EUSA Pharma Research Articles

Axicabtagene Ciloleucel Compared to Tisagenlecleucel for the Treatment of Relapsed or Refractory Large B-Cell Lymphoma in the Real World Setting in Spain

Axicabtagene Ciloleucel Compared to Tisagenlecleucel for the Treatment of Relapsed or Refractory Large B-Cell Lymphoma in the Real World Setting in Spain

Treatment of Relapsed/Refractory Waldenström Macroglobulinemia Patients: Final Clinical and Molecular Results of the Phase II Brb (Bendamustine, Rituximab and Bortezomib) Trial of the Fondazione Italiana Linfomi (FIL)

Treatment of Relapsed/Refractory Waldenström Macroglobulinemia Patients: Final Clinical and Molecular Results of the Phase II Brb (Bendamustine, Rituximab and Bortezomib) Trial of the Fondazione Italiana Linfomi (FIL)

Rreal-World Results from Anti-CD19 CAR-T Cell Therapy for Relapsed or Refractory Diffuse Large B-Cell Lymphoma in Spain and Comparison with Previous Standard of Care: A Geltamo/Geth Study

Rreal-World Results from Anti-CD19 CAR-T Cell Therapy for Relapsed or Refractory Diffuse Large B-Cell Lymphoma in Spain and Comparison with Previous Standard of Care: A Geltamo/Geth Study

Characterizing Serum Cytokine Levels in Idiopathic Multicentric Castleman Disease Reveals Increased Chemokines and a Potential Signature Compared to Related Diseases

Idiopathic multicentric Castleman disease (iMCD) is a heterogeneous and life-threatening hematologic disorder with unknown etiology. It involves extensive lymphadenopathy with characteristic histopathology, inflammatory symptoms, and life-threatening cytokine-driven multi-organ failure, if inadequately treatment. Diagnosis requires the presence of histopathological, clinical, laboratory, and radiologic findings as well as exclusion of other related diseases including infectious, autoimmune, and lymphoproliferative disorders. Despite these guidelines, definitive diagnosis remains challenging as histopathological changes, clinical features, and laboratory abnormalities are non-specific. Given that iMCD can be aggressive and life-threatening, timely diagnosis is crucial, and specific diagnostic biomarkers are needed. Interleukin-6 (IL-6) is a known disease driver in a portion of patients, but it is not consistently elevated at diagnosis and characterization of other cytokines has not been systematically performed. Previously, a plasma proteomics study identified upregulation of multiple cytokines, including several chemokines, such as C-X-C Motif Chemokine Ligand 13 (CXCL13) and C-C motif ligand 21 (CCL21), during disease flare in a small cohort. We sought to investigate whether these findings would be replicated in a larger cohort and to identify cytokines that could help to improve diagnosis of iMCD.Herein, we analyzed serum samples from 88 iMCD patients, 42 healthy donors, and 20 patients each with rheumatoid arthritis (RA), Hodgkin lymphoma (HL), and a subtype of multicentric Castleman disease caused by infection with human herpes virus 8 (HHV8+MCD). 1300 analytes were quantified by SomaLogic SOMASCAN; Uniprot database was used to select the 159 quantified cytokines for analysis. Data were log2 normalized and capped at the 2.5 th and 97.5 th percentiles. Linear models were used to identify significant differences among disease groups, with p values adjusted by Benjamini & Hochberg. Hierarchical clustering was performed using complete linkage.Of the 159 cytokines quantified, 54 (34%) were identified as significantly different between iMCD and healthy donors. The most upregulated cytokine was CXCL13 with a log2 fold-change (FC) of 1.7 (p<0.0001). The chemokines CCL21 (FC: 1.3, p<0.0001) and CCL23 (FC: 0.87, p<0.0001) were also noted among the top 10 most upregulated cytokines, consistent with the earlier plasma proteomic study. Of note, IL-6 (FC: 0.35, p=0.039) was also found, but it ranked 31 out of 54 in log2 FC magnitude. We next sought to compare cytokine elevation in iMCD to related disorders. Hierarchical clustering of all 159 cytokines appeared to differentiate iMCD from RA, HL, and HHV8+MCD (Figure 1), revealing a cluster with 72/88 (82%) iMCD and 4/60 (6%) related disease patients versus another with 16/88 (18%) iMCD and 56/60 (93%) related disease patients. Given this, we used linear models to test for significant differences in protein expression between iMCD and related diseases. We identified 12 cytokines that were significantly different between iMCD and each comparator disease (Table 1). Of these, 10 cytokines all trended in the positive direction in iMCD versus each comparator disease. CCL21 was again noted among this group and had the highest average FC for all three groups.Herein we validate earlier findings that cytokines, particularly chemokines are significantly upregulated in iMCD. While previous results compared disease flare to disease remission in a small pilot cohort, our patient sample is >10 times larger, represents a broader spectrum of disease severity, and is compared to a set of healthy donors and related diseases. Unbiased hierarchical clustering was able to separate iMCD from other diseases, and linear models identified specific cytokines that are significantly different in iMCD compared to each RA, HL, and HHV8+MCD. Further validation is need to assess whether a cytokine panel can differentiate iMCD from other related diseases, which would be crucial for timely diagnosis and treatment. Of note, CXCL13 and CCL21 are primarily produced by follicular dendritic cells and fibroblastic reticular cells, stromal cells responsible for coordinating B cell and T cell trafficking in the lymph node, respectively. Dysregulation of these cells may contribute to the dysmorphic appearance of lymph nodes and pathogenesis in iMCD. [Display omitted] DisclosuresFajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’.

