Porrata, Luis F.

Introduction: Richter transformation (RT) refers to transformation of chronic lymphocytic leukemia (CLL) to diffuse large B-cell lymphoma (DLBCL) or other aggressive lymphomas. The incidence, clinical characteristics, and outcomes of RT with CNS involvement remain undefined. Methods: Biopsy-confirmed RT diagnosed from 4/1993 to 4/2018 was identified from the Mayo Clinic CLL database. RT cases with CNS involvement were further reviewed, with clinical characteristics, treatment and follow-up data abstracted. Overall survival (OS) was defined as time from CNS involvement to death from any cause and analyzed using the Kaplan-Meier method. Results: Among 204 CLL patients with biopsy-proven RT, 15 patients had documented CNS involvement by imaging (parenchymal n=11, ocular n=1, parenchymal and ocular n=1, leptomeningeal n=1, cranial and spinal nerve roots n=1). Biopsy confirmation of CNS involvement was available in 11 patients. Of these 15 patients, 10 had CNS involvement at initial RT diagnosis, and 5 patients developed CNS involvement at RT progression, with a median time from RT diagnosis to CNS involvement of 14.9 months (range 2.8-41.1). Prior to RT, 11 patients (73.3%) received no treatment for CLL, 3 (53.4%) received chemoimmunotherapy (CIT) only (1-3 lines), and 1 patient (6.7%) received CIT (1 line) and ibrutinib. CLL FISH results were available in 9 patients, with del(17p) in 2, trisomy 12 in 2, del(13q) in 3, and normal results in 2. One patient had TP53 mutation (FISH result unavailable). IgHV mutation status was known in 3 patients and 1 was unmutated. The median time to RT was 4.4 years (range 0-11.4). The median age at RT diagnosis was 70 years (range 59-78), and 9 (60%) were male. The histology of RT was DLBCL in all 15 patients (diagnosed by CNS biopsy in 8 and other biopsies in 7), with GCB subtype in 6 and non-GCB subtype in 3. MYC rearrangement was detected in 4 of 6 patients tested, and 2 of those also had BCL-2 rearrangement (MYC/BCL-2 double hit). Of the 10 patients with CNS involvement at initial RT diagnosis, 4 had isolated CNS involvement (confirmed by brain biopsy [n=2] or vitreous biopsy [n=2]). All 4 patients were treated with high dose (HD) methotrexate (MTX) based regimen, and 3 patients achieved complete remission (CR) and underwent autologous stem cell transplant with continued CR, while 1 patient achieved partial remission and received whole brain radiotherapy (WBRT) at disease progression. Six patients had both systemic and CNS involvement (confirmed by brain biopsy [n=2] or CSF examination [n=2] in 4; the other 2 were diagnosed by imaging). All 6 patients received CNS directed therapy (HD MTX [n=5] or WBRT [n=1]) as well as systemic therapy (R-CHOP [n=5] or HyperCVAD [n=1]), with varied short duration of disease control (Figure 1A). Of the 5 patients who developed CNS involvement at RT progression (after 1-2 lines of therapy including first-line R-CHOP), 2 had isolated CNS involvement (1 was confirmed by CSF examination and the other was by imaging only). Both were treated with HD MTX based regimen, and 1 achieved a durable remission of 2 years but eventually had CNS relapse, while the other had no response and received WBRT with limited benefit. Three patients had both systemic and CNS involvement (2 were confirmed by CSF examination and the other was by imaging only), and all 3 patients were treated with HD MTX based regimen but all had CNS disease progression within 3 months (Figure 1A). The OS after CNS involvement for all 15 RT patients was 9.4 months (95% CI 2.3-19.1). Patients with CNS involvement at initial RT diagnosis had numerically longer OS compared to patients who developed CNS involvement at RT progression (median OS 13.0 vs 4.1 months, P = 0.137; Figure 1B). Patients with isolated CNS involvement had better OS compared to patients with both CNS and systemic involvement (median OS 32.0 vs 5.3 months, P = 0.009; Figure 1C). Three of the 4 patients who only had isolated CNS involvement at the time of RT diagnosis have ongoing long term remission and survival (Figure 1A). Conclusions: In this large series of RT, approximately 1 in 14 patients had CNS involvement. Patients with isolated CNS involvement appeared to have favorable long term outcome; however, RT patients with both systemic and CNS involvement had extremely poor survival. The incidence, molecular characteristics, and optimal management of RT with CNS involvement in the novel agent era warrant future multicenter studies. Disclosures Wang: Incyte: Research Funding; Innocare: Research Funding; Novartis: Research Funding. Parikh:GlaxoSmithKline: Honoraria; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MorphoSys: Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria. Kay:Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Sunesis: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees. Witzig:AbbVie: Consultancy; MorphSys: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Incyte: Consultancy; Spectrum: Consultancy; Celgene: Consultancy, Research Funding; Acerta: Research Funding. Nowakowski:MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding. Ansell:Trillium: Research Funding; AI Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Takeda: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding. Kenderian:MorphoSys: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; BMS: Research Funding; Juno: Research Funding; Gilead: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Humanigen: Consultancy, Patents & Royalties, Research Funding; Lentigen: Research Funding; Mettaforge: Patents & Royalties. Ding:DTRM: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Research Funding.

