ALBERT

Description: Background: Autologous stem cell transplantation (ASCT) is a curative therapy for a significant proportion of patients with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL). We previously developed a conditioning regimen for R/R cHL patients undergoing ASCT incorporating gemcitabine and vinorelbine (GN-BVC), which enabled a reduction in the BCNU dose and toxicity without compromising efficacy (BBMT 2010;16:1145-54). Since this publication, several novel agents have been approved for treatment of R/R cHL including brentuximab vedotin (BV) and the immune checkpoint inhibitors (ICIs), which may be changing outcomes and toxicities following ASCT. We sought to determine whether post-ASCT outcomes have improved for R/R cHL in the era of novel agents, and to evaluate how BV and the ICIs have impacted toxicities after ASCT in a large cohort of patients treated with the same conditioning regimen. Methods: We conducted a single-center, retrospective analysis of outcomes for a large cohort of patients with R/R cHL who underwent ASCT using GN-BVC conditioning at Stanford University from 2001-2017 (n=268). We divided the cohort into two treatment eras: Era A: 2001-2009 (n=137) and Era B (increasing use of novel agents): 2010-2017 (n=131). We used Kaplan-Meier and Cox models to compare overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) between treatment eras. We also compared outcomes between patients who underwent ASCT in complete remission (CR, n=126) or with a partial response (PR, n=142). For patients treated in era B, we compared outcomes and toxicity profiles for patients treated with standard platinum-based salvage regimens (n=102) to those who received BV-based salvage regimens prior to ASCT (n=29). Results: Patients who underwent ASCT in era B had improved OS compared to those transplanted in era A (4-year OS: 87.8% vs 77.9%, HR 0.51, 95% CI 0.28-0.91, p=0.022), but PFS did not differ significantly between treatment eras (4-year PFS: 70.2% vs 62.7%, HR 0.78, 95% CI 0.52-1.2, p=0.24, Figure 1). For patients who relapsed after ASCT, PPS was significantly higher for those transplanted in era B compared to era A (84.7% vs 62.8% at 2 years, HR 0.47, 95% CI 0.23-0.98, p=0.045). Overall, patients who underwent ASCT in CR compared to those with a PR had significantly improved OS (88.3% vs 78.3% at 4 years, HR 0.50, 95% CI 0.29-0.88, p=0.016) and PFS (78.4% vs 55.1% at 4 years, HR 0.44, 95% CI 0.28-0.67, p=0.00016). Among patients who relapsed, those in era B who received novel agents (BV and/or an ICI) at any point in treatment exhibited higher OS compared to historical controls in era A (4-year OS: 72.2% vs 53.1%) but were statistically different only at the p=0.083 level which is above the p=0.05 significance threshold. Of the patients who underwent ASCT in era B (n=131), 102 (78%) received standard platinum-based salvage regimens (e.g. ICE or DHAP) and 29 (22%) received BV-based salvage regimens prior to ASCT, including 11 patients (8%) who received both BV and an ICI pre-ASCT. Outcomes were excellent for patients who received BV-based salvage regimens pre-ASCT (4-year OS 97% and PFS 76%) but were not statistically different compared to patients who received platinum-based regimens (4-year OS 86% and PFS 69%; p=0.56 and p=0.76, respectively). Pneumonitis requiring corticosteroids occurred in 8% of patients treated in era B, including 10% of patients receiving BV-based salvage regimens pre-ASCT and 7% of patients receiving standard platinum-based regimens. One patient who received BV and nivolumab pre-ASCT died from grade 5 pneumonitis. Conclusions: In this cohort of R/R cHL patients who underwent ASCT using the same conditioning regimen, OS was significantly higher for patients transplanted within the past decade. A potential survival benefit was observed among patients who relapsed post-ASCT, likely reflecting the more widespread use of BV and ICIs in the post-ASCT setting. Patients who received BV-based salvage regimens pre-ASCT had excellent outcomes without an apparent increase in toxicity, but the small number of patients limits comparisons to standard platinum-based regimens. Further studies are needed to better define the optimal sequencing of novel agents and ASCT in the treatment of R/R cHL in the modern era. Figure 1 Disclosures Sica: Physician's Education Resources (PER): Honoraria. Advani:Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Regeneron: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Agensys: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Merck: Research Funding; Infinity Pharma: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Forty-Seven: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Miklos:AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Pfizer: Consultancy; Adaptive: Research Funding; KITE: Consultancy. Rezvani:Kaleido: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; Nohla Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; AbbVie: Other: Principal investigator ; U.S. Department of Justice: Other: Expert medical witness; Johnson & Johnson: Employment, Other: Brother is employed. Shizuru:Forty Seven Inc: Equity Ownership, Patents & Royalties.