Association of Donor and Recipient Interleukin-1 Gene Single Nucleotide Polymorphisms with Outcome after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for hematological malignancies, genetic diseases, and severe immune deficiencies. Despite the matching of the human leucocyte antigens (HLA), HSCT is still associated with a considerable rate of morbidity and mortality caused by infections, relapse, and graft-versus-host disease (GVHD). Therefore, non-HLA polymorphisms like cytokines and their receptors are considered as important contributing factors. Interleukin-1 (IL-1) is a cytokine that initiates and maintains the immune response as well as the development of GVHD in the recipient. Single nucleotide polymorphisms (SNPs) of the IL-1 gene are associated with a higher risk of malignancies, an elevated death rate because of infections, and a higher chance to suffer from autoimmune or chronic diseases. This study aimed to analyze the association of IL-1 gene SNPs with outcome in a pediatric population undergoing allogeneic HSCT.Methods: We included 270 pediatric patients with a median age of 9 years who underwent an allogeneic HSCT and their respective donors. We used TaqMan real-time polymerase chain reaction to analyze the SNPs IL-1-alpha rs1800587 (-889, A/T), IL-1-beta rs1143627 (-31, A/T), and IL-1-beta rs16944 (-511, A/T). The underlying diseases were acute lymphoblastic leukemia (n=89), acute myeloid leukemia (n=63), chronic myeloid leukemia (n=10), juvenile myelomonocytic leukemia (n=9), myelodysplastic syndrome (n=29), lymphoma (n=7), solid tumor (n=11), genetic disease (n=41), and aplastic anemia (n=11). The stem cell sources were bone marrow (n=178), peripheral blood (n=90) or umbilical cord blood (n=2). Two hundred donors were HLA-matched, and 70 donors were HLA-mismatched. Conditioning regimen was myeloablative in all cases and based on chemotherapy in 180 children or total body irradiation in 90 children. The predominant post-transplant immunosuppression was cyclosporine A and methotrexate in 148 patients or cyclosporine A alone in 55 patients. The genotyped SNPs were compared using the Kaplan-Meier method for event-free survival (EFS) and overall survival (OS) and the Gray test for acute GVHD, chronic GVHD, relapse rate (RR), and transplant-related mortality (TRM).Results: We observed a significant association between the SNP IL-1-alpha rs1800587 (-889, A/T) of the donor and the rate of acute GVHD. The genotypes of IL-1-alpha rs1800587 had the following distributions in the donor: CC genotype n=132 (49%), CT genotype n=114 (42%), and TT genotype n=24 (9%). Overall, 63 children (23%) suffered from moderate to severe acute GVHD (grade II-IV). We found a significantly increased incidence of moderate to severe acute GVHD (grade II-IV) if the patient was transplanted from a donor with the CC/CT genotype compared to the TT genotype (25% versus 4%; p=0.028). We found no significant associations of the SNP IL-1-alpha rs1800587 (-889, A/T) for chronic GVHD, RR, TRM, EFS, and OS. In addition, we observed no significant associations of the other studied genotypes IL-1-beta rs16944 (-511, A/T) and rs1143627 (-31, A/T) in either donors or recipients for acute and chronic GVHD, RR, TRM, EFS, and OS.Conclusion: Our study identified the IL-1-alpha rs1800587 CC/CT genotype of the donor as a genetic risk factor for the development of moderate to severe acute GVHD (grade II-IV) in pediatric allogeneic HSCT recipients. After confirmation in further studies, these findings could implicate the adjustment of prophylactic measures to reduce the risk of acute GVHD in children. DisclosuresGruhn: AmgenGmbh: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel costs; Bellicum Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees, Other: travel costs; EUSA Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: travel costs; Novartis Pharma Inc.: Honoraria, Other: travel costs; pfizer: Honoraria; servier: Honoraria, Other: travel costs; Neovii Biotech GmbH: Other: travel costs; medac GmbH: Other: travel costs.

Research and Care Networks in Acute Leukemia As a Model for Global Healthcare Collaboration

