and CNS relapse, we used a landmark analysis, including only patients who had not relapsed or died by 3 months post HSCT. Results We included 415 adult ALL patients (239 in CR1 and 176 in CR2) who were transplanted with a myeloablative total body irradiation based (MA-TBI, n=252), myeloablative non-TBI based (MA-nonTBI, n= 130), or reduced intensity conditioning regimen (RIC, n=33). Median age at HSCT was 37 years (range 18-70; 59% male). Sixty seven patients (16%) had a history of pre-HSCT CNS involvement either at diagnosis or at time of first relapse, while 339 patients (81%) had no CNS disease at any time before HSCT. Overall 175 patients (42%) received CNS prophylaxis after HSCT. CNS prophylaxis included intrathecal methotrexate, cytarabine, or both agents. Two patients received prophylactic cerebrospinal radiotherapy. The median follow-up for the 189 surviving patients was 4.2 years. Sixteen patients (3.8% of all patients, 13.2% of all relapses) developed CNS relapse (11 isolated and 5 combined with marrow relapse) at a median of 231 days (range 38-1397) after HSCT. Seven of these patients had pre-HSCT CNS disease. The 4-year cumulative incidence of relapse after HSCT among all patients was 31.7% and 28.2% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.51). The 4-year cumulative incidence of CNS relapse was 6% and 2.6% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.16) (Figure 1). When the analysis was limited to the patients without prior CNS involvement, there was still no benefit to post-HSCT CNS prophylaxis (P=0.63). Patients with a prior history of CNS involvement with leukemia had a significantly higher rate for CNS relapse, 11.6% vs. 2.7% (P=0.003) (Figure 2). The 4-year rate of CNS relapse was not impacted by intensity of the HSCT conditioning regimen and was 3%, 4%, and 6.5% for RIC, MA-TBI, and MA-nonTBI, respectively. Conclusion CNS relapse is an uncommon event following HSCT for ALL in CR1 or CR2. Furthermore, neither the intensity of the HSCT conditioning regimen nor the routine use of post-HSCT CNS prophylaxis made a significant difference in the rate of post-HSCT CNS relapse in patients who had received CNS prophylaxis prior to HSCT. Not surprisingly, patients with a pre-HSCT history of CNS involvement had a significantly higher risk of CNS relapse after HSCT. Disclosures: No relevant conflicts of interest to declare.