Description: Relapse of acute myeloid leukemia (AML) following myeloablative allogeneic stem cell transplantation portends a dismal prognosis. Therapy aimed at enhancing graft-versus-leukemia (GVL) effect, e.g., by donor leukocyte infusion, has limited success in AML, and a second ablative transplant is associated with prohibitive mortality in adults. From April 2001 to March 2006, nine patients, ranging in age from 21 to 57, with high risk myeloid malignancy (7 AML and 2 advanced myelodysplasia) and overt bone marrow relapse less than one year after ablative busulfan/cyclophosphamide conditioning have been treated with a cytoreductive regimen of fludarabine (30 mg/m2/day) and cytarabine (2g/m2/day) for 5 days (-7 through -3) and G-CSF administration (5 ug/kg daily starting day -8) with or without idarubicin (8 mg/m2 days -7, -5, and -3) (8 cases) or fludarabine 30 mg/m2 for 3 days and 200 cGy total body irradiation (1 case). G-CSF mobilized peripheral blood stem cells from their original HLA-matched donor (8 siblings, 1 unrelated) were infused. Graft versus host disease (GVHD) prophylaxis was mycophenolate mofetil for 30 days and cyclosporine with a rapid taper. The mean onset of relapse after the initial ablative transplant was day 172 (range 106–271). Fludarabine-based therapy was well tolerated with no treatment related mortality. Full donor chimerism was established by day 72 (range 26–113) in 6 patients (67%). Five patients died: 2 from relapse without GVHD at day +30 and +301 after RIST (one patient with complex and one with Ph+ cytogenetic abnormalities), 3 from relapse with evidence of GVHD. Four patients survive: one has relapsed at 91 days after RIST and is receiving alternate therapy, while three patients (30%) survive in complete remission at 100+, 635+ and 1795+ days after salvage RIST. In 5 cases (56%), the duration of complete remission after RIST was longer than after the initial ablative transplant. We conclude that fludarabine-based RIST is a safe and effective salvage therapy offering a chance for increased survival with low morbidity in patients relapsing after ablative transplant. In addition, RIST therapy has resulted in long-term disease free survival in over 20% of cases in this study.

Description: Adult T cell leukemia / lymphoma is a rare neoplasm with dismal cure rates and poor response to chemotherapy. The genetic basis of refractoriness against conventional agents is not known. We follow one of the largest cohorts of ATLL in the US and recently showed that North American ATLL (NA-ATLL) has a distinct mutational profile from Japanese ATLL (J-ATLL) with a higher incidence of epigenetic mutations (Shah et al, Blood, 2018; 132(14):1507-1518). Here, we analyze the mutational landscape of ATLL clones at diagnosis and at relapse in a pilot study of 7 NA-ATLL patients using deep targeted sequencing of 236 recurrently mutated genes. Our goal was to examine clonal evolution patterns that may result as a consequence of the selective pressure of chemotherapy by determining changes in mutational profiles as well as clonal abundance on patients with aggressive ATLL [acute and lymphomatous] (Table 1). All patients were treated with EPOCH (Etoposide, Prednisone, Vincristine, Cyclophosphamide and Doxorubicin) chemotherapy after initial diagnosis except one patient who received interferon therapy. Distinct patterns of clonal evolution were observed in patients with primary refractory disease when compared to those who relapsed after an initial remission. Group 1 has 3 cases (Pts 1 to 3), all of which experienced early relapse and showed mutation patterns suggestive of clonal replacement by a new emerging clone at relapse. Group 2 has 3 patients (Pts 4-6) that are characterized by worsening of primary refractory disease. Mutation patterns in the before-and-after sample pairs suggest linear progression from a previously existing clone during therapy. The clonal evolution status was not resolved in our third group (Pt#7) indicating that mutations outside the 236 genes evaluated might have been present. Frequent epigenetic mutations were found in both diagnostic and refractory/relapsed samples. Surprisingly, 4 epigenetic mutations (KMT2D, EP300, SPEN, SETBP1) identified in 4 cases were confirmed or suspected of germline origin. This suggests that ancestral genomic differences between the Caribbean and Japanese populations could contribute to the mutational and clinical disparities between NA- and J-ATLL. Multiple mutations with similar variant allele frequencies (VAF) at the time of relapse were