Introduction: Clinicians in academia face four major career challenges:1.Gaining clinical advice from colleagues experienced in a particular disease or treatment2.Experiencing Life-long coaching and mentoring from senior experienced clinicians3.Accessing high quality continuing medical education relevant for patient care4.Support to carry out medical researchAll four challenges have been adversely impacted during the Covid-19 pandemic as traditional face-to-face networks have become harder to access. This is especially pertinent when treating complex or rare diseases like acute lymphoblastic leukemia (ALL). Atypical or refractory patients, and those who experience toxicities often benefit from timely input from experts with considerable experience managing ALL. Online networks offer a robust pandemic-proof source of health and care support and advice. Until recently there have been few dedicated professional networks that provide a regular online forum dedicated to research and care on specific diseases across countries and none related to ALL.Methods: We describe the Resonance ALL Research and Care Network (ALL RCaN; https://resonancehealth.org/networks/all-rcan ) which includes a network of colleagues and a weekly, multidisciplinary online forum that brings together pediatric and adult hematologists and oncologists from around the world to share data, discuss cases and support patient care. In addition, there is a monthly ‘Fellows Fourth Friday’ to help fellows build their own professional network and gain scientific and clinical advice. The network was born out of a monthly meeting of study chairs (the “Study Chair Affinity Group”) for ALL research protocols which had been running for 10 years.Results: The network launched formally in June 2020 with 30 founding members but has expanded rapidly through word of mouth. The Acute Leukemia network grew by 850% by Dec 2020 and 1460% by March 2021 and as of July 2021 has 579 members across 18 time zones. It has succeeded in 'Building ALL Bridges“ between physicians that treat adults and pediatricians for joint discussions in acute leukemia. This collaboration has been severely lacking in the past. The network also presents selected abstracts from major national and international conferences every 4 weeks. This model has been replicated for other cancers including the Global Neuroblastoma Network (resonancehealth.org/networks/gnn) and High-dose Methotrexate Quality Improvement Network (resonancehealth.org/networks/hdmtx). Network software development, video conferencing, meeting coordination, and content hosting have been funded by volunteer network leaders, many volunteer presenters, philanthropic contributions, and unrestricted educational grants. Now that the Resonance infrastructure is fully developed (and available to all at no cost), most Networks function well without funding.Conclusions: Providing free video conferencing, content hosting, and network management tools combined with dedicated leadership and clinically relevant discussions and presentations has led to massive growth of the ALL Research and Care Network, which continues to grow. Networks for other cancers are in various stages of development since the tool set and methodology easily scales to new groups of colleagues and new diseases. [Display omitted] DisclosuresGuscott: EUSA Pharma UK Ltd: Ended employment in the past 24 months. Douer: Amgen: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Jazz: Consultancy; Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau. Howard: Cellworks Group Inc.: Consultancy; Sanofi: Consultancy, Other: Speaker fees; Servier: Consultancy.

Superior Overall Survival with Blinatumomab Versus Chemotherapy As Pre-Transplant Consolidation Treatment in Children with High-Risk First-Relapse B-Cell Precursor Acute Lymphoblastic Leukemia (B-ALL): Longer Follow-up (FU) of a Phase 3 Randomized Controlled Trial (RCT)

Superior Overall Survival with Blinatumomab Versus Chemotherapy As Pre-Transplant Consolidation Treatment in Children with High-Risk First-Relapse B-Cell Precursor Acute Lymphoblastic Leukemia (B-ALL): Longer Follow-up (FU) of a Phase 3 Randomized Controlled Trial (RCT)

A Longitudinal Population Level Analysis of Healthcare Resource Utilization, Comorbidity, and Survival in Idiopathic Multicentric Castleman Disease Patients

BACKGROUND: Human herpesvirus-8-negative/idiopathic multicentric Castleman disease (iMCD) is a heterogenous group of diseases characterized by proinflammatory hypercytokinemic state with a wide range of systemic manifestations ranging from generalized lymphadenopathy to death in severe cases. Limited data has shown an increased prevalence of organ dysfunction and cancers in iMCD patients either as a result of underlying disease pathophysiology or treatment received. The objective of this study was to assess the healthcare resource utilization, patterns of iMCD-related comorbidities, and survival of iMCD patients in a real-world setting. METHODS: We performed a retrospective analysis of administrative claims data for &amp;gt;30 million United States patients continuously enrolled over a three-year study period from January 1, 2017 and December 31, 2019. Patients were identified as iMCD if they had an ICD-10 diagnosis code for Castleman disease (D47.Z2) and ≥2 diagnostic codes corresponding to the minor criteria from the international evidence-based consensus diagnostic criteria for iMCD. Exclusion criteria included history of HIV, HHV-8, lymphoma, myeloma, lupus, or rheumatoid arthritis within one year of diagnosis of Castleman disease. Index diagnosis date (IDD) was defined as the first time a patient received a diagnosis for Castleman disease using the new ICD-10 code (D47.Z2) or the general code for lymphadenopathy (785.6) in ICD-9 that included Castleman disease, whichever was diagnosed first between 2006 and 2019. Included patients were followed for up to 5 years from IDD and evaluated for post-diagnosis hospitalizations, emergency room visits, hematologic malignancies, non-hematologic malignancies, thromboses, and organ dysfunction. Estimated average survival was calculated based on estimated incidence and prevalence rates for the iMCD patient population, assuming a stable incidence. RESULTS: We identified 191 iMCD patients including 109 women (57%) and 82 men (43%) with a mean age of 51 years (range: 6 - 90). The average post-diagnosis follow up was 3.2 years after IDD (range: 0.3 - 14.1). Within the first year of iMCD diagnosis, 58.9% of patients required inpatient hospitalization and 53.4% had at least one emergency room visit. Among the patients who remained enrolled after the first year, an average of 25.1% were hospitalized and 36.1% visited the emergency room during each subsequent year (Table 1). The annual rate of hospitalizations and emergency room visits for the entire database of &amp;gt;30 million patients was 9.0% and 20.6%, respectively. As shown in Table 2, the annual prevalence of iMCD-related comorbidities in this cohort was 18.2% for non-hematologic malignancies, 6.3% for hematologic malignancies (including lymphomas and myelomas from second year follow up onwards), 5.8% for thromboses, 5.7% for renal failure, and 5.2% for respiratory failure. Based on an average annual incidence of 2.45 (95% CI, 0.85 - 8.60) per million and average prevalence of 6.31 (95% CI, 3.25 - 13.05) per million, we estimated an average survival of 2.57 (95% CI, 1.59 - 4.25) years after diagnosis in this study time period. DISCUSSION: Using a large nationally representative health claims database, we identified a cohort of iMCD patients and found a high rate of hospitalizations and emergency room visits in the first five years following diagnosis. The annual prevalence of iMCD-related organ failure was approximately 5-6% primarily involving renal and respiratory systems. This study provides further evidence to support the previously reported increase in frequency of subsequent hematologic and non-hematologic malignancies in iMCD patients. In the five-year follow up period, the average estimated survival of iMCD patients was 2.57 (95% CI, 1.59 - 4.25) years after diagnosis, which is shorter than previously published average survival durations based on academic medical centers. The worse survival in this cohort may represent iMCD survival outside of academic medical centers or may reflect inaccuracies in estimated incidence and prevalence which were used to estimate average survival. Further studies are needed to compare outcomes to age-matched controls and to determine whether these adverse outcomes are broadly seen across iMCD patients or instead attributable to a smaller subset of more severe cases. Disclosures Mukherjee: Bristol Myers Squib: Honoraria; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees. Martin:EUSA Pharma: Current Employment. Sande:EUSA Pharma: Current Employment. Glen:HVH Precision Analytics: Current Employment. Paige:HVH Precision Analytics: Consultancy. Yarlagadda:HVH Precision Analytics: Current Employment. Fajgenbaum:EUSA Pharma: Research Funding; Janssen Pharmaceuticals: Research Funding.

