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Background: The incidence of multiple myeloma (MM) and enrichment of cytogenetic abnormalities differ significantly between racial/ethnic groups in the US, and their significance in determining myeloma progression and survival is not well understood. Whole genome sequencing has identified unique mutational signatures in MM, including an age-related process common in hyperdiploid myeloma. Our purpose was to describe racial and age-related differences in the impact of high-risk cytogenetic abnormalities (HRCAs) on survival in MM. Methods: We conducted a retrospective cohort study of adult MM patients starting first-line therapy between January 2011 and May 2021 using the nationwide Flatiron Health electronic health record-derived de-identified database. Patient-level demographic and clinical characteristics were ascertained using structured and unstructured data, curated via technology-enabled abstraction. Patients who had documented fluorescence in situ hybridization testing within 30 days prior to or 90 days following the start of first-line treatment were included. HRCAs, including gain or amplification 1q21, deletion 17p, t(4;14), t(14;16) and t(14;20), were identified and categorized as 0, 1, or 2+ HRCAs. Our outcomes of interest were real world progression free survival (rwPFS) and overall survival (rwOS). Cox proportional hazards models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI), adjusted for demographic and clinical characteristics and treatment including time-dependent receipt of autologous stem cell transplantation. Results: From a cohort of 4889 MM patients, there were 790 (16%) Black and 2995 (61%) White patients with median ages at diagnosis of 68 and 70 years, respectively. Compared to White patients, a higher proportion of Black patients had IgG M-protein (61% vs 55%) and a lower proportion had 1+ HRCAs identified (31% vs 34%). Among all racial groups, compared to patients aged Multivariable models showed evidence of significant statistical interaction between age and prevalence of HRCA for rwPFS (P-int: 0.02). Among White patients, having 2+ HRCAs ("double-hit MM") compared to no HRCAs was associated with worse rwPFS in both younger and older patients ( Similarly, we also found evidence of statistical interaction between age and prevalence of HRCA for rwOS (P-int: 0.02). Among White patients, double-hit MM was significantly associated with worse rwOS but the magnitude of increased risk differed for younger (HR 3.39, 95% CI 2.24-5.14, P Conclusions: In this cohort of newly diagnosed MM patients treated in routine practice, having double-hit MM was differentially predictive of poor survival across age groups. Double-hit MM was associated with worse rwPFS and rwOS among White patients, but these trends were less consistent among Black patients. Our current understanding of cytogenetic risk stratification of MM requires further study and additional data for identifying low- and high-risk subsets of patients across different ages and racial groups. Figure. Kaplan-Meier survivor functions for rwPFS in White (Panel A) and Black (Panel B) patients by age group and number of HRCAs Figure 1 Figure 1. Disclosures Calip: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company; Pfizer: Research Funding. Ascha: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wang: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Pierre: Flatiron Health, Inc: Current Employment; Roche: Current holder of stock options in a privately-held company. Maignan: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wadé: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Leng: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Seymour: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Current equity holder in publicly-traded company; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Flatiron Health Inc: Current Employment. Patel: Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding.

Opioid analgesics are used to treat cancer-related pain and improve quality of life, however overuse of these high-risk drugs has been associated with significant public health implications as exhibited by the national attention received during the opioid pandemic. In addition, pain associated with hematologic malignancies is frequent yet not well understood. There is no data examining opioid use and outcomes in patients with hematologic malignancies and recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we sought to describe chronic opioid use (COU) and its impact on long-term outcomes in patients undergoing allo-HSCT. We analyzed outcomes of adult patients ≥ 18 years (n=159) diagnosed with hematologic malignancies (n=151) or benign hematologic disorders (n=8) (excluding sickle cell disease) who received allo-HSCT between 2012 and 2019 at a single urban medical center. COU was defined as having a documented active prescription for 3 consecutive months. Daily opioid doses were converted to morphine milligram milliequivalents (MME) using standard conversion factors. Among the entire cohort, the median age was 55.4 (19.4-74.3) years, 94 (59.1%) were male, 70 (44%) were White, 42 (26.4%) were Hispanic, and 26 (16.4%) were Black. The majority of patients were diagnosed with acute leukemia, with 89 (56%) having AML and 16 (10%) having ALL patients. Of the remaining patients, 14 (8.8%) were CML-BP or CML-AP, 16 (10%) NHL/HD, and 15 (9.4%) MPDs. 33.5% of patients were found to have high or very high DRI prior to allo-HSCT. Most patients received either a myeloablative (n=102, 64.2%) or reduced-intensity (n=55, 34.6%) conditioning regimen. At baseline (immediately prior to allo-SCT), COU was observed in 38 (23.9%) patients, 20 (52.6%) of which were diagnosed with AML. Only 23 (60.5%) patients with COU had a documented indication for opioid analgesia. The baseline median MME per day was 23.5mg (range: 2-150). In logistic regression analysis including demographic and social factors such as insurance type (i.e. Medicare, Medicaid, private payer), education level, smoking, alcohol, illicit drug and/or benzodiazepine use, and employment status, only older age (RR 0.97, 95% CI 0.94-0.99; p=0.026) was associated with a lower likelihood of baseline COU. In total, 149 (93.7%) patients received opioids during the allo-HSCT admission, while 45 (28.3%) were discharged on opioids. The reason for being discharged on opioids was related to musculoskeletal pain (n=19), residual mucositis-related pain (n=7), and headache (n=3). This was found to persist over time, with 35 (92.1%) of the 45 patients discharged on opioids remaining on opioids at 180 days after allo-HSCT thus meeting the definition for COU. The only factor found to predict for COU at 6 months was discharge from initial transplant hospitalization with an opioid (RR 2.24, 95% CI 1.16-4.32, p=0.016). Not only did a significant number of post-transplant survivors meet the definition for COU, but the MME was found to be relatively high with a median of 50mg (range: 10-540) at discharge and 30mg (range: 4.5-202) on days +30, 90, 180 as well as at 1 and 5 years after allo-HSCT. In a multivariable modified Poisson regression with robust standard errors for binary outcomes, when adjusted for established prognostic characteristics (i.e., disease, DRI, HCT-CI), we found that COU prior to admission strongly predicted for worse overall survival (HR 2.99, 95% CI 1.59-5.64; p=0.001), progression free survival (HR 2.72, 95% CI 1.48-4.99), and GVHD free, relapse-free survival (HR 1.78, 95% CI 1.05-3.03; p=0.033). This study is the first to describe patterns of COU, an important public health problem, among patients undergoing allo-HSCT, and in particular in long term survivors. We demonstrate high rates of baseline COU in patients undergoing allo-HSCT as well as persistent long term COU, which is linked to prescribing patterns after the initial transplant hospitalization. In addition, we show the negative impact of baseline COU on overall survival, even when adjusted for disease- and transplant-related factors. These data highlight the need to improve understanding and management of pain in hematologic malignancies as well as to reinforce the need for continuous reassessment of the use of opioids prior to and after allo-HSCT. Disclosures Calip: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company; Pfizer: Research Funding. Rondelli: Vertex: Membership on an entity's Board of Directors or advisory committees. Patel: Celgene: Consultancy.

Background Vaccine hesitancy, defined as the delay in acceptance or refusal of safe vaccines, remains a challenge in the general population. Given that patients with hematologic malignancies frequently encounter healthcare professionals and are at high risk of severe COVID-19 infection, their attitudes towards vaccines may differ from other patient groups. We therefore performed a survey-based study to investigate vaccine hesitancy within an ethnically diverse group of patients diagnosed with hematologic malignancies. Methods We administered a 122-item questionnaire from December 2020 to January 2021 (prior to commercial availability of the COVID-19 vaccines) to 60 patients with hematologic malignancies. Questions were separated into the following categories: demographic and socioeconomic data; personal impact of COVID-19 infection; COVID-19 pandemic experience; COVID-19 infection perceptions; COVID-19 vaccine perceptions; and baseline COVID-19 vaccine knowledge. Results The majority of patients were Black (n=33, 55%) or Hispanic (n=11, 18.3%) and were undergoing active treatment (n=43, 71.7%) or had received prior hematopoietic stem cell transplantation (n=9, 15%). Eight (13.3%) patients had prior COVID-19 infection. Sixteen (26.7%) patients reported infection in an immediate family member while 15 (25%) reported infection in a friend. 20 of these cases were moderate in severity requiring healthcare interaction, and 17 of these cases were reported to result in severe infection (n=7, 9.6%) or death (n=10, 13.7%). Only 16 (29.6%) patients perceived themselves to be at high or very high risk of COVID-19 infection. The COVID-19 pandemic was reported to moderately or severely affect employment/income in 10 (22.8%) patients and led to worse mental health in 10 (22.3%) patients. However, the majority of patients reported no negative impact on their cancer treatment (n=37, 88.1%) or prognosis (n=45, 93.8%). Of the 60 patients, 22 (40.7%) reported that if a COVID-19 vaccine was made publicly available in the next 30 days, they would not vaccinate themselves, either due to safety concerns (n=4, 20%) or indifference (n=6, 30%). Despite this, 43 (78.2%) patients stated that vaccination was an important tool in ending the pandemic. More patients agreed to accept the vaccine if it was made available in 6 months from the time of survey (n=40, 76.9%). Only 32 (59.3%) patients were extremely or very likely to accept a yearly vaccine. In terms of perception on cancer outcomes, 31 (62%) patients were uncertain if the vaccine would interact negatively with their current chemotherapy treatment, while 27 (52.9%) believed the vaccine would make their cancer worse. The biggest fear patients had about COVID-19 vaccines were side effects or death (n=15, 38.5%) and complications to cancer/cancer therapy (n=5, 12.8%). Only 6 (15.4%) patients stated they had no fears related to COVID-19 vaccination. In fact, only 21 (39.6%) patients agreed or strongly agreed that the side effects of most vaccines outweigh the benefits. In a modified (age- and sex-adjusted) Poisson regression model (Table 1) that included baseline demographics and answers to select survey questions, older age was associated with a stronger likelihood of vaccine acceptance (RR 1.73, 95% CI 1.11-2.71; p=0.016), while female gender was associated with less likelihood to accept the vaccine (RR 0.58, 95% CI 0.37-0.90; p=0.016). Patients reported as "other" race (e.g., Asian) were more inclined to accept the vaccine (RR. 2.21, 95% CI 1.16-4.20; p=0.016) compared to White patients. Finally, when compared to patients who receive information primarily from medical professionals, those patients who received their information from social media or friends were far less likely to accept the vaccine (RR 0.02, 95% CI 0.01-0.04; p Conclusion This is the first study to report that although patients with hematologic malignancies experienced significant medical and social burdens from the COVID-19 pandemic and have frequent interaction with healthcare professionals, a high rate of COVID-19 vaccine hesitancy still exists. We provide in depth information on the potential reasons for vaccine refusal in a diverse patient population and highlight potential areas for improvement in patient education. In particular, we show that vaccine disinformation received from friends and social media is a significant reason for vaccine refusal. Figure 1 Figure 1. Disclosures Calip: Pfizer: Research Funding; Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Rondelli: Vertex: Membership on an entity's Board of Directors or advisory committees. Patel: Celgene: Consultancy.

Background Presently, acute myeloid leukemia (AML) risk stratification is estimated prior to treatment by incorporating patient and disease characteristics. However, apart from the limited use of minimal residual disease measurement, few methodologies assess AML relapse risk post-treatment. In attempts to correlate pre- and post-treatment blood cell counts with hematologic disease outcomes, the ratio, LNR, between absolute lymphocyte count (ALC) and neutrophils (ANC) has been utilized to approximate the relationship between the lymphoid system and the myeloid microenvironment (in particular myeloid-derived suppressor cells), and increased LNR is prognostic in myeloma and lymphoma. Similarly, increased LMR (lymphocyte to monocyte ratio), utilized as a crude marker of tumor-infiltrating lymphocytes and tumor-associated macrophages, predicts better outcomes in Hodgkin's disease (Romano et al. Ann Hematol2018). However, analyses correlating such ratios with AML outcomes have not been performed. Here we specifically investigate whether LNR, LMR, or neutrophil-monocyte (NMR) ratios, measured at multiple time-points, correlate with outcomes. Methods We identified patients >18 yrs receiving induction chemotherapy at our institution between 1/1/2005 - 12/31/2019. Data collected included demographics, comorbidities (Charlson Comorbidity Index [CCI]), AML subtype, cytogenetics/molecular data, ELN risk stratification, and response to therapy. We recorded patients' total WBC, ANC, ALC and AMC both prior to treatment, at first ANC recovery (ANC > 1.0 x 109/L with ALC and AMC > 0), and just prior to next therapy. We also identified a subset of patients who received consolidation chemotherapies with curative intent and collected their first WBC counts ~100 days post-therapy completion (range 50-150 days). The calculated LNR, LMR, and NMR at these time-points were correlated with Event-Free Survival (EFS), defined as time to relapse, death from any cause, or last follow-up. Data was censored on 6/1/2020. WBC ratios were categorized into tertiles. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models, survivor functions estimated using Kaplan-Meier and the equality of survivor functions tested using stratified log-rank tests. Outcomes were adjusted for CCI, age, sex, race, subtype, presence of inflammation/infection, and ELN risk. Results 145 patients met eligibility criteria, however 23 with primary refractory AML were excluded from EFS analysis. Using WBC ratios at first ANC recovery, both intermediate and high LNR trended towards a lower HR for EFS: HR 0.54 (95% CI 0.24-1.23,p= 0.142) and 0.68 (95% CI 0.32-1.33,p= 0.329), respectively, however differences were not statistically significant (Table 1 and Figure 1). A high NMR also trended towards a worse EFS: HR 1.71 (95% CI 0.74-3.99,p= 0.212), though it was also not statistically significant. LMR did not correlate with improved EFS. Notably, pre-induction ratios and the ratios measured just prior to next treatment were not associated with any differences in EFS. In a subset of patients who received curative intent consolidation chemotherapies (generally ELN favorable risk), a t-test correlating for relapse was performed, though limited by small numbers (16 without, 8 with relapse). Patients in this group who did not relapse trended toward a numerically higher LNR and LMR, 0.57 vs 0.50 (p =0.36) and 4.33 vs 3.97 (p= 0.39), respectively. Discussion In our patient population, high LNR after induction chemotherapy trended towards predicting an improved EFS. Thus, recovery WBC ratios, although crude approximations of the immune system and the tumor microenvironment, may predict patients at higher risk of relapse, however, more patients are clearly needed to show whether a statistically significant association exists. The optimal time to evaluate these counts is also not clear. Nonetheless, as blood counts are obtained routinely post-treatment, these ratios may represent a low-cost strategy to predict relapse risk, potentially allowing for earlier treatment and donor searches for allogeneic transplantation. We propose to repeat these analyses using a multi-center approach - we are especially interested in ratios measured at the 100 days post-therapy mark, as we suspect these may better reflect the immune system at steady state and, potentially, risk of relapse. Disclosures Arain: Astellas:Other: Spouse is employed.Calip:Flatiron Health:Current Employment.Khan:Takeda:Research Funding;Celgene:Consultancy;Incyte:Honoraria;Amgen:Consultancy.Patel:Amgen:Consultancy;Janssen:Consultancy;Celgene:Consultancy.Quigley:Amgen:Other: Advisory board;Agios:Speakers Bureau;Alnylam:Speakers Bureau.

Although myeloablative fludarabine/busulfan (FluBu4) has been widely adopted in clinical practice, considerable interpatient variability exists in systemic busulfan exposure (AUC) when using body weight or body surface area based-dosing, leading to decreased efficacy (i.e. relapse) or increased toxicity (i.e., mucositis, veno-occlusive disease). This well-defined dose-exposure-outcome relationship has led to the widespread clinical implementation of therapeutic drug monitoring (TDM). However, individualized TDM can be time and labor intensive as well as potentially biased due to the lack of incorporation of any previously established PK data (Bayesian prior). In contrast, Bayesian maximum a posteriori (MAP) PK models consider the Bayesian prior and individualized TDM to generate a revised probability distribution (Bayes conditional posterior) to more accurately and rapidly estimate the AUC with reduced bias. There are a paucity of data comparing busulfan AUCs using individualized PK versus MAP-Bayesian-based models in adults although these more sophisticated approaches may assist in optimizing dosing of busulfan in this vulnerable population. This was a retrospective, single-center study of patients who received FluBu4 with busulfan TDM between January 1999 and September 2019. 109 patients diagnosed with a hematologic malignancy who received either sequential (n=46) or concurrent (n=63) FluBu4 were analyzed. The median age was 48 (range: 18-66), and were Hispanic (n=38), White (n=46) or African-American (n=14). TDM was performed either after a test dose of 0.8 mg/kg (n=52) or after the first dose (3.2 mg/kg) of busulfan administered during the preparative regimen (n=71), with dosing was based on actual or adjusted body weight. For PK analysis, plasma busulfan concentrations were analyzed via gas chromatography with mass selective detection. Individualized PK data were generated using WinNonlin while the MAP-Bayesian approach utilized the Bayesian prior developed from McCune et al (Clin Cancer Res, 2014). An AUC of 4800 µM˖min/24 hours was targeted based on previous literature. Based on individualized PK data, total recommended busulfan doses ranged from 9.3-21.3 mg/kg (-27.1% to +66.7% compared to FDA labeled dose of 12.8 mg/kg). When first-dose busulfan PK was compared between busulfan given sequentially versus concurrently with fludarabine there was a trend towards a higher AUC with concomitant administration (4651 vs. 4988 µM˖min; p=0.13). A strong correlation between the AUC generated from both the individualized PK an MAP-Bayesian models was observed with both the test dose (R2=0.91) and first dose (R2=0.86) of busulfan. Using the MAP Bayesian model, AUC predictions were on average higher (mean AUC 5069 versus 4886 µM˖min, p Our individualized busulfan PK approach generated relatively similar AUC values compared to MAP-Bayesian estimates, although the higher AUC generated via MAP-Bayesian predictions may allow for lower doses of busulfan to be administered thereby potentially reducing toxicity while maintaining efficacy. Further, use of the MAP-Bayesian method may allow for more rapid dose optimization and a decreased number of serum concentrations. Further prospective studies including more patients are warranted to confirm these findings. Figure 1 Disclosures Calip: Flatiron Health: Current Employment. Patel:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy.

High dose melphalan and autologous stem cell transplantation is standard of care for the upfront treatment of multiple myeloma (MM). Several studies have shown upregulation of single DNA repair genes and whole DNA repair pathways as associated with melphalan resistance and poor outcomes after ASCT. Here we set out to identify the most important DNA repair enzymes and pathways to predict outcomes after ASCT using the MMRF CoMMpass dataset but instead found DNA repair gene expression to be a poor prognostic feature regardless of treatment. Of the 561 MM patients who received ASCT as part of frontline therapy, 378 (67%) patients had whole transcriptome sequencing data available for analysis in this study. The majority of patients in this cohort received a 3-drug novel agent-based regimen for first line treatment. We selected 81 genes of known function related to DNA damage repair across multiple pathways. Using the median mRNA expression as cutoff for each gene, we first compared PFS for high vs. low expressers and found 38 genes in non-homologous end joining (NHEJ), homologous recombination (HR), nucleotide excision repair (NER), base excision repair (BER) and Fanconi anemia (FA) pathway which predicted for inferior survival with higher expression (p≤0.05). We subsequently analyzed each gene individually in a multivariate Cox proportional hazards models adjusted for known prognostic and treatment-related factors (age, gender, race, ISS stage, LDH, normal/abnormal cytogenetics, high risk FISH/cytogenetics, cycles to first response, frontline treatment, and time to transplant) and found that 9 genes retained significance including 3 genes in NHEJ (POLL, PRKDC, NHEJ1), 3 in FA pathway (BRIP1, RMI1, FANCE) and 3 in MMR (MLH3, MSH2 and PMS1). In addition, increased pathway level gene overexpression for NHEJ (p=0.02) and MMR (0.009) pathways conferred worse PFS. Genes involved in NER did not retain significance despite this pathway being involved with repair of melphalan-induced bulky adducts formation. Additionally, high MMR pathway expression was significant despite this pathway not having a known role in repair of melphalan-induced DNA damage. To validate the specific importance of these genes in predicting response to ASCT, we tested whether high expression predicted outcomes in patients who did not undergo ASCT. In 387 non-ASCT patients with whole transcriptome sequencing available, NHEJ and MMR gene expression were significant predictors of PFS confirming that this finding was not specific to patients undergoing ASCT. We next correlated the expression of NHEJ and MMR genes and found significant co-expression of these genes (r=0.55-0.8), suggesting a common mediator leading to global upregulation of DNA repair. As increased MYC activity is a common finding in MM and is a master regulator of transcription, we hypothesized the DNA damage repair genes were upregulated by increased MYC activity. Gene Set Enrichment Analysis of hallmark gene sets confirmed that patients with increased DNA repair were also enriched for MYC targets (FDR=0.0063). Based on this, we hypothesized that oncogene-mediated constitutive DNA damage and replication stress (RS) are a hallmark of high risk and aggressive myeloma. Here we present novel findings to show that global DNA repair upregulation occurs in high risk disease as evidenced by the inferior PFS. We hypothesize that this could be attributed to MYC-related increased gene transcription resulting in DNA damage and RS which in turn recruits several DNA repair pathways. These specific DNA repair pathways and signal activation pathways involved with replication stress represent novel therapeutic targets in myeloma. Disclosures Calip: Flatiron Health: Current Employment. Hofmeister:Sanofi: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Nektar: Honoraria, Research Funding; Imbrium: Honoraria; Janssen: Honoraria, Research Funding; Oncopeptides: Honoraria; Karyopharm: Honoraria, Research Funding; Oncolytics Biotech: Research Funding. Patel:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy.

Multiple myeloma (MM) patients are predisposed to high rate of infectious complications, with viral infections and in particular varicella zoster virus infection having a more than 10-fold increased incidence compared to the general population. This risk increases with use of autologous stem cell transplant (ASCT), multiple lines of therapy for relapsed disease, and proteasome inhibitor (PI) or daratumumab treatment. An adjuvanted, recombinant vaccine, consisting of the varicella-zoster virus glycoprotein E antigen (Shingrix, GlaxoSmithKline; Triangle Park, NC) is now available but studies in MM patients have been limited to the post-ASCT setting. We aimed to analyze the initial seroconversion rates as well as persistence of seropositivity in our MM cohort undergoing active anti-myeloma treatment. We evaluated 85 MM patients undergoing active anti-myeloma treatment who were tested at baseline for VZV antibody (Ab) status. Nine (10.6%) patients were found to have high risk cytogenetics at diagnosis. The median number of prior lines of therapy was 1 (1-10), with 80 (94.1%) patients receiving a prior or current PI-based regimen, 66 (86.8%) receiving ASCT, and 15 (19.7%) receiving a prior or current daratumumab-based regimen. At the time of first vaccination, 35 (41.1%) patients were receiving post-ASCT immunomodulator (IMiD) maintenance. Seven (8.2%) patients had a prior history of VZV infection. 67 (78.8%) patients were actively receiving antiviral prophylaxis with either acyclovir or valacyclovir. To determine vaccine immunogenicity, we used an anti-VZV ELISA assay. Using this test, VZV Ab seropositivity was measured at baseline and after each of the 2 vaccinations. In the entire cohort, 41 (48.2%) patients were found to be VZV Ab negative at baseline. Multivariate modified Poisson regression models with adjustment for prognostic and clinical factors were used to estimate relative risk (RR) and 95% confidence intervals for baseline VZV Ab seropositive status. We identified ISS stage 2 (RR 0.31, 95% CI 0.21-0.61; p We report the first real world experience of the use of the adjuvanted, recombinant zoster vaccine in MM patients receiving active treatment. We show a high rate of initial VZV seronegativity and were able to show significant seroconversion after a single vaccine dose. In fact, despite studies showing benefit in patients receiving a total of 4 doses, we observed high seroconversion rates using 2 doses. Finally, we report for the first time strong predictors of baseline VZV seronegativity and maintenance of seropositivity in MM patients, in particular treatment with daratumumab. On the other hand, PI treatment was not associated with baseline seronegativity or loss of seropositivity. This data confirms that post-ASCT vaccination would be the optimal time to vaccinate patients, in particular when patients are immunocompetent while in remission on maintenance. The benefit of administering the vaccine in patients undergoing daratumumab or other treatment for progressive disease was not shown here and continued antiviral treatment rather than vaccination is likely to be the ideal prophylaxis strategy. Disclosures Calip: Flatiron Health: Current Employment. Patel:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy.

Cryopreservation of hematopoietic stem/progenitor cell (HPC) grafts and other cell based products to be infused in the future is a common practice. However, cryopreservation and conditions of storage can influence post thaw recovery of cellular products. HPC graft is composed of heterogeneous blood cells. Various assays detect viability based on different principles and their sensitivity differs. Less than 1 in 100,000 CD34+ cells possess in vivo hematopoietic reconstitution potential, therefore determination of viability and recovery need to be interpreted accordingly. We analyzed total 38 graft aliquots stored in liquid nitrogen (auto 10 yrs = 7, Auto 1 yr = 12, allo 10 yrs = 5, Allo 5 yrs = 5, allo 1 yr = 9). The viable CD34+ cell frequency in allo HPC grafts was higher than auto grafts cryopreserved 10 years ago (Auto 10 yrs = 0.39 ± 0.24%, Allo 10 yrs = 0.96 ±0.31%, Allo 5 yrs = 0.82 ± 0.3%, p = 0.018). When we compared both single and dual ISHAGE platform methods it displayed comparable post thaw viable CD34+ cell numbers (Figure 1A). The recovery of viable total nucleated cells (TNC) based on trypan blue dye exclusion was 46.83± 4.98% auto 10 years, 43.11 ± 7.76% allo 10 years, 48.74 ± 4.94% allo 5 years, 87.56 ± 6.93% allo 1 year. The viable CD34+ cell recovery between the groups were comparable (Figure 1B). Auto HPC grafts stored for more than 10 years displayed 64.05±16% while auto grafts stored less than a year yielded 85.4±15.15% viable CD34 recovery. The effects of storage duration on grafts is presented below by monitoring hematopoietic engraftment after transplantation. Interestingly, auto grafts in comparison to allo grafts stored for 5 to10 years displayed higher red fraction (JC-1); indicative of higher mitochondrial membrane potential (MMP) and viability (Auto 10 yrs = 72.24 ± 12.45%, Allo 10 yrs = 40.6 ± 13.92%, Allo 5 ysr = 47.2 ± 15.36%, p = 0.011). The higher fraction of cells with intact MMP (red fraction) within CD34+ cell compartment of post thaw suggesting likely higher resilience of auto grafts. Samples stored up to10 years displayed positive colony forming unit (CFU) growth but had poor CFU recovery. CFU recovery for HPC grafts stored for less than 1 year displayed 82.93 ± 25.68% for auto grafts while allo graft displayed 72.46 ± 34.76%. HPC grafts stored for 5 to 10 years which were utilized here to determine graft stability were transplanted within two months of storage and displayed timely neutrophil and platelet engraftment. When single ISHAGE platform method was used to enumerate viable CD34+ cells and HPC grafts are thawed within one year, viable CD34 recovery for auto HPC graft was 85.4 ± 15.15% and for allo graft recovery was 86.85 ±18.0%. Four patients which were transplanted (CD34+ cells infused mean ± SD, 4.35 ± 1.43 x 10e6/KG body weight) with autologous grafts stored for 5 to 8 years in liquid nitrogen (vapor phase) displayed timely neutrophil (9.5 ± 1 day) and platelet (16.5 ± 5 day) engraftment. Taken together, viability assays detect various aspects of cell integrity. The post thaw viable CD34 recovery corresponds well with in vivo hematopoietic reconstitution but in some instances functional potency assays particularly for samples stored longer than 5 years may be crucial. The relatively higher resilience of auto HPC grafts stored for longer than10 years is of note which will need to be further validated. Disclosures Patel: Celgene: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

The reduced-intensity conditioning (RIC) regimen consisting of fludarabine and melphalan 140 mg/m2 (Flu/Mel140) prior to allogeneic hematopoietic stem cell transplant (HSCT) has been widely adopted in clinical practice. However, pharmacokinetic (PK) studies report up to a 10-fold interpatient variability in melphalan exposure (AUC). Specifically, melphalan binds to proteins in the red blood cell membrane, leading to higher plasma concentrations in patients with lower hemoglobin. Likewise, since renal elimination contributes significantly to melphalan clearance (~ 40%), the presence of renal impairment also leads to higher concentrations. We previously identified lower hemoglobin and/or creatinine clearance as strong predictors of survival and toxicities after high dose melphalan and autologous transplant. Given this, we hypothesized that clinical variables, in particular, pre-treatment hemoglobin, could predict for outcomes after Flu/Mel140 and HSCT. We analyzed 67 consecutive patients who received Flu/Mel140. In addition to standard clinical parameters, hemoglobin (Hgb) and creatinine clearance (CrCl) on day -6 were obtained. Hemoglobin was grouped as low or high relative to the median ( The median overall survival (OS) was significantly shorter in patients with a lower Hgb (113 vs. 2536 days; p=0.004). This difference was attributed to an increased rate of transplant-related mortality (TRM) in patients with a lower Hgb (n=26; 81.3%) versus a higher Hgb (n=11; 36.7%) (p=0.0005). Time to relapse between patients with a lower and higher Hgb was not different (p=0.89). The median OS in patients with a lower CrCl was significantly worse (75 vs. 317 days; p=0.003). The rate of TRM was also found to be significantly worse in patients with a lower CrCl (n=10; 90.1%) compared to patients with a higher CrCl (n=27; 52.9%) (p=0.0023). Time to relapse was not different between patients with a lower and higher Cr Cl (p=0.29). Patients with both a low Hgb and CrCl experienced a shorter median OS (75 days vs. not reached; p We then analyzed regimen-related toxicities among patients with a lower and higher Hgb and lower and higher CrCl. In patients with a lower hemoglobin, the median duration of hospitalization (35 vs. 29 days; p=0.02) and the mean duration of diarrhea (14.6 vs. 7.2 days; p=0.008) were significantly longer. In patients with a lower CrCl, the median duration of hospitalization (40 vs. 29 days; p=0.06) and the mean duration of diarrhea (20.9 vs. 8.6 days; p=0.0009) were longer, and the rate of infection was higher (90.9% vs. 49.1%; p=0.02). We show for the first time that pre-treatment Hgb and CrCl represent important determinants of clinical outcomes after Flu/Mel140 and HSCT. A lower hemoglobin in particular was strongly associated with a shorter OS and TRM. This is consistent with PK studies showing increased melphalan exposure in patients with low Hgb and CrCl. We conclude that consideration of clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes in patients receiving FluMel140 and HSCT. Figure Disclosures Galvin: Incyte: Consultancy. Patel:Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Speakers Bureau.

High dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is standard of care after induction therapy for eligible patients with multiple myeloma (MM). However, ~40% of patients fail to achieve complete remission (CR), largely due to interpatient variability (~10-fold) in melphalan exposure (AUC). Thus, many patients experience subtherapeutic exposure and suboptimal response when using conventional body-surface-area (BSA)-based dosing. HDM, administered at a dose of 100mg/m2 on day -2 and -1, allows for potential modification of the day -1 dose if pharmacokinetic (PK) testing with rapid turnaround can be performed on day -2. Here we describe a clinically feasible, reproducible method of measuring melphalan PK that allows for real-time dose adjustments. We developed and validated a robust melphalan assay with quality control for intra-day and inter-day precision, sample processing, and final LC-MS/MS analysis. MM patients aged ≥ 18 years undergoing HDM at a dose of 140 or 200 mg/m2 were eligible. HDM was administered days -2 and -1 prior to ASCT as a 30-minute infusion followed by saline flush. Blood for PK sampling (5ml aliquots), drawn at 10 specific time points post-infusion, were placed on ice and delivered to the PK lab for centrifugation and storage within 5 minutes of being drawn. PK parameters were determined from plasma concentration versus time data by a noncompartmental analysis using WinNonlin 8.1. Toxicities were assessed up to 30 days after ASCT using NCI-CTAE, version 5.0 grading. Patients were also followed for day 90 disease response rates. Twenty MM patients were enrolled with 18 receiving 200mg/m2 and 2 receiving 140mg/m2 due to end stage renal disease and age over 70 years. Using the first 5 patients, we confirmed that the AUC from day -2 correlated with day -1 (r=0.8), establishing that day -2 PK could be used to adjust the day -1 dose using a linear, dose-proportional calculation for future PK-directed studies. Notably there was considerable variation in day -2 AUC parameters, further confirming melphalan interpatient variability among patients. The median single-day AUC on day -2 was 7.49 (4.95-11.28) mg*h/L with an interquartile range of 2.66 mg*h/L. When comparing the upper and lower quartiles, there was a 1.85 fold higher single-day AUC (10.2 vs. 5.5 mg*h/L). Based on each patient's PK profile, we then calculated the theoretical dose for day -1 in order to target the total median melphalan AUC and compared it to the BSA-based dose received. The change in absolute melphalan dose on day -1 to achieve the total median AUC ranged from -124 mg to +206 mg (Figure 1A). When expressed as a BSA-based mg/m2 dose, the total 2-day dose would range from 133-308 mg/m2 (Figure 1B). Using D-optimality approaches we determined that reducing blood sampling from 8 to 4 time points did not affect AUC prediction, as confirmed by paired comparison tests comparing the mean AUCs between the new (4 point) sampling time schedule and the original (7.76 vs. 7.80 mg*h/L; p=0.8193). Lastly, we examined clinical outcomes and whether AUC correlated with toxicity. One patient with a median single-day AUC of 10.58 mg*h/L died from sepsis. No patients developed grade 3/4 mucositis or GI-related toxicity. In modified Poisson regression, higher AUC correlated with increased risk of febrile neutropenia (RR 3.02, CI 1.00-9.26, p=0.05) and a trend towards increased use of antiemetics (RR 1.86, CI 0.95-3.65, p=0.07). Collection of disease response data is ongoing. Here we describe the potential impact of performing rapid melphalan PK testing in a clinical setting. We report minimal intrapatient variability in melphalan exposure from day-2 to day-1 allowing a linear, dose-proportional method of dose-adjustment without need for a pre-transplant test dose or modification of the initial dosing regimen. Significant interpatient variability is observed, and dose adjustment simulations based on patients' PK data demonstrate that large, bi-directional dose adjustments are required to target a median AUC, emphasizing the importance of PK-directed HDM dosing. Our study posits that individualized melphalan dosing will both decrease interpatient variability and improve myeloma outcomes, and through allowing development of PK-directed HDM studies, suggests a novel approach to dosing in MM patients undergoing ASCT. Figure 1 Disclosures Galvin: Incyte: Consultancy. Quigley:Alexion: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; TEVA: Research Funding. Patel:Amgen: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau.

Despite new targeted therapies, patients with high risk myeloproliferative neoplasms (MPNs) have an increased chance of transforming into acute myeloid leukemia (AML) and can only be cured with allogeneic hematopoietic stem cell transplant (HSCT). JAK2V617F mutation is common in MPNs and is associated with genomic instability, with baseline DNA double strand breaks and homologous recombination (HR) activity as a result of stalled replication forks. Poly(ADP-ribose) polymerase-1 (PARP-1) detects disrupted replication forks and recruits HR repair enzymes to restart DNA replication. Because busulfan, which is used in preparative regimens for HSCT, also leads to stalled replication forks through DNA strand crosslinking, we hypothesized that the PARP-1 inhibitor veliparib and busulfan may lead to synergistic cytotoxicity in MPN cells. We first treated two JAK2V617F positive MPN cell lines with increasing doses (from 0.1 to 100μM) of veliparib in liquid cultures and measured cell proliferation. SET2 and HEL cells were relatively sensitive to veliparib (IC50 of 11.3μM and 74.2μM respectively). We next treated the cell lines with increasing doses of busulfan in combination with a fixed subtherapeutic dose of veliparib (4μM) for 48 hours. With combination treatment, the busulfan IC50 decreased from 27μM to 4μM in SET2 cells and from 45.1μM to 28.1μM in HEL cells. The combination was synergistic with a mean combination index (CI) of 0.55 for SET2 and 0.40 for HEL cells. Combination treatment resulted in a higher fraction of cells in G2M arrest than with veliparib alone (p=0.03) or busulfan alone (p=0.04). Similarly, when the combination treatment was tested on CD34+ cells obtained from 5 patients with JAK2V617F mutated and 2 CALR mutated PMF in a standard clonogenic (CFU) assay, it caused a greater inhibition of colony formation than busulfan or veliparib alone (p=0.001). Veliparib alone did not show any effect on colony formation from healthy control CD34+ cells. Finally we utilized a xenograft model with NOD/SCID/IL-2Rγnull (NSG) mice to test the in-vivo effect of combined low doses of busulfan and veliparib in JAK2V617F MPNs. In order to establish disease, mice were injected with 5x106 SET2 cells via tail vein 12 hours after sub-lethal irradiation. Then, 14 days after SET-2 injection 4 groups of mice (n=5 each) were treated for up to 3 weeks with intra-peritoneal vehicle (control); or a subtherapeutic dose of veliparib (3mg/kg daily) for 5 days a week; or busulfan (25mg/kg weekly); or a combination of both drugs. Death from leukemia was documented by marrow and spleen cell immunophenotype using non-cross reactive anti-human CD33 and CD34 antibodies. Veliparib alone did not improve survival vs control. On the contrary, survival was increased by the combination treatment vs busulfan alone (p=0.02). Here we show that treatment with the PARP-1 inhibitor veliparib and busulfan elicits a synergistic cytotoxicity in MPN cells both in-vitro and in-vivo. Our data provide the rationale for testing novel pre-transplant conditioning regimens by combining veliparib with alkylating agents, such as busulfan or melphalan, in HSCT for high risk MPNs or MPN-AML. Disclosures Patel: Janssen: Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Background: Relapsed or refractory acute myeloid leukemia (R/R AML) portends a poor prognosis, thus salvage chemotherapy is commonly used as a bridge to HSCT, however the optimal salvage regimen remains unknown. For decades cytarabine (Ara-C) has served as the backbone of regimens frequently used in the R/R setting. MEC is among the most studied regimens for R/R AML; up to 66% of patients achieve complete remission (CR), with a median survival of 36 weeks (Arcese et al., J Clin Oncol. 1991). The Ara-C couplets regimen was shown to have a similar overall response rate (ORR) of 55%, in a single study (Larson et al., Leukemia & Lymphoma. 2012). Currently, there are no studies directly comparing these regimens. Here, in a multi-institution retrospective analysis we assessed the efficacy and toxicity of MEC and Ara-C couplets therapy. Methods: We analyzed the records of 136 patients treated between 1998 and 2017. There were 87 patients (15 from University of Illinois and 72 from Indiana University) treated with MEC (mitoxantrone 8 mg/m2 IV, etoposide 80 mg/m2 IV and Ara-C 1 g/m2 x 5 days) and 49 patients (36 from University of Illinois and 13 from University of Chicago) treated with Ara-C couplets (mitoxantrone 30 mg/m2 daily and Ara-C dosed at 2 g/m2 twice daily or 3 g/m2 daily; both drugs given on days 1 and 5). The primary endpoint was comparison of response rates. Secondary endpoints included progression free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and non-hematologic toxicities, and success in proceeding to HCT. Results: The median age of the MEC group was 52 years (yr) (range: 20-75 yr) vs 55 yr (22-75 yr) in the Ara-C couplets group. There were significantly more white patients in the MEC group (72% vs 41%; p = 0.004). The incidence of unfavorable cytogenetics was similar between groups; 32 in the MEC group (36.8%) and 19 in the Ara-C couplets group (38.7%). High-risk patients, as defined by Charlson Comorbidity Index (CCI) ≥4, comprised 29 of 87 (33.3%) of MEC, and 26 of 49 (53.1%) of Ara-C couplets patients (p = 0.03). Time from initial diagnosis to diagnosis of R/R AML was similar between groups, 303 days (MEC) and 306 days, respectively (p = 0.10). CR or CRi (ORR) was achieved in 44% of MEC, and 55% of the Ara-C couplets patients. OS was 159 days and 186 days, respectively (p = 0.055). PFS was 66 days in the MEC group and 113 days in the Ara-C couplets group (p = 0.56). In total, 27 (31%) of the MEC patients and 24 (49%) Ara-C couplets patients underwent HCT (p = 0.04). Within the MEC group, the median number of days to ANC and platelet recovery was 34 days and 35 days, respectively. ANC and platelet recovery was slightly longer within the Ara-C couplets group, at 41 days and 55 days, respectively (p = 0.02 for platelet recovery). The median duration of hospitalization was similar, 29 days for MEC and 30 days for Ara-C couplets. The most common adverse event was febrile neutropenia (FN), occurring in 93% of the MEC and 78% of the Ara-C couplets patients (p = 0.01). Notably, grade 3/4 GI toxicity occurred in 15 MEC (17.2%) and one (2.0%) of the Ara-C couplets patients (p = 0.01). There were no significant differences between groups in terms of pulmonary, liver, renal, cardiac or neurologic toxicities. Conclusions: This is the first large multi-institutional retrospective study directly comparing salvage regimens in a racially diverse population of R/R AML patients. While matched for a number of variables (including the incidence of unfavorable cytogenetics), patients receiving Ara-C couplets did have a significantly higher CCI. Despite this, use of the Ara-C couplets regimen resulted in improved ORR, significantly improved efficacy as a bridge to HCT, and led to a significant comparative decrease in the incidence of FN and grade 3/4 GI toxicities. Our retrospective analysis suggests that this regimen should be considered as an effective, safe salvage regimen in this population. Disclosures Patel: Janssen: Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Khan:Teva: Speakers Bureau. Stock:Jazz Pharmaceuticals: Consultancy. Odenike:ABBVIE: Honoraria, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding.

Although melphalan 200mg/m2 (Mel200) and autologous stem cell transplantation (ASCT) significantly prolong progression-free survival for multiple myeloma (MM) patients, clinical outcomes and toxicities vary greatly. Pharmacokinetic studies report a 5-fold interpatient variability in melphalan exposure with increased exposure being associated with higher rates of toxicity yet superior survival. Renal impairment, low hematocrit and low fat free mass (FFM) have been shown to decrease melphalan clearance and increase exposure. Specifically, melphalan binds to proteins in the red blood cell membrane, leading to higher plasma concentrations in anemic patients. Likewise, since renal elimination contributes significantly to melphalan clearance (approximately 40%), the presence of renal impairment also leads to higher concentrations. Given this, we hypothesized that clinical variables associated with increased melphalan exposure would predict not only for improved post-ASCT survival but also increased treatment toxicity. To test this hypothesis, we analyzed 133 MM patients who received Mel200 and ASCT. In addition to standard clinical parameters, the following laboratory values were obtained: average hemoglobin (Hgb) from Day -2 and -1, creatinine clearance (CrCl) on Day -2, and FFM. Hemoglobin and FFM were grouped as low or high relative to their sample medians, and CrCl was divided into two groups (≥ 60 or < 60 ml/min). The median age was 59 (34-77) years and most patients were male (n=72, 54%), IgG subtype (n=68, 55%), and ISS stage 3 (n=58, 59%). Fifty percent (n=66) of patients received more than 1 prior treatment, the majority of which were IMiD- (n=78, 59%) or PI-(n=69, 52%) based. The median time to transplant was 8 months (3-144), and 55 (41%) patients received post-transplant maintenance. Pre-transplant response was VGPR (n=23, 18%) or PR (n=53, 41%) in most patients. For the entire cohort, the median hemoglobin, FFM, and CrCl were 10.65 g/dL, 52.9 kg, and 73 ml/min, respectively. No difference in treatment free survival (TFS) was observed between a low and high FFM (21 vs. 27 months, p=0.36). However, the median TFS was significantly longer in patients with a lower hemoglobin ( We show for the first time that hemoglobin and creatinine clearance represent important determinants of clinical outcomes after Mel200 and ASCT. A lower hemoglobin and creatinine clearance, individually and when combined, were associated with longer TFS yet increased short term toxicity. This is consistent with PK studies showing increased melphalan exposure in patients with low hematocrit or renal impairment. In the future, consideration of clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes. Figure 1. Figure 1. Disclosures Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

INTRODUCTION Bevacizumab, an angiogenesis inhibitor targeting vascular endothelial growth factor A, is used for the treatment of recurrent glioblastoma, the most common primary brain malignancy in adults. Multiple studies demonstrate the efficacy of bevacizumab on progression-free and overall survival of patients with recurrent glioblastoma. However, real world safety data of bevacizumab in patients with glioblastoma is limited on serious adverse outcomes including arterial and venous thrombosis. Our study aimed to evaluate the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) in a population-based sample of adult patients with high grade gliomas. METHOD We conducted a nested case-control study within a retrospective cohort of patients receiving treatment for high grade gliomas under the protocol by Stupp, et al. (radiotherapy plus concomitant/adjuvant temezolomide). Patients were sampled from the Truven Health MarketScan® Research Database, containing administrative health claims data of over 40 million commercially insured enrollees and their dependents, between 2009 and 2015. A validated algorithm was used to identify patients with high grade gliomas that underwent craniotomy (index time) with external beam radiation and temozolomide-based treatment occurring within 91 days (cohort entry time). Patients were excluded if they received craniotomy, radiation, temozolomide or bevacizumab during year prior to surgery or had one of our outcomes of interest (ATE or VTE) during the cohort ascertainment period (between index and cohort entry dates). Patients were required to have continuous health plan enrollment during the 12-month baseline and follow up periods (unless died). Surgical procedures and chemotherapy treatments were identified using diagnostic and procedural medical and pharmacy claims data. These data sources were also used to identify VTE risk factors, including medical conditions, procedures and medication use, and to calculate modified Charlson comorbidity index scores at baseline. Cases of ATE and VTE were each identified in the overall cohort using a validated algorithm for administrative claims data. For ATE and VTE separately, each case was matched to up to ten controls on sex, age group, index time and follow-up duration using incidence density sampling with replacement. Exposure to bevacizumab was characterized as any use (yes vs. no) and recent use (last bevacizumab infusion within 30 days prior event or control censoring). We estimated relative risk of ATE and VTE associated with bevacizumab in separate models using conditional logistic regression models to calculate adjusted odds ratios (aOR) and 95% confidence interval (CI). All multivariable models were adjusted for sex, age, and comorbidity index scores; models for risk of VTE were also adjusted for number of baseline VTE risk factors and VTE prophylaxis received. RESULTS Our final study cohort included 2157 patients undergoing treatment for high grade gliomas. We identified 25 ATE cases and 99 VTE cases and matched incidence density-sampled controls (n=170 for ATE; n=819 for VTE) for our nested case-control analysis. A higher proportion of ATE cases received bevacizumab during follow up compared to the controls (28% vs. 17%). In multivariable analyses, no statistically significant increase in ATE risk was observed with bevacizumab overall (aOR 1.51, 95% CI 0.54-4.24), although confidence intervals were wide given the few events observed. Compared to controls in the VTE analysis, cases had a slightly higher proportion of baseline VTE risk factors (2 or more: 17% vs. 13%) and treatment with bevacizumab (13% vs. 9%). However, we found no significant increased risk of VTE associated with bevacizumab overall (aOR 1.40, 95% CI 0.71-2.75) or recent infusion of bevacizumab (aOR 1.40, 95% CI 0.65-3.01). CONCLUSIONS Our findings from this large retrospective cohort of patients undergoing treatment for high grade glioma provide little evidence in support of the increased risk of ATE and VTE reported with use of bevacizumab in other cancer sites. Our study was limited by an overall small number of ATE events observed, and further research is needed to confirm safety of bevacizumab with respect to arterial thrombosis. These population-based estimates show no significant increase in risk of VTE associated with bevacizumab and suggest its safe use in the treatment of high grade gliomas. Disclosures Lee: AbbVie Inc.: Research Funding. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

INTRODUCTION: Multiple myeloma (MM) induces a hypercoagulable state with increased risk of venous thromboembolism (VTE) due to higher blood viscosity, circulating immunoglobin, inflammatory cytokines, procoagulant monoclonal protein and cytotoxic therapies. Thromboprophylaxis is typically indicated for immunomodulator-based treatment or if a patient has multiple VTE risk factors, though evidence on the patterns and effectiveness of antithrombotic medications in this setting is lacking. Our objective was to describe VTE prophylaxis interventions in patients with MM in a large commercially-insured U.S. population. METHODS: We performed a retrospective cohort study of patients with incident MM initiating first-line treatment between 2009 and 2015 using medical and pharmacy administrative claims data from the Truven Health MarketScan Research Database. Patients were required to have continuous enrollment for at least 12 months prior to MM diagnosis and 6 months following treatment initiation (unless died). Information on MM treatments including immunomodulatory drugs (IMiDs: thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (PIs: bortezomib) and other oral and intravenous chemotherapy agents was collected. Baseline characteristics related to risk of VTE were documented, including medical conditions, procedure-related risk factors, other medications associated with increased VTE risk and MM-treatment related risk factors defined by the International Myeloma Working Group. Medications used for VTE prophylaxis following MM treatment initiation (and prior to the occurrence of a subsequent VTE event) included antiplatelet agents, low molecular weight heparin (LMWH), warfarin and direct oral anticoagulants (DOAC). We used multivariable logistic and polytomous regression models to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) associated with receipt of VTE prophylaxis and specific antithrombotic medications used respectively. RESULTS: Among 7405 MM patients, the mean age was 64.9 years (standard deviation: 11.6), 43% were female, and more than half of patients received IMiD-based treatment (52%). Overall, 20% of patients in the cohort received VTE prophylaxis with any agent [antiplatelet agent (5%), LMWH (6%), warfarin (7%) and DOAC (2%)]. Patients treated with IMiDs had fewer VTE risk factors at baseline compared with MM patients receiving non-IMiD based treatment (2 or more risk factors: 24% vs. 38%, p CONCLUSIONS: VTE prophylaxis is generally recommended with the presence of 2 or more VTE risk factors or when initiating IMiD therapy in patients with multiple myeloma. In our cohort, half of newly diagnosed MM patients initiated IMiD-based first-line therapy; of which; one in four IMiD initiators also received prophylaxis with antithrombotic or anticoagulant medications. Comprehensive evidence on the comparative effectiveness of VTE prophylaxis strategies in multiple myeloma is needed to guide prevention of this serious adverse outcome. Disclosures Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to substantial morbidity and a heavy burden on the health care system. Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) regimens using HLA-matched related donors have recently demonstrated high rates of engraftment and a favorable safety profile in adults with SCD. The long term effects of these HSCT regimens on health care utilization, particularly in SCD adults who have had a high burden of SCD-related acute and chronic complications, has not been previously reported. Between 8/2011 and 4/2016, 86 SCD patients who received their routine care at our institution were referred to the Blood & Marrow Transplant Clinic. Sixteen patients received a HSCT from an HLA-match related donor during this time period. Reasons for not proceeding to transplantation in the 70 patients included lack of an HLA-matched related donor in 36 (51%), patient/family declining in 21 (30%), insurance denial in 11 (16%), and the presence of RBC antibodies to potential donors in 2 (3%) patients. We compared health care utilization patterns between 1) 1-year pre-HSCT vs. 1- and 2-years post-HSCT in 16 transplanted SCD adults and 2) 16 transplanted vs. 70 non-transplanted SCD patients at 1- and 2-years from the time of HSCT or referral. Comparisons of linear variables and categorical variables were performed using the Kruskal-Wallis and Chi-square test, respectively. In the 16 SCD patients who met standard transplant eligibility criteria and underwent HSCT, the median age at the time of HSCT was 33 years (interquartile range [IQR], 24 - 34 years), 56% were male, and 94% were HbSS genotype. Treatment prior to HSCT was hydroxyurea in 10 (63%), chronic red blood cell (RBC) transfusion therapy in 5 (31%), and no disease modifying therapy in 1 (6%) patient. Thirteen of 16 (81%) transplanted SCD patients maintained a stable graft. Emergency room (ER) visits were lower 1-year and 2-year post-HSCT compared to 1-year pre-HSCT (P=0.03) (Table 1). In the 2nd year post-HSCT, ER visits, hospital length of stay, RBC transfusion requirements, and rates of documented infections were all lower compared to 1-year pre-HSCT (P We then compared health care utilization patterns between the 16 SCD patients that underwent HSCT vs. the 70 SCD patients that were not transplanted. The HSCT and non-HSCT patients were similar with respect to median age (33 vs. 31 years old; P=0.2), gender (35% vs. 56% male, P=0.1), number of eligibility criteria met for HSCT (PMID: 24319206) (2 for each group; P=0.4) and SCD genotype (80% vs. 94% HbSS genotype, P=0.4), respectively. During the first year after transplant or of observation, we observed lower rates of emergency room visits but a greater number of inpatient hospital days in the HSCT vs. no HSCT groups (Figure 1). During the second year, both the number of emergency room visits and the number of inpatient hospital days were lower in the HSCT vs. the no HSCT patients (Figure 1). In conclusion, we demonstrate that allogeneic HSCT leads to lower health care utilization by the second year post-HSCT in adults with SCD. These results support the role for HSCT to lower the morbidity, health care burden and costs associated with SCD and should encourage universal insurance coverage for HSCT in adults with SCD. Disclosures Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria. Khan:Teva: Speakers Bureau.

INTRODUCTION: Biologic disease-modifying antirheumatic drugs (DMARDs) are used more frequently and earlier in the course of rheumatologic conditions in a treat-to-target approach. These medications act on proteins and cytokines with potential pro- and anti-malignancy roles, including tumor necrosis factor-alpha (TNF), human interleukin (IL) receptors and B- and T-cell functions. There is concern for hematologic malignancy with some but not all biologic DMARDs. Little is known about possible associations between these medications and development of multiple myeloma (MM). Our purpose was to determine risk of MM in relation to biologic DMARD treatment, duration of use and by biologic target in a large cohort of patients with rheumatologic conditions. METHODS: We conducted a nested case-control study within a cohort of adults undergoing active treatment for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Patients were sampled from a population of commercially-insured U.S. health plan enrollees in the Truven Health MarketScan Research Database between 2009 and 2015. MM cases were ascertained using validated algorithms for administrative data. Up to ten controls from the overall cohort were matched to each MM case on age, sex and rheumatologic indication using incidence density sampling with replacement. Index date was defined as the date of MM diagnosis for a case and corresponding time at-risk for matched controls. Exposure was defined as both treatment and duration of biologic DMARD use including TNF inhibitor (etanercept, infliximab, adalimumab, golimumab, certolizumab pegol), IL-6 receptor antagonist (tocilizumab), T-cell targeted (abatacept) and B-cell depleting (rituximab) agents and were determined from health claims and pharmacy dispensing data. Data on rheumatologic indication, comorbid conditions and treatment with prescription nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and conventional synthetic DMARDs (hydroxychloroquine, sulfasalazine, methotrexate, leflunomide) were documented in the 12 month baseline period and during follow up as potential confounders. An exposure lag time of 365 days was used to minimize protopathic bias. Multivariable conditional logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of MM associated with biologic DMARDs. RESULTS: From a retrospective cohort of 56866 adult patients with rheumatologic conditions, 287 MM cases and 2760 matched controls were identified. Compared to controls, a higher proportion of cases had Charlson comorbidity scores of 2 or greater (24% vs 18%) and used oral corticosteroids during follow up (67% vs 61%). Cases and controls were similar with respect to use of prescription NSAIDs (56% vs 59%) and use of conventional DMARDs (63% vs 67%). Use of biologic DMARDs overall was similar between cases and controls (14% vs 15%), although cases had a slightly lower proportion of etanercept users (5% vs 7%) and a slightly higher proportion of tocilizumab users (1.4% vs 0.4%). Biologic DMARD users were younger, more likely to have psoriatic arthritis or ankylosing spondylitis, lower comorbidity and greater use of concomitant NSAIDs and oral corticosteroids. Risk of MM was neither associated with biologic DMARD use overall (OR 0.84; 95% CI 0.57, 1.26; P=0.40) nor with longer duration of biologic DMARD use (>2.5 years: OR 0.72; 95% CI 0.34, 1.52; P=0.39). However, compared to patients treated with only conventional DMARDs, those receiving concomitant conventional plus biologic DMARDs had a 48% lower risk of developing MM (OR 0.52; 95% CI 0.30, 0.88; P=0.02). Associations with MM appeared to differ by specific biologic DMARD agent with estimates suggesting a lowered risk of MM with use of etanercept (OR 0.55; 95% CI 0.30, 1.02; P=0.06) and greater risk with use of tocilizumab (OR 4.33; 95% CI 1.33, 14.19; P=0.02) that was statistically significant, although confidence intervals were wide. CONCLUSIONS: The potential influence of biologic DMARDs on multiple myeloma is complex. We found that immune suppression with conventional plus biologic DMARDs is inversely associated with MM risk in patients with rheumatologic conditions, but this association differed by biologic drug target. Further research is needed to understand the roles of DMARDs targeting TNF and IL-6 in relation to subsequent myeloma pathogenesis. Disclosures Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

High dose chemotherapy followed by autologous stem cell transplant (ASCT) prolongs progression-free survival (PFS) of patients with multiple myeloma (MM). However, there is wide variability in response and survival after ASCT and therefore prediction of prognosis remains a challenge. Biomarkers of immunologic and inflammatory changes, such as the peripheral blood monocyte and lymphocyte counts have been shown to impact clinical outcomes in other cancers and may have prognostic value in MM. We hypothesized that clinically available surrogates for immune suppression and systemic inflammation occurring in MM including the lymphocyte to monocyte ratio (LMR) and immunoglobulin (Ig) levels tested pre-transplant and at day 90 after ASCT may predict treatment-free survival (TFS). We also determined whether a composite immune score predicts disease progression. One hundred and thirty patients who received melphalan 200 mg/m2 and ASCT between 2002 and 2016 were included in the final analysis. The median age was 59 (range: 34-77) years and most patients were male (n=71, 55%), IgG subtype (n=65, 50%), and ISS stage 3 at diagnosis (n=55, 57%). Sixteen (12%) patients were diagnosed with high risk FISH/karyotype. Median number of prior treatments was 2 (range: 1-5), with the majority being IMiD- (n=82, 63%) or PI-(n=72, 55%) based. The median time to transplant was 8 months (range: 3-144), and approximately half of patients received post-ASCT maintenance treatment (n=60, 46%). Treatment response was at least a very good partial response or better in 28 (27%) patients pre-transplant and 59 (59%) patients post-transplant (p=0.0001). We collected the following values at baseline (Day -2) and Day +90 post-ASCT: absolute lymphocyte count (ALC); absolute monocyte count (AMC); lymphocyte to monocyte ratio (LMR); and the number of Ig levels suppressed. Values were separated into upper and lower quartiles for analysis. For the entire cohort, the median PFS was 25 months. At Day 90 post-ASCT, a high ALC (18 versus 23 months, p=0.04) and low AMC (13 versus. 25 months, p=0.02) predicted for superior TFS. When combined into a lymphocyte-monocyte ratio, we were able to demonstrate that a lower LMR (defined as We then developed an immune score by combining the LMR and Ig values. Patients were divided into either poor (low LMR and 2-3 suppressed Ig levels), good (high LMR and normal Ig levels) and intermediate (all other patients) risk groups. The median TFS for poor, intermediate and good risk groups was 7.5 versus 27 versus 79 months respectively (p=0.0004). In order to examine whether autograft composition impacted lymphocyte and monocyte counts at day 90, we compared total infused cell numbers by automated differential counts and CD3 and CD14 expression between the poor and good risk groups. Total infused lymphocyte (1.74x108 versus 2.46x108, p=0.72), monocyte (3.18 x108 versus 3.39 x108, p=0.86), CD3 (1.52 x108 versus 1.37 x108, p=0.92), and CD14 (2.7 x108 versus 1.9 x108, p=0.44) cell numbers were similar between the 2 groups, suggesting that LMR at Day +90 was independent of the infused graft lymphocyte and monocyte numbers. With long-term follow-up, we demonstrate the importance of two readily available biomarkers, the lymphocyte to monocyte ratio and immunoglobulin levels, in determining risk of progression in MM patients after ASCT. We observed that independent of the infused autograft cell composition, at day +90 a combination of the LMR and Ig levels could identify patients who will either have a long duration of remission or patients with very poor prognosis who may thus benefit from more intensified post-ASCT consolidation/maintenance or use of immunotherapy. Disclosures Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Multiple myeloma is a complex disease requiring adherence to treatment and supportive care guidelines, patient education, medication management, and timely delivery of anti-myeloma drugs to achieve optimal patient care. Clinical pharmacists play an important role in the management of cancer patients and could potentially assist in several aspects of care. We hypothesized that a multidisciplinary collaborative physician-pharmacist multiple myeloma (MM) clinic would reduce polypharmacy, improve adherence to MM guidelines as well as reduce delays in receiving oral anti-myeloma therapy. Under the collaborative model, an oncology pharmacist provided consultation on all patients in a specialist myeloma clinic. This included reviewing medications, providing medications lists. ensuring physician adherence to supportive care guidelines, managing treatment-related side effects and navigating issues involving access to oral specialty medications. Outcome measures were compared to those of patients being treated by the same physician during the previous year, where ad-hoc pharmacist consultation was available (traditional clinic). The collaborative clinic led to significant improvements in adherence to supportive medications such as bisphosphonates (96% vs. 68%, p=0.0002), calcium and vitamin D (100% vs. 41%, p We also observed improved medication management in patients treated in the collaborative clinic. These patients took fewer medications on average (9 vs. 7, p=0.045). Although the median number of myeloma-related medications (medications related to treatment or supportive care for MM) was higher (2 vs. 4, p Here we show that incorporating another sub-specialized individual such as a clinical pharmacist into the care of multiple myeloma patients resulted in increased adherence to core supportive care measures and a reduction in delays in acquiring oral IMiDs. Importantly, although we illustrate a high incidence of polypharmacy among patients in both clinics, consultation by a pharmacist led to a significant reduction in the number of non-myeloma-related medications. The collaborative model may be of benefit in the management of other complex malignant diseases and further studies in other cancer clinics are warranted. Impact on long term clinical outcomes will also highlight the potential benefits of this collaborative model of patient care. Disclosures Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) is routinely administered to patients undergoing hematopoietic stem cell transplantation (SCT) or intensive chemotherapy. There is continued risk of PJP particularly in SCT recipients when they require prolonged immunosuppression or high dose corticosteroids. Trimethoprim-sulfamethoxazole is the drug of choice but its use is limited by hematologic toxicities. Inhaled pentamidine is an alternative, but frequently causes bronchospasm, needs to be given by a respiratory therapist, and requires use of a private room during administration due to its teratogenicity. Intravenous (IV) pentamidine is FDA approved for PJP treatment, and overcomes these challenges. We conducted the first ever prospective study of IV pentamidine for PJP prophylaxis in adult patients undergoing SCT or intensive chemotherapy. Fifty patients were enrolled in a single-arm trial. Patients requiring PJP prophylaxis according to institutional guidelines received pentamidine 4 mg/kg (maximum 300 mg) intravenously with ondansetron pre-medication. Patients were followed for the occurrence of PJP pneumonia. Adverse events were recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4. Patient satisfaction was assessed by conducting the Treatment Satisfaction Questionnaire for Medication (TSQM Version 1.4) survey. Thirty-two (64%) patients were male, and the median age was 55 years (range: 19-72). Twenty-four patients (48%) were undergoing intensive chemotherapy while 26 (52%) were undergoing SCT. Of the latter group, 62% received autologous SCT and 38% allogeneic SCT. At the time of IV pentamidine administration, 58% of patients were neutropenic (absolute neutrophil count < 0.5 thous/µL) and 86% of patients were lymphopenic (absolute lymphocyte count < 1 thous/µL). All patients received at least one dose of IV pentamidine (range: 1-9). There were no cases of PJP documented during the 12 month study period. There were no NCI-CTCAE grade 3/4 events. Seventeen (34%) patients experienced a grade 1 or 2 adverse event. The most common adverse events were nausea (n=4) and hypotension (n=6). Hypotension typically occurred at the end of the infusion, was transient, and asymptomatic. Grade 1/2 acute kidney injury developing within one week of pentamidine occurred in 2 patients (4%). In both patients, serum creatinine increased within 3 days, peaked within 7 days, and normalized within 10 days. Two treatment-related interruptions of drug infusion occurred; one due to infusion-related perioral and facial numbness which resolved as soon as the drug was stopped and one due to nausea which resolved after intravenous ondansetron. IV infusion was resumed successfully in both cases. Engraftment was not adversely affected in patients undergoing SCT. The median time to neutrophil and platelet engraftment was 12 (range: 11-15) and 14 (range: 10-16) days in autologous SCT recipients and 13 (range: 13-31) and 14 (range: 14-31) days in allogeneic SCT recipients. Results from the TSQM questionnaire indicate that the majority of patients found that IV pentamidine was "not at all bothersome" (n=33, 69%), "did not interfere with physical health and ability to function" (n=37, 77%), and was "extremely easy to receive" (n=29, 60%). The most common adverse events reported in the TSQM questionnaire were nausea (n=6), nasal congestion (n=2), and mouth numbness (n=2). However, they had "minimal" or "no effect at all" on patient satisfaction with the drug. Overall patients were satisfied with the administration of IV pentamidine (n=43, 86%, p Our study illustrates the safety and feasibility of using IV pentamidine for PJP prophylaxis in patients undergoing SCT or intensive chemotherapy. In SCT patients, IV pentamidine did not delay engraftment. The incorporation of patient centered outcomes showed a high degree of satisfaction with this method of prophylaxis. Thus, although comparative studies are required, IV pentamidine overcomes many of the respiratory and logistic challenges faced when administering inhaled pentamidine and appears to be better tolerated. In particular, patients undergoing SCT who require PJP prophylaxis over a prolonged period may derive benefit from the improved safety and patient satisfaction profile of IV pentamidine. Disclosures No relevant conflicts of interest to declare.

Introduction Individuals with multiple myeloma (MM) are at a greater risk of thrombotic complications than those with other cancers. Cancer-related venous thromboembolism (VTE) including pulmonary embolism and deep vein thrombosis is associated with increased morbidity and mortality. Both incidence of MM and VTE differ by race/ethnicity. Blacks have a higher incidence of MM compared to Whites, whereas Asian/Pacific Islanders (API) and Hispanics have a lower incidence. In the general population, the risk of VTE and prevalence of its associated risk factors are higher in Blacks. The hypercoagulable state induced by MM and its treatment could further modify any pre-existing VTE risk in different racial/ethnic groups. Our objective was to describe the incidence of VTE following diagnosis and treatment of MM by race/ethnicity. Methods We conducted a retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) - Medicare linked database. Individuals 66 years or older with myeloma as their first primary malignancy diagnosed between 2001 - 2011 were identified. These individuals were required to have age related eligibility for Medicare, continuous enrollment in the 12 months period prior and post myeloma diagnosis, and Medicare as their primary payer. Using SEER registries and administrative claims, we collected data on race/ethnicity, cancer characteristics and treatment, and chronic comorbidities. VTE events were defined as having an inpatient hospitalization or 2+ outpatient visits with ICD-9 diagnosis codes 415.1x, 451.xx, and 453.xx. Long-term risk of VTE was assessed by determining the annualized incidence of VTE at 12, 24, and 36 months following MM diagnosis. In each 12-month period, MM patients were followed from diagnosis until the earliest of the following: a VTE event, death, or end of 12-month period since diagnosis. Additionally, we calculated VTE incidence rates in the 12-month period following stem cell transplantation for those that received it. Overall and race-specific crude incidence rates with 95% confidence intervals (CIs) were calculated in each period using person-time contributed per observation period. Poisson regression was used to compare age- and gender-adjusted incidence rate ratios (IRRs) and 95% CIs comparing different racial/ethnic groups with White patients. Results In a final analytic cohort of 9,480 patients, most were White (73%) and fewer patients were Black (15%), Hispanic (6%) or API (4%). The median age at diagnosis was 77 years (interquartile range [IQR]: 71-82). Half the cohort (51%) were women, 28% had diabetes and 21% had a history of heart failure at diagnosis. Overall, the median time to first VTE event post-MM diagnosis was 140 days (IQR: 46-409). More patients that developed VTE were female, Black, younger at MM diagnosis, and treated with stem cell transplantation. The overall incidence rate of VTE during the first 12 months following the diagnosis of MM was 170 per 1,000 person-years (95% CI 160-180). Adjusting for age and gender, Blacks had a higher incidence of VTE compared to Whites (IRR 1.24; 95% CI 1.07-1.44) and APIs had a lower incidence (IRR 0.55; 95% CI 0.37-0.81). In the second post-diagnosis year, there were 6,257 individuals remaining that contributed 5,443 person-years. Overall, the incidence rate was 82 per 1,000 person-years (95% CI 75-90). Incidence was greater in Blacks vs. Whites (adjusted IRR 1.25; 95% CI 0.98-1.59). Consistent with findings from the first analysis period, APIs continued to have lower incidence vs. Whites (adjusted IRR 0.44; 95% CI 0.22-0.89). In the third post-diagnosis year, the overall incidence rate was 80 per 1,000 person-years (95% CI 72-89) and any racial disparities observed in age and gender adjusted IRRs were no longer significant. For patients in the first year following stem cell transplantation, annualized incidence rates of VTE were elevated (overall incidence rate of 148, 95% CI 117-188). Conclusion In this large population-based cohort of older MM patients, we observed racial disparities in the incidence of VTE within the first 24 months of diagnosis. A risk-adapted method of VTE prophylaxis should be considered. Understanding risk factors and groups vulnerable to development of thromboembolic events can help guide clinical decision making regarding VTE prophylaxis. Disclosures No relevant conflicts of interest to declare.

Temporary or long-lasting decrease of one or more blood cell lineages following allogeneic hematopoietic stem cell transplant (allo-HSCT) can lead to increased morbidity and mortality. Post-transplant cytopenia is often secondary to drug toxicity, viral infections, graft versus host disease (GVHD), or relapse. Less is known about the significance of cytopenia of unknown cause. Here we retrospectively analyzed 91 consecutive adult patients (median age 46 years; range: 19-63) who had received allo-HSCT conditioned with myeloablative fludarabine/ I.V. busulfan at our institution. Diagnoses included: acute myeloid leukemia (AML) or myelodysplatic syndrome (MDS) (n=57), acute lymphoblastic leukemia (ALL) (n=15), chronic myeloid leukemia (CML) (n=9), non-Hodgkin lymphoma (NHL) (n=5), B cell chronic lymphocytic leukemia (B-CLL) (n=2), myelofibrosis (n=1), unclassified myeloproliferative neoplasms (MPN) (n=2). Stem cell source was granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSC) in 81, bone marrow in 8 and cord blood in 2 patients. Median follow up for the entire cohort was 20 months (range 1-162 months). Patients with cytopenia of unknown cause were identified if they had full donor chimerism, negative cytomegalovirus (CMV) by molecular analysis, no active infections, acute GVHD Disclosures No relevant conflicts of interest to declare.

Purpose Clinical trials for treatment of diffuse large B-cell lymphoma (DLBCL) exclude the very elderly, ages 80 years and older. Treatment differences by race/ethnicity in very elderly DLBCL patients may result from disparities in health care access and other socioeconomic factors, but it remains unclear whether disparities in treatment lead to poorer survival. Our purpose was to (1) examine differences in utilization of chemotherapy and immunotherapy for DLBCL in very elderly patients and (2) characterize the comparative effectiveness of these treatments for all-cause and cancer-specific mortality in this population. Patients and Methods We conducted a retrospective cohort study of very elderly patients ages 80 years and older diagnosed with first primary DLBCL between 2001-2011 from the Surveillance Epidemiology and End Results (SEER)-Medicare linked database. Patients were included if they had at least 12 months of continuous enrollment on Medicare Parts A and B prior to and following diagnosis. Using SEER-Medicare administrative claims, we determined types of primary DLBCL treatment (e.g., observation, radiation, chemotherapy and immunotherapy). We also collected information on cancer stage, clinical characteristics, comorbid conditions and census tract level sociodemographic data. We used multivariable logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for likelihood of being treated with chemotherapy/immunotherapy. We examined possible differences in risk of all-cause and cancer-specific mortality by race and ethnicity using Cox proportional hazards models to account for differences in treatment. We also estimated hazard ratios (HR) and 95% CIs to determine the comparative effectiveness of rituximab-based combination chemotherapy for these mortality endpoints by racial/ethnic group. Results Among 4,404 very elderly DLBCL patients, the median age was 84 years (interquartile range: 82-87) and more patients included in the analysis were female (59%), non-Hispanic White (86%) and slightly more advanced stage at diagnosis (Ann Arbor stages III-IV, 51%). Forty five percent of patients received infused chemotherapy and/or immunotherapy. Of those treated patients, 77% received rituximab plus combination chemotherapy, either CHOP or CVP. Greater proportions of Black (63%) and Hispanic (63%) patients were not treated with chemotherapy/immunotherapy compared to White patients (54%). The observed treatment disparities were not significant after accounting for sociodemographic variables including Medicare supplementation and census tract poverty level (Black vs. White: OR=0.72, 95% CI 0.43-1.22; Hispanic vs. White: OR=1.04, 95% CI 0.72-1.49). No differences were observed in all-cause or cancer-specific mortality by race/ethnicity. When analyzing the comparative effectiveness of rituximab combination therapy in these populations, the benefit of treatment in all-cause mortality was equal or greater in Black (HR=0.28, 95% CI 0.16-0.50) and Hispanic (HR=0.22, 95% CI 0.15-0.34) patients compared to White patients (HR=0.33, 95% CI 0.30, 0.36); similar results were found for reduced cancer-specific mortality in Black (HR=0.14, 95% CI 0.07-0.31), Hispanic (HR=0.20, 95% CI 0.12-0.34) and White patients (HR=0.28, 95% CI 0.25-0.32). Conclusions In this population-based sample of very elderly Medicare beneficiaries with DLBCL, we observed low rates of treatment with systemic therapy. Racial/ethnic differences in treatment utilization were explained by socioeconomic factors. When accounting for these factors, we demonstrated no differences in risk of all-cause or cancer-specific mortality by race/ethnicity and similar effectiveness of treatment across racial/ethnic groups. Determining barriers to access for highly effective DLBCL therapies in the very elderly, particularly for racial and ethnic minorities, is of public health importance. Disclosures Smith: Gilead: Consultancy; Juno: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Pharmacyclics: Consultancy; Celgene: Consultancy; Portola: Consultancy; AbbVie: Consultancy; TGTX: Consultancy; Amgen: Other: Educational lecture to sales force.

African Americans (AA) have a 2- to 3-fold higher incidence of multiple myeloma (MM) when compared to other racial groups. Evidence suggests that there may be differences in the biology of MM, which confer a more favorable prognosis in AA patients. Prior studies are conflicted as to whether AA patients achieve equal or improved outcomes compared to non-African American (non-AA) patients. Our purpose was to evaluate the impact of AA race on outcomes of MM patients undergoing ASCT at a single center in both the chemotherapy and novel agent era. One hundred and twenty-nine patients who received melphalan 200 mg/m2 and ASCT between 2000 and 2013 were included in the analysis. Sixty-one (47%) patients were African-American and 68 (53%) were non-AA. Baseline characteristics including age, FISH, cytogenetics, paraprotein subtype, median number of prior therapies and International Staging System (ISS) stage were similar between racial groups. Overall, 77 (60%) patients received any novel agent prior to transplant and 52 (40%) received only chemotherapy. More non-AA patients were male (59% vs. 38%, p=0.02), received initial induction with a proteasome inhibitor (59% vs. 28%, p=0.0007), and were treated with post-ASCT maintenance therapy (41% vs. 23%, p=0.008). Time from diagnosis to ASCT in AA patients was 10 (range: 4-144) versus 8 (range: 3-54) months in non-AA patients (p=0.01). The ASCT hospital course was similar between both groups with no significant differences in time to neutrophil and platelet engraftment as well as the duration of hospitalization. Additionally, there was no significant difference in the extra-hematologic toxicity between the two groups including the incidence of diarrhea, mucositis, and infection. Response was measured using the International Myeloma Working Group criteria and was assessed immediately prior to transplant and between 90 to 180 days after transplant. No differences were observed in pre-transplant (p=0.13) or post-transplant (p=0.28) response rates between the two groups. African American patients had a significantly improved median OS compared to non-AA patients (not reached vs. 108 months, p=0.03). We further stratified analyses of OS by those treated in the chemotherapy versus novel agent era. Improved OS was observed in both the chemotherapy (93 vs. 68 months, p=0.02) and novel agent (not reached vs. 79 months, p=0.01) treatment era. In a multivariate Cox proportional hazards model, AA race was associated with improved overall survival (adjusted HR 0.30, 95% CI 0.11 to 0.81; p=0.017). Multiple myeloma has one of the most apparent ethnic disparities in incidence and outcomes among cancers. In our study, AA patients had a longer time to transplant and received less proteasome inhibitor-based induction and post-ASCT maintenance suggesting disparities in access to care. Despite these differences in treatment, we observed improved overall survival after ASCT compared to non-AA patients. We demonstrated this improved OS in patients who had received either chemotherapy or novel agents prior to ASCT. These findings provide further evidence for more favorable outcomes among AA patients. One explanation could be a difference in disease biology that may result in a lower risk disease. Investigation of these biologic differences between AA and non-AA MM patients may increase our understanding of the pathogenesis and future treatments of myeloma. Disclosures No relevant conflicts of interest to declare.

High dose melphalan is commonly used in patients with multiple myeloma (MM). Resistance to melphalan has been linked to the ability to repair DNA damage. To test whether DNA repair inhibitors overcome resistance to melphalan and and also have a direct anti-MM effect, we tested MM cell lines RPMI8226 and U266 in-vitro and in-vivo, using a NOD/SCID/ gamma null (NSG) xenograft model. RPMI8226 and U266 cells were initially treated in-vitro with the PARP inhibitor ABT-888. Using a proliferative assay, myeloma cells appeared sensitive to ABT-888 with low GI50 values (8.7μM for RPMI8226 cells, 49μM for U266 cells) and increased γH2AX foci, which persisted at 24 hours after treatment. This was confirmed in methycellulose colony assay where ABT-888 treatment reduced RPMI8226 colonies by 35% (p=0.002). Next we showed synergistic cytotoxicity between ABT-888 and melphalan. In both RPMI8226 and U266 cells strong synergy was displayed with a combination index (CI) less than 1 in proliferative assays (CI 0.5 and 0.3 at 50% proliferation respectively). Combination ABT-888 and melphalan treated cells underwent accelerated senescence compared to cells treated by melphalan alone (27% versus 51% βGal+ staining at 24 hours, p=0.02). This was confirmed by upregulation of senescence related genes p16 (1.6 fold increase) and p21 (1.5 fold increase). We did not find significant difference in apoptosis by Annexin V/ PI staining. Given that increased non-homologous end joining (NHEJ) activity has been shown to lead to resistance to melphalan, we tested whether an inhibitor of NHEJ could be synergistic with PARP inhibition and melphalan. Treatment with the DNA-PK inhibitor NU7026 at 10μM in addition to ABT-888 at 4μM resulted in 46% reduction in proliferation in RPMI8226 cells and 52% in U266 cells. When used in combination with melphalan chemotherapy, the dual DNA repair inhibitor therapy showed marked synergy in RPMI8226 cells with a combination index of 0.39. Finally we tested the ability of the combination of ABT-888 and melphalan to treat myeloma in-vivo. NSG mice were injected via tail vein with 5x106 RPMI8226 cells. Control (untreated) mice subsequently developed myeloma infiltrating the marrow, spleen and axial skeleton, with hind limb paralysis occurring at a median of 42 days. Treated mice received intraperitoneal injections of ABT-888 (3 times a week), or melphalan (weekly) or a combination of both agents starting on day 28 post-injection of MM cells for a total of 3 weeks. Using ABT-888, melphalan and a combination of both agents, median survival of mice was progressively prolonged (44 vs. 67 vs. 107 days, respectively) (p=0.02). Here we show that PARP and DNA-PK inhibition synergizes with melphalan in myeloma cells lines, providing a rationale for the addition of these agents to conditioning chemotherapy. In addition, we also show a direct anti-myeloma activity of these agents without the use of alkylator chemotherapy. Disclosures No relevant conflicts of interest to declare.

In the majority of low-middle-income countries (LMIC) worldwide, cancer care is limited by lack of patients' access to care and/or unaffordable cost of treatment. In contrast with many other LMIC, Cuban government provides cancer therapy to every citizen. Therefore, any standard treatment for acute leukemias, including BMT, is available for free. However, because of limited financial resources laboratories do not always provide immunophenotypic, cytogenetic or molecular tests to support the diagnosis or the management of leukemias, and only standard chemotherapy protocols are available. In this retrospective study we analyzed the results of BMT in adult acute leukemia patients transplanted at the Hermanos Ameijeiras Hospital in Havana (Cuba) from June 1986 to January 2016. A total of 101 consecutive cases (83 acute myeloid leukemia [AML] and 18 acute lymphoblastic leukemia [ALL]) were transplanted. Eligibility criteria for BMT included: age >16 and 60 years old. Support of training and development of research infrastructures remain of key importance in global health cancer care and global BMT. Disclosures No relevant conflicts of interest to declare.

Fatty acid synthesis (FAS) or oxidation (FAO) are important regulatory pathways in immune response. In fact, FAS plays a pivotal role in antigen presentation and T cells activation and FAO leads to fatty acid degradation which has been previously shown to regulate hematopoietic stem cell maintenance. Here we hypothesized that FAS can be a new target to suppress T cell alloimmune responses in solid organ or stem cell transplantations. Therefore, we tested if the FAS inhibitor C75 could suppress T cell alloreactivity without impairing normal hematopoiesis. The immuno-suppressive (IS) effect of moderate FAS inhibition was demonstrated in mixed leukocyte cultures (MLC) where C75 at 10 mkg/ml significantly reduced T cell proliferation and prevented the expansion of CD3+CD25+ and CD3+CD69+ T cells. In T cells stimulated by alloantigen, C75 also induced the downregulation of NF-kB gene expression and the upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) gene involved in ubiquitination and degradation of NF-kB protein. When compared to other standard IS agents, such as anti-thymocyte globulin (ATG), Cyclosporine A, Rapamycin or inhibitor of FAO Etomoxir, C75 showed similar anti-T cell activity. The same dose of C75 (10 mkg/ml) did not cause apoptotic death of human CD34+ cells in vitro, nor affected CD34+ cell clonogenicity in vitro. In fact, C75 increased the number of BFU-E and CFU-GM colonies (P < 0.05). We observed that the expression of de novo DNA methyltrasferases DNMT3A and DNMT3B, which are important regulators of stem cell renewal, was strongly reduced in CD34+ cells co-cultured for 3 days with allogeneic T cells. On the contrary, in the presence of C75 the expression of DNMT3A and DNMT3B was not different from baseline control. To test the in-vivo effect of C75 we utilized a xenograft model of stem cell rejection where 2 x 105 human CD34+ cells and HLA incompatible T lymphocytes were injected in immunodeficient nonobese diabetic/ltsz-scid/scid - IL2 receptor gamma chain knockout (NSG) mice at 1:1 ratio. Four weeks after transplantation, control NSG mice showed complete rejection of huCD45+CD34+ cells and the expansion of T cells in the marrow and spleen. NSG mice treated with intra-peritoneum injections of C75 every 3 days for 2 weeks, instead, showed 10-15% human CD45+ myeloid cells in the marrow and spleen at week 4 after transplant, suggesting at least a partial effect on preventing rejection of incompatible stem cells. We showed here that moderate FAS inhibition may represent a novel immunosuppressive strategy and our findings will prompt preclinical investigations exploiting the effect of FAS inhibitors alone or in combination with standard IS agents in models of allogeneic transplantation or bone marrow failure. Disclosures No relevant conflicts of interest to declare.

Alkylator chemotherapy remains important in pretransplant conditioning for multiple hematologic malignancies. Resistance to alkylators such as busulfan and melphalan results in part from the ability to repair DNA damage. DNA repair inhibition has therefore become an attractive treatment target. Here we tested the hypothesis that inhibitors of DNA repair overcome resistance to alkylator therapy. We initially treated REH, K562, HL60, NB4, RPMI8226 and U266 cells with the PARP inhibitor ABT-888. We noted widely varying GI50 values from 8.7 - 11x104 μM. Acute leukemia cells were overall insensitive to ABT-888 alone. However myeloma cells appeared relatively sensitive to ABT-888 with lower GI50 values (8.7μM for RPMI8226 cells, 49μM for U266 cells) and increased γH2AX foci at 24 hours after treatment. Synergy between ABT-888 and alkylator chemotherapy was observed in proliferative assays in all cell lines when treated with a fixed dose of ABT-888 (4μM) and increasing doses of either melphalan or busulfan. Combination index for RPMI8226 and HL60 cells was 0.5 at 50% proliferation. These findings were confirmed in a clonogenic assay. Increased cytotoxicity did not appear to be a result of apoptotic cell death as shown by Annexin V/PI co-staining. Instead combination treated RPMI8226 cells underwent accelerated senescence compared to melphalan treated cells at 24 hours as shown by βGal staining (27% vs. 51%, p=0.02). This was confirmed by upregulation of senescence related genes p16 (1.6 fold increase) and p21 (1.5 fold increase). Combination treated RPMI8226 cells were also noted to arrest in G2/M phase (43% vs. 50%). We hypothesized that cells may acquire the senescence associated secretory phenotype. We noted a 1.5-fold upregulation in IL6 gene expression in combination treatments compared to melphalan alone. CD86 gene expression increased by 1.6-fold and mean fluorescence intensity also increase by a factor of 1.3 compared to melphalan treatment. In mixed lymphocyte culture of treated RPMI8226 cells and CD3+ T cells, the stimulation index was 1.2 for melphalan treated cells and 3.2 for combination treated cells (p=0.003) showing that potentially RPMI8226 cells were able to directly present antigen to T-cells following combination treatment. As combination treatment resulted in upregulation of double strand repair genes such as BRCA1, BRCA2, FANCD2 and DNA-PK in HL60 cells we hypothesized that inhibitors of double strand repair may be synergistic with the alkylator chemotherapy and ABT-888. Treatment with NU7026 at fixed concentrations (10μM) to inhibit DNA-PK in addition to ABT-888 (4μM) resulted in 46% reduction in proliferation in RPMI8226 cells and 52% in U266 cells. No effect was seen in HL60 cells. However when used in combination with alkylator chemotherapy we were able to show marked synergy with alkylator and PARP inhibition in HL60 and RPMI8226 cells. Combination index in melphalan, ABT888 and NU7026 treated RPMI 8226 cells was 0.6. Finally we hypothesized that efficacy of DNA repair inhibition combination treatments was reliant on abnormal DNA repair in malignant cells in comparison to normal cells. To illustrate this we tested the impact of treatment on CD34+ cell hematopoietic colony formation. We show that NU7026, ABT-888 or a combination of both drugs with alkylator chemotherapy did not decrease colony formation over alkylator chemotherapy alone. Here we show that PARP and DNA-PK inhibition synergizes with alkylator chemotherapy in AML, ALL and myeloma cells lines, providing a rationale for the addition of these agents to conditioning chemotherapy. In addition we show the activity of these agents in myeloma without the use of alkylating agents. Disclosures No relevant conflicts of interest to declare.

Renal impairment (RI) is a common complication of multiple myeloma (MM) and is reported in up to 40 percent of patients. There is limited data on the outcomes of melphalan 200 mg/m2 (MEL200) and autologous stem cell transplantation (ASCT) in patients with serum creatinine > 2 g/dL since they have been excluded from most studies. Therefore we retrospectively evaluated the impact of RI on outcome of patients with MM treated with MEL200 and ASCT at our institution. One hundred and forty nine consecutive patients who received MEL200 and ASCT between 2000 and 2011 were included in the analysis. Forty-six patients had a CrCl< 60 ml/min and 103 had a CrCl ≥ 60 ml/min. Baseline characteristics were similar between the two groups including measures of disease risk and treatment history. Median creatinine clearance was 50 ml/min (20-59) in the RI cohort and 83 ml/min (60-128) in the normal renal function cohort. Patients with a CrCl < 60 ml/min experienced a longer median time to neutrophil (10 vs. 9 days, p=0.008) and platelet (12 vs. 10 days p60 ml/min group. Response was measured using the International Myeloma Working Group criteria and was assessed immediately prior to transplant and again between 90 to 180 days after transplant. Although there was an increase in the number of patients achieving CR in both groups, this was found to be significant only in the CrCl This represents one of the largest analyses of outcomes of MEL200 in MM patients with RI. We report that although short-term toxicity is increased in the RI group, long-term outcomes may be superior to those patients without renal impairment. We propose that this may be due to greater melphalan exposure in patients with RI. Based on these findings, we would consider MEL200 safe and effective in select patients with creatinine clearance between 30 and 60 ml/min. Disclosures No relevant conflicts of interest to declare.

The aims of this study were to analyze the role of T cells on the engraftment of allogeneic CD34+ cells after transplantation in immunodeficient nonobese diabetic/ltsz-scid/scid (NOD/SCID) IL2 receptor gamma chain knockout (NSG) mice and to test the in-vivo ability of abatacept (CTLA4-Ig) in preventing graft failure. Human CD34+ cells (0.2x106 cells/animal) were co- transplanted with allogeneic CD3+ T cells into sublethally irradiated NSG mice at ratios ranging from 1:50 to 1:0.5, or without T cells as a control. The engraftment of huCD45+ cell subsets in the bone marrow and spleen was measured by flow cytometry after 4-8 weeks. An expansion of T cells without engraftment of CD34+ cells was detected in each group of mice transplanted with CD34:T cells at ratios ≥ 1:0.5. To test whether T cells prevented any engraftment of CD34+ cells, or caused rejection after initial CD34+ cell homing in the bone marrow, kinetics experiments were performed by analyzing the marrow and spleen of mice at 1,2 or 4 weeks after transplant of CD34+ and T cells at 1:1 ratio. These experiments showed that at two weeks after transplant, CD34+ cells had repopulated the bone marrow but not the spleen, while T cells were found primarily in the spleen. Instead, in mice sacrificed at 4 weeks after transplant the marrow and the spleen contained only T cells and the CD34+ cells had been rejected. Based on our previous in-vitro studies showing that CD34+ cell immunogenicity is mainly dependent on B7:CD28 costimulatory signaling, we then tested whether costimulatory blockade with abatacept (CTLA4-Ig, Bristol Myers Squibb) would block stem cell rejection. Three groups of mice were transplanted with CD34+ and allo-T cells at 1:1 ratio and injected with Abatacept at 250 ug i.p. every other day from: a) day -1 to +28, b) day -1 to day +14 or c) day +14 to +28, then the animals were sacrificed at day +56 (8 weeks) after transplant to assess the engraftment. In Group a) the overall engraftment of huCD45+ cells was only 98% huCD45+ cells of myeloid or B cell lineage and In this preclinical xenograft model we demonstrated that costimulatory blockade with Abatacept at the time of allogeneic transplant of human CD34+ cells can prevent T cell mediated rejection provide the basis for the future non-myeloablative protocols for incompatible stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure SCD but chemotherapy-based conditioning regimens are associated with substantial morbidity and mortality, particularly in adult patients. A chemotherapy-free, non-myeloablative HSCT with alemtuzumab 1mg/kg divided over 5 days followed by total body irradiation (TBI) 300cGy was recently developed at the National Institute of Health and obtained stable mixed chimerism and clinical cure in 90% of SCD patients receiving an HLA and ABO-matched, related HSCT. The same study was replicated in high risk SCD adult patients at the University of Illinois at Chicago. Thirteen patients aged 17 - 40 years were transplanted between November 2011 and June 2014. Indications included ≥3 vaso-occlusive crises (VOC) per year (n=7), stroke (n=4) and >1 episode of acute chest syndrome (ACS) requiring intensive care (n=2). Unmanipulated, G-CSF mobilized peripheral blood cells were collected from HLA-matched, related donors (MRD) with Hb AS (n=4) or Hb AA (n=9). Four patients had red blood cell (RBC) alloimmunization and 2/13 patients received a graft with major ABO incompatibility. The median number of CD34+ cells infused was 8.1 x 106 cells/kg. Of 13 patients, 10 had severe neutropenia for a median duration of 5 days (range: 1 - 14) and 3 patients had a platelet count < 50 x109/L requiring a platelet transfusion. All patients engrafted and are alive with a median follow-up of 337 days (range: 53 – 986). Cytokine levels involved in T-cell regulation (IL-5, IL-10, and IL-13) increased post-alemtuzumab compared to pre-HSCT levels while no differences were observed in IL-2, IL-4, IL-12 or TNF-α. One secondary graft failure occurred in a patient not compliant with sirolimus and no acute or chronic GVHD has been observed. The median donor chimerism at 1 and 6 months was 96% (range: 63 – 98%) and 84% (range: 41 – 96%), respectively, in blood mononuclear cells; and 48% (range: 20 – 97%) and 25% (range: 20 – 48%), respectively, in CD3+ T cells (Figure 1a). Median hemoglobin concentration increased from 8.4 g/dL (range: 6.6 – 12.4 g/dL) to 12.9 g/dL (range: 11.0 – 16.8 g/dL) and the median reticulocyte percentage decreased from 12.1% (range: 4.8 – 19.6%) to 1.9% (range: 1.3 – 6.2%). Changes in hemoglobin fractionation in HSCT recipients from Hb AA donors are shown in Figure 1b. No episodes of ACS or stroke have been observed following hospital discharge after HSCT. Two patients have been tapered off of sirolimus with stable chimerisms, laboratory values, and no repeat episodes of SCD-related complications. Non-myeloablative HSCT from MRD with alemtuzumab and TBI in SCD adult patients provides a clinical cure in the majority of patients with low toxicity and no transplant-related mortality. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Total body irradiation has been decreasingly utilized in hematopoietic stem cell transplant due to extra-hematologic toxicity. However, patients with a high risk of relapse may benefit from a combination of chemotherapy and radiation. Intensity modulated total marrow irradiation (IM-TMI) represents an innovative technique to irradiate the bone marrow with limited radiation to surrounding tissues and was tested here in combination with fully myeloablative chemotherapy. We designed a phase I trial with escalating doses of IM-TMI to standard myeloablative fludarabine/ IV targeted busulfan conditioning. All patients received fludarabine 40mg/m2 on days -8 to -5 and IV busulfan on days -5 to -2 targeting an AUC of 4800microM/min based on a pretransplant test dose. In addition patients received IM-TMI at one of three dose levels (3Gy, 6Gy or 9Gy). Radiation was delivered in 2 daily doses at 3Gy/day on day -5 (first cohort), days -6 and -5 (second cohort) or days -7 to -5 (third cohort). Graft versus host disease prophylaxis was with standard methotrexate, tacrolimus and ATG in patients receiving unrelated transplants. A total of 13 patients with high risk malignant disease were enrolled in the study with 12 patients receiving a matched related (n=7) or unrelated (n=5) peripheral blood stem cell transplant. One was excluded due to relapse prior to transplant. Median age was 52 years (range 20-65). Patients underwent transplant for ALL (n=1) or AML (n=8) with high risk cytogenetics or >CR1, multiple myeloma (n=2) with high risk cytogenetics and relapse after autologous transplant and accelerated phase CML (n=1) resistant to therapy with tyrosine kinase inhibitor. Three patients were enrolled in cohorts 1 (3Gy) and 2 (6Gy), and 6 patients in cohort 3 (9Gy). Toxicity was measured on the Bearman scale. No grade 3-4 extrahematologic toxicity was observed in any cohort. Grades 1-2 mucositis was observed in 9 patients. Grade 1 gastrointestinal toxicity was observed in 2 patients and 1 patient in cohort 2 had grade 2 cardiac toxicity. All patients engrafted and no patients suffered transplant related mortality on or before day +30. Median time to engraftment of neutrophils >0.5x109/L was 14.5 days (range 10-20 days) and platelets >20x109/L was 14.5 days (range 8-19 days). After median follow up of 692.5 days (range 68-1319 days), 8 patients (66%) are alive and 7 remain in remission. 1 patient with multiple myeloma is alive after relapse. Of 4 deaths, 2 were due to transplant related mortality (liver disease at day 253 and sepsis at day 68) and 2 were due to relapse (1 patient with AML and 1 with ALL). Three patients developed grade 2-4 acute graft versus host disease (GVHD) and 4 patients have extensive chronic GVHD. This is the first study showing that IM-TMI in doses up to 9Gy can be safely added to a busulfan based myeloablative conditioning regimen. It is unknown at this time whether higher doses of IM-TMI can be utilized with myeloablative preparative regimens. The use of a linear accelerator platform to deliver IM-TMI, will allow almost any transplant center to utilize this approach. Disclosures: No relevant conflicts of interest to declare.

Our previous studies have shown the ability of human CD34+ cells to stimulate T cell alloproliferative responses in-vitro. Here, we investigated anti-CD34 T cell alloreactivity in-vivo by co-transplanting human CD34+ cells and allogeneic T cells of an incompatible individual into NSG mice. Human CD34+ cells (2x105/animal) were transplanted with allogeneic T cells at different ratios ranging from 1:50 to 1:0.5, or without T cells as a control. No xenogeneic GVHD was detected at 1:1 CD34:T cell ratio. Engraftment of human CD45+ (huCD45+) cells in mice marrow and spleen was analyzed by flow cytometry. Marrow engraftment of huCD45+ cells at 4 or 8 weeks was significantly decreased in mice transplanted with T cells compared to control mice that did not receive T cells. More importantly, transplantation of T cells at CD34:T cell ratios from 1:50 to 1:0.5 resulted in stem cell rejection since >98% huCD45+ cells detected were CD3+. In mice with stem cell rejection, human T cells had a normal CD4:CD8 ratio and CD4+ cells were mostly CD45RA+. The kinetics of human cell engraftment in the bone marrow and spleen was then analyzed in mice transplanted with CD34+ and allogeneic T cells at 1:1 ratio and sacrificed at 1, 2, or 4 weeks. At 2 weeks post transplant, the bone marrow showed CD34-derived myeloid cells, whereas the spleen showed only allo-T cells. At 4 weeks, all myeloid cells had been rejected and only T cells were detected both in the bone marrow and spleen. Based on our previous in-vitro studies showing that T cell alloreactivity against CD34+ cells is mainly due to B7:CD28 costimulatory activation, we injected the mice with CTLA4-Ig (Abatacept, Bristol Myers Squibb, New York, NY) from d-1 to d+28 post transplantation of CD34+ and allogeneic T cells. Treatment of mice with CTLA4-Ig prevented rejection and allowed CD34+ cells to fully engraft the marrow of NSG mice at 4 weeks with an overall 13± 7% engraftment of huCD45+ marrow cells (n=5) which included: 53±9% CD33+ cells, 22±3% CD14+ monocytes, 7±2% CD1c myeloid dendritic cells, and 4±1% CD34+ cells, while CD19+ B cells were only 3±1% and CD3+ T cells were 0.5±1%. We hypothesize that CTLA4-Ig may induce the apoptotic deletion of alloreactive T cells early in the post transplant period although we could not detect T cells in the spleen as early as 7 or 10 days after transplant. Here we demonstrate that costimulatory blockade with CTLA4-Ig at the time of transplant of human CD34+ cells and incompatible allogeneic T cells can prevent T cell mediated rejection. We also show that the NSG model can be utilized to test immunotherapy strategies aimed at engrafting human stem cells across HLA barriers in-vivo. These results will prompt the design of future clinical trials of CD34+ cell transplantation for patients with severe non-malignant disorders, such as sickle cell anemia, thalassemia, immunodeficiencies or aplastic anemia. Disclosures: No relevant conflicts of interest to declare.