identified, suggesting simultaneous acquisition of several mutations during clonal evolution. Clonal replacement by an emerging clone (Group 1) such as GATA3 (Pt#3) or KMT2D (Pt#1) (either germline or founding mutation) was observed in patients who achieved an initial response. On the other hand, in primary refractory disease (Group 2), relapse was driven by dominant TBL1XR1 mutations in 2 out of the 3 cases either alone (Pt#6) or in combination with mutated SMARCB1 (Pt#5). The protein encoded by TBL1XR1 is a negative regulator of the nuclear receptor corepressor (NCoR) /histone deacetylase 3 (HDAC3) complex. Therefore, TBL1XR1 inactivation is expected to result in hyper-activity of NCoR/HDAC3, an epigenetic abnormality targetable by HDAC inhibitors. SMARCB1 is also an epigenetic regulator associated with several malignancies and has been targeted with alisertib. A subclonal expansion of EP300 (a histone acetyltransferase) appears to drive relapse in the other case of this group (Pt#4). Therefore, our primary refractory cases show that epigenetic mutations seem to be of utmost importance not only at diagnosis as we have previously shown, but as the driving force behind chemotherapy refractoriness and subsequent relapse. Conclusion: To our knowledge, this is the first mutation-based clonal evolution study aimed to examine dynamic changes induced by chemotherapy among NA-ATLL patients. Early relapse appears to be driven by the emergence of new mutant clones. On the other hand, primary refractory disease appears to have epigenetic drivers that convey chemotherapy refractoriness and evolve from linear progression of a previously existing clone. Serial mutational testing can provide critical information on clonal architecture and identify actionable molecular vulnerabilities in a cohort without effective therapeutic options and a dismal prognosis. Disclosures Sica: Physician's Education Resource (PER): Honoraria. Shah:Physicians' Education Resource: Honoraria. Steidl:Aileron Therapeutics: Consultancy, Research Funding; Stelexis Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Co-Founder; Pieries Pharmaceuticals: Consultancy; BayerHealthcare: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Consultancy. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding.

Description: Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy with a dismal prognosis, caused by HTLV-1. Although our previous study, mainly using whole-exome sequencing and SNP array karyotyping, discovered many driver mutations and copy number alterations (CNAs), the whole-genome landscape of ATL still remains elusive. To this end, we have performed high-depth whole-genome sequencing (WGS) of 155 ATL cases with a median sequencing depth of 96-fold for tumors. Among them, 75 cases were also analyzed by RNA sequencing (RNA-seq). In total, we detected 1,952,490 single nucleotide variants (SNVs) and 159,141 insertion-deletions (4.0 SNVs and 0.3 indels/Mb/case), 10,279 SVs (66.3 SVs/case), and 3,975 CN altered segments (25.7 segments/case). Using several driver discovery algorithms (dNdScv, MutSig2CV, and DriverPower), we identified 47 significantly mutated genes, 19 of which were mutated in more than 10% of cases. These included several novel mutations, such as those affecting XPO1 (7.1%), ZNF292 (6.5%), and ITGB1 (5.2%). Using GISTIC2.0, we identified 13 significant CNAs, such as IRF4 amplifications and CDKN2A deletions, consistent with previous SNP array data. To detect significantly recurrent SVs, we calculated SV breakpoint frequency and identified 13 genes affected by SVs, including the previously identified genes (such as CARD11, CD274, and TP73). In addition, we investigated recurrent mutations in non-coding elements by DriverPower and LARVA and discovered 12 recurrently mutated elements. Among them, the most frequent were splice site mutations, including those of HLA-A and HLA-B, most of which caused loss of function as revealed by RNA-seq. By contrast, we found recurrent mutations in TP73 splice site, which induced skipping of exons 2 and 3, generating a dominant-negative variant similar to their SVs. In addition, recurrent non-coding elements contained several novel regions, such as 3´-untranslated region (UTR) of NFKBIZ and 5´- UTR of TMSB4X. Altogether, a total of 56 genes were recurrently altered. The median number of driver alterations was eight per case, and at least one driver alteration was found in 149 cases (96.1%). Among 56 driver genes, 40 (71.4%) genes were affected by more than one alteration class. Some drivers, such as