Outcomes of Patients Requiring ICU Admission after CD19 Directed CAR T-Cells

Introduction:Chimeric antigen receptor (CAR) T-cells are engineered T-cells that target specific antigens on tumor cell surfaces. CD19 directed CAR T-cells have demonstrated efficacy in B-cell lymphomas and B-cell acute lymphoblastic leukemia (B-ALL); however, patients are at risk for life-threatening complications including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Grade 3 ICANS and higher have been reported in 12-28% and Grade 3 CRS and higher in 1-23% in pivotal studies for B-cell lymphoma.1 The majority, if not all, patients with Grade 3 ICANS and CRS require intensive care unit (ICU) admission. The long-term outcomes of patients requiring ICU admission after CD19 directed CAR T-cells are unknown. Methods:Clinical data were retrospectively reviewed from consecutive patients with relapsed or refractory B-cell lymphomas and B-ALL treated with axicabtagene ciloleucel or tisagenlecleucel at a single institution from January 1, 2016 to July 1, 2020. Diagnosis of CRS and ICANS was based on the American Society for Transplantation and Cellular Therapy consensus grading.2 Demographics, medical co-morbidities, therapeutic interventions, relapse rate, and all-cause mortality were assessed. Results:Thirty-seven patients received CAR T-cells. Sixty-seven percent (n=25) of patients were male with a median age of 55 years (range 23 - 77). Eighty-nine percent of patients had large B cell lymphoma. Patients received a median of 3 prior therapies (range 1 - 6). The median IPI and ECOG scores at time of CAR T-cells administration were 3 and 1, respectively. Forty-three percent (n=16) of patients required ICU admission. The median length of ICU stay was 3.5 days (range 1 - 18). The median CRS and ICANS grades in patients requiring ICU admission were 2 and 3, compared to 2 and 0 in patients not requiring ICU admission, respectively. Thirty-one percent of ICU admitted patients had CRS grade 3 or above, and 61% had ICANS grade 3 or above. All 4 patients with B-ALL experienced grade 3 or above CRS and required ICU admission. Only 1 of the 37 patients (2.7%) patients died from CRS. Fifty-six percent of ICU patients experienced disease progression during follow-up, compared to 33% of non-ICU patients (OR 2.50, p = 0.20, 95% CI 0.55-12.11). Over a median follow up of 399 days, 56% of ICU patients died compared to 14% of non-ICU patients (OR 7.23, p = 0.01, 95% CI 1.32-54.27). The majority of deaths (58%) were due to disease progression. Conclusions:A significant number of patients who receive CD-19 direct CAR T-cells require ICU admission. Patients requiring ICU admission after CAR T-cell have a worse outcome and overall survival, compared to non-ICU patients. The mortality rate of ICU admitted patients is primarily driven by death from disease. Disclosures Tzachanis: MS:Research Funding;EUSA Pharma:Consultancy;Fate:Research Funding;Genetech:Research Funding;Gilead Sciences:Consultancy, Research Funding, Speakers Bureau;Incyte:Research Funding;Jazz Pharmaceuticals:Consultancy;Kyowa Kirin:Consultancy;Magenta:Consultancy;Takeda:Consultancy, Speakers Bureau.Goodman:Seattle Genetics:Consultancy;EUSA Pharma:Consultancy.