Background: Anti CD-19 chimeric antigen receptor T-cell therapy (CAR-T) is approved to treat relapsed/refractory (R/R) aggressive NHL after 2 or more lines of therapy. Randomized clinical trials are ongoing comparing CAR-T and autologous stem cell transplant (ASCT) in second line. In standard of care practice, patients refractory to second line chemotherapy are sometimes treated with third line chemotherapy and taken to ASCT if disease is chemo-sensitive. Current study aims to evaluate the impact of prior lines of therapy on the efficacy of CAR-T and ASCT. Methods: A retrospective review of patients who received ASCT and/or axicabtagene ciloleucel (axi-cel) for R/R aggressive NHL from June 2016 - January 2020 at Mayo Clinic, Rochester was performed. The lymphoma types included in the study were DLBCL, transformed lymphoma (TFL), high grade B-cell lymphoma (HGBL), and primary mediastinal large B-cell lymphoma (PMBCL). Response to all lymphoma-directed therapy was evaluated using 2014 Lugano criteria. Overall survival (OS) was defined as time from CAR-T or ASCT infusion to death, and progression free survival (PFS) was defined as time from CAR-T or ASCT infusion to disease progression, or next treatment. Categorical data was analyzed as Chi-square or fishers exact test as appropriate. Continuous variables were analyzed using Wilcoxon Rank Sum test. Analysis was performed in R3.6.3. Results: A total of 105 patients underwent ASCT and 53 patients underwent CAR-T therapy in the study period with at least 6 months follow-up. Of the 105 ASCT patients, 87 received ASCT after 2 lines of chemotherapy, ASCT(2), and 18 received ASCT after 3 lines of chemotherapy, ASCT(3). Twenty six of the ASCT [n=19, ASCT(2) and n=7, ASCT(3)] patients received CART in subsequent therapy. Baseline characteristics were comparable between the two groups except ASCT(3) had higher percent of refractory disease after first line (table 1). With a median follow up of 17.4 months, the PFS was significantly longer for the ASCT(2) group with a trend toward longer OS (Figure 1; PFS @ 1 year: ASCT(2) 67%, 95%CI 58-79%; ASCT(3) 27%, 95%CI 27-74%; p = 0.036). Among the CAR-T recipients, only 18 (33%) patients received CAR-T in the earliest possible indication, CAR-T(2): after 2 lines of chemotherapy (n=12) and/or after ASCT(2) (n=6), table 1. Compared to patients who received CAR-T in later lines (CAR-T 3+), OS was significantly longer for patients who received CAR-T(2), with a trend toward longer PFS (Figure 1; OS @ 1 year: CAR-T (2) 82%, 95%CI 65-100%; CAR-T later lines 62%, 95%CI 47-82%; p = 0.05). Additionally, 12 (23%) of patients received CAR-T immediately after ASCT (9 after ASCT(2), 3 after ASCT(3)). Baseline demographics in these 12 patients, CAR-T(ASCT), were comparable to the others who had chemoimmunotherapy as the last salvage therapy prior to CAR-T [CAR-T(chemo)], except a smaller proportion received bridging therapy (33% vs. 73%, p = 0.01). The CAR-T (ASCT) group had significantly prolonged PFS (median PFS - not reached [95%CI 3-not reached (NR)] vs. 3 months [95% CI 3-4 months]), and OS (median OS - NR, [95%CI 10.34-NR] vs. 15.1 months, [95%CI 11.9 - NR], p = 0.03). Updated analysis will be presented at the meeting with longer follow up (Figure 1). Conclusion: CAR-T use at the earliest current approved indication may confer survival advantage. Referral for earlier use of CAR-T remains low at only one third of our CAR-T practice volume. CAR-T use for relapse immediately after ASCT appear to have longer PFS and OS than after other systemic salvage therapy, although contributing parameters such as the need for bridging therapy requires further study. While patients who are chemo-refractory to second line chemotherapy may demonstrate chemo sensitivity with third line chemotherapy, PFS is shorter for ASCT(3). Comparison between ASCT(3) and CAR-T (2, chemorefractory) require larger cohorts with longer follow-up. Disclosures Bennani: Affimed: Research Funding; Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding; Verastem: Other: Advisory Board. Ansell:Takeda: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding. Lin:Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding.