CDKN2A, IKZF2, and CD274, were affected almost exclusively by CNAs and/or SVs, while showing quite high alteration frequencies (11.6-29.0%). These observations suggest that WGS presented a substantially different overview of driver alterations from our previous study. The overall numbers of mutations and SVs were linked to these driver alterations, suggesting their etiology. In particular, inactivation of EP300 and immune-related molecules, such as HLA-A, HLA-B, and CD58, were associated with an increased number of mutations and SVs, especially deletions and tandem duplications. By contrast, cases with TP53-altered cases harbored more inversions and translocations. These results emphasize a pivotal role of immune evasion for acquiring genetic alterations to drive ATL progression. To define molecular subgroups in ATL, we integrated the 56 identified genetic drivers using non-negative matrix factorization clustering and identified two robust subgroups with discrete clinical and genetic characteristics. Group 1 was enriched with alterations affecting distal components of T-cell receptor (TCR)/NF-κB signaling (such as CARD11, PRKCB, and IRF4) and immune-related molecules (HLA-A, HLA-B, and CD58), whereas proximal regulators of TCR/NF-κB signaling (PLCG1, VAV1, and CD28) and a JAK/STAT signaling molecule (STAT3) were more frequently altered in group 2. In addition, group 1 cases had a larger number of mutations, SVs, and CNAs than group 2 cases. Clinically, most cases with lymphoma subtype were classified into group 1, whereas group 2 mainly consisted of cases with leukemic subtypes. Moreover, group1 cases showed a worse overall survival than group 2, independently of clinical subtype. These results suggest the biological and clinical relevance of the molecular classification of ATL. In summary, our WGS analysis not only identifies novel somatic alterations but also extends the overview of ATL genome. We also propose a new molecular classification of ATL, with its clinical relevance, which can lead to the future improvement of patient management. Disclosures Kogure: Takeda Pharmaceutical Company Limited.: Honoraria. Nosaka:Kyowa Kirin Co.Ltd: Honoraria; Chugai pharmaceutical Co. Ltd: Honoraria; Novartis international AG: Honoraria; Celgene K.K: Honoraria; Eisai Co., Ltd: Honoraria; Merck Sharp & Dohme K.K.: Honoraria; Bristol-Myer Squibb: Honoraria. Imaizumi:Kyowa Kirin Co. Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Eisai: Honoraria. Utsunomiya:Kyowa Kirin: Honoraria; Celgene: Honoraria. Shah:Celgene: Research Funding; BMS: Research Funding; Physicians Education Resource: Honoraria. Janakiram:Takeda, Fate, Nektar: Research Funding. Ramos:NIH: Research Funding. Takaori-Kondo:Astellas Pharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Thyas Co. Ltd.: Research Funding; Takeda: Research Funding; CHUGAI: Research Funding; Eisai: Research Funding; Nippon Shinyaku: Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; OHARA Pharmaceutical: Research Funding; Sanofi: Research Funding; Novartis Pharma: Honoraria; MSD: Honoraria. Miyazaki:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Novartis Pharma KK: Honoraria; Astellas Pharma Inc.: Honoraria. Matsuoka:Chugai Pharmaceutical Co. Ltd: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Kirin Co. Ltd.: Research Funding. Ishitsuka:Takeda: Other: Personal fees, Research Funding; mundiharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other, Research Funding; Genzyme: Other; Sumitomo Dainippon Pharma: Other, Research Funding; Eisai: Other, Research Funding; Mochida: Other, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other; Ono Pharmaceutical: Other, Research Funding; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Daiichi Sankyo: Other; Huya Japan: Other; Celgene: Other: Personal Fees; Kyowa Hakko Kirin: Other: Personal fees, Research Funding; BMS: Other: Personal fees; Chugai Pharmaceutical: Other: Personal fees, Research Funding. Ogawa:Asahi Genomics Co., Ltd.: Current equity holder in private company; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding. Shimoda:Takeda Pharmaceutical Company: Honoraria; Bristol-Myers Squibb: Honoraria; Shire plc: Honoraria; Celgene: Honoraria; Perseus Proteomics: Research Funding; PharmaEssentia Japan: Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma: Research Funding; Merck & Co.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding; Novartis: Honoraria, Research Funding. Kataoka:CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Genomics: Current equity holder in private company.

Description: Background: Adoptive immunotherapy using CD19-targeted Chimeric Antigen Receptor T-cells (CAR-T) has revolutionized the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We have demonstrated the efficacy of FDA-approved axicabtagene ciloleucel (Yescarta) in a multiethnic New York City underserved population with 80% complete response (CR) rate in the first ten patients treated at our institution (Abbasi et al., 2020). There is limited data on the propensity of infections and lymphohematopoietic reconstitution after Day 30 (D30) following CAR-T cell therapy. In this study, we evaluated the prevalence and nature of infectious complications in an expanded cohort of DLBCL patients treated with CD19 CAR-T therapy and its association with the dynamics of leukocyte subpopulation reconstitution post-CAR-T cell therapy. Methods: We conducted a retrospective study of patients who received CAR-T therapy at our institution between 2018-2020. Variables collected include patient demographics, absolute neutrophil (ANC), lymphocyte (ALC) and monocyte counts (AMC) at Day 30, hematologic reconstitution (ANC≥ 1500/µL) at Day 90 (D90), presence or absence of infections after D30 by clinical and/or microbiological parameters. Associations between presence of infection and D30 ANC, ALC, AMC, ANC/ALC ratio, AMC/ALC ratio were assessed using Kruskal-Wallis test. Association between infection and hematologic reconstitution at D90 was done using Chi-square test. Kaplan-Meier curves with log-rank test were used to evaluate overall survival (OS) and progression-free survival (PFS). Results: Nineteen patients were evaluated in our study, consisting of 42% (8) Hispanic, 32% (6) Caucasian, 21% (4) African-American, and 5% (1) Asian subjects. Based on clinical and microbiologic data, 47% (9) developed an infection after D30 (infection group) while 53% (10) of subjects remained infection-free after D30 (non-infection group). The most common infection type observed was viral (11 patients) followed by bacterial (8 patients) and fungal (3 patients) (Table 1). Of 25 total infectious events, 44% (11) were grade 1 or 2 and 48% (12) were grade 3 with 10 being viral in etiology. Two deaths occurred due to an infectious process. Three patients tested SARS-CoV-2 positive and were hospitalized with COVID-19 pneumonia. Median OS and PFS has not been reached in either group. To determine the kinetics of lymphohematopoietic reconstitution and its association with infection risk, we evaluated the relationship between cytopenias and rates of infection after D30. Notably, compared to non-infection group, infection group had a higher median ALC (1000/µL vs 600/µL p=0.04), a lower median ANC/ALC ratio (1.4 vs 4.5 p1500/µL) at D90. We observed that only 22% (2) of patients had recovered ANC 〉 1500/µLin the infection group as opposed to 80% (8) in the non-infection group at D90 (p= 0.038). Rates of cytokine release syndrome (CRS) were comparable between the two groups (55.6% vs 70% p=0.52). Surprisingly, rates of immune-effector cell associated neurotoxicity syndrome (ICANS) was lower (55.6%) in the infection group compared to (90%) non-infection group (p=0.09). Fourteen of 19 patients had follow-up over one year, of which 8 (57%) remained in complete remission (CR). Conclusions: We demonstrate an infection rate of 47% (9) beyond D30 in patients undergoing CD19 CAR-T. Increased ALC, lower ANC/ALC and AMC/ALC ratios at D30 may be predictive of infectious complications. Median OS has not been reached in our cohort. Given the potential clinical impact, our observations should be corroborated using larger datasets. Disclosures Steidl: Pieris Pharmaceuticals: Consultancy; Bayer Healthcare: Research Funding; Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Janakiram:ADC Therapeutics, FATE therapeutics, TAKEDA pharmaceuticals: Research Funding. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; stelexis: Current equity holder in private company; Medpacto: Research Funding.

Description: Introduction: Adult T-cell leukemia lymphoma (ATLL) is a rare hematologic malignancy caused by human T-cell lymphotropic virus (HTLV-1) with dismal cure rates and poor response to conventional chemotherapy. Allogeneic Hematopoietic Stem Cell Transplantation (AlloSCT) is the only therapeutic option which may offer the chance of long-term remission and cures in a subset of patients. We sought to investigate the outcomes of transplantation in one of the largest cohorts in North America. Methods: A retrospective chart review study was conducted using the North-American ATLL and the Hematopoietic Precursor Cell transplantation databases at Montefiore Medical Center from 2011 to 2020. Variables collected include age, sex, ethnicity, ATLL subtype, molecular profile, previous treatments, conditioning regimens, type of transplant, immunosuppressive regimen, progression free survival (PFS) post-transplant and overall survival (OS) post-transplant. Results: Fourteen patients with ATLL who received an AlloSCT from 2011-2020 were identified. Fifty-seven percent (8/14) of patients were male. Seventy-one percent (10/14) of patients were African American and twenty-nine percent (4/14) were Hispanic. Median age was 51 years. Sixty-four percent (9/14) of patients had Stage IV disease at the time of diagnosis. Forty-three percent (6/14) patients had acute and fifty-seven percent (8/14) had lymphomatous ATLL. Almost all patients (92%) were treated initially with EPOCH combination chemotherapy. Twenty-eight percent (4/14) of patients received