Response to CAR-T Therapy Can be Monitored Using Genome-Wide Sequencing of Cell-Free DNA in Patients with DLBCL

Response to CAR-T Therapy Can be Monitored Using Genome-Wide Sequencing of Cell-Free DNA in Patients with DLBCL

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor (CITADEL-205)

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor (CITADEL-205)

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with Ibrutinib (CITADEL-205)

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with Ibrutinib (CITADEL-205)

Initial Treatment Vs Watch and Wait in Advanced-Stage Follicular Lymphoma in the Rituximab Era - an Analysis of the National Cancer Database (NCDB)

Initial Treatment Vs Watch and Wait in Advanced-Stage Follicular Lymphoma in the Rituximab Era - an Analysis of the National Cancer Database (NCDB)

Long-Term Sustained Minimal Residual Disease (MRD) Negativity in Patients with Multiple Myeloma Treated with Continuous Lenalidomide Maintenance Therapy: A Clinical and Correlative Phase 2 Study

Long-Term Sustained Minimal Residual Disease (MRD) Negativity in Patients with Multiple Myeloma Treated with Continuous Lenalidomide Maintenance Therapy: A Clinical and Correlative Phase 2 Study

Outcomes of Front-Line Therapy for Adult T Cell Leukemia/Lymphoma: A Pooled Analysis of Two Institutions

Introduction: Adult T cell leukemia/lymphoma (ATLL) is an aggressive mature T cell neoplasm caused by Human T lymphotropic virus type 1/2 (HTLV1/2) infection. HTLV1/2 is endemic in several geographic areas such as Latin America, Japan and intertropical Africa with estimated 5-10 million individuals infected worldwide. There is no standard therapy for ATLL and most patients are treated with regimens used for aggressive lymphomas. We hereby reviewed the outcome of patients treated in two US academic medical centers with a high prevalence of ATLL. Methods: We retrospectively evaluated all of the patients with a confirmed diagnosis of ATLL seen in two academic medical centers in Florida, USA. Baseline characteristics, treatments regimens and clinical outcomes where evaluated. First line therapies were categorized as treatment with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), Intensive chemotherapy (HyperCVAD, VCAP-AMP-VECP, or EPOCH), vs others (Interferon and zidovudine, Gemcitabine Oxaliplatin, Pralatrexate, and Gemcitabine cisplatin dexamethasone). Patient and disease characteristics were compared using Chi-square. Progression free survival (PFS) and overall survival (OS) for different chemotherapy regimens were compared using log-rank testing. Results A total of 61 patients were included in the analysis. The median age was 58 (32-75) years. Two thirds of the patients were female. The majority were of African American descent (82.5%) (Table 1), and 35.6% were originally from Jamaica, followed by 13.6% from Haiti. Patients were more likely to have CR/PR to CHOP (72%) compared to those treated with intensive chemotherapy or others (27.3% and 29.4% respectively) (p=0.007) (figure 1A). While there was no statistically difference in baseline characteristics in patients receiving the three categories of treatments (i.e. age, stage, ECOG, CD30 status), patients with acute subtype were less likely to be treated with CHOP (21.1% vs 47.4% respectively, p=0.096) which might explain the discrepancies in response. There was no statistical difference in PFS and OS between the three CHOP, Intensive chemotherapy and others (6.4 mo, 3.1 mo, 2.1 mo, p=0.23) and (14 mo, 8.9 mo, 18.5 mo, p=0.14) respectively. Patients responding to first line therapy (CR/PR) had improved OS when compared to those having stable/progressive disease (15.9 mo vs 7.2 mo) (p=0.004) (Figure 1B). Conclusions: Our study results reflect the poor outcomes of ATLL patients, especially in the ones with primary refractory disease to frontline treatments. We also showed the suboptimal activity of frontline regimens for ATLL and lack of unifying therapeutic approach for this lymphoma in the US. Multi-institutional clinical trials exploring novel therapeutic frontline options to improve response rates, which translate in better OS are desperately needed in this population. Disclosures Sandoval-Sus: Massive Bio: Consultancy; Janssen: Consultancy; MorphoSys US: Consultancy; Celgene: Speakers Bureau. Sokol:Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Speakers Bureau.

Initial Whole Genome Sequencing of Plasma Cell Neoplasms in First Responders and Recovery Workers Exposed to the World Trade Center Attack of September 11, 2001

Initial Whole Genome Sequencing of Plasma Cell Neoplasms in First Responders and Recovery Workers Exposed to the World Trade Center Attack of September 11, 2001

A Phase II Study of CPX-351 As a Novel Therapeutic Approach for Patients with Myelodysplastic Syndromes (MDS) after Hypomethylating Agent Failure

