ALBERT

Description: Introduction: We have previously reported that clinically relevant, dramatic reductions occur in intestinal bacterial diversity during allogeneic hematopoietic stem cell transplant (allo-HSCT). These are likely attributable to antibiotic exposure, nutritional alterations, and intestinal mucosa injury from high-dose chemotherapy. Patients undergoing autologous hematopoietic stem cell transplantation (AHCT) also receive antibiotics and experience nutritional alterations due to mucositis and other gastrointestinal toxicities. We hypothesized that the pattern of dysbiosis seen in AHCT patients would reflect the changes in allo-HSCT patients. Here, we present a novel analysis of microbiota diversity in AHCT patients from two independent institutions. Methods: We retrospectively identified a cohort of 365 patients (median age 60 years) who underwent AHCT for treatment of hematologic malignancy between May 2009 to February 2018 at two large-volume transplant centers in the US. The population was diverse in terms of histology, conditioning regimens and remission status prior to transplant, with 179 (49%) patients diagnosed with multiple myeloma, 153 (42%) patients diagnosed with lymphoma, and 33 (9%) patients with other diseases. Stool samples from the selected patients were collected approximately weekly during inpatient hospitalization. Sequencing of the V4-V5 region of the bacterial 16S rRNA genes from all samples was performed on the Illumina platform at a central site. Microbial diversity was measured by the Simpson reciprocal a-diversity index (S). We defined the pre-AHCT period as days -10 to 0, and computed median values for patients with multiple samples within that period. We additionally defined monodomination of the microbiota as a single operational taxonomic unit comprising 〉30% of bacterial abundance. For comparison, we sequenced samples from 17 healthy volunteers and used a public dataset of sequences from 313 healthy volunteers from the NIH Human Microbiome Project (HMP). Median pre-transplant microbial diversity in the healthy patient and AHCT groups was compared by a pairwise Wilcox test to a retrospective cohort of allo-HSCT patients. Results: We evaluated 857 samples from 365 adult patients undergoing AHCT, with 316 patients from Memorial Sloan Kettering Cancer Center (MSKCC) and 49 patients from Duke University Medical Center (DUMC). Median pre-transplant diversity in AHCT patients from both centers was significantly lower than in normal controls (Fig 1A) (HMP vs MSKCC AHCT, S=12.05 vs. 9.19, p75% by day +14. Conclusion: Microbial diversity is reduced prior to transplant in both AHCT and allo-HSCT patients. Loss of diversity after AHCT occurs across centers and the degree of injury is comparable to the dysbiosis in allo-HSCT patients. Preliminary analysis suggests that lower diversity may correlate with worse progression-free survival (PFS) in myeloma patients in our diverse AHCT cohort. Given the known associations of alterations in microbiota composition with toxicities and overall survival in allo-HSCT patients, further evaluation of microbiota injury and its associations with toxicities, PFS, and overall survival (OS) in AHCT patients is warranted. Figure 1: A: The median Simpson reciprocal a-diversity index (S) of pre-transplant (days -10 to 0) samples of AHCT and allo-HSCT patients from two centers, as well as two cohorts of healthy volunteers, was plotted and a pairwise Wilcox test was performed, with p-values as indicated. B: (S) was plotted against time relative to allo-HSCT (on L) and AHCT (on R), for samples collected from day -10 to day +30. Larger values indicate greater diversity. C: Microbiota composition and changes in bacterial monodominance after transplant (days -14 to +28); the most common genus post-transplant is Streptococcus. Figure 1. Figure 1. Disclosures Peled: Seres Therapeutics: Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Perales:Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees. Jenq:Ziopharm Oncology: Consultancy; Seres Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees; MicrobiomeDx: Consultancy; Seres Therapeutics, Inc.: Patents & Royalties.