interferon/zidovudine as bridge-to-transplant. Fifty-seven percent (8/14) of patients achieved complete remission (CR) prior to AlloSCT, 7% (1/14) were in partial remission, and 28% (4/14) were relapsed or refractory. Forty-three percent (6/14) of patients received SCT from a matched-related donor (MRD), 36% (5/14) from a haplo-identical donor and 21% (3/14) from a matched-unrelated donor (MUD). Ninety-three percent (13/14) of patients received a reduced-intensity conditioning (RIC) regimen pre-transplantation. Seven percent (1/14) received a myeloablative conditioning (MAC) regimen. RIC regimens consisted of fludarabine with melphalan +/- anti-thymocyte globulin (ATG) or fludarabine with cyclophosphamide with total-body irradiation in doses less than 500 cGy. Patients receiving haplo-identical SCT also received post-transplant cyclophosphamide (PTCy) for prevention of graft vs host disease (GVHD). The MAC regimen used included busulfan with cyclophosphamide at myeloablative doses. Twenty-eight percent (4/14) of patients relapsed post-alloSCT with a median relapse-free survival of 6 months (range 4-18 months). The median OS of the whole cohort was 27 months (8-82 months). Graft-versus-host disease (GVHD) developed in 28% (4/14) percent of patients. The most common manifestation was skin GVHD. Fifty-percent (7/14) of the patients are surviving to-date. Transplant-related mortality (TRM) at day 100 was 21% (3/14) of patients. Causes of death were complex and included several diagnoses in certain patients. The most frequent diagnoses associated with death were infection (28%), graft failure (14%), GVHD (14%), veno-occlusive disease of the liver (VOD) (7%), disease progression (14%) and unknown due to patient lost to follow-up (14%). The main infectious events included fungal (2), bacterial (1), and COVID-19 (1) infection. Forty-three percent (6/14) of patients remain in complete remission to date. Conclusions: Allogeneic Stem Cell Transplantation offers long-term survival with a TRM of 21% in a disease with an inherently dismal prognosis. AlloSCT using several graft sources, is thus, a safe and well tolerated treatment modality and offers long term remissions. Disclosures Steidl: Pieris Pharmaceuticals: Consultancy; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Research Funding; Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; Medpacto: Research Funding; stelexis: Current equity holder in private company. Janakiram:ADC Therapeutics, FATE therapeutics, TAKEDA pharmaceuticals: Research Funding.

Description: Introduction: We sought to compare outcomes among patients with hematologic neoplasms diagnosed with COVID-19 infection in a multiethnic urban academic medical center. Methods: A retrospective analysis of patients with hematologic neoplasms diagnosed with COVID-19 from March 17th to June 8th2020 was conducted. Subjects included were censored at last point of contact. Variables collected included age, gender, race/ethnicity, hematologic diagnosis, cancer treatment status, baseline and follow-up COVID-19 testing, neutrophil count, and lymphocyte count at time of diagnosis. Associations between hematologic diagnosis, cancer treatment status, age, gender, race/ethnicity, neutrophil-to-lymphocyte ratio (NLR), and overall survival (OS) were assessed using the Kaplan-Meier method with logrank test. Results: A total of 102 subjects with hematologic neoplasms and COVID-19 infection treated in Montefiore Health system were identified (Table 1). Thirty-nine (38%) subjects were undergoing active treatment, including 17 (16%) receiving conventional chemotherapy agents, 12 (12%) targeted therapy, and 10 (10%) combination therapy. Of those subjects, twenty (50%) experienced delay or discontinuation of treatment due to COVID-19 infection. Four subjects (4%) showed persistent infection by PCR at median duration of 25.1 days after initial diagnosis. Ten subjects (9.8%) showed clearance of the virus by PCR with median time-to-clearance of 51.8 days. Of 9 subjects with serologic testing, 8 tested positive for COVID-19 IgG antibody at median time of 62 days after initial COVID-19 diagnosis. Forty-seven (47%) subjects expired as a result of COVID-19 disease at the time of analysis. Disease type, treatment status, race/ethnicity, age, and gender showed no significant association with mortality. Patients older than 70 had worse outcomes than the younger population (p = 0.0082). Median neutrophil and lymphocyte count at time of diagnosis was 4500 and 900, respectively. NLR greater than 9 was associated with worse survival when compared to NLR less than 9 (p=0.0067). Conclusions: COVID-19 infection has adverse effects on patients with hematological neoplasms. Subjects older than 70 years had a significantly worse prognosis. Notably, subjects actively being treated with chemotherapy did not have worse outcomes than those not being treated in our cohort, supporting the notion than active COVID-19 infection per se should not result in treatment delays. In addition, high NLR correlates with worsened survival, suggesting that this could be a potential prognostic factor for COVID-19 mortality in the hematologic neoplasms population. Disclosures Steidl: Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Research Funding; Pieris Pharmaceuticals: Consultancy; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:stelexis: Current equity holder in private company; BMS: Consultancy, Research Funding; Medpacto: Research Funding; Janssen: Research Funding; acceleron: Consultancy, Honoraria.

Description: Introduction: Adult T cell leukemia lymphoma (ATLL) is a rare T cell neoplasm caused by the human T-lymphotropic virus (HTLV-1) virus. Although there are indolent subtypes it is often a highly aggressive and chemotherapy refractory malignancy. We follow one of the largest cohorts in the United States and in this study, we sought to elucidate the prognostic factors associated with inferior survival. Methods: A retrospective analysis of patients diagnosed with ATLL at Montefiore Medical Center was conducted. Subjects included were censored at last point of contact. Variables collected included age, gender, race, ethnicity, ATLL subtype, white blood cell count (WBC), absolute lymphocyte count (ALC), corrected calcium level, lymphadenopathy (LAD) (two or more non-contiguous sites). Associations between WBC, ALC, corrected calcium level, LAD and median overall survival (mOS) were assessed using the Kaplan-Meier method with log-rank test. A four-point prognostic system was designed assigning one point to each: WBC 〉 11,000; ALC〉4000; Corrected Ca≥10.5 and presence of LAD. Three risk groups were assigned based on the number of risk factors as follows: low (0-1 points), intermediate (2 points) and high (3-4 points) (Table 2). Association between these groups and OS was investigated using the Kaplan-Meier method with log-rank test. Results: A total of 61 ATLL subjects were included in this study (table 1). Hypercalcemia (Ca ≥10.5) was observed in 60.6% of subjects at diagnosis and was associated with inferior mOS (234 days) when compared to calcium 〈 10.5 (747days) (p=0.046), Figure 1A. WBC 〉11,000 had a strong association with inferior survival (175 days) compared to patients with a WBC ≤11,000 (666 days) (p= 0.0067) (Figure 1B). ALC 〉 4000 was also associated with inferior mOS (222 days) compared to ALC ≤4000 (666 days) (p=0.015) (Figure 1C). LAD was associated with mOS (188 days) compared with no LAD (847 days) (p=0.022) (Figure 1D). Based on these observations, we designed a prognostic system (0-4 points) (see above) to risk stratify newly diagnosed ATLL patients into: low (0-1 points), intermediate (2 points) and high (3-4 points) risk (Table 2). We divided our cohort into the above-mentioned risk groups and calculated their mOS. Kaplan Meier analysis (Figure 2) revealed a distinct mOS difference between the groups based on their risk score: Low: 419 days, Intermediate: 234 days and High: 181.5 days (p= 0.0042). Conclusions: We identify hypercalcemia (Ca≥10.5), leukocytosis (WBC〉 11,000), lymphocytosis (ALC〉 4000) and generalized LAD as poor prognostic factors in newly diagnosed ATLL. Using readily available information from basic laboratory and clinical parameters we propose a prognostic system to identify high risk individuals. Further validation will be needed using larger cohorts of this very rare disease. Disclosures Steidl: Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Pieris Pharmaceuticals: Consultancy; Bayer Healthcare: Research Funding. Verma:stelexis: Current equity holder in private company; BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; Medpacto: Research Funding. Janakiram:Takeda, Fate, Nektar: Research Funding. Shah:Celgene/BMS: Research Funding; Physicians Education Resource: Honoraria.