Treatment options are limited for patients (pts) diagnosed with MDS at the time of hypomethylating agent (HMA) failure. One goal is to introduce another line of therapy to reduce tumor burden and enable patients to undergo hematopoietic stem cell transplant (HSCT), which may prolong survival for a subset. CPX-351, has shown better overall response rates and improved overall survival in patients with acute myeloid leukemia with underlying MDS changes compared to 7+3, suggesting that CPX-351 can be used in an MDS patient population. We hypothesized that treating MDS pts, who were failed by HMAs or were intolerant with CPX-351 would overcome HMA resistance. This is a phase II study of single agent CPX-351 administered at the standard FDA approved dose of 44 mg/m2 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) intravenously on days 1, 3, 5 of the induction cycle. If patients achieve complete remission (CR), marrow CR, partial remission or hematologic improvement per 2006 IWG criteria they will be eligible to continue on to consolidation therapy, which consists of CPX-351 at a dose of 15.4 mg/m2 (daunorubicin 15.4 mg/m2 and cytarabine 35 mg/m2) every 28 days. Pts can receive up to 4 cycles of consolidation therapy in the absence of toxicity. The primary objective of the trial is to evaluate the efficacy of CPX-351 as measured by overall response rate (ORR) by IWG 2006 criteria. Secondary objectives include: ,1) determine the time to response (TTR), 2) evaluate the duration of response (DOR), 3) evaluate the event-free survival and the overall survival probability during trial period. Pts are risk stratified into lower vs higher-risk prior to enrollment using the Post-HMA model (Nazha A, et al. Hematologica 2016). Eligibility includes: pts &amp;gt;18 years with primary or secondary resistance to HMA, ECOG performance status &amp;lt; 2 and adequate organ function. Pts are excluded if they have uncontrolled infection or active malignancy. A total of 18 pts will be enrolled to each arm (lower and higher risk). To date, three pts were enrolled. One with MDS refractory to HMA who achieved complete remission and proceeded with 4 cycles of consolidation. The pt remained in remission 6+ months after the completion of consolidation. Another patient achieved a marrow CR but had a fungal pneumonia and then was taken off the trial (patient choice for going to hospice). The third patient had MDS/MPN, completed induction and achieved stable disease with improvement in platelets and neutrophils. All patients were lower-risk per the stratification model. No unexpected toxicity was observed. In conclusion, preliminarily CPX-351 is effective in MDS patients after HMA failure who are eligible to receive intensive chemotherapy. The treatment was well tolerated and toxicities were similar to what was observed in pivotal CPX-351 trials. The trial is ongoing and the results will be updated in the meeting. Disclosures Nazha: MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Jazz: Research Funding. Mukherjee:Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding; Takeda: Research Funding. Carraway:Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC). Gerds:AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Apexx Oncology: Consultancy; Pfizer: Research Funding. Patel:Alexion: Other: educational speaker. Sekeres:Takeda/Millenium: Consultancy; Pfizer: Consultancy; BMS: Consultancy. OffLabel Disclosure: CPX-351 in MDS

A Personalized Clinical-Decision Tool to Improve the Diagnostic Accuracy of Myelodysplastic Syndromes

Background While histo- and cytomorphological examinations are central to the diagnosis of myelodysplastic syndromes (MDS), significant inter-observer variability exists. The diagnosis can be challenging in pancytopenic patients (pts) without evidence of dysplasia and is contingent on observer expertise. We developed and externally validated a geno-clinical model that uses mutational data and peripheral blood counts/clinical variables to distinguish MDS from other myeloid malignancies. Methods Clinical and genomic data, including commercially available next-generation sequencing panels, were obtained for patients (pts) treated at the Cleveland Clinic (CC; 652 pts), Munich Leukemia Laboratory (MLL; 1509 pts), and the University of Pavia in Italy (UP, 536 pts). All patients had carried a diagnosis of MDS, chronic myelomonocytic leukemia (CMML), MDS/myeloproliferative neoplasm overlap (MDS/MPN), myeloproliferative neoplasm (MPN; either polycythemia vera, essential thrombocythemia, or myelofibrosis), clonal cytopenia of undetermined significance (CCUS), or idiopathic cytopenia of undetermined significance (ICUS). All diagnoses were established with bone marrow aspiration and according to World Health Organization 2017 criteria. The training cohort included data from CC and UP and randomly divided into learner (80%) and test (20%) cohorts. The final model was independently validated in the MLL cohort. A machine learning algorithm was used to build the model; multiple extraction algorithms were used to extract genomic/clinical variables on both the cohort and individual levels. Performance was evaluated according to the area under the curve of the receiver operating characteristic (ROC-AUC) and accuracy matrices. Results Among the 2697 pts included from all sites, the median age was 70 years [36 - 86]. Median hemoglobin (Hb) was 10.4g/dl [6.9 - 15.7], median platelet count (PLT) was 132 k/dL [14 - 722], median WBC count was 5.3 k/dL [1.4 - 49.9], median ANC was 2.8 k/dL [0.3 - 27.7], median monocyte count was 0.3 k/dL [0 - 9.9], and median lymphocyte count (ALC) was 1.1 k/dL [0.1 - 5.4], and median peripheral blast percentage 0% [0 - 8]. The most commonly mutated genes in all patients were (list top 5 genes) and among pts with MDS were SF3B1 (27%), TET2 (25%), ASXL1 (19%), SRSF2 (16%), and DNMT3A (11%); among patients with MDS-MPN/CMML, the most commonly mutated genes were MDS-MPN/CMML (TET2 46%, ASXL1 34%, SRSF2 29%, RUNX1 13%, CBL 12%) ; among patients with MPNs, the most commonly mutated genes were (JAK2 64%, ASXL1 27%, TET2 14%, DNMT3A 8%, U2AF1 7%); among patients with CCUS the most commonly mutated genes were (TET2 41%, DNMT3A 27%, ASXL1 19%, SRSF2 17%, ZRSR2 10%). The most important features for model predictions (ranked from the most to the least important) included: number of mutations detected/sample, peripheral blast percentage, AMC, JAK2 status, Hb, basophil count, age, eosinophil count, ALC, WBC, EZH2 mutation status, ANC, mutation status of KRAS and SF3B1, platelets, and gender. The final model achieved an average AUROC of 0.95 (95% CI 0.93-0.96) when applied to the test cohort and 0.93 (95% CI 0.91 - 0.94) when it was applied to the MLL cohort. The model also provides individual-level explanations for predictions, providing top differential diagnoses and individual-level explanations of how features influence a putative diagnosis (Figure 1b). Conclusions We developed and externally validated a highly accurate and interpretable model that can distinguish MDS from other myeloid malignancies using clinical and mutational data from a large international cohort. The model can provide personalized interpretations of its outcome and can aid physicians and hematopathologists in recognizing MDS with high accuracy when encountering pts with pancytopenia and with a suspected diagnosis of MDS. Disclosures Sekeres: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy. Gerds:Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Apexx Oncology: Consultancy; Celgene: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy; Gilead Sciences: Research Funding; Pfizer: Research Funding. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Nazha:Jazz: Research Funding; Incyte: Speakers Bureau; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee.