Description: Introduction: BCMA targeted CAR T cell therapy has shown promising results in patients with relapsed/refractory multiple myeloma (MM). Herein, we report on the safety and efficacy of MCARH171, a second generation, human derived BCMA targeted autologous 4-1BB containing CAR T cell therapy, including a truncated epidermal growth factor receptor safety system (Smith EL. Mol Ther 2018). Methods: This is a phase I first in human, dose escalation trial of MCARH171. Patients received conditioning chemotherapy with cyclophosphamide (Cy) 3 gm/m2 as a single dose or fludarabine 30 mg/m2 daily and Cy 300 mg/m2 daily for 3 days followed by MCARH171 infusion in 1-2 divided doses. The trial followed a standard 3+3 design with 4 dose levels where patients received the following mean doses per cohort: (1) 72x106, (2) 137x106, (3) 475x106, (4) 818x106 viable CAR+ T cells. The primary objective was to demonstrate safety, and secondary objectives included efficacy and expansion, and persistence of CAR T cells using PCR from the peripheral blood. The last accrued patient received MCARH171 on Dec 6, 2017 and the data cut-off is July 16, 2018. The study is closed to accrual. Results: 11 patients with relapsed and/or refractory MM were treated. Median number of prior lines of therapy was 6 (range: 4-14), and all patients received prior therapy with a proteasome inhibitor, IMiD, anti-CD38 monoclonal antibody, and high dose melphalan/stem cell transplant. Nine (82%) patients had high-risk cytogenetics and 9 (82%) were refractory to their immediate prior line of treatment. One patient was not evaluable for DLTs given the need for early radiation and steroids for impending spinal cord compression by tumor. There are no DLTs reported. Cytokine release syndrome (CRS) grade 1-2 occurred in 4 patients (40%), grade 3 occurred in 2 (20%), and there was no grade 4-5 CRS. Grade 2 encephalopathy occurred in 1 patient (10%) in the setting of high fevers which resolved in less than 24 hours. There was no grade 3 or higher neurotoxicity observed. Tocilizumab was administered to 3 patients; 2 in cohort 2, and 1 in cohort 3. Laboratory values correlating with CRS reaching grade 3 or requiring Tocilizumab (N=4) compared to those with no or milder CRS (N=6) included peak CRP (mean: 28.5 vs 4.6 mg/dL, p

Description: Background: Several studies have indicated that the depth and duration of treatment response in multiple myeloma are both reduced in the relapsed setting. With further lines of therapy, responses continue to weaken in depth and shorten in duration. The National Comprehensive Cancer Network (NCCN) Guidelines suggest that regimens may be repeated in the relapsed setting if there has been a duration of at least 6 months since that regimen was given; however, there is limited information regarding treatment response and duration in the setting of re-treating patients with agents previously utilized. Moreover, preliminary data has suggested that carfilzomib-based regimens in the frontline may be able to attain deeper and longer responses than alternative therapies, which has led to carfilzomib being used more frequently in the frontline. This motivated us to investigate the treatment response, depth, and safety of re-challenging patients with carfilzomib in the relapsed setting. Methods: In this retrospective chart review, we identified all patients who were treated with multiple courses of carfilzomib-based regimens at Memorial Sloan Kettering Cancer Center between January 1, 2014 and November 30, 2018. Our primary objectives were to assess the response, duration of response and treatment, and safety of re-exposure to carfilzomib-based regimens. Responses were assessed as per IMWG 2016 consensus criteria (Lancet Oncol 2016). In this review we describe the clinical course, safety, and efficacy of re-challenging patients with carfilzomib in the relapsed and refractory settings. Results: Fifteen patients were identified as having received multiple, independent lines of carfilzomib-based therapy. The median age of the cohort was 58 years (49-76) with 53% male (8); two patients had R-ISS stage 1, eight stage 2, and five stage 3 disease. Five of these patients received their initial carfilzomib in the frontline as part of KRD; four of whom attained a sCR with the fifth attaining a VGPR. The remaining ten patients received their initial carfilzomib in the second-line (4) or 3rd and subsequent lines (6). Upon re-exposure to carfilzomib, patients were heavily treated with a median of four lines of therapy (2-15). All but three patients had at least one adverse cytogenetic abnormality; eight with 17p-, five with 13q-, three with t4;14, and six with 1q+. Regimens utilized in the relapsed setting included KRD (N=4), KPD (N=3), Cyklone (N=2), KD + HDAC inhibitor (N=3), KD (N=1), KCD (N=1), and KRD + daratumumab (N=1). Four patients received carfilzomib at a dose of 27 mg/m2 while the remaining 10 received 〉 36 mg/m2. Responses were seen in all but four patients (two VGPR, five PR, and four MR), with one patient experiencing progression during carfilzomib with no response; notably, this patient only attained a MR to primary carfilzomib therapy and their second exposure was the 15th line of therapy. The median time to next therapy was 4.8 months (1.9-19.4) with one patient being bridged to autologous hematopoietic cell transplantation (HCT), one to allogeneic HCT, and three are currently receiving ongoing carfilzomib treatment (13.9, 2.8, 2.5 months with VGPR, MR, and PR, respectively). Exacerbation of baseline hypertension was identified in three patients, but these instances were treated successfully with standard medications with no further complications. No additional cardiovascular events were identified in the frontline or re-treatment settings. Conclusions: We report that in a heavily pre-treated, high risk patient cohort, patients previously treated with carfilzomib-based regimens may be safely re-challenged with carfilzomib. Importantly, none of these patients experienced cardiovascular adverse effects other than exacerbation of underlying hypertension, further supporting the ability to safely re-treat a select group of patients with carfilzomib. We conclude that depending on the patient and treatment history, re-challenging with carfilzomib at relapse may be appropriate salvage therapy, particularly as a bridge towards HCT and/or clinical trials. Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Lesokhin:Genentech: Research Funding; Serametrix Inc.: Patents & Royalties; Janssen: Research Funding; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landau:Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Giralt:Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Jazz Pharmaceuticals: Consultancy; Actinium: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Kite: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; 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; Theradex: Other: IDMC; Merck: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background Minimal residual disease (MRD) negativity is a strong predictor for outcome in multiple myeloma. Next generation sequencing (NGS) for immunoglobulin heavy chain and kappa light chain VDJ rearrangements has become increasingly more common for MRD assessment. One of the known challenges with NGS for VDJ rearrangements is the vast diversity of sequences that are present, resulting in a need for a multiplex approach as common primers cannot be used to amplify all rearrangements. Also, somatic hypermutation may affect the annealing of primers and decrease the capture rate. The NGS VDJ assay developed by Adaptive Biotechnologies targets all theoretical combinations of VDJ sequences and has been used in several recent large randomized trials in multiple myeloma. The reported ~80% capture rate of the first version of the Sequenta/Adaptive 1.3 assay limited the ability to track MRD status post therapy. The assay has recently been updated and validated to increase resilience to somatic hypermutation. As there is no published reference data using this assay, we were motivated to assess VDJ capture in the clinical setting. Methods In total, 147 patients with newly diagnosed multiple myeloma (NDMM, n=101) or relapse/refractory multiple myeloma (RRMM, n=46) seen at Memorial Sloan Kettering Cancer Center were identified and included in the study. At bone marrow collection, patient samples were sorted for mononuclear cells and a subset of samples were sorted for CD138+ plasma cells. Stored bone marrow samples from these patients underwent DNA extraction and were sequenced with the Adaptive NGS VDJ assay. The same samples were also sequenced for genomic events using our internal NGS panel myTYPE. myTYPE is a custom capture panel targeting the most frequent multiple myeloma associated-somatic mutations, copy number alterations, and IGH translocations. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of detection success in relation to clinical parameters such as age, gender, percent bone marrow plasma cells, as well as immunoglobulin heavy and light chain types, and myTYPE positivity. Results There overall capture rate for a unique VDJ sequence was 80%, 75% in NDMM samples and 89% in RRMM samples, respectively. The VDJ capture rate in samples that were myTYPE positive, e.g. samples with at least one genomic aberration detected by myTYPE, was 94%. In univariate analysis, the ORs of detecting a clonal VDJ sequence was 1.8 (95% CI 1.3-2.5) and 1.5 (1.2-1.9) for every 10% increase in plasma cells on bone marrow aspirate and biopsy, respectively. For every 1g/dL increase in M-spike, the OR of VDJ capture was 1.6 (1.2-2.2). Samples with at least one genomic aberration detected by myTYPE had a significantly higher detection rate of VDJ sequence, the OR of VDJ capture in myTYPE positive samples was 8.8 (3.2-31.3). Conversely, age, gender, type of immunoglobulin heavy chain (IgG or IgA), or light chain type (kappa or lambda) had no significant effect on the VDJ detection rate (Table). In multivariate analysis, myTYPE positivity was found to be an independent predictor of VDJ capture, with an OR of 4.9 (1.6-18.4, p=0.009) for myTYPE positive samples. The ORs were 1.4 (1.1-2.2, p=0.052) for an increase in 10% plasma cells on bone marrow aspirate and 1.5 (0.97-2.3, p=0.083) every 1g/dL increase in M-spike. Conclusion The VDJ capture rate using the updated Adaptive NGS VDJ assay was 94% in multiple myeloma samples of high quality as indicated by myTYPE positivity. The capture success rate was higher in samples with a greater disease burden. As expected, the assay was less sensitive in samples with insufficient DNA content. Our results are supportive of the use of this NGS VDJ in multiple myeloma, but also illustrate the importance of optimal sample ascertainment and processing. Disclosures Jacob: Adaptive Biotechnologies: Employment, Equity Ownership. Korde:Amgen: Research Funding. Mailankody:Juno: Research Funding; Physician Education Resource: Honoraria; Janssen: Research Funding; Takeda: Research Funding. Lesokhin:Serametrix, inc.: Patents & Royalties: Royalties; Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding.

Description: Anti-CD19 chimeric antigen receptor modified T-cells (CAR T) produce remarkable responses for relapsed/refractory diffuse large B-cell lymphoma but over half of patients will relapse. Disease progression post CAR T therapy remains challenging and without standard guidelines. Radiotherapy is potentially an important salvage approach, but limited data exists to guide optimal utilization. We reviewed the first 15 patients treated with salvage radiotherapy (SRT) following CAR T progression. All but two patients had DLBCL; one had blastoid variant mantle cell lymphoma and the other patient was best classified as a CD5+ high grade lymphoma not otherwise specified. Outcomes included post RT response, freedom from subsequent relapse (FFSR) and overall survival (OS). Patients were heterogeneous and heavily-treated with a median of 4 prior lines of pre-CAR T therapy (range 2-8). Median time to first post-CAR T relapse was 82 days and RT was part of the first salvage regimen for 73%. Most received SRT to a site that was previously avid pre-CAR T. Post SRT, there were 6 evaluable patients with limited stage relapse; objective response rate was 100% (n=3 CR and n=3 PR). For advanced-stage relapse, while many had in-field PR, nearly all had concomitant out-of-field progression. Median OS from first post-CAR T relapse was 11 months. Patients with localized vs. advanced stage relapse had significantly improved FFSR (hazard ratio, HR=0.11, p=0.009) and OS (HR 0.10, p=0.003). By second-line age-adjusted IPI (sAA-IPI), 40% were low or low-intermediate risk and lower sAA-IPI risk prognosticated improved OS post SRT (p=0.004). Four patients were bridged to allogeneic transplantation with SRT and at analysis, 3 were alive and NED with 4.9, 7.2 and 36.2 months of post-allogeneic transplant follow-up. The fourth patient was also NED but deceased from transplant-related complications. SRT following CAR T is feasible with powerful and diverse utility including local palliation for transplant-ineligible patients. For lower risk and localized relapses, SRT may be integrated with novel targeted agents, immunotherapies or transplantation to attempt durable remissions. Disclosures Palomba: Hemedicus: Other: Immediate Family Member, Speakers Bureau ; 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; Kite Pharmaceuticals: 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; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Sauter:Novartis: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; GSK: Consultancy; Spectrum Pharmaceuticals: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Celgene: Consultancy; Kite/Gilead: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Perales: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; MolMed: 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; Bellicum: 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; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sadelain:Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy, Patents & Royalties; Memorial Sloan Kettering Cancer Center: Employment.