Description: Background: Patients with hematologic malignancy (HM) are hypothesized to be at high risk of poor outcomes with coronavirus disease 2019 (COVID-19), due to disease and therapy-related immunosuppression. Despite this, there are minimal reported data describing the outcomes of HM patients with COVID-19. Methods: The COVID-19 and Cancer Consortium (CCC19) (NCT04354701) is an international registry aimed at investigating the clinical course and complications of COVID-19 in patients with cancer. The CCC19 cohort includes patients with active cancer or a history of cancer with presumed or laboratory-confirmed COVID-19. The registry contains de-identified patient demographics, information regarding cancer diagnosis and treatment history, COVID-19 treatments, and clinical outcomes. Patients greater than 18 years of age with laboratory-confirmed, symptomatic COVID-19 and HM diagnoses were included in this study. The primary outcome is a composite of severe COVID-19 illness (composed of mechanical ventilation, severe illness requiring hospitalization, intensive care unit (ICU) requirement, or death); mechanical ventilation, ICU level of care, supplemental oxygen, and 30-day mortality are reported as secondary outcomes. Baseline characteristics are reported for the entire cohort. Reported clinical outcomes are stratified by cancer type, cancer status, line of therapy received (never treated, first, second or later), receipt of cellular therapy or transplant (none, within 12 months, 〉12 months prior to COVID-19 diagnosis), last receipt of cytotoxic therapy (within 4 weeks, 1-3 months, 3-12 months prior to COVID-19 diagnosis), and receipt of HM therapies under investigation as repurposed treatments for COVID-19 (Bruton tyrosine kinase (BTK) inhibitors, Janus kinase (JAK) inhibitors, Bcr-Abl kinase inhibitors). Results: From March 17, 2020 to July 31, 2020, a total of 757 patients with HM and COVID-19 were enrolled and met inclusion criteria. Median follow-up was 30 days (IQR 17-70 days). Median age was 65 years (IQR 55-75), 62% (470) were over age 60, 57% were men, 45% were non-Hispanic white (22% Black, 18% Hispanic, 5% other), 39% were former or current smokers, 27% were obese, 18% had Eastern Cooperative Oncology Group (ECOG) performance status ≥2, and 51% were on active treatment within 3 months of COVID-19 diagnosis. Among patients with HM, 281 (37%) developed the primary endpoint. Five-hundred and eleven patients (67%) were hospitalized (some with non-severe disease), 188 (25%) required ICU level of care, 133 (18%) required mechanical ventilation, 409 (54%) required supplemental oxygen, and 143 (19%) died within 30 days of COVID-19 diagnosis. Stratified rates of severe outcomes are shown in the Table. The rate of severe COVID-19 was highest in patients with chronic lymphocytic leukemia (53%), and lowest in patients with Hodgkin lymphoma (23%). Patients receiving cytotoxic systemic therapy within 3 months of COVID-19 diagnosis had higher rates of severe COVID-19 (41%) and 30-day mortality (28%) than patients who completed treatment 3-12 months (26% severe COVID-19, 16% 30-day mortality) or more than 12 months (29% severe COVID-19, 13% 30-day mortality) prior to COVID-19 diagnosis. Patients receiving cellular therapy or transplant within a year prior to COVID-19 diagnosis had similar rates of severe COVID-19 (36% v. 38%) and 30-day mortality (23% v. 19%) to patients who had not received such therapies within a year prior to COVID-19 diagnosis. Patients on second-line or later therapy experienced similar rates of poor outcomes (42% severe COVID-19, 20% 30-day mortality) to patients on first-line therapy (39% severe COVID-19, 18% 30-day mortality) and untreated patients (42% severe COVID-19, 20% 30-day mortality). Outcomes for patients receiving therapies under investigation as repurposed COVID-19 treatments were similar to the cohort at large. Conclusions: This is the largest cohort study to date describing COVID-19 outcomes in patients with HM. Rates of severe COVID-19 outcomes including death were high. Unadjusted rates of severe COVID-19 outcomes were higher in patients with previously described risk factors such as advanced age, poor performance status, and progressive disease, as well as those receiving recent cytotoxic therapy. Outcomes varied widely by malignancy but were similar across treatment contexts. Additional data collection and analyses are ongoing. Disclosures Lynch: Bayer: Research Funding; Rhizen Pharmaceuticals: Research Funding; Incyte: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Juno Therpeutics: Research Funding; Genentech: Research Funding; MorphoSys: Consultancy; Cyteir: Research Funding. Bakouny:BMS: Research Funding; Genentech: Research Funding. Bhutani:Sanofi: Consultancy, Research Funding. Shah:American Cancer Society and the Hope Foundation for Cancer Research: Research Funding; National Cancer Institute: Research Funding. Lyman:Mylan: Consultancy; Beyond Spring: Consultancy; Samsung: Consultancy; Sandoz: Consultancy; Invitae: Consultancy; Spectrum: Consultancy; G1 Therapeutics: Consultancy; Amgen: Research Funding. Kuderer:Janssen: Consultancy; G1 Therapeutics: Consultancy; Beyond Springs: Consultancy; Spectrum Pharmaceuticals: Consultancy; Bayer: Consultancy; Bristol-Myers Squibb: Consultancy; celldex: Consultancy; Total Health: Consultancy; Invitae: Consultancy. Warner:HemOnc.orgLLC: Other: Shareholder/Stockholder/Stock options; National Cancer Institute: Research Funding; IBM Watson Health: Consultancy; Westat: Consultancy. Mesa:Bristol Myers Squibb: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Novartis: Consultancy; Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy. Thompson:AIM Specialty Health, BMS, GlaxoSmithKline, Takeda, Via Oncology: Membership on an entity's Board of Directors or advisory committees; Doximity: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Synapse Precision Medical Council: Other: Travel expenses.