Prediction of Clinical Response for Frontline Treatment of Acute Myeloid Leukemia (AML) Patients Using the Cellworks Omics Biology Model (CBM): Mycare-021-02

Background: AML is a heterogeneous hematological cancer, characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow and other tissues. Among adults, AML is the leading cause of leukemia-associated death. Patients are often elderly and have comorbid conditions. Response to remission induction therapy varies by biologic subtype and by the drugs used for induction, but responses to each therapy are not predictable, even within specific biologic subgroups. To improve prognostication and identify new therapeutic options, Cellworks developed the Cellworks Omics Biology Model (CBM) that relies on multi-omics inputs from malignant cells to predict response and identify potential therapies tailored to the unique mechanisms of each patient's disease. Aim: To predict the response to induction chemotherapy regimens in AML patients and identify predictive genomic signatures, pathways, and personalized treatment options for refractory patients. Method: 57 AML patients with known therapy response were selected from 8 PubMed publications (Table 1). The cohort was split into 3 groups with CBFB-MYH11 fusion (n=19), RUNX1-RUNX1T1 fusion (n=10) and CEBPα del (n=28). All data was anonymized, de-identified and exempt from IRB review. NCCN offers specific recommendations for AML patients with these mutations and they are associated with high rates of remission after induction therapy. The available genomic data for each profile was processed using Cellworks' CBM to generate an AML subtype-specific protein network map using published information from PubMed and other online resources permitting patient-specific biomarkers to be mapped to sensitivity and resistance pathways. Drugs selected from a digital drug library were simulated for each patient across the three cohorts. Benefit was assessed by measuring each drug's effect on a cell growth score, a composite of proliferation, viability, and apoptosis indices. Results: Of 57 patients with favorable-risk AML, 6 (11%) experienced induction failure. 1/19 patients harboring CBFB-MYH11 fusion failed to respond to induction therapy (Table 2) and CBM identified co-occurring gene aberrations responsible for resistance in the patient with resistant disease (ID:757637), who harbored trisomy 6 with amplification of GSTA1, GSTA2, GSTA4, DEK, TFAP2A, NFYA and EHMT2 causing dysregulation of pathways involved in treatment failure. CBM also identified 3 prospective therapies that target this patient's specific biomarkers (Table 3). Similarly, 2/10 patients with RUNX1-RUNX1T1 fusion failed to respond to induction therapy. CBM identified a loss of function mutation in EZH2 causing increased levels of HOXA5 and HOXA9 as key orchestrators of treatment failure (Patient ID: 757805). Furthermore, CBM also identified 3 prospective therapies for this patient, targeting patient-specific resistance mechanisms (Table 3). In the CEBPα cohort, 3/28 patients did not respond to induction therapy (Table 2). For Patient ID:755125, CBM identified a DNMT3A loss of function mutation and consequential gain in the levels of HOXA5 and HOXA9 as key orchestrators of treatment failure. Again, CBM identified 3 novel therapies for this patient targeting patient-specific biomarkers (Table 3). Conclusion: Even in biological subgroups of AML expected to have sensitive disease, induction failure is not rare. Fortunately, the CBM could identify causes of failure and suggest alternative therapies based on co-occurring genomic abnormalities to mitigate the ineffectiveness of standard induction regimens in patients with resistant disease despite their favorable biology. The identification of patient-specific resistance mechanisms characterizes a new therapeutic imperative founded on deep molecular diagnosis that promises to enhance disease outcomes, inform treatment planning, avoid adverse events from ineffective therapies, and reduce costs. Also, computational modeling identifies alternate therapy regimens for refractory patients by incorporating patient-specific disease biomarkers. For all the non-responders, CBM identified 3 potential therapies across each fusion subgroup. Although these combinations need further validation in the clinic, the Cellworks CBM biosimulation platform allows for precision medicine approaches that target patient-specific disease biomarkers and treatment resistance mechanisms. Disclosures Castro: Cellworks Group Inc: Consultancy. Nair:Cellworks Research India Private Limited: Current Employment. Grover:Cellworks Research India Private Limited: Current Employment. Kumar:Cellworks Research India Private Limited: Current Employment. Agarwal:Cellworks Research India Private Limited: Current Employment. Suseela:Cellworks Research India Private Limited: Current Employment. Gopi:Cellworks Research India Private Limited: Current Employment. Ganesh:Cellworks Research India Private Limited: Current Employment. Shyamasundar:Cellworks Research India Private Limited: Current Employment. Kulkarni:Cellworks Research India Private Limited: Current Employment. Sauban:Cellworks Research India Private Limited: Current Employment. Balla:Cellworks Research India Private Limited: Current Employment. Chafekar:Cellworks Research India Private Limited: Current Employment. Choudhury:Cellworks Research India Private Limited: Current Employment. Mundkur:Cellworks Group Inc.: Current Employment. Macpherson:Cellworks Group Inc.: Current Employment. Kapoor:Cellworks Research India Private Limited: Current Employment. Howard:Boston Scientific: Consultancy; Cellworks: Consultancy; EUSA Pharma: Consultancy; Sanofi: Consultancy, Other: Speaker; Servier: Consultancy, Other: Speaker.