Description: Background: HDT-ASCT with TBC conditioning has emerged as a common consolidation strategy for patients (pts) with relapsed/refractory (rel/ref) primary (PCNSL) or secondary (SCNSL) (Welch et al, Leuk & Lymph 2014). In a prospective study, chemosensitive PCNSL pts in first remission after induction with R-MPV (rituximab, MTX, procarbazine and vincristine) proceeding to HDT-ASCT with TBC conditioning, experienced an encouraging 2-year PFS and OS of 75% and 81%, respectively (Omuro et al, Blood, 2015). Three of these patients experienced transplant-related mortality (TRM, 11.5%), which appears greater than HDT-ASCT for other lymphomas. The purpose of this report is to correlate characteristic toxicities of TBC conditioning for CNSL to pre-HDT-ASCT clinical variables. Methods: The MSKCC IRB approved this retrospective chart review. Eligible pts (n=34) were ≥ 18 years of age with PCNSL or SCNSL that was chemosensitive to induction therapy after which they proceeded to HDT-ASCT conditioned with TBC between December 2006 and April 2015. All pts included were treated outside of prospective clinical trials. Clinically significant grade 3-5 non-hematologic toxicities per CTCAE 4.0 occurring in 〉20% of pts were recorded from the initiation of conditioning until 6 months post ASCT (Figure 1). Pre-HDT-ASCT variables for analysis include: age, gender, disease (PCNSL or SCNSL), Karnofsky performance status (KPS), hematopoietic cell transplant comorbidity index (HCT-CI), number of prior regimens, prior use of whole-brain radiotherapy (WBRT), and disease status prior to HDT-ASCT (CR/CRu or PR). We evaluated the association of these pre-HDT-ASCT characteristics with the number of clinically significant grade 3-5 non-hematologic toxicities (≥4 vs. 2) was significantly associated with incurring more grade 3-5 non-hematologic toxicities, p=0.04 (Table 1). With a median follow-up for survivors of 12 months (range, 1.5-86.2 months), PFS was 79% (95% CI, 65-96) and OS was 82% (95% CI, 68-98) at 1 year (Figures 2 and 3). During the follow-up period, there were 7 pt deaths: 4 died of disease, 2 died secondary to TRM (5.9%), and one died of a secondary malignancy (squamous cell carcinoma) 86.2 months after HDT-ASCT. There were no progression events beyond 12 months. In a limited subset analysis wherein n=22 had first dose bu pharmacokinetics evaluated, pre-HDT-ASCT variables were not associated with higher bu AUC levels, though 64% of these pts required a dose reduction. Conclusions: We reaffirmed that HDT-ASCT with TBC conditioning is effective consolidation for CNSL, but it is associated with more grade 3-5 non-hematologic toxicity in pts having had 〉2 prior regimens. Risk-adapted dose attenuation of TBC conditioning for this group of pts may mitigate observed toxicity. Table 1. Association of Pre-ASCT Variables & Grade 3-5 Non-hematologic Toxicities Number of Clinically Significant Grade 3-5 Toxicities Pre-ASCT Variables All (N=34) Fewer than 4 (N=21) 4 or more (N=13) p-value Age 0.71 2 13 (38%) 5 (24%) 8 (62%) WBRT 0.17 No 28 (82%) 19 (90%) 9 (69%) Yes 6 (18%) 2 (10%) 4 (31%) Disease state prior 0.99 CR/CRu 29 (85%) 18 (86%) 11 (85%) PR 5 (15%) 3 (14%) 2 (15%) Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 2. Kaplan-Meier Curve for PFS Figure 2. Kaplan-Meier Curve for PFS Figure 3. Kaplan-Meier Curve for OS Figure 3. Kaplan-Meier Curve for OS Disclosures Bhatt: Spectrum: Consultancy. Moskowitz:GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.

Description: Background: High-dose therapy and autologous stem cell transplantation (HDT-ASCT) with thiotepa/busulfan/cyclophosphamide (TBC) conditioning is effective consolidation for patients with newly diagnosed & relapsed/refractory primary (PCNSL) or secondary CNS (SCNSL) lymphoma. A prospective study by Omuro et al (Blood 2015) showed that chemosensitive patients proceeding to HDT-ASCT with TBC conditioning in first remission resulted in encouraging 2-year PFS and OS, but with significant toxicity & transplant related mortality compared to HDT-ASCT for other lymphomas. To our knowledge, there is limited evidence defining the optimal PK directed busulfan (bu) dosing strategy in patients with CNSL undergoing TBC conditioned HDT-ASCT. We report PK targeted bu in TBC and HDT-ASCT in 22 patients with CNSL between 2011 and 2014. Methods: Twenty two patients with CNSL who underwent TBC conditioned ASCT from 2011-2014 with PK targeted busulfan were included. TBC is thiotepa IV 250mg/m2 on days -9,-8, -7; bu 3.2mg/kg IV on days -6, -5,-4; and cyclophosphamide 60mg/kg IV on days -3 & -2 with stem cell infusion on day 0. Adjusted ideal body weight was used in all patients 〉125% of ideal body weight. PK analysis of bu levels obtained after first dose was by high performance liquid chromatography with mass spectrometry. Predicted area under the curve (AUC) was reported based on 6 point kinetics. Target AUC was 4100-5200 umol*min/L (goal 4700 umol*min/L). Dosage adjustments per PK were made on the 3rd dose of bu. All PK modeling was performed using WinNonLin® 6.0 (Centara, Princeton, NJ). Results: Twenty-two patients with primary CNSL (PCNSL, n = 12, 55%) or secondary CNSL (SCNL, n = 10, 45%) from 2011-2014 received TBC conditioning with PK targeted bu. Thirteen (59%) were men and median age was 56 years (range 25-72). Twelve (55%) & 10(45%) patients received 1-2 & 3-6 lines of prior therapy, respectively for remission induction. All patients were chemosensitive prior to HDT-ASCT with 18(82%) patients in complete remission (CR) & 4(18%) in partial remission (PR). Median pre-transplant HCT-CI was 2.5 (range 0-4) and KPS of ≥80 in 20(91%). Median first dose bu AUC was 5550 umol*min/L (range 3268-7464 umol*min/L with median total bu exposure of 14939 umol*min/L (range 11236-19240 umol*min/L). Five (23%) patients were within therapeutic range, 3(14 %) required a median dose increase of 78%, and 14 (64%) required a median dose reduction of 55% to achieve goal bu exposure. Median time to neutrophil and platelet engraftment was 11 (11-14) & 17.5 (13-52) days respectively. All patients experienced grade 3/4 non-hematologic toxicities [11 (50 %) 0-3 & 11 (50 %) ≥ 4 non-hematologic toxicities, respectively]. The incidence of potential treatment related AST/ALT elevations 〉3 x ULN & t-bili 〉1.5 mg/dl was n=5(23 %) & n=7(32 %), respectively. Age and pretransplant HCT-CT 〉2 were not associated with higher bu AUC or exposure (Table 1). Patients who received ≥ 3 prior regimens had a lower initial bu AUC (p = 0.04), but no difference in total bu exposure (p=0.25). There was no difference in requirement for dose reduction by pre-transplant characteristics (e.g. age, HCT-CI, or prior regimens). Median progression free survival (PFS) by 1 year was 68% (95% CI 39-86) & overall survival (OS) 74% (95% CI 44-90). Conclusion: TBC conditioning is effective consolidation for CNSL. PK directed dosing of bu in our study population resulted in a higher than expected bu AUC. Receipt of 〉 3 prior regimens was the only pre-transplant patient factor associated with lower initial bu AUC. Although we were not able to correlate any other pre transplant patient factors and bu AUC, the overall incidence of regimen related grade 3-5 non hematologic toxicities remain high. With favorable PFS & OS, future studies targeting lower bu AUC per PK are warranted to reduce toxicity. Table 1. Pre-ASCT characteristics with Bu AUC and Total Bu Exposure N Median Bu AUC umol*min/L (Range) p-value Median Total Bu Exposure umol*min/L (Range) p-value Age 0.15 0.48 2 11 5182 (3718 - 6882) 14904 (12136 - 17038) Prior Regimens 0.04 0.25 1-2 12 5769 (3718 - 7464) 15497 (12136 - 19240) 3-6 10 5113.5 (3268 - 6510) 14785 (11236 - 15994) *Groups were compared using Wilcoxon rank sum test Disclosures Bhatt: Spectrum: Consultancy. Moskowitz:Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; GSK: Research Funding. Giralt:JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding.

Description: Abstract 3130 Background: Allogeneic stem cell transplantation (alloSCT) remains the only curative therapy for patients with indolent B cell non-Hodgkin's Lymphoma (B-NHL) as well as patients with aggressive B-NHL that have failed prior autologous stem cell transplants (ASCT). Non-myeloablative (NMA) alloSCT has been universally implemented for B-NHL given the extensive prior therapy and advanced age of the typical patient undergoing alloSCT for these diseases and resultant 40–50% incidence of transplant-related mortality (TRM) with myeloablative conditioning per registry series'. NMA alloSCT relies on graft-versus-lymphoma (GVL) effect for disease control. While the literature has suggested improved event-free survival (EFS) for B-NHL patients with a negative fluorine-18-deoxyglucose positron emission tomography (FDG-PET) scan prior to ASCT in chemosensitive patients, this has not been elucidated in a conventional NMA alloSCT treatment platform. Our hypothesis is that FDG avidity pre-NMA alloSCT is not prognostic to progression-free survival (PFS) in chemosensitive patients with B-NHL. Methods: This is a retrospective study of adult B-NHL patients with disease assessed by CT and FDG-PET prior to undergoing a T-cell replete NMA alloSCT from a 9/10 or 10/10 HLA matched related or unrelated donor conditioned with cyclophosphamide 50 mg/kg x1, fludarabine 25 mg/m2 daily over 5 days and 2 Gy total body irradiation, with or without peri-allo-SCT rituximab 375 mg/m2 administered approximately day (d) -8, d+21, d+28, d+25, d+42 as per an internal protocol. Patients receiving an unrelated donor graft received equine anti-thymocyte globulin 30 mg/kg administered daily d-3 and d-2. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, sirolimus and methotrexate (n=51) or cyclosporin-A and mycophenolate mofetil (n=15). Event-free survival (EFS) was calculated using Kaplan-Meier method. An event is defined as progression of disease (PD) or death from any cause. Results: This analysis includes 66 patients with a median age of 54 (range 33–69) years at the time of allo-SCT. Diagnoses included: 16 CLL/SLL, 30 FL, 11 DLBCL/transformed B-NHL, 6 MCL and 3 other. Patients were previously treated with a median of 3 prior chemotherapy regimens (range 1–6) and 12 patients had undergone a previous ASCT. Fifty-one patients (77%) were chemosensitive at the time of alloSCT by CT criteria, as defined by either a complete or partial remission (Cheson et al, JCO 1999; Hallek et al, Blood 2005 for CLL/SLL). Of these 51 patients, 18 had FDG-avidity on FDG-PET at time of allo-SCT above liver background per Deauville criteria (Meignan et al, Leukemia and Lymphoma 2009). The median hematopoietic comorbidity index (HCT-CI) was 1 (range 0–8). Twenty-six patients received a graft from a 10/10 HLA matched related donor, 34 from a 10/10 HLA matched unrelated donor and 6 from a 9/10 HLA mismatched unrelated donor. Eighty-six percent of the patients received peri-alloSCT rituximab. The median follow-up for survivors is 29 (range 3–67) months. Of the 15 events, 10 were TRM (7 GVHD-related deaths) and 5 PD (3 chemosensitive patients and 2 chemorefractory patients pre-alloSCT). Only 1 event has occurred beyond 13 months. The estimated 2 year EFS is 77%. There was no difference in EFS according to: CR vs PR, graft source, number of previous lines of therapy, GVHD prophylaxis, peri-alloSCT rituximab, previous ASCT, or HCT-CI. The estimated EFS at 2 years for chemosensitive patients per CT criteria is 86% compared to 50% for patients without chemosensitivity pre-allo-HCT (figure 1, p

Description: Introduction: Ex-vivo CD34+ selected allogeneic hematopoietic cell transplantation (alloHCT) after myeloablative conditioning (MAC) has been successfully utilized in the treatment of hematologic malignancies, with high rates of survival and a reduced incidence of graft-vs-host disease (GVHD). However, as MAC is associated with higher toxicity than reduced intensity conditioning (RIC), a comprehensive evaluation of toxicities and the effect on survival and non-relapse mortality (NRM) within the first year (yr) after myeloablative allo-HCT is necessary. Methods: Toxicities (≥ grade 3 by CTCAE 4.0) were retrospectively collected on 200 pts within the 1st yr of alloHCT (CD34+ selection with the ClinicMACS® CD34 Reagent System) after MAC from 2006-2012. Individual toxicities were organized into 91 toxicity categories and further into 17 organ-based groups. One toxicity per group per specified time period was used for statistical analyses. Overall survival (OS) and NRM were calculated using Kaplan Meier methods, and Cox regression was used for univariate analysis of risk of toxicities and survival outcomes across patient and treatment characteristics. Results: 200 pts (median age 57, range 19 -73) were included in the study. Indications for HCT were AML/ALL/MDS (n=144, 72%), multiple myeloma (n=30, 15%), other (n=26, 13%). Donors were MRD or MMRD (n=77, 38%), MUD (n=78, 39%) or MMUD (n=45, 23%). Median HCT-comorbidity index (HCT-CI) score was 2 (0-10). MAC was chemotherapy (n=144, 72%) or total body irradiation (TBI, n=56, 28%) based. The follow up period for surviving pts was 12 months. At day 100, 23 pts (11.5%) experienced grade 2-4 acute GVHD, while 6 pts (3%) developed grade 3-4 acute GVHD. The 5 most common grade 〉 3 toxicities, with associated cumulative incidences by day 365, were infection (0.91, 95% CI 0.86-0.94), metabolic (0.91, 0.86-0.94), hematologic (0.87, 0.81-0.91), oral/ gastrointestinal (GI) (0.66, 0.59-0.72), and pulmonary (0.24, 0.18-0.30). At 1 year post alloHCT, OS and progression-free survival (PFS) for the cohort were 75% and 67%, respectively (Fig 1A). The median number of toxicities at day 100 was 6. Pts experiencing 〉6 toxicities at day 100 had the same 1yr OS as pts with 〈 6 toxicities (80%, p=0.92). NRM was 17% at 1 yr (Fig 1B). Univariate analysis of risk factors identified associations with common toxicities occurring in the 1st yr. While no specific factors increased the risk of infection, age and male gender were associated with a decreased risk [HR 0.98 (0.97-1.0), p=0.02, HR 0.6 (0.47-0.78), p=0.002 respectively]. Patients with a high absolute lymphocyte count (ALC) [HR 0.41 (0.26 to 0.63), p= 2500 [HR 3.46 (1.9 to 6.32), p= target [HR 2.79 (1.32 to 5.91), p= 3 [2.45 (1.08 to 5.57), p=0.01] increased the risk of death and NRM [HR 3.09 (1.33 to 7.18), p=0.001, HR 3 (1.03 to 8.7), p=0.02] respectively. Factors such as age, male gender, male donor, disease type, URD, CMV+ donor, TBI, palifermin use, and albumin levels did not impact OS or NRM. Table 1 summarizes individual toxicity groups associated with OS and NRM. Conclusion: In the 1st yr after MAC alloHCT, pts experienced grade 〉 3 hematologic, metabolic, infectious, GI and hepatic complications, which would be expected with MAC. This is consistent with BMT-CTN data indicating CD34+ grafts with MAC seem to be associated with similar 〉3 toxicities as unmanipulated grafts. Further toxicity may be related to methotrexate and calcineurin inhibitors used in conventional transplants. The pts in this analysis still exhibited high OS and PFS with a low rate of acute GVHD. This analysis can contribute to identifying toxicities and methods to mitigate them through patient selection and post alloHCT management. These results are also highly relevant to the ongoing prospective exploration of CD34+ selection in pts with hematologic malignancies in the BMT-CTN 1301 randomized phase 3 trial. Disclosures No relevant conflicts of interest to declare.