Introduction Day 15 absolute lymphocyte count (ALC-15) recovery after autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) is recognized as a prognostic factor for survival. ALC-15 recovery is directly dependent on the amount of collected and infused autograft-absolute lymphocyte count (A-ALC). Our group published a double-blind phase III study which showed that patients infused with an A-ALC ≥ 0.5 x 109 cells/kg experienced superior survival post-APBHSCT. Based on the results from our phase III study, on April 1, 2017, our Bone Marrow Transplant Program changed our standard clinical practice to collect an A-ALC ≥ 0.5 x 109 cells/kg in addition to stem cells for lymphoma patients undergoing APBHSCT. To continue to assess the prognostic ability of A-ALC, we evaluated the overall survival (OS) and progression-free survival (PFS) of diffuse large B-cell lymphoma (DLBCL) patients that underwent APBHSCT after April 1, 2017 compared with a matched-control group in a 1:1:1 ratio with DLBCL patients infused with an A-ALC < 0.5 x 109 cells/kg or an A-ALC ≥ 0.5 x 109 cells/kg prior to April 1, 2017. Methods Eight-five consecutive DLBCL patients after our practice changed on April 1, 2017 received an A-ALC ≥ 0.5 x 109 cells/kg. For each DLBCL patient infused with an A-ALC ≥ 0.5 x 109 cells/kg after April 1, 2017, the set of potential controls was restricted to those DLBCL patients infused with an A-ALC < 0.5 x 109 cells/kg and an A-ALC ≥ 0.5 x 109 cells/kg prior to April 1 2017 . Within this group of potential controls, the subjects were chosen who best matched for the cases in terms of clinical risk variables, including gender, age, stage, lactate dehydrogenase (LDH), performance status, extra-nodal disease, International prognostic index (IPI), and disease status prior to APBHSCT (complete or partial response), using the GREEDY algorithm. Cases were defined as DLBCL patients infused with an A-ALC ≥ 0.5 x 109 cells/kg starting from April 1 2017. Control 1 was defined as DLBCL patients infused with an A-ALC < 0.5 x 109 cells/kg prior to April 1 2017. Control 2 was defined as DLBCL patients infused with an A-ALC ≥ 0.5 x 109 cells/kg prior to April 1 2017. We truncated the survival follow-up to 3 years starting from the date of transplant to match follow-up time between cases and controls. Both matched cases and control groups patients received BEAM conditioning. This retrospective study was approved by the Mayo Clinic Institutional Review Board according to the regulation of the Declaration of Helsinki. Results Cases, control 1 and control 2 were balanced to the clinical risk variables; age (p = 0.8); gender (p = 0.9); LDH (p = 0.6); stage (p = 0.3); performance status (p = 0.5); extra-nodal disease (p = 0.2); IPI (p = 0.6); and clinical status prior to transplant (p = 0.2). Figure 1A showed the OS and figure 1B the PFS. Both the cases and control 2 showed superior OS and PFS in comparison to control 1. Cases and control 2 showed overall similar OS and PFS. Multivariate analysis including all patients continue to depict the A-ALC ≥ 0.5 x 109 cells/kg as an independent predictor for OS (HR = 0.382, 95%CI=0.241-0.605, p < 0.0001) and PFS (HR = 0.437, 95%CI = 0.279-0.629, p <0.0001). Subgroup analysis, including all patients, shows superior OS and PFS for patients infused with an A-ALC ≥ 0.5 x 109 cells/kg for each of the following clinical variables: age [> 60 years: OS (p <0.0001); PFS (p <0.0001) or ≤ 60 years: OS (p <0.01); PFS (p , 0.02)]; extra-nodal disease [> 1: OS (p <0.008); PFS (p <0.01) or ≤1: OS (p < 0.001): PFS (p <0.0005)]; IPI [> 2: OS (p <0.01); PFS (p <0.02) or ≤ 2: OS (p <0.0008); PFS (p <0.0006)]; LDH [abnormal: OS (p <0.006); PFS (p <0.005) or normal: OS (p <0.002); PFS (p <0.002)]; performance status [> 1: OS (p <0.04); PFS (p <0.03) or ≤ 1: OS (p <0.0001); PFS (p <0.0001)]; stage [I/II: OS (p <0.006); PFS (p <0.006) or III/IV: OS (p <0.002); PFS (p <0.001)]; response prior to transplant [complete response: OS (p <0.0007); PFS (p <0.0001) or partial response: OS (p <0.01); PFS (p <0.02)]. Conclusion Our match-control study continues to support the results of our Phase III study showing that the infusion of A-ALC is a prognostic factor for survival of DLBCL patients undergoing APBHSCT. Our studies support the practice of not only collecting enough stem cells (i.e., CD34) for hematologic engraftment, but also enough immune effector cells (i.e., A-ALC) to improve clinical outcomes in DLBCL patients post-APBHSCT. Figure 1 Disclosures Ansell: Regeneron: Research Funding; Bristol Myers Squibb: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding.

Magnesium is an essential element that is involved in the regulation of cell growth, division and differentiation. Epidemiologic studies have demonstrated that a diet poor in magnesium is associated with an increased risk of developing cancer. There are few studies investigating whether magnesium deficiency is associated with a poor prognosis in lymphomas. The recent discovery of X-linked immunodeficiency with magnesium defect, Epstein-Barr virus, and neoplasia (XMEN) disease, suggests a role of magnesium in the development of hematologic malignancies and lymphocyte function. Furthermore, a recently published study found that hypomagnesemia prior to chemotherapy is associated with inferior overall survival (OS) in patients with Burkitt Lymphoma. We hypothesized that low magnesium levels prior to autologous hematopoietic stem cell transplant (AHSCT) may lead to inferior outcomes via impaired lymphocyte recovery. We evaluated whether low serum magnesium levels were associated with inferior survival in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who underwent autologous hematopoietic stem cell transplant (AHSCT) between January 1998 and May 2020 using a retrospective study design. We cross-referenced our search with patients who had a magnesium level as part of their pre-transplant workup between 7 and 28 days prior to their first transplant. Two-sided Wilcoxon rank sum test and Chi square/Fischer's exact test were used to compare the continuous and categorical variables, respectively. Kaplan-Meier and log-rank tests were used to perform all time to event analysis. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards. Our study included 581 patients of which 82 (14.1%) had hypomagnesemia (magnesium < 1.7 mg/dL) prior to AHSCT. Our study found that hypomagnesemia was associated with inferior OS and event-free survival (EFS) defined as re-transplant, relapse or death, compared to those with a normal magnesium level; median OS: 7.3 years (95% CI: 2.91 - upper limit not estimable) versus 9.7 years (95% CI: 6.92 - 12.3 years), p=0.0041; and median EFS: 3.9 years (95% CI: 1.63 - 8.98 years) versus 6.29 years (95% CI: 4.73 - 8.95 years), p = 0.016 respectively(B). Higher serum magnesium (HR 0.199 per doubling, 95% CI 0.078 - 0.503; p<0.001) and higher albumin (HR 0.090 per doubling, 95% CI 0.021 - 0.394; p=0.001) were associated with lower mortality rates, and higher creatinine (HR 1.669 per doubling, 95% CI 1.03 - 2.52; p=0.04) was associated with greater mortality up to 1 year post-transplantation. In a multivariate Cox regression excluding albumin, hypomagnesemia (p < 0.001) and elevated creatinine (p = 0.038) were independent predictors of poor overall survival(A). There was no significant difference between day 15 absolute lymphocyte count between patients with normal magnesium levels and low serum magnesium levels prior to their conditioning regimen. Although we hypothesized that we would find a significant difference between 15 day absolute lymphocyte count recovery and hypomagnesemia, this was not apparent. However, magnesium is an important nutrient for immune function and immune recovery is important after the bone marrow is restored post ablative therapy. Thus, low serum magnesium levels may lead to impaired OS and EFS via impaired lymphocyte function. In vitro studies will be necessary to understand this mechanism further. Magnesium may simply be a marker of illness and replacement of magnesium may not improve outcomes. However, further investigations are needed to determine whether outcomes would improve with replacement of magnesium in patients with hypomagnesemia, which our study did not address. Overall, our preliminary data suggests that hypomagnesemia is an independent prognostic factor and predictor of inferior OS and EFS in this cohort of patients. Figure Disclosures Ansell: ADC Therapeutics:Research Funding;AI Therapeutics:Research Funding;Trillium:Research Funding;Affimed:Research Funding;Regeneron:Research Funding;Seattle Genetics:Research Funding;Bristol Myers Squibb:Research Funding;Takeda:Research Funding.Witzig:Spectrum:Consultancy;Celgene:Consultancy, Research Funding;Immune Design:Research Funding;Karyopharm Therapeutics:Research Funding;Acerta:Research Funding;Incyte:Consultancy;AbbVie:Consultancy;MorphSys:Consultancy.

Introduction: Transformation of low grade follicular lymphoma (FL) to diffuse large B cell lymphoma (DLBCL) carries a poor prognosis. In retrospective studies, 5-year survival of transformed DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) without autologous stem cell transplant is 40-60%, underscoring need to improve frontline treatment of transformed DLBCL beyond R-CHOP. The overall response rate (ORR) to lenalidomide used as a single agent for relapsed transformed non Hodgkin lymphoma was 45% with 21% complete response (CR) rate and a median duration of response of 12 months (Witzig et al, Ann Onc 2011). These data provided the rationale to include patients with transformed DLBCL (with historical and concurrent FL) in MC078E, a phase II clinical trial testing lenalidomide plus R-CHOP (R2CHOP) for patients with new and untreated de novo and transformed DLBCL (NCT00670358). Here we present analysis of the subset of transformed DLBCL patients. Methods: Adult patients with transformed DLBCL and either historical or concurrent FL, stage >=2, measurable disease by Positron Emission Tomography/computed tomography (PET/CT) and adequate organ function were included. Patients with Central Nervous System (CNS) involvement, significant comorbidities, active non-lymphomatous malignancy, life-threatening thromboembolism (TE) and contraindication to aspirin prophylaxis were excluded. Study participants received up to 6 cycles of rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg /m2) on day 1, prednisone (100 mg) on day 1-5, pegfilgrastim on day 2, and Lenalidomide 25 mg day 1-10 of 21 day cycle. Tumor lysis prophylaxis was per local practice; patients also received TE prophylaxis with aspirin. Primary outcome was event free survival (EFS) at 12 months, where an event was defined as death, progression or subsequent anti-lymphoma therapy. Secondary outcomes included ORR, CR, progression free survival (PFS), and overall survival (OS). Response was evaluated by PET/CT after cycle 2 and cycle 6 with revised response criteria (Cheson et al, 2007). Adverse events were recorded according to CTCAE version 3.0. The Kaplan-Meier method was used to estimate time to event endpoints. Results: Thirty-nine patients were accrued from August 5, 2013 to July 28, 2020 and 33 were eligible by central pathology review. Median age was 64 (range 24-80) years and 18 (54%) were >60 years old. Eighteen (54%) were male, and 32 (97%) had ECOG performance status <2. Twenty-three (70%) had historical FL and 10 (30%) had concurrent FL. Twenty-six (79%) had advanced stage (III-IV). Median number of extra nodal sites were 1 (0-4). Thirteen (39%) had high international prognostic index (IPI) (4-5). Thirty-two (97%) completed at least 2 cycles (30 completed all 6 cycles) and were evaluable for response. ORR was 97% (32/33), 29 (88%) had CR and 3 had PR. EFS at 12 months was 87.9% (95% CI: 71.8, 96.6). Two-year PFS and OS were 84.5% (95% CI: 72.8%-98%) and 96.9% (95% CI: 91-100%) (Figure 1). Twenty nine completed study protocol, 4 discontinued protocol early for disease progression (1), adverse event (AE) (1), refusal (1) and noncompliance (1). Thirty (91%) had hematologic AE of grade 3 or above, 27 (82%) had neutropenia, 16 (48%) had thrombocytopenia, and 7 (21%) had anemia. Sixteen (48%) had grade 3 or above non-hematologic AE. Eight (24%) had febrile neutropenia. There were 3 deaths on this study, 1 due to progressive DLBCL, 1 due to AML and 1 due to malignant melanoma. Conclusion: R2CHOP appears effective in transformed DLBCL with high response rates, event free, progression free and overall survival seen in current study. This study supports the inclusion of anthracycline naive patients with transformed DLBCL in future randomized studies of lenalidomide or other novel immunomodulatory (IMiD) analogues. Disclosures Wang: Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Nowakowski:Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Kymera: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; NanoString: Research Funding.

Introduction The molecular basis for the clinical heterogeneity observed in DLBCL was initially elucidated with gene expression profiling, identifying three distinct subgroups with prognostic relevance based on COO namely activated B-cell like (ABC), germinal center B-cell like (GCB) and a type 3 subtype. Shortly afterwards the Han's algorithm was developed allowing for widespread applicability and correlation of gene expression with protein expression. GCB profile at diagnosis is generally associated with superior long term outcomes compared to non-GCB in patients treated with conventional chemo-immunotherapy. Patients with relapsed/refractory disease (R/R) after front-line therapy undergo salvage treatment and, upon demonstration of objective response, proceed with high dose therapy and autologous transplantation (auto-HCT). Whether COO by Han's algorithm retains its prognostic significance post auto-HCT in patients with R/R DLBCL is not well established. Methods A retrospective analysis was carried out using the Mayo database across all three sites. It included all patients between 18-75 years of age who were diagnosed with de-novo DLBCL and underwent first auto-HCT for R/R disease. Patients must have received salvage treatment and shown chemotherapy sensitive disease. Patients with transformed DLBCL or other variants and those who underwent auto-HCT in first complete remission for high risk disease were excluded. Patients who had less than a partial response at time of transplantation and still underwent auto-HCT were also excluded. Primary endpoints included overall survival (OS); relapse and relapse-free survival (RFS). Continuous variables were summarized as mean (standard deviation) and median (range). Categorical variables were reported as frequency (percentage). Continuous baseline variables were compared between GCB and non-GCB using Wilcoxon rank sum test and categorical baseline variables were compared with Chi-squared test. Kaplan-Meier method was used to estimate 5 and 10-year rates of freedom from long-term events and draw corresponding survival curves. Multivariate Cox regression models were used to evaluate the impact of cell of origin on long-term survival after adjusting for baseline factors. All tests were two-sided with alpha level set at 0.05 for statistical significance. Results A total of 357 patients underwent auto-HCT between 2005 and 2018. Cell of origin was determined for 284 patients and these were included in the analysis. Median age was 61 (range: 19-78) years, and 64% patients were male. GCB and non-GCB patients did not differ significantly with regards to baseline factors (Table 1). During a median follow up of 1.7 years, 139 patients died, 151 had relapse and 175 either died or had relapse. Five year OS for GCB patients versus (vs) non-GCB was at 44% vs 64% (p=0.004) (Figure 1); relapse was at 67% vs 49% (p=0.012) and RFS was at 28% vs 50% (p=0.003). The difference between GCB and non-GCB groups remained statistically significant in multivariate analysis, with GCB patients 60% more likely to die and 50% more likely to experience relapse compared to non-GCB patients. The only other factor that retained significance in multivariate analysis for both endpoints was response at the time of transplant (Table 2A-C). Conclusions In this analysis, GCB DLBCL results in worse OS and higher relapse vs. non-GCB DLBCL following an auto-HCT. It is unclear if relapse/progression of GCB subtype after front-line therapy alters its natural history into a more aggressive disease. Disclosures Ansell: Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; Bristol Myers Squibb: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding. Foran:Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy; H3Biosciences: Research Funding; Agios: Honoraria, Research Funding. Tun:Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding; Bristol-Myers Squibb: Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

AbstractTransplant‐associated thrombotic microangiopathy (TA‐TMA) has a wide range of presentations after hematopoietic stem‐cell transplantation (HSCT). We retrospectively studied the risk factors and outcomes of patients with early (≤day 100) and late (>day 100) TA‐TMA. Among the 1451 HSCT recipients, early TA‐TMA occurred in 45 (3.1%) patients at a median of 27 (3‐91) days, and late TA‐TMA in 39 (2.7%) patients at a median of 303 (122‐2595) days. Patients with early TA‐TMA were more likely to have high blood calcineurin‐inhibitor levels (P < .001) and acute graph‐vs‐host disease (GVHD, P < .001), while late TMA patients were more likely to have chronic GVHD (P < .001). The estimated median overall survival after onset of TMA for the entire cohort was 6 months. The estimated median overall survival was not reached in patients with an improvement of TMA vs 2 months in patients with no improvement (P < .001). In the early TMA group, older age (for every 10 years, HR 1.40; 95% CI 1.00‐1.94; P = .049) and bacterial infection (HR 2.42; 95% CI 0.98‐6.00; P = .056) were positively associated with mortality. Switching to MMF treatment (HR 0.40; 95% CI 0.16‐0.99; P = .047) and improvement of TMA (HR 0.08; 95% CI 0.03‐0.25; P < .001) were negatively associated with mortality in the multivariate analysis. In the late TMA group, the improvement of TMA was the only independent predictor associated with a lower risk of death (HR 0.05; 95% CI 0.02‐0.19; P < .001). Mortality rates in both early and late TMA remain unacceptably high. Future studies are needed for early diagnosis, trigger identifications, and use of targeted treatments.

3028 Background: Chimeric antigen receptor T-cell (CAR-T) therapy induces complete remission (CR) in 30-40% of patients with non-Hodgkin lymphoma (NHL). However, for patients who do not achieve CR as their first response, predictors for achieving CR as best response can guide management between careful observation or early intervention. Increased absolute lymphocyte count to absolute monocyte count ratio (ALC/AMC) predicts better response rates and survival in NHL patients receiving chemotherapy and/or autologous stem cell transplant. We evaluated the prognostic impact of ALC/AMC in CAR-T therapy for NHL. Methods: This was a retrospective review of patients who received CAR-T for NHL from June 2016-August 2019. ALC/AMC was assessed at the start of lymphodepletion (LD) chemotherapy. The receiver operator curve (ROC) was used to determine the best cutoff for ALC/AMC in predicting CR at 3 months. Event-free survival (EFS) was defined from time of CAR-T infusion to relapse or death, whichever occurred first. Overall survival (OS) was defined from time of infusion to death of any cause. Results: Forty-seven patients received axicabtagene ciloleucel, with a median follow-up of 14 months. By ROC, ALC/AMC > 0.8 before LD chemotherapy was predictive of achieving CR at 3 months. Baseline characteristics were similar between the high (n = 30) and low (n = 17) ALC/AMC groups. Patients with an ALC/AMC > 0.8 at the time of LD chemotherapy were more likely to achieve CR at 3 months (46% vs. 12%, p = 0.01), 6 months (52% vs. 0%, p < 0.0005), and 12 months (42% vs. 0%, p = 0.01). Correspondingly, the EFS and OS were significantly shorter in patients with ALC/AMC≤0.8 vs. those > 0.8 (median EFS: 2 vs. 13 months, P < 0.0001) and (median OS: 15 months vs. not reached, P = 0.03), respectively. Association between ALC/AMC ratio and EFS and OS remained consistent in multivariate Cox models after adjusting for other prognostic variables, including abnormal lactate dehydrogenase and increased ferritin level at infusion day. Conclusions: ALC/AMC > 0.8 before lymphodepletion chemotherapy is a strong predictor for complete remission as well as improved event-free and overall survival for axicabtagene ciloleucel in NHL.

Abstract Introduction: The immunoglobulin free light chain (FLC) is the precursor protein of amyloid in primary systemic amyloidosis (AL). Historically, the ability to monitor the amyloid protein precursor has been crude. There is now a test that reproducibly measures serum levels of FLC. We evaluated the utility of this assay in patients with AL undergoing peripheral blood stem cell transplant (PBSCT). Methods: Between March 1, 1996 and July 31, 2004, 98 patients with AL undergoing PBSCT had serial FLC measurements performed either prospectively or on stored sera. Patients who died before their 100 day evaluation were excluded because response could not be estimated. FLC levels were performed using Freelite™ reagents on a Dade-Behring Nephelometer. In order to pool the data of the monoclonal kappa and lambda patients, the clonal free light chain was considered the involved] immunoglobulin free light chain for the purpose of these analyses and is henceforth referred to as FLC. The prognostic effects of the initial concentration and the extent of reduction of monoclonal FLC on survival were evaluated. Results: Pre-transplant, 94% of patients had an abnormal FLC ratio, with a median involved FLC of 152 mg/L [15.2 mg/dL]. Only 14% of 98 patients had a “measurable” serum M-spike (i.e. ≥ 10 g/L [1 g/dL]) on electrophoresis with a median of 1 g/L [0.1 g/dL]. Ten patients have died of their disease during a median follow-up time of 19.5 months, range 3.3 to 103 months. The 2- year and 4-year estimated survivals are 92% and 76%, respectively. Using the 75th percentile value of pre-PBSCT FLC (382 mg/L [38.2 g/dL]) as a grouping variable, there was a significantly higher risk of death 5.4 (95% confidence interval 1.5–19.3) in the patient quartile with the highest baseline FLC. Baseline FLC correlated with serum cardiac troponin T levels (rho 0.51, p&lt;0.0001), suggesting that high FLC levels are associated with more advanced disease. After PBSCT, the median percent reduction of FLC was 81%. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. The hazard ratio for death for not achieving a post-transplant FLC of 20 mg/L [2 mg/dL] post-transplant was 5.1 (95% confidence interval 1.1–24.1). Of 91 patients evaluable for complete response by EBMT criteria, 45 had a complete hematological response. Sixty-five percent of the patients achieving a FLC level of less than 20 mg/L [2 mg/dL] also had a complete hematologic response. Free light chain response as defined by a post transplant FLC level 20mg/L [2 mg/dL] or lower was a more powerful predictor of survival than complete hematologic response, as defined by the EBMT multiple myeloma criteria. Post-PBSCT FLC level only weakly predicted for organ response, but median follow-up for surviving patients is relatively short at 19.6 months. Conclusion: FLC measurements both pre- and post-PBSCT are important predictors of patient outcome.

Abstract Introduction: The association of amyloidosis with immunoglobulin light chain disorders is well recognized. It is less commonly appreciated that amyloidosis can be associated with IgM monoclonal gammopathies. One of the available therapies for treating amyloidosis is stem cell transplantation. It is unknown whether the clinical outcomes in patients with IgM amyloidosis differs from those patients with light chain amyloidosis. Patients: Among 242 amyloidosis patients receiving stem cell transplants 10 (4%) had an IgM monoclonal protein. Eight were Mλ. One was biclonal Mλ Mκ and one was biclonal Mκ Gλ. The age range was 56 to 71, median 64 years. Seven were men. The monoclonal protein ranged in size from 0.1 to 2.3 g/dL (median 1.2 g/dL). Patients were transplanted from 2 to 8 months (median 4 months) following histologic diagnosis of amyloid. The median time from the recognition of the IgM monoclonal protein to the diagnosis of amyloid was 1.3 months, but 2 patients, both of whom had overt Waldenström’s macroglobulinemia, were diagnosed 45 and 115 months respectively before amyloidosis developed. Of the cohort of 10, 3 fulfilled the criteria for symptomatic Waldenström’s macroglobulinemia. Results: Amyloid syndromes were recognized in the kidney, heart, peripheral nerve and liver in 8, 3, 3 and 1 patient, respectively. Of the 3 peripheral neuropathy patients one also had autonomic failure. Seven of the 8 renal amyloid patients were confirmed with a renal biopsy. Their urinary protein loss ranged from 0.1 to 9.5 g/24h with a median of 4.7 g/24h. Six of the 10 patients had single organ involvement, 3 had 2 organ involvement and 1 had 3 organ involvement. All 3 Waldenström’s patients had prior exposure to cytotoxic chemotherapy. Amyloid deposits were seen in the bone marrow, fat and lymph node in 6, 5 and 1 patient, respectively. Patients underwent from 1 to 7 (median 3) apheresis with a median CD34 yield of 4.5 x 106/kg. Conditioning was Melphalan at 140 and 200 mg/m2 in 2 and 8 patients respectively. Neutrophil engraftment 500/μL occurred between day 11 and 30 (median 14) and for platelets 20,000/μL between day 11 and 406 (median day 16). The median number of hospitalization days ranged from 0 to 32 (median 12). Nine of the 10 patients fulfilled criteria for a hematologic response and to date 3 of these 9 have also achieved an organ response, including normalization of urinary protein loss in 2 nephrotic patients and a greater than 50% reduction in urinary protein loss in the third. None of the patients with amyloid neuropathy responded. One of the patients with cardiac amyloid showed echocardiographic evidence of improvement. At this time 8 survive and 2 died; 1 a treatment-related death (day +40) and 1 of relapse post transplant with progressive amyloid at 45 months. The median follow-up of surviving patients is 29 months. Conclusion: The outcomes in patients with IgM amyloidosis following transplantation do not appear to be different from those with immunoglobulin light chain amyloidosis. There is no suggestion that the response rates are lower or that alternate conditioning schemes such as BEAM should be considered.