Survival Outcomes in Blastic Plasmacytoid Dendritic Cell Neoplasm By First-Line Treatment and Stem Cell Transplant

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with dismal clinical outcomes. Conventional chemotherapies were previously shown to have some clinical efficacy, however, long-term outcomes of BPDCN patients remain poor. In a recent clinical trial, SL-401 demonstrated an overall response rate (ORR) of 90% in previously untreated BPDCN patients. Despite promising outcomes observed in SL-401 studies, there remains a lack of data regarding the optimal first-line therapy. In this single institution retrospective study, we explored the survival outcomes based on front-line treatment and allogeneic stem cell transplant (allo-SCT). A total of 49 patients with confirmed diagnosis of BPDCN were included in the study. Median age at diagnosis was 71.4 (32.0-91.4) years with a male predominance (82%). Among these, 11 (22%) patients had concurrent hematologic neoplasms at the time of BPDCN diagnosis. The most common site of disease involvement was skin (n=42, 86%) followed by bone marrow (BM) (n=32, 65%), lymph node (LN) (n=13, 27%), and nasopharynx (n=2, 4%) with 14 (29%) and 5 (10%) patients having skin and BM involvement only, respectively. Of note, 17 (35%) patients had both skin and BM disease and 8 (16%) had simultaneous skin, BM, and LN involvement. In the front-line setting, CHOP-based regimens, hyper-CVAD, and SL-401 were used in 10 (20%), 11 (22%), and 12 (24%) patients, respectively. The median cycle number of SL-401 treatment was 6 (1-73). Allo-SCT was performed in 10 (20%) patients and 4 (8%) patients received autologous stem cell transplant (auto-SCT). Transplant was performed following first-line therapy in 11 patients (CR, n=10; PR, n=1) and second-line therapy in 3 patients (CR, n=3). Among 21 vs. 12 patients who received chemotherapy vs. SL-401 as their first-line therapy, a total of 11 (52%) and 3 (25%) patients underwent transplant. A total of 23 (55%), 13 (31%), and 6 (14%) patients achieved a complete response (CR), partial response (PR), and progressive disease (PD), respectively. CR rate was higher in patients who were treated with hyper-CVAD compared to others, however, it was not statistically significant (50% in CHOP-based regimens vs. 91% in hyper-CVAD, P=0.064; 50% in SL-401 vs. 91% in hyper-CVAD, P=0.069). The median PFS was 9.9 months and the median OS was not reached when all patients were included for the analyses. In the subgroup analyses, patients who were treated with hyper-CVAD had longest PFS compared to patients treated with CHOP-based regimens (HR=0.217, 95%CI=0.050-0.933, P=0.003) or SL-401 (HR=0.385, 95%CI=0.126-1.179, P=0.075) although the PFS difference between hyper-CVAD and SL-401 did not reach the statistical significance. There was no PFS difference between SL-401 and CHOP-based regimen treated groups (HR=0.931, 95%CI=0.321-2.70, P=0.894). In the OS analysis based on first-line therapy, there was no difference between patients treated with SL-401 compared to patients treated with chemotherapy regimens (HR=1.597, 95%CI=0.460-5.548, P=0.431). Further, there was no OS difference between individual types of front-line therapies (P=0.678). In contrast, patients who received allo-SCT showed significantly longer OS outcomes compared to patients with no transplant (HR=0.160, 95%CI=0.0453-0.56, P=0.041). Additional OS analyses based on age (&amp;lt;60 vs. ≥60) (HR=0.481, 95%CI=0.146-1.582, P=0.258), ASXL1 mutation (HR=1.705, 95%CI=0.2773-10.48, P=0.5649), or presence of previous or concurrent hematologic malignancy (HR=2.97, 95%CI=0.65-13.57, P=0.1602) did not show any statistical difference. In a multivariate Cox model (adjusting for age, front-line therapy, gender, and transplant) allo-SCT was significant factor for OS (HR=0.137, 95%CI=0.020-0.959, P=0.045). In conclusion, our study supports current recommendations of using SL-401 or hyper-CVAD as the first-line treatments followed by consolidation with allo-SCT in the eligible responders to induction therapy to further improve survival outcomes in BPDCN patients. Disclosures Lancet: Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Sokol:Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees.