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Background. Consensus from prior studies shows that the use of maintenance therapy after completion of combination therapy leads to longer progression-free survival (PFS) for patients with multiple myeloma with some studies showing an overall survival (OS) benefit. Currently, lenalidomide is the standard of care; however, there are limited published data on long-term use regarding ability to sustain minimal residual disease (MRD)-negativity and late toxicities. We were motivated to develop a study focusing on continuous, induction-agnostic lenalidomide maintenance with integration of clinical and correlative data. Here, we report formal results of this phase II study with focus on MRD dynamics and tolerability. Methods. This single arm, phase II trial enrolled 100 evaluable patients. Lenalidomide 10 mg is given days 1-21 on a 28-day cycle. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT at baseline, annually, at progression/end of study; blood work was done every 3 months. The study was statistically powered for the primary endpoint of PFS at 36 months. Correlative assays included MRD testing (10-color single-tube flow cytometry and IGHV sequencing; sensitivity ≤10-5), genomic characterization of detectable disease, and profiling of the bone marrow microenvironment performed on serially banked samples. Results. 100 evaluable patients were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-87 years) and median ECOG score 1 (range 0-1). Prior to enrollment, 22 (30%) patients had high-risk FISH/SNP signature defined as one or more of: 1q+, t(4;14), t(14;16), t(14;20), and 17p- and 48 patients had undergone autologous hematopoietic cell transplantation (AHCT). At abstract submission, median cycles delivered is 39 (range 9-62). 74% of patients have completed ³24 cycles and 55% have completed ³36 cycles. Overall PFS at 36 months was 77% (95% CI: 0.69-0.87) and PFS at 60 months was 63% (95% CI: 0.51-0.78). All patients had MRD testing at least once. 46% were MRD-negative at enrollment. 7 patients who were MRD+ at enrollment converted to MRD-negative. At median follow up 39.4 months (range 7-56 months), 20/100 patients (20%) have progressed. In consideration of the entire follow-up time from initial MRD-negativity, 44 (of 95 tested; 46%) and 37 (of 73 tested; 51%) achieved sustained MRD-negativity at 1 and 2 years, respectively. 22 patients were MRD-negative at 3 years (of 51 tested; 43%). Among those who sustained MRD-negativity for 2 years, with median follow-up of 19 months past the 2-year landmark analysis (max 120 months), there were no progression events. Age, induction regimen, and MRD status at enrollment were the only significant variables associated with PFS regardless of cytogenetic risk or transplant status. At 1 and 2-year landmark analysis, MRD-negativity superseded all else as the most significant factor associated with PFS with HR 0.06(p=0.0004) and HR 1/Inf (p=0.015), respectively. Toxicities (grade 3) included neutrophil count decrease (20%), hypertension (3%), diarrhea (3%), lung infection (2%), and maculo-papular rash (2%), and toxicities (grade 4) include sepsis (2%) and platelet count decrease (7%). The most common non-grade 3/4 toxicities were diarrhea (55%), fatigue (36%), and upper respiratory infection (30%). 7% developed a secondary malignancy on study: 3 adenocarcinoma, 1 squamous cell carcinoma, 1 CMML, 1 MDS, 1 ALL, and 1 glioblastoma. One evaluable patient required dose reduction due to toxicities/tolerability. Conclusions. This prospective study of continuous lenalidomide maintenance, agnostic to induction regimen or AHCT usage, was designed to evaluate the dynamics of MRD-negativity in relation to PFS. It expands on the importance of MRD as a predictor of outcome and illustrates how continuous maintenance therapy can deepen and sustain MRD-negative responses achieved with modern combination therapy. For this cohort, MRD-negativity at each landmark profoundly outweighed the impact of all other variates. Among those who had sustained MRD-negativity at 2 years (37% of the cohort), regardless of MRD status at enrollment, none have had progression events at median 43 months. Our results support cross-sectional MRD testing as a surrogate endpoint for drug approval, and the use of longitudinal MRD tracking in clinical management. Disclosures Korde: Amgen: Research Funding; Astra Zeneca: Other: Advisory Board. Lesokhin:Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; BMS: Consultancy, Honoraria, Research Funding. Smith:Precision Biosciences: Consultancy; Bristol Myers Squibb: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy. Shah:Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Mailankody:Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Chung:Genentech: Research Funding. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Thoren:Sebia: Research Funding; The Binding Site: Research Funding. Ho:Invivoscribe, Inc.: Honoraria. Dogan:AbbVie: Consultancy; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; National Cancer Institute: Research Funding. Giralt:MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; KITE: Consultancy; OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; TAKEDA: Research Funding. Landgren:Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Karyopharma: Research Funding; Merck: Other; Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria.

Background Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. The relationship between acquired gene mutations and mCAs in CH and their joint roles in leukemia development have not been systematically investigated. Methods We developed a method to reliably map mCAs at low cell fractions from deep targeted sequencing data. We applied this method in a cohort of 32,442 solid tumor patients who have undergone prospective clinical sequencing (MSK-IMPACT). We characterized gene mutations in our patient cohort using an established variant calling procedure from our previous studies. Results We jointly characterized 383 mCA events (median aberrant cell fraction 32%, range 10%-90%) and 14,789 mutations across 457 genes. mCA was significantly associated with age (OR=1.8, P20% VAF, compared to 1% of the general cohort. We identify co-mutational patterns characteristic of diverse mechanisms of clonal selection. We observe that mutations in DNMT3A, TET2, JAK2, MPL, EZH2, TP53 and ATM form recurrent double-hits with deletions or CNLOHs, resulting in either oncogene mutant dosage adjustment or inactivation of tumor suppressors. Notably, certain mCA events were highly directed events acting on previously acquired gene mutations in the corresponding loci. Of six events of 7qCNLOH, all six co-localized with an EZH2 (7q36.1) mutation (q During patient follow-up, the 3-year cumulative incidence of leukemias was significantly higher in patients with composite CH genotypes (14.6%, CI: 7-22%) as compared to patients with either mCA, gene mutation alone or no CH, of which all had a 3-year cumulative incidence of Conclusions Our joint characterization of gene mutations and mCAs in a large prospective sequencing cohort reveals a previously unrecognized layer of complexity in the evolutionary dynamics of clonal hematopoiesis that converges towards characteristic genotypes associated with distinct leukemia subtypes. This puts mCAs in the context of the continuous evolutionary process of oncogenesis that can often span years and sheds new lights on its patterns of acquisition and progression. We demonstrate that the integration of chromosomal aberrations provides additional resolution to risk stratification as well as interpretation of clinical phenotypes and that mCAs should be screened in conjunction with gene mutations to improve existing CH surveillance programs in cancer patients. Disclosures Bolton: GRAIL: Research Funding. Medina:Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Mantha:MJH Associates: Honoraria; Physicians Education Resource: Honoraria. Solit:Pfizer: Honoraria; Loxo Oncology: Honoraria; Lilly Oncology: Honoraria; Illumina: Honoraria; Vivideon Therapeutics: Honoraria. Diaz:Neophore: Consultancy, Current equity holder in private company; Merck: Consultancy; Johns Hopkins University: Patents & Royalties; Jounce Therapeutics: Current equity holder in private company; Thrive Earlier Detection: Current equity holder in private company; Personal Genome Diagnostics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Berger:Illumina: Research Funding; Roche: Consultancy; Grail: Research Funding. Levine:Lilly: Consultancy, Honoraria; Janssen: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Prelude Therapeutics: Research Funding; Gilead: Honoraria; Amgen: Honoraria; Morphosys: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Zehir:Memorial Sloan Kettering Cancer Center: Current Employment; Illumina: Honoraria. Papaemmanuil:Celgene: Consultancy, Honoraria, Research Funding; Prime Oncology: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Illumina: Consultancy, Honoraria; Kyowa Hakko Kirin: Consultancy, Honoraria; Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; MSKCC: Patents & Royalties.

8040 Background: Passive monitoring using wearables can objectively measure sleep over extended time periods. MM patients (PTs) are susceptible to fluctuating sleep patterns due to pain and dexamethasone (dex) treatment. In this prospective study, we remotely monitored sleep patterns on 40 newly diagnosed MM (NDMM) PTs while administering electronic PT reported outcome (ePRO) surveys. The study aim was to establish sleep bioprofiles during therapy and correlate with ePROs. Methods: Eligible PTs for the study had untreated NDMM and assigned to either Cohort A – PTs < 65 years or Cohort B – PTs ≥ 65 years. PTs were remotely monitored for sleep 1-7 days at baseline [BL] and continuously up to 6 therapy cycles. PTs completed ePRO surveys (EORTC - QLQC30 and MY20) at BL and after each cycle. Sleep data and completed ePRO surveys were synced to Medidata Rave through Sensorlink technology. Associations between sleep measurement trends and QLQC30 scores were estimated using a linear mixed model with a random intercept. Results: Between Feb 2017 - Sep 2019, 40 PTs (21 M and 19 F) were enrolled with 20 in cohort A (mean 54 yrs, 41-64) and 20 in cohort B (mean 71 yrs, 65-82). Regimens included KRd 14(35%), RVd 12(30%), Dara-KRd 8(20%), VCd 5(12.5%), and Rd 1(2.5%). Sleep data was compiled among 23/40 (57.5%) PTs. BL mean sleep was 578.9 min/24 hr for Cohort A vs. 544.9 min/24 hr for Cohort B (p = 0.41, 95% CI -51.5, 119.5). Overall median sleep trends changed for cohort A by -6.3 min/24 hr per cycle (p = 0.09) and for cohort B by +0.8 min/24 hr per cycle (p = 0.88). EPRO data trends include global health +1.5 score/cycle (p = 0.01, 95% CI 0.31, 3.1), physical +2.16 score/cycle (p < 0.001, 95% CI 1.26, 3.07), insomnia -1.6 score/cycle (p = 0.09, 95% CI [-3.47, 0.26]), role functioning +2.8 score/cycle (p = 0.001, 95% CI 1.15, 4.46), emotional +0.3 score/cycle (p = 0.6, 95% CI -0.73, 1.32), cognitive -0.36 score/cycle (p = 0.44, 95% CI -1.29,0.56), and fatigue -0.36 score/cycle (p = 0.4, 95% CI -1.65, 0.93). No association between sleep measurements and ePRO were detected. Difference in sleep on dex days compared to all other days during the sample cycle period for cohort A was 81.4 min/24 hr (p = 0.004, 95% CI 26, 135) and for cohort B was 37.4 min/24 hr (p = 0.35, 95% CI -41, 115). Conclusions: Our study provides insight into wearable sleep monitoring in NDMM. Overall sleep trends in both cohorts do not demonstrate significant gains or losses, and these trends fit with HRQOL ePRO insomnia responses. Upon further examination, we demonstrate objective differences (younger PTs) in intra-cyclic sleep measurements on dex days compared to other cycle days (less sleep by > 1 hr). For older patients, less variation in sleep profiles was detected during dex days, possibly due to higher levels of fatigue or longer sleep duration. Sleep is an integral part of well-being in the cancer patient. Future studies should continue to characterize sleep patterns as it relates to HRQOL.

In the version of this article initially published, the affiliation provided for author Matteo Giovanni Della Porta (37Cancer Center, Humanitas Research Hospital & Humanitas University, Milan, Italy) was incorrect, and a second affiliation was missing. The correct affiliations are as follows (with subsequent affiliations renumbered accordingly): 37Humanitas Clinical and Research Center–IRCCS, Humanitas Cancer Center, Milan, Italy. 38Department of Biomedical Sciences, Humanitas University, Milan, Italy. The errors have been corrected in the HTML and PDF versions of the article.

The availability of cord blood (CB) and haploidentical (haplo) donors in all patient populations is not established. We have investigated the addition of haplo-CD34+ cells to CB grafts (haplo-CBT) to speed myeloid engraftment. Thus, we have prospectively assessed CB and haplo donor availability in adult patients without 8/8 HLA-allele matched unrelated donors (URDs). Analysis of 89 patients eligible for haplo-CBT revealed 4 distinct patient groups. First, 6 patients (7% of total, 33% non-European) underwent CBT only as they had no suitable family members to type. In group 2, 49 patients (45% non-European) received haplo-CBT using the first haplo donor chosen. Group 3 (n = 21, 76% non-European) underwent CBT with/without haplo. In this group, the first haplo donor chosen failed clearance in 20 patients and transplantation was too urgent to permit donor evaluation in 1. Fifty-three haplo donors were evaluated (2 to 6 per patient) for 21 group 3 patients, and 43 of 53 (81%) haplos failed clearance for predominantly medical and/or psychosocial reasons. Group 4, (n = 13, 85% non-European with a high median weight of 96 kilograms) had no CB grafts with/without no haplo donors. Overall, African patients had the worst donor availability with only 65% having a suitable CB graft and only 44% having a suitable haplo donor. Additionally, in non-European patients, a greater number of haplos required evaluation/patient to secure a suitable haplo graft. Although these data should be confirmed in a larger study, it suggests that there are barriers to the availability of both CB and haplo grafts in adult patients without 8/8 URDs, especially in those with African ancestry, and has multiple practical implications for patient management.

Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell–replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

We aimed to identify whether the use of autologous hematopoietic cell transplantation (HCT) impacts outcomes for multiple myeloma patients with gains of chromosome 1q (+1q). We retrospectively identified 95 patients, 21% having +1q. For patients with +1q, the overall response rate to induction was 85%, with 40% having ≥ VGPR and 20% achieving a CR, similar to non +1q patients (p = .64). The median PFS from diagnosis with +1q was 2.1 years (95% CI: 1.2-not reached (NR)) vs 4.3 years (95% CI: 3.3 yrs-NR) without +1q (p = .003). Median OS from diagnosis was 4.4 years (95% CI: 2.9-NR) vs not reached, respectively (p = .005). On molecular analysis using the Foundation One Heme assay, the most common mutations seen in +1q patients included TP53 (38%) and KRAS (25%). Overall, gain of 1q portends worse PFS and OS which was not negated by auto HCT. Such patients will likely require additional therapy to improve their survival.

To evaluate the association between the hematopoietic cell transplantation-comorbidity index (HCT-CI) and the recently developed age-adjusted HCT-CI (HCT-CI/age) and transplant outcomes in the setting of CD34-selected allogeneic HCT, we analyzed a homogeneous population of patients undergoing allogeneic HCT with CD34-selected grafts for acute myeloid leukemia and myelodysplastic syndrome (n = 346). Median HCT-CI and HCT-CI/age scores were 2 (percentile 25 to 75, 1 to 4) and 3 (percentile 25 to 75, 1 to 5), respectively. Higher HCT-CI and HCT-CI/age scores were associated with higher nonrelapse mortality (NRM) and lower overall survival (OS). The HCT-CI distinguished 2 risk groups (0 to 2 versus ≥3), whereas, with the HCT-CI/age, there was a progressive increase in NRM and decrease in OS with increasing scores in all 4 groups (0 versus 1 to 2 versus 3 to 4 versus ≥5). Higher scores in both models were associated with lower chronic graft-versus-host disease relapse-free survival but not with higher relapse. Both models showed a promising predictive accuracy for NRM (c− = .616 for HCT-CI and c− = .647 for HCT-CI/age). In conclusion, the HCT-CI and HCT-CI/age predict transplant outcomes in CD34-selected allo-HCT, including NRM, OS, and chronic graft-versus-host disease relapse-free survival and may be used to select appropriate patients for this approach.

Calcineurin inhibitor-sparing T cell depleted (TCD) hematopoietic stem cell transplants HSCTs are presumed less nephrotoxic than conventional HSCTs. We evaluated incidence and risk factors for kidney failure and chronic kidney disease (CKD) in 231 TCD and 212 conventional HSCT recipients. Kidney failure required a median glomerular filtration rate (GFR) 60 mL/min/1.73 m2 only exposure to nephrotoxic medications was associated with CKD (p=0.033). In the myeloablative conditioning subgroup only total body irradiation was associated with CKD (p=0.013). Of all patients, five (1.13%) required dialysis. These results confirm an impact of TCD on kidney failure but not CKD for which other risk factors such as radiation or nephrotoxic drug exposure may play a role.

Introduction Despite the remarkable activity of chimeric antigen receptor T (CAR T) cells in relapsed/refractory aggressive B cell non-Hodgkin Lymphoma (B-NHL), they possess unique and significant adverse effect profiles, notably cytokine release syndromes (CRS) and neurological toxicity (ICANS). Although there have been data demonstrating impacts of CRS and ICANS on short term outcomes after CAR T cells, the burden and impact of organ-based toxicities on long-term outcomes is largely unknown. Here, we describe toxicity patterns stratified by organ involvement and their association with overall survival (OS) in aggressive B-NHL patients treated with CD19 CAR T cells. Methods We conducted a retrospective analysis of 60 aggressive B-NHL patients who received CD19 targeted CAR T cell products (tisagenleucel or axicabtagene ciloleucel) at our center between January 2018-June 2019. We collected all CTCAE v5.0 grade ≥2 toxicities from the date of CAR T cell infusion (except hematologic toxicities which were recorded after day +30) and classified into 17 organ-based toxicity categories. Relapse, progression, and death were competing events for toxicities. Risk factors, cumulative incidence, and survival impacts of toxicities were reported. Results Figure 1 summarizes baseline characteristics of 60 patients in this study cohort. With a median follow up of 121 days (range 21-365), 59 of 60 patients (98%) developed at least one CTCAE grade ≥2 toxicity. There were 435 individual toxicity events stratified among 14 different organ systems. Among all patients, the most common grade ≥ 2 organ-based toxicities were: infectious, metabolic, cardiovascular, hematologic, neurological, pulmonary, gastrointestinal, and hepatic. The corresponding 1-year cumulative incidence of grade ≥2 toxicities were 86.7%, 70%, 53.3%, 52.8%, 41.7%, 33.6% 31.6%, and 18.3% respectively (Figure 2A), whereas the corresponding 1-year cumulative incidence of grade ≥3 toxicities were 81.7%, 28.4%, 16.7%, 36.3%, 18.3%, 12.2%, 8.7%, and 5% respectively (Figure 2B). Incidence of toxicities were similar between CAR T cell products except infectious complication which was higher in axicabtagene (p=0.011). Most toxicities (74%) developed within the first 30 days after CAR T cell infusion. At the time of analysis, 16 patients had died. Causes of death included disease progression (n=15) and infection (n=1). The 1-year non-relapse mortality, disease free survival and overall survival were 2%, 44.1% and 66.9% respectively (Figure 3). CAR T cell related organ-based toxicities were not associated with increased risk of death. Conclusions There is a high incidence and burden of toxicities in aggressive B-NHL patients treated with CD19 CAR T cell therapy. However, most CAR T cell organ-based toxicities are manageable and not associated with an increased risk of death.

Introduction The BMT CTN 0901 phase 3 trial showed improved relapse-free survival (RFS) in patients with AML or MDS with myeloablative-conditioning (MAC) vs. Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT). However, overall survival (OS) increase was not statistically significant because of higher non-relapse mortality (NRM) compared to RIC allo-HCT. HCT-CI ≥ 3 also predicts for poor OS related to high NRM in patients undergoing MAC CD34+ selected allo-HCT. Objectives We aimed to evaluate impact on OS, NRM and RFS of MAC CD34+ selected vs. RIC allo-HCT in patients with high comorbidity burden. Methods We retrospectively compared the outcomes of 221 patients with AML or MDS with HCT-CI ≥ 3 who underwent MAC CD34+ selected (n=157) vs. RIC allo-HCT (n=64) at our institution from 2009 to 2017. The indication for MAC CD34+ vs. RIC allo-HCT was based on multidisciplinary consensus and primary physician's choice. Results Patients in the RIC group were older, had a higher proportion of high disease risk index (DRI), and higher use of matched unrelated donors compared to the MAC CD34+ group. HCTCI grades were balanced between the two cohorts, but the RIC group had a higher though non-significant proportion of patients with HCTCI > 5 (Figure 1). When comparing the MAC CD34+ vs. unmodified RIC cohorts, respectively, no difference was seen in OS [43% (95% CI 32-59) vs. 53% (95% CI 46-52), p=0.37], NRM [31% (95% CI 19-44) vs. 30% (95% CI 23-38), p=0.74], and relapse-free survival (RFS) [34% (95% CI 23-49) vs. 48% (95% CI 41-57) p=0.1], even when adjusting for age, DRI, and donor differences (Figure 2). However, incidence of acute and chronic graft versus host disease (GVHD) was lower for MAC CD34+ allo-HCT. When evaluating outcomes by HCT-CI subgroups (3, 4-5 and >5), MAC CD34+ allo-HCT resulted in higher 3-year estimated RFS [54% (95% CI 44-68) vs. 28% (95% CI 14-58), p=0.03] in patients with HCT-CI = 3, though this did not translate into an OS advantage [44% (95% CI 27-73) vs 59% (95% CI 48-72), p=0.26], possibly related to higher though non-significant NRM [16% (95% CI 4-35) vs. 28% (95% CI 18-39), p=0.26] (figure 3). When adjusting for differences in age, DRI, and donor, the difference in RFS was no longer statistically significant (p=0.13). Conclusions Though limited by their retrospective nature, our data suggest that CD34+ selected allografts after myeloablative conditioning can be feasible in selected patients with comorbidity scores over 3 with low rates of acute and chronic GVHD. However, further prospective studies are needed to reduce NRM and optimize this treatment platform in older patients with comorbidities.

Introduction Patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have historically shown very poor post-relapse overall survival (prOS). Objective To study the factors and treatment strategies associated with the best prOS. Methods We conducted a retrospective analysis of all pts at our institution who received a first allo-HCT between 2010 and 2017 for AML or MDS but relapsed post-transplant. Bone marrow (BM) and peripheral blood stem cells (PBSC) grafts were included, either T-cell depleted (TCD) by ex-vivo CD34+ selection (Miltenyi CliniMACS) or unmodified. Univariate (UVA) Cox proportional hazards regression was used to examine the association between prOS and patient-, disease-, and transplant-related variables. Receipt of second cell therapy (sCT) after relapse was a time-dependent covariate. Results Key characteristics of the study population are listed in Table 1. Median time to relapse (TTR) was 6 months (range: 1-61) and median prOS was also 6 months (95%CI: 4.8-8.8) in the whole population. AML pts showed shorter median prOS compared with MDS pts (5.3 [95%CI: 3.9-8] vs. 9.4 [95%CI: 5.7-24] months, p=0.026). No statistically significant associations were observed between prOS and conditioning intensity (reduced vs. ablative) or graft manipulation (TCD vs. unmodified). There was a significant association between TTR and prOS (Fig. 1). Forty-five pts received sCT after relapse, either a second allo-HCT (28) or donor lymphocyte infusions (17). The hazard of death after relapse for these patients was lower (HR 0.53, 95%CI: 0.32-0.87, p=0.01) and 2-year survival after sCT was 44.9% (95%CI: 31.1-64.8, Fig. 2). We used a 4-level categorization of TTR ( Conclusion Although limited by the retrospective nature and potential selection bias, we show in a large, contemporary cohort that pts who relapse after ≥ 12 months from a first allo-HCT and receive sCT have the best prOS.

Background Allogeneic hematopoietic cell transplantation (allo-HCT) allows for the possibility of cure in patients (pts) with Non-Hodgkin Lymphoma (NHL) as it provides an immunologic graft-versus-lymphoma effect. Non-relapse mortality (NRM) was prohibitive in myeloablative regimens, but technical advances with the advent of reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) regimens have decreased these rates. RIC regimens are generally associated with more toxicity and higher NRM than NMA regimens. Though studies showed both approaches are safe and effective, there is lack of direct comparison between these different intensities in NHL. Methods This retrospective study identified pts aged ≥ 18 years who underwent allo-HCT for relapsed/refractory NHL between 3/2008-6/2017 at our center. Outcomes were compared between pts who received NMA and RIC conditioning, with intensity defined per CIBMTR. Progression-free survival (PFS) was the primary outcome. Secondary outcomes included overall survival (OS) and non-relapse mortality (NRM). Additional outcomes included rates of acute GVHD at Day 100, chronic GVHD, and CMV reactivation at Day 100. Regimen intensity and other variables significant by univariate analysis were included in the multivariate analysis Results For the 144 pts identified, median age was 56 years (range, 19-79). More pts received NMA regimens (n=80, 56%) and most did not undergo prior autologous HCT (n=103, 72%). NMA regimens were given more frequently to pts with indolent B-cell lymphoma and were more likely to receive ATG and/or rituximab (p = 0.008, p Conclusion Our study suggests that there are comparable and favorable outcomes between RIC and NMA regimens in allo-HCT for NHL with careful patient and regimen selection. Further studies are needed to better define criteria in choosing between NMA and RIC allo-HCT regimens for pts with NHL.

Background Body surface area-based dosing of melphalan prior to AHCT for MM and AL patients causes inter-patient variability in exposure measured by area under the curve (AUC). Higher AUC is associated with increased toxicity, but prolonged survival (Shaw et al., BBMT 2012). Using Evomela (PGF-MEL, Acrotech Biopharma LLC), a more stable and possibly less toxic intravenous formulation of melphalan, we examined the feasibility of PK-directed dosing to individualize and optimize therapy. Methods Prospectively, patients received 100mg/m2 of PGF-MEL on day -2 prior to AHCT. Serum samples were collected at 5, 15, 30, 40, 75, and 150 min after the dose and AUC PK modeling (Phoenix WinNonlin v6.4) was used to determine the dose required to achieve a target AUC of 13.5mg/L*h (+/-1). On day -1, patients received the balance of the calculated dose with samples collected at the same timepoints to calculate the total AUC. After 5 patients were enrolled, the protocol was amended to increase the maximum allowable dose to the equivalent of 260mg/m2 from 220mg/m2. On day +1, 6, 11, 30, 60, and 90, patients reported symptom burden was collected using the MD Anderson Symptom Inventory – MM (MDASI-MM). Results Results of 15 patients are presented with 11 having MM and 4 AL, 60% male, median age 62yr (range 48-71), median body surface area 1.9 (range 1.5-2.2), and median creatinine on day of Mel 0.8mg/dL (range 0.7-1.6). Target doses were calculated and given in 100% of patients. Thirteen of 15 patients (87%) achieved the target AUC. The median AUCs on day -2 and day -1 were 6.3 mg/L*h (range 4.2-11.4) and 5.6 (range 3.1 – 8.4) respectively, with a median total AUC of 13.2 (range 9.6-15.2, Figure 1). Three patients received the capped dose of 220mg/m2 prior to the amendment and achieved their predicted AUC; 1 patient received the minimum 140mg/m2 and also achieved the predicted AUC which was higher than the target AUC, as expected. 9/15 patients had AUCs between 12.5-14.5 with 4/6 patients out of range for the above reasons. Neutropenic fevers occurred in 40% and grade 2 diarrhea for at least 1 day in 80% (median 2 days, range 0-7). Median time to neutrophil engraftment was 9 days (range 9-12). The median number of red cell and platelet transfusions required were 0 (range 0-3) and 1 (range 0-8), respectively. Engraftment syndrome was seen in 30% of patients. The hematologic response rate post AHCT was 100%, including complete remission in 20% and ≥ very good partial response 73%. With median follow-up of 6.4 months (range 2.8-13.1 months), one patient with MM whose AUC was below the target (10.1 units) has relapsed. No patient has died. Conclusion We show for the first time that personalization of therapy to a target AUC using PK-directed PGF-MEL was logistically feasible and prevented underdosing. Full trial results for 35 patients, as well as patient-reported outcomes and toxicities will be presented at the meeting.

Background Studies evaluating the impact of 11q23 / KMT2A / MLL translocations on post-transplant outcomes as compared to other intermediate- and adverse-risk cytogenetic characteristics are lacking. Methods We considered 8709 AML patients from the CIBMTR database for inclusion. We evaluated relapse, non-relapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) for patients who were transplanted in CR1 stratified by presence of 11q23 rearrangement, intermediate- or adverse-risk disease. Assignment of cytogenetic risk was performed by hand, based on the 2010 AML-MRC Classification System. A multivariate analysis was performed using a Cox proportional hazards model. Results Characteristics of 3779 patients, selected based on disease and donor type, HSCT in CR1, and availability of data, are shown in Figure 1. Of these, 426 patients had an 11q23-rearrangement, 2384 had intermediate-risk disease, and 969 had adverse-risk disease. Of the patients with 11q23 translocations, 112 (26%) had t(9;11), 62 (15%) had t(11;19), 41 (10%) had t(6;11), 28 (7%) had t(10;11), and 47 (11%) had other partners. No partner was provided in 136 cases (32%). Figures 2 and 3 show the DFS, OS, NRM, and relapse data stratified by cytogenetic category. Based on the multivariate analysis, DFS was lowest in adverse-risk patients (HR for death 1.47, 1.26 for MLL, p Stratification of outcomes by translocation partner did not yield any statistically significant differences between groups, however a descriptive analysis of these data will be presented. Measurable residual disease (MRD) status did not appear to play an independent role in NRM or in OS. However, the multivariate HR for relapse in patients with MRD-positivity was 1.23, p Conclusions Patients with MLL-rearranged AML had post-HSCT DFS and OS that were more similar to patients with adverse-risk disease than to those with intermediate-risk characteristics. MLL patients had a higher probability of relapse than intermediate-, but not adverse-risk, patients. NRM was similar among all groups. Both prognostic classification and MRD status independently contributed to the risk of relapse and DFS, but MRD was not an independent factor in predicting NRM or OS. Our study suggests that patients with MLL rearrangements do almost as poorly as those with adverse-risk disease and that novel approaches for this high-risk population represent an urgent unmet clinical need.

Retrospective studies indicate that the use of unrelated hematopoietic stem cell donors with Killer Ig-like Receptor (KIR) genotypes resulting in low inhibitory interactions with recipient HLA are associated with lower relapse and higher survival in patients with myeloid neoplasia undergoing allogeneic hematopoietic cell transplantation (allo HCT). To validate these findings in a prospective fashion and to determine if advantageous KIR donors can readily be identified for patients with myeloid neoplasia, we prospectively KIR genotyped and provided KIR/HLA-based ranking for unrelated donors (URD) evaluated for patients with a diagnosis of acute myeloid leukemia or myelodysplastic syndrome undergoing workup at our center for allo HCT. Donors were prioritized first to minimize inhibitory KIR3DL1 - HLA-Bw4 interactions, followed by prioritization of donors with non-tolerized activating KIR2DS1, and finally prioritizing donors homozygous for the centromeric B haplotype. We evaluated 2,079 donors for 527 patients (median 4 donors per patient), among whom 263 ultimately underwent allo HCT. In a multivariate analysis adjusting for age, HCT-CI, and conditioning intensity, we found that the use of a KIR3DL1-low-inhibition donor was associated with an improved hazard for survival (HR = 0.58 (95% confidence interval (CI): 0.35 – 0.96), P = 0.035) and event-free survival (HR = 0.61 (95% CI: 0.39 – 0.93), P = 0.023) due to a decreased hazard for relapse (HR = 0.52, 95% CI: 0.30 – 0.90, P = 0.021) without increased non-relapse mortality when compared to KIR3DL1-non-interacting or -high-inhibition donors. Donor KIR2DS1/HLA-C1 status and centromeric haplotype B content were not predictive of relapse or survival in this cohort. Among 339 HLA-Bw4+ patients evaluated for transplant, 242 (71.4%) had an available KIR3DL1-low-inhibition donor and 205 (60.5%) had a mixture of KIR3DL1-low-inhibition with either -high-inhibition or -non-interacting donors facilitating a choice using donor KIR3DL1 genotyping. Evaluating greater numbers of donors associated with an increased probability of identifying an advantageous donor based on inhibitory KIR3DL1 interactions (P

Introduction Cytokine release syndrome (CRS) and immune effector cells associated neurotoxicity syndrome (ICANS) are common CAR T cells toxicities. Various grading systems that attribute different grades of severity to symptoms are currently used, preventing comparisons of different products and possibly leading to management implications. Methods We included 53 patients (pts) with B acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T cells (NCT01044069) and 49 pts with diffuse large B cell lymphoma (DLBCL) who received axicabtagene ciloleucel (axi-cel, n=36) or tisagenlecleucel (tisa-cel, n=13) after FDA approval. CRS and ICANS were retrospectively graded according to the new ASTCT consensus grading system, for comparison with other available systems: Lee, Penn, Memorial Sloan Kettering Cancer Center, CARTOX and CTCAEv5.0 for CRS; CTCAEv4.03 and CARTOX for ICANS. We then used ASTCT grades to predict management according to current guidelines for DLBCL pts (axi-cel and tisa-cel insert packages, CARTOX and NCCN guidelines) and compare it to the actual treatment received at our center. Results According to the ASTCT grading, B-ALL pts had 87% CRS (28% grade ≥3), while DLBCL pts had 86% CRS (14% grade ≥3) with axi-cel, and 54% (no grade ≥3) with tisa-cel. B-ALL pts had 55% ICANS (45% grade ≥3), while DLBCL pts had 55% ICANS (33% grade ≥3) with axi-cel, and 15% with tisa-cel (no grade ≥3) (fig. 1). When comparing grading systems, agreement on CRS and ICANS diagnosis was found in 99% and 91% cases, respectively. However, when evaluating toxicities grade by grade, only 27% pts had the same grade in each system for CRS, and 55% for ICANS (fig. 2). When predicting management for DLBCL pts, we found some relevant differences across current guidelines (fig. 3). At our center 58% and 13% of patients with CRS received tocilizumab (toci) and steroids, respectively, similarly to what predicted according to axi-cel's, CARTOX and NCCN guidelines, but differently from tisa-cel's label (10% and 5%). For ICANS, while tisa-cel's label does not provide any recommendations, other guidelines-based predictions were mostly overlapping. Indications for treatment vary across current guidelines, which were developed on single products and different grading systems, thus, should not be universally applied. This discrepancy becomes particularly relevant for cases with discordant CRS/ICANS grades. As such, we gave toci to 66% pts upgraded to grade 3 by Penn (grade 2 by ASTCT), while they would receive both toci and steroids according to axi-cel/CARTOX/NCCN guidelines, but would not be treated according to tisa-cel's. Conclusions Different grading systems provide inconsistent CRS/ICANS scores. To avoid discrepancies in assessing and managing toxicities of different products, a unified grading should be used and paired management guidelines with product-specific indications should be developed.

Background Cytopenias are observed post-CAR T, yet there is minimal data delineating the pathobiology and trends thereof. We report the largest series to our knowledge thus far, of hematopoietic recovery post-CAR T and factors affecting this recovery. Methods We retrospectively reviewed 115 adult patients who received CAR T, at our center, for relapsed/refractory (R/R) B cell lymphomas after FDA approval, R/R B cell acute lymphoblastic leukemia (ALL, NCT01044069) and multiple myeloma (MM, NCT03070327). Blood counts were collected for 12 months or until censored for relapse, progression or initiation of chemotherapy/ conditioning for autologous or allogeneic stem cell transplantation (HCT)/ subsequent treatment with CAR T. Only patients with follow-up > 30 days were included. "Recovery" for the respective blood count was defined to signify absence of transfusions or risk of infections: hemoglobin > 8g/dL and platelets > 50,000/µL without transfusion support in 2 weeks and 1 week, respectively; absolute neutrophil count (ANC) > 1,000/µL and white cell count (WBC) > 3,000/µL without growth factor support in 2 weeks. "Complete countrecovery" refers to recovery per above criteria in all 4 counts. Results Eighty three patients were included (Figure 1). By 1 month (n = 83), hemoglobin, platelets, ANC and WBC recovery was noted in 61%, 51%, 33% and 28%, respectively. At 3 months (n = 41), these were 93%, 90%, 81% and 59%. Figure 2 shows recovery at subsequent months. Upon examination of potential variables in a univariate model, lack of recovery of hemoglobin, platelets, ANC and complete count recovery at 1 month was statistically significantly associated with type of CAR construct, higher grade (3-4 vs 1-2 vs none) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) as well as a higher peak CRP and ferritin (data for complete count recovery in Figure 3). Additionally, lack of hemoglobin recovery at 1 month was associated with lymphodepletion using high dose cyclophosphamide (recovered vs no recovery in 58% vs 42%, p = 0.01) and diagnosis of ALL (65% vs 35%, p = 3 prior lines of therapy (78% vs 22%, p = 0.04). At 3 months, absence of complete count recovery was associated only with the CAR T construct utilized. We also performed a sensitivity analysis using data for all 115 patients and no significant difference in univariate analysis was seen. Conclusions Our study shows that blood counts recover in most patients who have not progressed or received additional therapy by 3 months following CAR T. The association of count recovery with severity of CRS, ICANS as well as inflammatory marker levels indicates that inflammatory response post-CAR T influences hematological recovery in these patients.

PURPOSE Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment. METHODS We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/μL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/μL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point. RESULTS The mean platelet count at enrollment was 62,000/μL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/μL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/μL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT. CONCLUSION This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.

How cord blood (CB) CD34+ cell content and dose, and 8-allele human leukocyte antigen (HLA)-match, vary by patient ancestry is unknown. We analyzed cell content, dose and high-resolution HLA-match of units selected for CB transplantation (CBT) by recipient ancestry. Of 544 units (286 infused, 258 next best back-ups) chosen for 144 racially diverse adult patients (median weight 81 kilograms), the median total nucleated cell (TNC) (x 10(7)) and CD34+ (x 10(5)) content was higher for Europeans than for non-Europeans: 216 versus 197 (p = 0.002) and 160 versus 132 (p = 0.007), respectively. There were marked cell content disparities between ancestry groups with units selected for Africans having the lowest TNC (189 × 10(7)) and CD34+ cell (122 × 10(5)) contents. Units for non-Europeans were also more HLA-mismatched (p = 0.017). When only the 286 transplanted units were analyzed, the adverse effect of reduced cell content was exacerbated by higher weight in some groups. For example, northwestern Europeans (high patient weight, high unit cell content) had the best dosed units whereas Africans (high weight, low unit cell content) had the lowest. In Asians, low cell content was partially compensated by lower weight. Marked differences in 8-allele HLA-match distribution were also observed by ancestry group (e.g. 23% of units for northwestern Europeans were 3–4/8 HLA-matched versus 40% for southern Europeans, 46% for White Hispanics and 51% for Africans). During the study period, 20 additional patients (17 non-European, median weight 98 kilograms) did not receive a CBT due to lack of a suitable graft. CB extends transplant access to most patients but racial disparities exist in cell content, dose and HLA-match.

Treatment for AL amyloidosis aims to eradicate clonal plasma cells, thereby disrupting the amyloid deposition causing organ damage. Risk-adapted high-dose melphalan plus autologous stem cell transplantation (RA-ASCT) is an effective therapy. We conducted a prospective pilot analysis of a comprehensive approach using bortezomib and dexamethasone (BD) before and after RA-ASCT in 19 patients. BD induction (up to 3 cycles of bortezomib 1.3 mg/m2 i.v. and dexamethasone 40 mg orally [p.o.] or i.v. on days 1, 4, 8, and 11) was followed by RA-ASCT and then BD consolidation (6 cycles of bortezomib 1.3 mg/m2i.v. and dexamethasone 20 mg p.o. or i.v. weekly for 4 weeks, every 12 weeks). The overall hematologic response rate (partial response or better) was 95%, including 37% minimal residual disease negative [MRD(-)] complete response (CR) by flow cytometry (sensitivity up to 1/106 cells). At 2 years, progression-free survival (PFS) and overall survival were 68% (95% confidence interval [CI], 50% to 93%) and 84% (95% CI, 69% to 99%), respectively, with median duration of follow-up in survivors of 61 months (range, 42 to 84 months). In a landmark analysis, patients achieving MRD(-) CR had superior PFS (P= .008). This approach is safe and yields deep and durable remissions promoting organ recovery. Each treatment phase deepened the response. Future aims include improving the efficacy and toxicity of each phase.

BACKGROUND: Subgroups of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) exhibit suboptimal outcomes after standard therapies, including oral kinase inhibitors. We and others have previously reported on the safety and efficacy of autologous CD19-targeted CAR T cells for these patients. Here, we report safety and long-term follow-up of CAR T cell therapy with or without conditioning chemotherapy for patients with R/R CLL and indolent B cell non-Hodgkin lymphoma (B-NHL). METHODS: We conducted a phase I clinical trial investigating CD19-targeted CAR T cells incorporating a CD28 costimulatory domain (19–28z). Seventeen of twenty patients received conditioning chemotherapy prior to CAR T cell infusion. Five patients with CLL received ibrutinib at the time of autologous T cell collection and/or CAR T cell administration. RESULTS: This analysis included 16 patients with R/R CLL and 4 patients with R/R indolent B-NHL. Cytokine release syndrome (CRS) was observed in all 20 patients, but grade 3 and 4 CRS and neurological events were uncommon (10% for each). Ex vivo expansion of T cells and proportions of CAR T cells with the CD62L(+)CD127(+) immunophenotype were significantly greater (P = 0.047; CD8 subset, P = 0.0061, CD4 subset) in patients on ibrutinib at leukapheresis. Three of twelve evaluable CLL patients receiving conditioning chemotherapy achieved complete response (CR) (2 had minimal residual disease–negative CR). All patients achieving CR remained progression free at median follow-up of 53 months. CONCLUSION: Conditioning chemotherapy and 19–28z CAR T cells were acceptably tolerated across investigated dose levels in heavily pretreated patients with R/R CLL and indolent B-NHL, and a subgroup of patients achieved durable CR. Ibrutinib therapy may modulate autologous T cell phenotype. TRIAL REGISTRATION: ClinicalTrials.gov NCT00466531. FUNDING: Juno Therapeutics and NIH/National Cancer Institute Cancer Center Support Grant (P30-CA08748).

While histopathologic differences have been reported between acute graft-versus-host disease (aGVHD) and non-aGVHD rash in CD34(+)-selected peripheral blood stem cell transplantation (PBSCT) recipients, skin biopsies alone are usually insufficient to determine rash etiology. As such, distinguishing inflammatory non-aGVHD rashes, such as drug eruptions, from cutaneous aGVHD after CD34(+)-selected PBSCT remains challenging and relies on clinical presentation. This study aimed to identify etiologies of skin rash in the first year after CD34(+)-selected PBSCT and to assess whether laboratory serologic markers, transplant characteristics, and rash morphology and symptomatology aid in differentiation of cutaneous aGVHD versus non-aGVHD rash. We conducted a retrospective study of 243 adult patients who received a CD34(+)-selected PBSCT at Memorial Sloan Kettering Cancer Center between 2008 and 2011. Among this cohort of transplant recipients, only 43 patients (17.7%) developed cutaneous aGVHD. In total, 152 patients (63%) were identified with rash within one year after PBSCT. The proportion of patients who experienced peripheral eosinophilia was not different between those with an aGVHD versus non-aGVHD rash (p ≥0.9), nor when stratified by CD34(+) selection method (Isolex p=0.7; CliniMACS p ≥0.9). The proportion of patients with pruritus was also not different between those with an aGVHD versus non-aGVHD rash (p=0.20), nor when stratified by CD34(+) selection modality (Isolex p=0.2; CliniMACS p=0.5). The most common cause of non-aGVHD rash among those with a clear etiology was drug (39% of Isolex; 26% of CliniMACS). Single drug culprits were identified in 51% of drug rashes. The most commonly reported offending agents included antibiotics, keratinocyte growth factor (KGF), chemotherapy, and recombinant glycosylated human interleukin-7 (IL-7).

Cytomegalovirus (CMV) is serious viral infection in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. November 2017, the novel CMV DNA terminase complex inhibitor letermovir was approved for prophylaxis of CMV infection in CMV-seropositive allo-HCT recipients. Here we sought to determine the effectiveness of letermovir in preventing CMV infection in CMV-seropositive patients undergoing haploidentical or mismatched adult unrelated donor allo-HCT using post-transplantation cyclophosphamide-based graft-versus host-disease prophylaxis. Sixty-four patients underwent transplantation between 2014 and 2019, of whom 32 received letermovir and 32 did not receive letermovir. The day 180 cumulative incidence of CMV infection requiring therapy was 45.3% (95% confidence interval [CI], 32.7% to 57.1%) in the entire cohort, 68.8% (95% CI, 48.9% to 82.2%) in the patients who did not receive letermovir, and 21.9% (95% CI, 9.5% to 37.6%; P.001) in patients who received letermovir. Adjusting for regimen intensity, disease histology, and age, the hazard ratio for CMV infection was .19 (95% CI, .08 to .47; P.001) in patients who received primary prophylaxis with letermovir. The 1-year cumulative incidence of treatment- related mortality was similar between patients with and without letermovir treatment (16.9% versus 18.9%), as was overall survival (64.0% versus 49.0%). Persistent CMV infection requiring28 days of therapy was more common in patients who did not receive letermovir (31.2% versus 6.2%; P = .02). In summary, letermovir was effective in preventing CMV infection in this high-risk population of HLA-mismatched allo-HCT recipients.

Background: Several clinical prediction scores have been designed to assess the risk of cancer-associated thrombosis (CAT). The most commonly used in current clinical practice is the Khorana score, however it is applicable only to patients prior to initiation of chemotherapy. We now apply machine learning with clinical, demographic, and genomics parameters to predict CAT events. Methods: The random survival forest (RSF) ensemble learning method was selected to illustrate a machine approach to CAT prediction. The cohort consisted of 14,223 individuals with a solid tumor malignancy and MSK IMPACT somatic genomic data collected during the years 2014 to 2016. CAT was defined as the diagnosis of lower extremity deep vein thrombosis (proximal or distal) or pulmonary embolism, incidental or symptomatic. Covariates considered for inclusion in the model consisted of tumor type, metastatic status, age, exposure to cytotoxic chemotherapy in the month before cohort entry, time elapsed since cancer diagnosis, time elapsed since tumor sampling, normalized mean blood cell counts (white cell count, hemoglobin, platelet count) in the prior 3 months, normalized mean prothrombin time (PT) and activated partial thromboplastin time (aPTT) in the prior 3 months, body mass index (BMI), and presence or absence of a somatic genetic alteration for oncogenes/tumor suppressor genes with an alteration frequency ≥ 1.5% (n = 56). The primary endpoint consisted of time to CAT episode. The C-index for models including different covariates was derived from the test holdout sample using repeated 10-fold cross-validation. The C-index, measuring the relative agreement between the RSF predicted risk and the CAT times of patients, has values between 0.5 and 1.0 with the latter indicating perfect agreement. Results: 12,040 patients were included in the final analysis. There were 855 CAT events during the observation period. The most common tumor types were lung (17%), breast (15%) and colorectal cancer (9%). Blood cell count data and coagulation parameters were missing for 8% and 51% of patients respectively. Using cross-validation, the baseline model with cancer type and metastatic status had a C-index of 0.62 (95% CI = 0.61-0.64), which increased to 0.65 (95% CI = 0.63-0.66) with the addition of chemotherapy, age, time from tissue sampling, time from cancer diagnosis and BMI. Further adding genetic data increased the C-index to 0.68 (95% CI = 0.66-0.69). Replacing genetic data in this model with cell counts and coagulation parameters resulted in a C-index of 0.69 (95% CI = 0.68-0.70). The model with all available covariates had a C-index of 0.70 (95% CI = 0.69-0.71). The cumulative incidence of CAT at 6 months for 5 categories of predicted risk using the model with all available covariates is plotted in Figure A. Scaled Ishwaran-Kogalur Variable Importance (VIMP) values, presented in Figure B, indicate that cancer type and prior chemotherapy are the two top factors for model performance. Conclusions: Machine learning is a promising approach in the search of more accurate and generalizable models for prediction of CAT. In the application described here, the use of random survival forests performed well without information about future chemotherapy administration. Additional work is needed to identify the optimal algorithm and covariates, including better delineation of which cancer genomic information should be retained. Future models will have to be validated independently before being used for patient care. Disclosures Mantha: Physicians Education Resource: Honoraria; MJH Associates: Honoraria. Bolton:GRAIL: Research Funding. Soff:Bristol-Myers Squibb, Pfizer: Honoraria; Dova Pharmaceuticals: Honoraria; Janssen Scientific Affairs: Honoraria; Amgen: Research Funding; Janssen Scientific Affairs: Research Funding; Amgen: Honoraria; Dova Pharmaceuticals: Research Funding.

We described the clinical features and outcomes for 63 adult patients with acute myeloid leukemia (AML) with a translocation involving the 11q23 locus (MLL) who were treated at Memorial Sloan Kettering Cancer Center (MSK). The population included 40 female (63 %) and 23 male (37 %) patients, with a median age of 51 years old (range 18-82 years). Of the 31 patients who had had an antecedent malignancy, 14 (45 %) had had breast cancer or DCIS and 22 (71 %) had received anthracycline-based systemic chemotherapy. The translocation partner for the 11q23 rearrangement was identified in 60 of the 63 patients (95 %) studied. The distribution of translocation partners differed for those who had previously received cytotoxic chemotherapy. Most patients with therapy-related disease had a 9p22 or 19p13 partner, as compared to those with de novo disease (95 % vs. 68 %, p = 0.023). Of the 30 patients who received all therapy under observation, 15 (50 %) patients had de novo disease and 15 (50 %) had received antecedent chemotherapy. No significant difference in survival was observed between groups (p = 0.44). Twenty-two patients received induction as up-front therapy, of whom 11 (50 %) achieved CR / CRi. The achievement of CR / CRi with one course of induction was associated with improved OS, with a 6-month OS of 73 % as compared to 23 % for those who did not (p = 0.018). The achievement of CR / CRi with a single course of induction may be a marker of favorable survival in this subtype of high-risk AML. KEY POINT: Response to a single induction was associated with favorable survival in this population.

Autoimmune hemolysis (AH) and immune thrombocytopenic purpura (ITP) are recognized complications after cord blood transplantation (CBT). We evaluated the incidence and characteristics of AH/ ITP after double-unit CBT in a day 100 landmark analysis of 152 patients (median age 36 years, range 0.9–70) transplanted for hematologic malignancies with myeloablative or non-myeloablative conditioning and calcineurin-inhibitor (CNI)/ mycophenolate mofetil. With a median 5.2 year (range 1.6–9.7) survivor follow-up, 10 patients developed autoimmune cytopenias (8 AH, 1 ITP, 1 both) at a median of 10.4 months (range 5.8–24.5) post-CBT for a 7% cumulative incidence 3 years after the day 100 landmark. Six patients presented with severe disease (hemoglobin ≤ 6 g/dl and/ or platelets < 20 × 109/L). All AH patients were direct anti-globulin test positive. All 10 cases developed during immunosuppression taper with 8 having prior acute graft-versus-host disease. All 10 patients received rituximab 2–18 days after diagnosis, and corticosteroids combined with rituximab within < 7 days was the most effective. No patient died of AH/ ITP. AH/ ITP occurs infrequently after CBT but may be life-threatening requiring emergency therapy. Rituximab combined with corticosteroids at diagnosis is warranted in patients with severe disease.

Stem cell transplantation (SCT), an effective therapy for amyloid light chain (AL) amyloidosis patients, is associated with low treatment-related mortality (TRM) with appropriate patient selection and risk-adapted dosing of melphalan (RA-SCT). Consolidation after SCT increases hematologic complete response (CR) rates and may improve overall survival (OS) for patients with

We report results of a retrospective analysis of 44 patients with relapsed and high-risk multiple myeloma (MM) undergoing allogeneic CD34-selected hematopoietic stem cell transplantation (HSCT) from HLA-compatible donors. Patients had multiply relapsed disease including relapse at15 months after autologous transplantation and most patients (28 of 44; 65%) also had high-risk cytogenetics. Before transplantation, patients received busulfan (.8 mg/kg × 10 doses), melphalan (70 mg/m(2) × 2 days), fludarabine (25 mg/m(2) × 5 days), and rabbit antithymocyte globulin (2.5 mg/kg × 2 days). Patients with 10/10 HLA- matched donors were treated prophylactically with low doses of donor lymphocyte infusions (.5 to 1 × 10(6) CD3(+)/kg) starting 4 to 6 months after CD34-selected HSCT. Acute (grade II to IV) graft-versus-host disease (GVHD) and transplantation-related mortality at 12 months were 2% and 18%, respectively. Chronic GVHD was not observed in any patient. Overall and progression-free survival at 2 years were 54% and 31%, respectively. By multivariate analyses, the outcomes of CD34-selected HSCT were influenced by presence of extramedullary disease, disease status before CD34-selected HSCT, and age. This study demonstrates notable safety and efficacy of CD34-selected HSCT in patients with multiply relapsed MM, including those with high-risk cytogenetics.

While there are many validated prognostic classifiers used in practice, often their accuracy is modest and heterogeneity in clinical outcomes exists in one or more risk subgroups. Newly available markers, such as genomic mutations, may be used to improve the accuracy of an existing classifier by reclassifying patients from a heterogenous group into a higher or lower risk category. The statistical tools typically applied to develop the initial classifiers are not easily adapted toward this reclassification goal. In this article, we develop a new method designed to refine an existing prognostic classifier by incorporating new markers. The two-stage algorithm called Boomerang first searches for modifications of the existing classifier that increase the overall predictive accuracy and then merges to a prespecified number of risk groups. Resampling techniques are proposed to assess the improvement in predictive accuracy when an independent validation data set is not available. The performance of the algorithm is assessed under various simulation scenarios where the marker frequency, degree of censoring, and total sample size are varied. The results suggest that the method selects few false positive markers and is able to improve the predictive accuracy of the classifier in many settings. Lastly, the method is illustrated on an acute myeloid leukemia data set where a new refined classifier incorporates four new mutations into the existing three category classifier and is validated on an independent data set.

Cyclophosphamide plus G-CSF (C+G-CSF) is one of the most widely used stem cell (SC) mobilization regimens for patients with multiple myeloma (MM). Plerixafor plus G-CSF (P+G-CSF) has demonstrated superior SC mobilization efficacy when compared with G-CSF alone and has been shown to rescue patients who fail mobilization with G-CSF or C+G-CSF. Despite the proven efficacy of P+G-CSF in upfront SC mobilization, its use has been limited, mostly due to concerns of high price of the drug. However, a comprehensive comparison of the efficacy and cost effectiveness of SC mobilization using C+G-CSF versus P+G-CSF is not available. In this study, we compared 111 patients receiving C+G-CSF to 112 patients receiving P+G-CSF. The use of P+G-CSF was associated with a higher success rate of SC collection defined as ⩾ 5 × 10(6) CD34+ cells/kg (94 versus 83%, P = 0.013) and less toxicities. Thirteen patients in the C+G-CSF arm were hospitalized owing to complications while none in the P+G-CSF group. C+G-CSF was associated with higher financial burden as assessed using institutional-specific costs and charges (P

Logistic regression is widely used to evaluate the association between risk factors and a binary outcome. The logistic curve is symmetric around its point of inflection. Alternative families of curves, such as the additive Gompertz or Guerrero-Johnson models, have been proposed in various scenarios due to their asymmetry: disease risk may initially increase rapidly and be followed by a longer period where the rate of growth slowly decreases. When modeling binary outcomes in relation to risk factors, an additive logistic model may not provide a good fit to the data. Suppose the outcome and an additive function of the risk factors are indeed related through an asymmetric function, but we model the relationship using a logistic function. We illustrate - both from a mathematical framework and through a simulation-based evaluation - that higher-order terms, such as pairwise interactions and quadratic terms, may be required in a logistic regression model to obtain a good fit to the data. Importantly, as significant higher-order terms may be a manifestation of model misspecification, these terms should be cautiously interpreted; a more pragmatic approach is to develop contrasts of disease risk coming from a good fitting model. We illustrate these concepts in 2 cohort studies examining early death for late-stage colorectal and pancreatic cancer cases, and 2 case-control studies investigating NAT2 acetylation, smoking, and advanced colorectal adenoma and bladder cancer.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). Donor T cells are critical for the graft-versus-tumor effect but carry the risk of graft-versus-host disease (GVHD). CD34 selection with immunomagnetic beads has been an effective method of depleting alloreactive donor T cells from the peripheral blood graft and has been shown to result in significant reduction in acute and chronic GVHD. We analyzed the outcomes of 102 adults (median age, 57.6 years) with advanced MDS who received a CD34-selected allo-HSCT between January 1997 and April 2012 at Memorial Sloan Kettering Cancer Center. The cumulative incidences of grades II to IV acute GVHD were 9.8% at day 100 (95% confidence interval [CI], 5.0% to 16.5%) and 15.7% at day 180 (95% CI, 9.4% to 23.4%). The cumulative incidence of chronic GVHD at 1 year was 3.9% (95% CI, 1.3% to 9.0%). The cumulative incidences of relapse were 11.8% at 1 year (95% CI, 6.4% to 18.9%) and 15.7% at 2 years (95% CI, 9.4% to 23.4%). Forty-eight patients were alive with a median follow-up of 71.7 months. Rates of overall survival (OS) were 56.9% at 2 years (95% CI, 48% to 67.3%) and 49.3% at 5 years (95% CI, 40.4% to 60.2%). Rates of relapse-free survival (RFS) were 52.0% at 2 years (95% CI, 41.9% to 61.1%) and 47.6% at 5 years (95% CI, 37.5% to 56.9%). The cumulative incidences of nonrelapse mortality were 7.8% at day 100 (95% CI, 3.7% to 14.1%), 22.5% at 1 year (95% CI, 15.0% to 31.1%), and 33.4% at 5 years (95% CI, 24.2% to 42.6%) post-transplant. The incidence of chronic GVHD/RFS overlapped with RFS. These findings demonstrate that ex vivo T cell–depleted allo-HSCT by CD34 selection offers long-term OS and RFS with low incidences of acute and chronic GVHD and without an increased risk of relapse.

Because cord blood (CB) lacks memory T and B cells and recent decreases in herd immunity to vaccine-preventable diseases in many developed countries have been documented, vaccine responses in CB transplantation (CBT) survivors are of great interest. We analyzed vaccine responses in double-unit CBT recipients transplanted for hematologic malignancies. In 103 vaccine-eligible patients, graft-versus-host disease (GVHD) most commonly precluded vaccination. Sixty-five patients (63%; engrafting units median HLA-allele match 5/8; range, 2 to 7/8) received protein conjugated vaccines, and 63 patients (median age, 34 years; range, .9 to 64) were evaluated for responses. Median vaccination time was 17 months (range, 7 to 45) post-CBT. GVHD (n = 42) and prior rituximab (n = 13) delayed vaccination. Responses to Prevnar 7 and/or 13 vaccines (serotypes 14, 19F, 23F) were seen in children and adults (60% versus 49%, P = .555). Responses to tetanus, diphtheria, pertussis, Haemophilus influenzae, and polio were observed in children (86% to 100%) and adults (53% to 89%) even if patients had prior GVHD or rituximab. CD4+CD45RA+ and CD19+ cell recovery significantly influenced tetanus and polio responses. In a smaller cohort responses were seen to measles (65%), mumps (50%), and rubella (100%) vaccines. No vaccine side effects were identified, and all vaccinated patients survived (median follow-up, 57 months). Although GVHD and rituximab can delay vaccination, CBT recipients (including adults and those with prior GVHD) have similar vaccine response rates to adult donor allograft recipients supporting vaccination in CBT recipients.

Recent studies among healthy individuals show evidence of somatic mutations in leukemia-associated genes, referred to as clonal hematopoiesis (CH). To determine the relationship between CH and oncologic therapy we collected sequential blood samples from 525 cancer patients (median sampling interval time = 23 months, range: 6-53 months) of whom 61% received cytotoxic therapy or external beam radiation therapy and 39% received either targeted/immunotherapy or were untreated. Samples were sequenced using deep targeted capture-based platforms. To determine whether CH mutational features were associated with tMN risk, we performed Cox proportional hazards regression on 9,549 cancer patients exposed to oncologic therapy of whom 75 cases developed tMN (median time to transformation=26 months). To further compare the genetic and clonal relationships between tMN and the proceeding CH, we analyzed 35 cases for which paired samples were available. We compared the growth rate of the variant allele fraction (VAF) of CH clones across treatment modalities and in untreated patients. A significant increase in the growth rate of CH mutations was seen in DDR genes among those receiving cytotoxic (p=0.03) or radiation therapy (p=0.02) during the follow-up period compared to patients who did not receive therapy. Similar growth rates among treated and untreated patients were seen for non-DDR CH genes such as DNMT3A. Increasing cumulative exposure to cytotoxic therapy (p=0.01) and external beam radiation therapy (2x10-8) resulted in higher growth rates for DDR CH mutations. Among 34 subjects with at least two CH mutations in which one mutation was in a DDR gene and one in a non-DDR gene, we studied competing clonal dynamics for multiple gene mutations within the same patient. The risk of tMN was positively associated with CH in a known myeloid neoplasm driver mutation (HR=6.9, p Citation Format: Kelly L. Bolton, Ryan N. Ptashkin, Teng Gao, Lior Braunstein, Sean M. Devlin, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine Coombs, Nicole M. Caltabellotta, Mike Walsh, Ken Offit, Zsofia Stadler, Choonsik Lee, Paul Pharoah, Konrad H. Stopsack, Barbara Spitzer, Simon Mantha, James Fagin, Laura Boucai, Christopher J. Gibson, Benjamin Ebert, Andrew L. Young, Todd Druley, Koichi Takahashi, Nancy Gillis, Markus Ball, Eric Padron, David Hyman, Jose Baselga, Larry Norton, Stuart Gardos, Virginia Klimek, Howard Scher, Dean Bajorin, Eder Paraiso, Ryma Benayed, Maria Arcilla, Marc Ladanyi, David Solit, Michael Berger, Martin Tallman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Luis Diaz, Ross Levine, Lindsay Morton, Ahmet Zehir, Elli Papaemmanuil. Oncologic therapy shapes the fitness landscape of clonal hematopoiesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5703.

e13537 Background: Patients with cancer have an increased risk of arterial thromboembolic events (ATE). Clinical characteristics such as medical comorbidities, cancer type, cancer stage and a history of smoking are established risk factors for ATE, but scant data exist about the effect of cancer-specific genomic alterations. We aimed to determine whether individual tumor mutations influence ATE risk. Methods: We performed a retrospective cohort study using tumor mutational data from adults with solid cancers who had MSK-IMPACT testing at Memorial Sloan Kettering Cancer Center between 2014 and 2016. MSK-IMPACT is an FDA-authorized DNA sequencing panel targeting 341+ oncogenes and tumor suppressor genes identifying mutations, copy number alterations, and gene fusions in solid malignancies. The primary ATE outcome was defined as ischemic stroke, myocardial infarction or coronary revascularization and detected by systematic electronic health record assessments. Patients were followed up to one year from the date of tissue-matched blood control sampling to the first ATE or death. We used Cox proportional hazards regression adjusting for age, cancer type, cytotoxic chemotherapy treatment (time-dependent) and tobacco use to determine hazard ratios (HR) of individual genes for ATE risk. We adjusted for multiple comparisons using the Benjamini-Hochberg method. Results: Among 11,317 patients, mean age was 59 years (SD = 14 years) and 55% were women. The most frequent cancers were lung (16%), breast (15%), and colorectal (10%), and 73% were metastatic. During a median follow-up of 253 days, 151 patients had an ATE (1.3%). In multivariable analysis, genomic alterations in KRAS (HR, 2.11; CI, 1.41-3.16), STK11 (HR, 2.62; 95% CI, 1.49-4.59), and ROS1 (HR, 5.3; 95% CI, 1.93-14.58) were independently associated with an increased risk of ATE. Presence of clonal hematopoiesis was not found to be associated with an increased risk of ATE in this cohort (HR, 0.96; 95% CI, 0.63-1.47). Conclusions: In a large genomic tumor-profiling registry of patients with solid cancers, alterations in KRAS, STK11, and ROS1 were associated with an increased risk of ATE independent of cancer type. [Table: see text]

Background Co-morbidities are essential for risk-stratification before allogeneic hematopoietic stem cell transplantation (HCT). We hypothesized that only certain components of the co-morbidity index (HCT-CI) are predictive of outcomes, and that their impact is conditioning-regimen dependent. Methods This retrospective single-center analysis included 580 adult patients who underwent HCT with ex-vivo CD34+ selection following myeloablative conditioning between 2008 and 2018. Results Chemotherapy and total body irradiation (TBI)-based conditioning were given to 75% and 25% of patients, respectively. Common co-morbidities in the population included mild/severe hepatic dysfunction (25%), moderate and severe pulmonary disease (32% and 11%, respectively), prior malignancy (14%), and psychiatric disorders (13%). The median HCT-CI was 2 (IQR 1-3). Among co-morbidities meeting statistical criteria for analysis (prevalence >5% and association with at least 5 outcome events), only severe and moderate pulmonary dysfunction (Figure 1) were associated with decreased overall survival (OS) and increased non-relapse mortality (NRM; HR 1.37, p .023; HR 1.94 p Conclusions Our findings suggest that, in CD34+ selected HCT, only certain co-morbidities included in the HCT-CI are likely to contribute to the prognostic assessment of transplantation candidates. Reevaluation of the additive role of co-morbidities in this setting is warranted. In addition, the hazard of co-morbidities may be regimen-dependent, introducing another consideration when selecting the conditioning modality.

Background We recently showed that empiric weight-based ATG dosing in heavier patients (pts) prior to ex vivo CD34-selected allogeneic hematopoietic cell transplantation (allo-HCT) is associated with high non-relapse mortality (NRM) and poor survival. A more precise method is to assess the relationship between ATG pharmacokinetic (PK) exposure and outcomes. Therefore, we estimated ATG exposure using a population PK model and hypothesized that peri-HCT ATG overexposure would similarly result in unfavorable outcomes secondary to poorer immune reconstitution (IR). Methods We studied 415 consecutive adult pts who underwent first myeloablative ex vivo CD34-selected allo-HCT with ATG (Thymoglobulin) between 2006 and 2017. We estimated pre-/post-HCT and total ATG area under the curve (AUC, in mg*d/L) for all pts using an established PK model (Admiraal et al., Lancet Hematol 2017). We evaluated the association between ATG exposure and outcomes using a nonparametric estimate of median relapse-free survival (RFS) by ATG exposure to define an optimal ATG AUC cut point (highest RFS) that was used to estimate RFS and NRM. We also evaluated how CD4+ T cell IR related to NRM in a subgroup of 232 pts with sufficient data. IR was defined according to prior studies as absolute CD4+ ≥ 50 at ≥ 2 time points before day +100 and 1 subsequent time point within 60 days. Results Among all pts, median age was 55 (range, 19-73), 228 (55%) were male, 204 (49%) had AML, 105 (25%) MDS, 50 (12%) ALL, and 56 (14%) other hematologic diseases. HCT-CI was 0 in 85 (20%), 1-2 in 146 (35%), and ≥ 3 in 184 (45%) of pts. Allografts were HLA matched related in 150 (36%), matched unrelated in 202 (49), and mismatched in 63 (15%). CMV serostatus was positive in 251 (60%). Conditioning regimens were chemotherapy based in 279 (67%) and TBI based in 136 (33%). All but 2 pts, who were inevaluable given early deaths, engrafted. All pts received 1-3 doses of ATG 2.5 mg/kg between days -4 and -1: 361 (87%) received 2 doses, 47 (11%) 3 doses, and 7 (2%) 1 dose. Among all pts, median estimated ATG AUC values were: pre-HCT 19 (range, 9-36), post-HCT 48 (range, 17-101), and total 66 (29-125). Median follow-up among survivors was 3.9 years (range, 0.7-12). A post-HCT ATG AUC of >60 was associated with poorer median predicted RFS (Figure 1). Pts with an estimated post-HCT ATG AUC of >60 and Conclusions Population PK modeling confirms that post-HCT ATG overexposure in certain pts undergoing ex vivo CD34-selected allo-HCT leads to inferior RFS and markedly higher NRM possibly due to poor IR. Identifying the optimal ATG exposure and individualizing ATG dosing may improve early CD4+ IR and ultimately improve survival in these pts.

Background Using preliminary search National Marrow Donor Program (NMDP) HapLogic™ predictions, we have developed a search prognosis algorithm that accurately predicts the likelihood of patients having an 8/8 HLA-matched URD (Davis et al, BBMT 2018). An alternative approach is to categorize search prognosis by patient HLA genotype frequency & ancestry (Wadsworth et al, BMT 2016). We compared these search prognosis assessment methods. Methods We performed a preliminary URD search on 830 potential adult allograft recipients & categorized the patients into 3 prognosis groups (Good, Fair, Poor) using HapLogic™-based & recipient genotype-based definitions. The HapLogic™-based prognosis groups of Very Good/ Good were classified as "Good", the Fair/ Poor as "Fair", & the Very Poor /Futile as "Poor". Search outcomes (8/8 URD(s) identified & of those transplanted the percentage receiving an 8/8 URD) by prognosis category for each method were then compared. Results The 2 methods resulted in different distributions of patients in the Good, Fair & Poor categories (p Of the 445 patients transplanted in the study period with either a 7-8/8 URD or other alternative donor, the distribution of the patients into Good/ Fair/ Poor groups was different with more patients being classified as Fair by the recipient genotype method. Moreover, the percentage receiving an 8/8 URD was different with a lower number of Fair patients by recipient genotype receiving an 8/8 URD (p Conclusions Search prognosis using HapLogic™ predictions obtained from the preliminary search allows better identification of patients who are very unlikely to have an 8/8 URD. Search prognosis should incorporate preliminary search HapLogicTM predictions to improve search accuracy & efficiency. This is especially important for minorities who are less likely to have 8/8 URDs.