The alkylator Busulfan (Bu) is used in conditioning regimens for acute leukemia prior to allogeneic stem cell transplant. Multiple DNA repair mechanisms including mismatch repair and base excision repair have been implicated in resistance to Bu. The enzyme PARP is central to base excision repair. We hypothesized that treatment of acute leukemia cell lines with both ABT888 (Veliparib), an inhibitor of PARP 1 and 2, and Bu would lead to synergistic cell kill and that this effect is maximal in mismatch repair deficient cells. Two mismatch repair proficient cell lines (K562 and HL60) and 2 mismatch repair deficient cell lines (NB4 and REH) were treated with ABT888 alone, Bu alone or a combination of both. In single drug experiments, doses of drug treatment ranged from 0-400mcg/ml. In combination experiments a fixed dose of ABT888 of 1.25mcg/ml was utilized with Bu doses varying from 0-200mcg/ml. This dose of ABT888 was chosen as it approximated to patient blood levels in clinical trials. After 24 hours of treatment, cells were washed and resuspended in fresh medium. Proliferation of cells was measured by standard 3H-thymidine uptake assay at 48 hours. Sigmoidal dose response curves and GI50 values were then calculated. In addition, cells were tested for apoptosis by flow cytometry using activated caspase 3 and annexin/ PI staining at 24 and 48 hours after treatment. All 4 cell lines were found to be resistant to single agent ABT888. Despite mismatch repair deficiency in REH cells, therapeutic doses of ABT888 did not cause significant decreases in proliferation. The effect of ABT888 was, as expected, much less evident in the mismatch repair proficient K562 cells. These cells were also relatively resistant to single agent Bu in vitro. The combination of Bu and ABT888 was synergistic in all cell lines with GI50 (micromoles/ml) for Bu decreasing from 67.8 to 45.7 in K562, from 23.3 to 8.0 in HL60, from 46.6 to 36.1 in NB4 and from 34.4 to 17.0 in REH cells. The Combination Index was To our knowledge, this is the first study to show synergy of a clinically available PARP inhibitor with Bu. We believe this data warrants further study with the potential clinical application of increasing the antileukemic effect of stem cell transplantation conditioned with Bu containing preparative regimens. Disclosures: No relevant conflicts of interest to declare.

The alkylating agent Busulfan (Bu) is commonly used in the pre-transplant conditioning regimen for patients with acute myeloid leukemia (AML). Relapse after transplant is in part due to resistance to Bu. Our study was aimed at identifying a genomic signature that could predict resistance to Bu in AML cells. In order to obtain a list of candidate genes which may correlate with increasing resistance to Bu we performed a linear regression analysis controlled for cancer type on NCI60 Stanford cDNA data and GI50 values. This produced a list of 111 genes correlating with increasing Busulfan GI50 (p To our knowledge, this is the first attempt to obtain a list of genomic biomarkers to predict Bu resistance in AML using a genome wide approach. This data provides a rationale for validation of these 4 genes in a clinical dataset with the potential future application of predicting relapse after Bu based high dose therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 4474 Pulmonary function post allogeneic hematopoietic stem cell transplant (HSCT) can be impaired by previous exposure to chemotherapy, infection, or underlying chronic graft versus host disease (cGVHD). In this retrospective study, we selected 21 long term transplant survivors with a median follow up of 48 months who had received a related (60%) or unrelated (40%) HSCT conditioned with a myeloablative busulfan-based regimen. All patients had routine pulmonary function tests (PFTs) repeated within two years from transplant and none had respiratory symptoms or a history of chronic lung infection at the time of analysis. Median age was 45 years (range 18–54). Patients had a diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (52%), acute lymphoblastic leukemia (ALL) (14%), chronic myeloid leukemia (CML) (14%), non-Hodgkin lymphoma (NHL) (9%), or chronic lymphocytic leukemia (CLL) (2%). Survival rate at the time of analysis is 90%. We initially compared single parameters of PFTs including corrected diffusion limiting capacity of oxygen (DLCO), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity (TLC) obtained before and after transplant. Post transplant, all PFT parameters showed some degree of reduction compared to pre-transplant values (Figure 1). FEV1 and FEV1/FVC were significantly decreased (108 vs 92,p=0.04 and 86 vs 80%, p=0.04, respectively). Median values of corrected DLCO prior to and after transplant were 83% (range 55–148) and 77%(range 44–146) (p=0.2), respectively. In order to test whether patients with >10% reduction of PFTs had an increased rate of overall cGVHD, we analyzed intra-patient changes in DLCO and FEV1 values. We then divided patients into groups with extensive, limited, or no cGVHD. No correlation was found between the degree of cGVHD and FEV1 or DLCO values. A decrease in pulmonary function was detected in patients who received a busulfan based myeloablative HSCT despite the absence of lung infection or pulmonary cGVHD. This finding, however, did not affect long term survival. Disclosures: No relevant conflicts of interest to declare.

Abstract 4491 The treatment of chronic ocular graft-versus-host disease (GVHD) is empirical, mainly due to the lack of knowledge of its pathogenesis. The goals of this study were to describe the histopathologic and immunophenotypic characteristics of conjunctival biopsies from patients with chronic ocular GVHD and to determine whether these findings can guide immunomodulation or palliative management strategies of GVHD associated dry eye disease. A conjuctival biopsy was obtained in eleven patients who previously received an allogeneic hematopoietic stem cell transplant (HSCT) and presented with chronic GVHD and dry eye symptoms. Hematoxylin and eosin (H&E) and immunohistochemical staining of conjunctival biopsies were analyzed for presence of inflammatory cells (B and T cells), fibrosis, and apoptosis. All conjunctival biopsies showed the presence of keratosis and parakeratosis and 7/11 (64%) biopsies had evidence of conjunctival epithelial apoptosis. Immunohistochemistry demonstrated the presence of inflammatory cells in 72% (8/11). These cells were predominantly CD3+ T lymphocytes (54%), with a CD4:CD8 cell ratio of 1:1.7. No biopsies showed B cells. Fibrosis was noted in 54% of biopsies (6/11). Conjunctival apoptosis detected by caspase-3 antibody staining showed significant moderate positive correlation with goblet cell loss (r=0.6, p=0.04). Presence of inflammatory cells showed a stronger correlation with conjunctival apoptosis as compared with fibrosis (r=0.38 and 0.26 respectively), however both correlations were not significant (p A standard dry eye treatment regimen in chronic ocular GVHD remains to be determined, thus examining the histopathologic features may help guide a more focused management strategy. In this study conjunctival apoptosis was associated with significant goblet cell loss and it more frequently accompanied inflammation as compared to fibrosis. Aggressive topical immunomodulation may reduce inflammation and goblet cell loss in patients with conjunctival biopsies positive for apoptosis. Disclosures: No relevant conflicts of interest to declare.

Abstract 2076 Myeloproliferative neoplasms (MPN) have similar incidence rates across different ethnicities in the United States. However, reported clinical studies rarely address the outcome in patients with different ethnicities. In this study, we retrospectively analyzed 127 patients with a diagnosis of MPN followed at the University of Illinois Hospital between January 2005 and July 2011. Of these patients, 69 were Caucasian and 58 Non-Caucasian (mostly African-American and Hispanic). The median age was 50 years (range: 20–85) in non-Caucasians and 51 years (range: 22–89) in Caucasians. Among 127 patients, 53 had polycythemia vera (PV), 52 essential thrombocythemia (ET), and 22 primary myelofibrosis (PMF). In each disease group, the following parameters were compared at diagnosis between Caucasian and non-Caucasian patients: age/gender, JAK2 V617F mutation status, cytogenetic abnormalities, family history of MPNs, constitutional symptoms, white blood cell (WBC) and platelet count, hemoglobin level, and spleen size. In addition, the two groups were compared for thrombotic or hemorrhagic events, cardiovascular complications, progression of disease, secondary cancer and overall survival. Among 53 PV patients, Caucasians (n=33) had higher WBC counts (11.7 vs. 8.1 ×103 cells/μL, p=0.03) and a greater spleen size (14 vs. 10 cm longitudinal diameter, p=0.03) at diagnosis compared to non-Caucasians (n=20). However, more frequent hemorrhagic (38.9% vs. 6.1%, p=0.003) and cardiovascular (27.8% vs. 3%, p=0.009) complications were seen in the non-Caucasian cohort of patients compared to the Caucasian cohort. Use of hydroxyurea (55% vs. 57%), aspirin (88% vs. 76%), anagrelide (10% vs. 24%), interferon (18% vs. 5%) and anticoagulation (21% vs. 20%) were not significantly different between Caucasians and non-Caucasians. In the ET patients (non-Caucasian: n=27; Caucasian: n=25), there were no significant differences in presenting characteristics, type of therapies, or clinical outcomes between the two groups. The 22 patients with PMF were classified according to the international prognostic scoring system (IPSS) at diagnosis. In 11 non-Caucasian and 11 Caucasian patients, differences of patients at low risk (18% vs. 9%), intermediate-1 (55% vs. 27%), intermediate-2 (27% vs. 55%), or high risk (9% vs. 0%) were not statistically significant. In a multivariate logistic regression analysis, we demonstrated that prior history of thrombosis and older age are independent prognostic factors for subsequent thrombotic or hemorrhagic events (p=0.03 and p=0.003, respectively). Neither WBC at diagnosis nor ethnicity were independent prognostic indicators in this series of patients. With a median follow-up of eight years (range 1–23 years), median overall survival was not reached for PV, ET, or PMF and no significant differences were detected in Caucasian or non-Caucasian groups. Our observations suggest that when given equal access to care, similar clinical outcomes are achieved in Caucasian and non-Caucasian patients with MPNs. Disclosures: No relevant conflicts of interest to declare.

Abstract 4213 Multiple myeloma (MM) accounts for 10% of hematologic malignancies in the U.S. African Americans (AA) have twice the risk of developing multiple myeloma and, in previous studies, a higher mortality rate when compared to non-African Americans (non-AA). In recent years, clinical outcomes for patients with MM have improved as a result of new agents, such as immunomodulatory drugs (IMiDs) and bortezomib. However, the therapeutic impact of these new therapies in AA vs. non-AA patients has not been evaluated. In this study, 53 consecutive patients (23 AA, 30 non-AA) with newly diagnosed MM were retrospectively analyzed after induction treatment with thalidomide/dexamethasone (n=22), lenalidomide/dexamethasone (n=8), bortezomib/dexamethasone (n=5), bortezomib/thalidomide/dexamethasone (n=3), lenalidomide/bortezomib/dexamethasone (n=12), or an IMiD plus melphalan (n=3). AA and non-AA patients were comparable for age, immunoglobulin isotype, MM stage of disease, serum β2microglobulin and albumin levels, and cytogenetic abnormalities including del13 (27% vs. 38%, respectively, p=NS). When measured according to international uniform criteria, the response rate to induction therapy was not statistically different between AA and non-AA patients: complete remission (CR, 22% vs. 21.4%), very good partial remission (VGPR, 26% vs. 21.4%), or partial remission (PR, 43.4% vs. 32.1%). However, the rate of stable/progressive disease following induction therapy was significantly higher in non-AA patients (p = 0.03). Of 53 patients, 34 received high-dose chemotherapy followed by autologous stem cell transplant (ASCT). In this group, the CR + VGPR rate following ASCT was significantly higher in AA compared with non-AA patients (59% vs. 35%, p=0.0007). At a median follow up of 47 months, the relapse rate was 59% in AA and 46% in non-AA patients (p=NS) and the median time to progression (TTP) was 9.1 months in both groups. Five patients (9%) died. All deaths occurred in the non-AA cohort and in 4/5 cases death was due to disease progression. In conclusion, our findings demonstrate that despite their increased disease risk, AA patients with MM have a favorable outcome that is equivalent to that of non-AA patients when treated with IMiDs and/or bortezomib. Disclosures: No relevant conflicts of interest to declare.

Abstract 4526 Intensity modulated total marrow irradiation (IM-TMI) represents an innovative technique to irradiate the bone marrow in hematologic malignancies. IM-TMI has been performed previously using tomotherapy in combination with a reduced intensity preparative regimen. Here we report 2 cases where IM-TMI 300cGy was delivered using a linear accelerator in combination with fludarabine/IV busulfan. To plan IM-TMI, 5 mm-slice CT scanning from top of the head to the mid femur was performed with immobilization using a customized whole body alpha cradle. All bones (excluding the arms and lower extremities) were contoured as the clinical target volume. A 3 mm margin was added to obtain the planning target volume (PTV). The organs at risk (OAR) including the brain, lenses, lungs, liver, kidney, small bowel and heart were identified and contoured. The IM-TMI technique consisted of three separate treatment plans: the head and neck; trunk; and pelvis. Patients received fludarabine 40mg/m2 on days -8 to -5. IV busulfan was given on days -5 to -2 targeting an AUC of 4800microM/min based on a pretransplant test dose. IM-TMI was delivered on day -5. The patients received a total of 300 cGy IM-TMI dose in two fractions, 8 hours apart. Two patients were treated: one is a 63 year old male with multiple myeloma who relapsed within 6 months after an autologous transplant with new cytogenetic abnormalities; and the second is a 52 years old female with AML who failed initial induction chemotherapy and at the time of transplant was in complete remission after receiving a second induction and one consolidation chemotherapy. Both patients received PBSC from HLA matched siblings. IM-TMI technique achieved 95% coverage of the PTV. The mean doses to the lenses and lungs were 99 and 195 cGy, respectively. Overall doses delivered to OAR were reduced by 20–67% on average when compared to standard total body irradiation. Treatment time was 44 min and 32 min for the beam-on and set-up, respectively, using the Varian 21 EX linac and MV imaging. Both patients suffered Bearman grade 1 mucositis. No other extramedullary toxicities were observed. Both engrafted in a timely manner achieving neutrophil >0.5 × 109/L at day 13 and 14, and platelet >20 × 109/L at day 8 and 9, respectively. Full donor chimerism was noted by day +30. After follow up of 246 and 218 days, respectively, both patients are alive and in remission. One developed a grade 2 acute GVHD and none of them has chronic GVHD. This study demonstrates for the first time the use of IM-TMI using a linear accelerator. The possibility of adding higher doses of IM-TMI to a myeloablative regimen without toxicity will be tested in a dose escalating clinical trial. Disclosures: No relevant conflicts of interest to declare.