Background Anti-thymocyte globulin-free dCBT is associated with high rates of acute GVHD (aGVHD) especially involving the GI tract. Investigation of augmented aGVHD prophylaxis is indicated. Methods We are investigating the addition of a single dose of tocilizumab 8 mg/kg (day -1) to CSA/ MMF (starting day -3) aGVHD prophylaxis in adult patients (pts) with hematologic malignancies undergoing dCBT with intermediate intensity Cy 50/ Flu 150/ Thio 10/ TBI 400 conditioning (NCT03434730). Outcomes of the first 26 patients (with survivor follow-up of at least 100 days) were analyzed & compared to 54 dCBT historic controls transplanted with identical conditioning & only CSA/ MMF. All patients received letermovir if CMV seropositive. Results 26 pts [median age 47 years (range 26-60), median weight 82 kg (range 59-125), 11 AML, 8 ALL, 2 MPAL, 3 MDS/ CML, 2 NHL, median age-adjusted HCT-CI 2.5 (range 0-6)] received dCB grafts with a median CD34+ cell dose of 1.5 × 105/kg/unit (range 0.23-5.94) & median unit-recipient 8-allele HLA-match of 5/8 (range 3-6). One patient had graft failure in the setting of low graft viability/ disseminated adenovirus & a second pt had early transplant-related mortality (TRM) with incomplete count recovery. The remaining 24 patients engrafted at a median of 24 days (range 18-40) for a cumulative incidence of 92% (95%CI:67-98). 88% (95%CI:59-97) of pts engrafted platelets at a median of 43 days (range 32-78). Of evaluable pts, 68% & 83% had 100% single-unit donor chimerism in the blood at days 30 & 100, respectively; single-unit dominance was observed in the remaining cases. Six of 26 pts (23%) developed pre-engraftment syndrome (PES) at a median of 12.5 days, & only 3 of these (12%) required systemic corticosteroids. Additionally, 16 pts (62%) had no neutropenic fever prior to engraftment. The day 100 cumulative incidence of grade II-III & grade III aGVHD was 62% (95%CI:39-78) & 4% (95%CI: Conclusions Tocilizumab-based dCBT appears safe with reduced PES & grade III-IV aGVHD. While many pts developed upper GI aGVHD, the marked reduction in lower GI aGVHD supports preferential reduction of T-cell homing to the lower gut. Investigation of this approach including aGVHD treatment responses, immune recovery & correlative biomarker/ microbiota studies are ongoing.

Background. Prior studies consistently show that the use of maintenance therapy after completion of combination therapy translates into longer progression-free survival (PFS) in patients with multiple myeloma. Some studies show that maintenance therapy prolongs overall survival (OS). Typically, maintenance therapy is used in the setting of newly diagnosed multiple myeloma; however, emerging data suggest that (at least a subset of) patients in the early relapse setting, for example those who achieve MRD negativity, may also be candidates for maintenance therapy integrated with careful disease monitoring. Currently, lenalidomide is considered the standard of care for maintenance; however, there is only limited published data on long-term use, with respect to the ability to sustain MRD negativity, mechanisms of relapse, and late toxicities. We were motivated to develop a study focusing on long-term lenalidomide maintenance therapy and to study clinical and correlative data. Here, we report on sustained MRD negativity and clinical tolerability. Methods. This single arm, phase 2 was designed to enroll 100 evaluable patients. Per protocol, maintenance therapy with lenalidomide 10 mg is given days 1-21 on a 28-day cycle. The initial study design had a total duration of 36 months; it was subsequently extended with additional 24 months (i.e., total of 60 months). Per standard procedures for protocol amendments, patients were offered to re-consent for the extension. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT exams at baseline, annually, at progression/end of treatment; blood work was done every 3 months. Bone marrow and blood samples were banked longitudinally per the research protocols. Based on practical considerations, the study was statistically powered for the primary end-point progression-free survival, which provided sufficient numbers of samples for the planned correlative assays focusing on MRD testing, genomic characterization of detectable disease, and profiling of the bone marrow microenvironment. All these assays were conducted in serial samples collected over time and assessed in relation to clinical outcomes. Results. A total of 100 evaluable patients meeting eligibility criteria were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-86 years) and median ECOG score 1 (range 0-1). At the submission of this abstract, the median number of cycles delivered is currently 26 (range 1 to 48); 86 patients have completed 12 or more cycles, 57 patients have completed 24 or more cycles, and 29 patients have completed 36 or more cycles. MRD testing had been completed at least once in all patients. Thirty-four patients were MRD negative at enrollment. At median followup time of 28 months (range 3.4 to 45.6), 15/100 (15%) patients have progressed. Considering the entire follow-up time from initial MRD negativity to last follow-up on study, we found 39 (of 85 tested; 46%) and 25 (of 57 tested; 44%) to have evidence of 1 and 2 years sustained MRD negativity, respectively. Only 19 patients were tested for MRD at 3 years and 16 (84%) had sustained MRD negativity. Toxicities (grade 3) include neutrophil count decrease (N=9), hypertension (N=3), diarrhea (N=2), lung infection (N=2), and rash maculo-papular (N=2), and toxicities (grade 4) include sepsis (N=2) and platelet count decrease (N=1). The most common 1/2 toxicities were diarrhea (N=51), fatigue (N=33), and upper respiratory infection (N=23). Among evaluable patients, dose reductions of lenalidomide due to toxicities and tolerability issues were done in 6 (6%) patient. Conclusions. Among evaluable patients who were treated with lenalidomide 10 mg maintenance therapy days 1-21 on a 28-day cycle on this study, at a median followup of 28 months, we found 46% and 44% to have evidence of 1 and 2 years sustained MRD negativity, respectively. Currently, 19 patients have been tested for MRD at 3 years; 16 (84%) show evidence of 3 years sustained MRD negativity. The toxicity profile was in accord with prior studies and tolerability was quite good reflected in only 6 patients requiring dose reductions due to toxicities. Correlative assays focusing on mechanisms of sustained MRD negativity in this study are presented in a separate abstract at this meeting. Disclosures Landgren: Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC. Lesokhin:Genentech: Research Funding; GenMab: Consultancy, Honoraria; Janssen: Research Funding; Serametrix Inc.: Patents & Royalties; Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Janssen: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Landau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Roshal:Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy.

Background: Anemia and thrombocytopenia are common in myelofibrosis (MF), and portend adverse outcomes. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently causes anemia and thrombocytopenia. Thrombocytopenia, in particular, often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, both alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could improve both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report updated analysis of this study (NCT03069326). Methods: We conducted a multicenter, two-stage, phase II trial designed to assess the effect of combined RUX and THAL in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had a suboptimal response (less than PR per IWG-MRT/ELN 2013 criteria) or be refractory to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and on a stable dose of RUX for a minimum of 4 weeks prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria (in patients with baseline thrombocytopenia) included: Major response (≥75% increase in platelet count), Intermediate Response (50-74% increase) and Minor Response (25-49% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: 23 patients have been accrued (planned total accrual 25), 15 of whom are evaluable for response at the time of this writing. The median age was 70 (43-77). 8 patients had received prior therapies other than RUX, including momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 10 patients enrolled to the run-in phase. 12 patients had received RBC transfusions prior to study enrollment. A significant increase in platelet count after cycle 3 of combination therapy in evaluable patients, compared to baseline, was observed (Figure 1A; P Conclusions: The combination of THAL and RUX continues to demonstrate a promising efficacy signal in this analysis of an ongoing phase II study, and appears to be well tolerated. Reductions in spleen size and symptom burden were observed. Platelet count increases were observed in 75% patients with baseline thrombocytopenia. This result is particularly important given the lack of treatment modalities for thrombocytopenia in this patient population, and the constraints thrombocytopenia places on RUX dosing, optimization of which is important for spleen response and survival. These data indicate a potential role for this regimen in patients with cytopenias and/or persistent disease manifestations while on RUX. Updated data on responses rate in all accrued patients will be presented. Disclosures Rampal: Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Verstovsek:Astrazeneca: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding. King:Incyte: Other: Advisory Board; Genentech: Other: Advisory Board ; Astrazeneca: Other: Advisory board. Stein:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; incyte: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding. Mauro:Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Takeda: Consultancy. Kadia:AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Bose:CTI BioPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding.

Background: CAR T therapy is FDA approved for specific relapsed/ refractory (R/R) B cell lymphomas and acute lymphoblastic leukemia (ALL), and clinical trials are ongoing for R/R multiple myeloma (MM). Cytopenias have been observed post-CAR T, yet there is minimal data delineating the pathobiology and trends. We report the largest series to our knowledge thus far, of hematological recovery and factors affecting count recovery after CAR T. Methods: We retrospectively reviewed adult patients who received CAR T for R/R B cell lymphomas after FDA approval and those treated for R/R B cell ALL (NCT01044069) and MM (NCT03070327) at our center. Blood counts were collected for up to 12 months or until censored for relapse, progression or initiation of chemotherapy/ conditioning for autologous or allogeneic stem cell transplantation (HCT)/ subsequent treatment with CAR T. Only patients with follow-up > 30 days were included. "Recovery" for the respective blood count was defined as hemoglobin > 8g/dL and platelets > 50,000/µL without transfusion support in 2 weeks and 1 week, respectively; absolute neutrophil count (ANC) > 1,000/µL and white cell count (WBC) > 3,000/µL without growth factor support in 2 weeks. "Normalization" was defined as normal range for the laboratory; hemoglobin > 11.2g/dL in women and 12.5g/dL in men, platelets > 160,000/µL, ANC > 1,500/µL and WBC > 3,000/µL without transfusion support as above. "Complete count recovery" refers to recovery per above criteria in all 4 counts. Categorical variables were compared using Fisher's exact test and continuous variables using the Wilcoxon rank-sum test. Results: Eighty three patients were included (Table 1). Using the noted nadir values, grade 1-2 and 3-4 anemia was seen in 22% and 78%, thrombocytopenia in 29% and 66%, neutropenia in 3% and 96% while leucopenia in 0% and 100%, respectively. During the follow-up, 66% patients received packed red cell transfusion, 52% received platelet transfusion and 62% received growth factor support. By 1 month (n=83), recovery of hemoglobin, platelets, ANC and WBC was noted in 61%, 51%, 33% and 28%, respectively. At 3 months (n=41), these respective percentages were 93%, 90%, 81% and 59%. All patients had recovered hemoglobin and platelet count by 4 months (n=17), and ANC by 9 months (n=14). By 3 months, normalization of hemoglobin, platelets, ANC and WBC was noted in 39%, 34%, 71%, and 39%, respectively. Upon examination of potential variables in a univariate model, lack of recovery of hemoglobin, platelets, ANC and complete counts recovery at 1 month was statistically significantly associated with type of CAR construct, higher grade (grade 3-4 vs grade 1-2 vs none) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) as well as a higher peak CRP and ferritin (data for complete count recovery in Table 2). Additionally, lack of hemoglobin recovery at 1 month was associated with lymphodepletion using high dose cyclophosphamide (recovered vs no recovery in 58% vs 42%, p=0.01) and diagnosis of ALL (65% vs 35%, p = 3 prior lines of therapy (78% vs 22%, p = 0.04). At 3 months, absence of complete count recovery was associated only with the CAR T construct utilized. A multivariate logistic regression model resulted in wide confidence intervals due to small size of subgroups, hence leading to unreliable point estimates (data not shown). Conclusions: Our study shows that blood counts recover in most patients who have not progressed or received additional therapy by 3 months post-CAR T. The association of count recovery with severity of CRS, ICANS as well as inflammatory marker levels indicates that inflammatory response post-CAR T influences hematological recovery in these patients. The association of count recovery and CAR construct can be influenced by underlying diagnosis as specific CAR constructs were used for specific diagnosis. Since patients with no disease response were excluded and were censored at progression, these effects are less likely to be affected by disease response; however the association of depth of response could not be evaluated in this study. These results warrant future studies to understand underlying mechanisms of inadequate recovery. Disclosures Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy. Sauter:Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; Celgene: Consultancy; GSK: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy. Santomasso:Novartis: Consultancy; Kite/Gilead: Consultancy; Juno/Celgene: Consultancy. Palomba:Noble Insights: Consultancy; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Shah:Amgen: Research Funding; Janssen: Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Brentjens:Celgene: Consultancy; JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding. Park:Takeda: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Incyte: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy. Perales:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mailankody:Celgene: Research Funding; Juno: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria.

Background In patients with Myelodysplastic Syndromes (MDS), TP53 mutations associate with high-risk presentation, complex karyotype, acute myeloid leukemia (AML) progression and poor response to hematopoietic stem cell transplantation. These associations highlight the relevance of TP53 as a prognostic and predictive biomarker. Consistent with its role as a tumor suppressor, bi-allelic targeting of the TP53 locus is a frequent but not an obligatory event. Despite the central role of TP53 in MDS, the clinical implications of TP53 mutations in the context of allelic state have not been extensively studied. Methods Under the auspices of the International Working Group for Prognosis in MDS, we sequenced a representative cohort of 3,324 peri-diagnosis MDS patients on a next generation sequencing (NGS) panel optimized for myeloid disease. Conventional G-banding analysis (CBA) was available for 2,931 patients. Focal (~3MB) gains and deletions and regions of NGS-derived copy-neutral loss of heterozygosity (cnLOH) were assessed using an in-house algorithm CNACS. Putative oncogenic mutations in TP53 were characterized by consideration of normal controls and established population databases. A validation cohort of 1,120 samples with independent but comparable molecular and clinical annotation was sourced from a compendium of Japanese MDS data to include JALSG-MDS212, JMDP registry, and regional registries. Results NGS-derived ploidy alterations and CBA show a high genome-wide concordance. From NGS profiles, 11% of patients (n=360) are subject to cnLOH, of which 80 target the TP53 locus. We characterize 490 TP53 mutations in 380 patients, representing 11% of the cohort. Amongst those patients, 22% (n=85) and 21% (n=78) have a deletion or a cnLOH involving the TP53 locus, respectively. Taken together, these segregate patients into two TP53 states: a mono-allelic state where one wild type allele remains (33% of TP53 mutated patients, n=126); and a multi-hit state where TP53 is altered multiple times by either mutations, deletions or cnLOH (67% of TP53 mutated patients, n=254). We find that TP53 state shapes clinical presentation and outcomes. Mono-allelic TP53 patients present with more favorable disease than multi-hit TP53 patients: they are less cytopenic, have lower bone marrow blasts (median 4 vs. 9%, p Conclusions TP53 is a natural candidate for incorporation in molecularly informed risk stratification schemas (molecular IPSS-R). We show that TP53 state rather than mutation alone is an independent diagnostic and prognostic biomarker in MDS. We propose that ascertainment of TP53 state is critical in prospective clinical sequencing for risk estimation, disease monitoring and future correlative research into predictors of response to established and investigational therapies. Disclosures Bernard: Celgene: Research Funding. Hasserjian:Jazz Pharmaceuticals: Consultancy; Promedior, Inc.: Consultancy. Germing:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Cargo:Celgene: Research Funding. Santini:Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kotsianidis:Celgene: Research Funding. Takaori-Kondo:Pfizer: Honoraria; Chugai: Research Funding; Janssen: Honoraria; Kyowa Kirin: Research Funding; Takeda: Research Funding; Ono: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria. Savona:Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding. Ades:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Stevenson:Celgene: Research Funding. Fenaux:Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Aprea: Research Funding; Celgene Corporation: Honoraria, Research Funding. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Heuser:Synimmune: Research Funding; Bayer Pharma AG, Berlin: Research Funding. Valent:Blueprint: Research Funding; Pfizer: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Deciphera: Honoraria, Research Funding. Miyazaki:Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Otsuka: Honoraria; Chugai: Research Funding; Novartis: Honoraria; Kyowa-Kirin: Honoraria. Finelli:Novartis: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Gattermann:Novartis: Honoraria; Takeda: Research Funding; Alexion: Research Funding. Ebert:Broad Institute: Other: Contributor to a patent filing on this technology that is held by the Broad Institute.; Celgene: Research Funding; Deerfield: Research Funding. Bejar:Celgene: Consultancy; Takeda Pharmaceuticals: Research Funding; AbbVie/Genentech: Consultancy, Honoraria; Astex/Otsuka: Consultancy; Modus Outcomes: Consultancy; Daiichi-Sankyo: Consultancy. Greenberg:Notable Labs: Research Funding; Celgene: Research Funding; Genentech: Research Funding; H3 Biotech: Research Funding; Aprea: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Ogawa:Qiagen Corporation: Patents & Royalties; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; RegCell Corporation: Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; Kan Research Laboratory, Inc.: Consultancy; Asahi Genomics: Equity Ownership. Papaemmanuil:Celgene: Research Funding.

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT). However, survival outcomes, especially non-relapse mortality (NRM) in these patients remain suboptimal due to multi-morbidity and geriatric vulnerabilities. We and others have shown previously that pre-transplant multi-morbidity, and functional limitation and post-HCT geriatric syndromes of delirium and fall significantly impact allo-HCT outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized to affect HCT outcomes. However, it remains unknown whether sarcopenia is a simple surrogate of multi-morbidity or functional impairment and whether post-transplant sarcopenia also impacts outcomes. From our institutional database and the electronic medical record, we identified 146 lymphoma patients 50 years or older who were transplanted at our institution from 2008 to 2018 using reduced-intensity/nonmyeloablative conditioning and a matched related or unrelated, mismatched unrelated, or haploidentical donor, and who had either a PETCT or CT within 60 days of HCT. Two adjacent axial images within the same series at the third lumbar vertebra were selected for the analysis of total muscle cross-sectional area (cm2) and of total fat (subcutaneous and visceral adipose tissues) cross-sectional area (cm2) using MIM software. Skeletal muscle cross-sectional area was normalized for stature and reported as skeletal muscle index in cm2/m2. Sarcopenia was defined as a skeletal muscle index Before allo-HCT, 80 (55%) patients were sarcopenic. Baseline demographic, transplant, and geriatric characteristics were well matched among the two groups except for slightly more females in the sarcopenic group (38% versus 21%, p=0.046). In multivariable analysis (Table 1), pre-HCT sarcopenia was significantly associated with overall survival (OS) with hazard ratio (HR) of 2.12 (95% CI 1.18 - 3.80, p=0.01); progression-free survival (HR 1.78, 95% CI 1.07 - 2.98, p=0.03); and NRM (HR 2.06, 95% CI 1.02 - 4.19, p=0.044). Multi-morbidity (HCT-CI ≥3) was independently associated with OS, PFS, and NRM, while functional impairment as measured by prior fall was significantly associated with PFS (Table 1). One hundred twenty-eight patients had CT images within 3-6 months post-HCT. Comparing to pre-transplant values, there were median decrease in total lean body mass of -2.86 kg (range -16.68 -9.87, p While limited by the retrospective design, single diagnosis of lymphoma, and inability to establish causal relationships among GVHD, steroid use, and post-HCT sarcopenia, our findings nevertheless illustrated the high prevalence of sarcopenia in older allo-HCT recipients. Importantly, we demonstrated significant negative impact of both pre- and post-HCT sarcopenia on survival which were independent of geriatric multi-morbidity, functional impairment, and acute GVHD. While requiring prospective confirmation, the temporal pattern and adverse survival impact of sarcopenia warrants preemptive, targeted, longitudinal, and multidisciplinary interventions to improve HCT outcomes for older patients. Disclosures Sauter: Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; GSK: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Giralt:Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Actinium: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kite: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding.

Background: Cancer-associated thrombosis (CAT) is a leading cause of death in cancer patients after cancer itself. Risk factors for CAT include tumor type/stage, body mass index (BMI), blood cell counts and chemotherapy exposure. These factors form the basis of prediction algorithms for CAT risk, including most notably the Khorana Risk Score. However, significant limitations exist with these currently-available risk prediction models. Emerging data suggest that a tumor's molecular profile can impact venous thromboembolism (VTE) risk. Mutations of ALK, EGFR, IDH1, ROS1, and KRAS for example have been shown to modulate the risk of CAT; however, these studies were limited by the number of mutations and specific tumor types analyzed. We hypothesized that extended molecular testing in a large patient cohort would allow for improved detection of molecular signatures associated with CAT. We analyzed deep-coverage targeted sequencing data (up to 341 genes) of tumor samples from 11,776 cancer patients to identify gene mutations associated with VTE. Methods: Adult patients with any solid tumor diagnosis who had their tumors sequenced using MSK-IMPACT from 1/2014 to 12/2016 were retrospectively assessed for CAT events using redundant algorithmic methods and individual chart reviews. The endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis (DVT). An episode of upper extremity DVT was considered a competing event. The observation period was limited to 365 days after IMPACT blood control sampling. Cause-specific Cox proportional hazards regression was used to test for an association between gene and CAT risk, adjusting for clinical covariates including age, cancer type, cytotoxic chemotherapy (time-dependent), anticoagulant use, stage (metastatic/non-metastatic) and prior history of VTE. Separate multivariate models evaluated the association for the 60 most frequently-mutated genes identified, along with ALK, MET, ROS1 which were included based on existing literature suggesting an effect on VTE risk. Final p-values were adjusted for false discovery using the Benjamini-Hochberg procedure, and the threshold for statistical significance was set at 0.10. Patients with multiple cancer diagnoses were excluded. Results: Out of 11,776 individuals we observed 727 CAT events (6.2% of cohort). The most commonly represented tumor types were lung (18%), breast (15%) and colorectal cancer (10%); see Figure for a breakdown of CAT incidence by tumor type. Most (72%) of patients were metastatic at time of IMPACT testing and 4% were on anticoagulation therapy. Statistically significant predictors of CAT included cytotoxic chemotherapy (HR 1.61 [1.37-1.9]; p Conclusions: This work is the first large-scale analysis to elucidate cancer-specific genomic determinants of CAT. Using a large patient cohort, we found that somatic tumor mutations in STK11, KRAS, IDH1, KEAP1, and MET modulate the risk of venous thromboembolism in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types. We hope these findings will ultimately translate into improved risk stratification for patients at risk of CAT. Disclosures Mones: Janssen: Research Funding. Iyengar:Puma Biotechnology: Consultancy; Novartis: Consultancy. Hyman:AstraZeneca: Consultancy, Research Funding; Fount: Consultancy, Equity Ownership; Pfizer: Consultancy; Chugai Pharma: Consultancy; Loxo Oncology: Research Funding; Boehringer Ingelheim: Consultancy; Bayer Pharmaceuticals: Consultancy, Research Funding; Genentech / Roche: Consultancy; PUMA Biotechnology: Research Funding; CytomX Therapeutics: Consultancy. Park:Merck: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Astellas: Research Funding; Ipsen: Consultancy. Khorana:Bayer: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy. Soff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Mantha:Medical Case Management Group: Consultancy; MJH Live Events: Other: Give CME talk; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; Daboia Consulting LLC: Equity Ownership; Janssen: Research Funding.