Determining Clinical Course of Diffuse Large B-Cell Lymphoma Using Targeted Transcriptome and Machine Learning Algorithms

Introduction: Multiple studies have demonstrated that diffuse large B-cell lymphoma (DLBCL) can be divided into subgroups based on their biology. However, these biological subgroups overlap clinically. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard of care for treating patients with DLBCL, predicting which patients will not benefit from such therapy is important so that alternative therapy or clinical trials can be considered. Most of the studies stratifying patients select biomarkers first, then explore how these biomarkers can stratify patients based on outcome. We explored the potential of using machine learning to first group patients with DLBCL based on survival, then isolating the biomarkers necessary for predicting these survival subgroups. Methods: RNA was extracted from tissue paraffin blocks from 379 R-CHOP treated patients with de novo DLBCL, and from 247 patients with extranodal DLBCL. A targeted hybrid capture RNA panel of 1408 genes was used for next generation sequencing (NGS). Sequencing was performed using an Illumina NextSeq 550 System platform. Ten million reads per sample in a single run were required, and the read length was 2 × 150 bp. An expression profile was generated from the sequencing coverage profile of each individual sample using Cufflinks. A machine learning system was developed to classify patients into four groups based on their overall survival. This machine learning approach based on Naïve Bayesian algorithm was also used to discover the relevant subset of genes with which to classify patients into each of the four survival groups. To eliminate the underflow problem commonly associated with the standard Naïve Bayesian classifiers, we applied Geometric Mean Naïve Bayesian (GMNB) as the classifier to predict the survival group for each patient. Results: Using machine learning, patients were first divided into two groups: short survival (S) and long survival (L). To refine this model, we used the same approach and divided the patients in each group into two subgroups, generating four groups: long survival in the long group (LL), short survival in the long group (LS), long survival in the short group (SL), and short survival in the short group (SS). The hazard ratio for this model was 0.174 (confidence interval: 0.120-0.251), and P-value <0.0001. After defining these four groups, a machine learning algorithm was used to discover the biomarkers from the expression data of the 1408 genes from NGS data. To reduce the effects of noise and avoid overfitting, we employed a 12-step cross validation to obtain a robust measure. For an individual gene, a generalized Naïve Bayesian classifier was constructed on the training of one of the 12 subsets and tested on the other 11 testing subsets. This allowed us to limit the prediction process to 60 genes for each separation step. Using the selected biomarkers, we classified the patients in the original set (379 patients) into LL, LS, SL, and SS groups and then evaluated the survival pattern of these groups. As shown in Fig. 1A, the selected biomarkers predicted survival as expected in the overall survival groups prior to biomarker selection. For additional validation of the system, we used the selected biomarkers to classify a completely new set of 247 samples of patients with extranodal DLBCL. As shown in Fig. 1B, these selected biomarkers successfully predicted the overall survival in this group of patients with an HR of 0.530 (confidence interval: 0.234-1.197, P=0.005). This classification correlated with cell of origin classification, TP53 mutation status, MYC expression, and IRF4 expression. However, in a multivariate analysis, only TP53 mutation was independent in predicting prognosis (P=0.005) and age (below or over 60) (P=0.01) along with the survival grouping (P<0.000001). Conclusions: Using a novel machine learning approach with the expression levels of 180 genes, we developed a model that can reliably stratify patients with DLBCL treated with R-CHOP into four survival subgroups. This model can be used to identify patients who may not respond well to R-CHOP to be considered for alternative therapy and clinical trials. Figure 1 Figure 1. Disclosures Hsi: AbbVie Inc, Eli Lilly: Research Funding. Ferreri: Ospedale San Raffaele srl: Patents & Royalties; BMS: Research Funding; Pfizer: Research Funding; Beigene: Research Funding; Hutchison Medipharma: Research Funding; Amgen: Research Funding; Genmab: Research Funding; ADC Therapeutics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; x Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Membership on an entity's Board of Directors or advisory committees. Piris: Millenium/Takeda, EUSA, Jansen, NanoString, Kyowa Kirin, Gilead and Celgene.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board; Actinium Pharma: Consultancy; Janssen: Other: Husband: Consultancy; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Epizyme: Other: Husband: Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria.

Pembrolizumab and Chemotherapy As First-Line Treatment of Patients with Newly Diagnosed Early Unfavorable or Advanced-Stage Classical Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study

Background: Immunotherapeutic strategies targeting the PD-1/PD-L1 pathway have become part of standard of care for patients with classical Hodgkin lymphoma (cHL). Recent studies have investigated combinations of anti-PD-1 antibodies with conventional chemotherapy and demonstrated significant clinical benefits in the first-line setting. A phase 2 trial demonstrated that induction with pembrolizumab monotherapy followed by chemotherapy was highly effective and safe in patients with newly diagnosed, early unfavorable, or advanced-stage cHL (Allen PB et al. Blood. 2020;137[10]:1318-1326). The KEYNOTE-C11 open-label phase 2 study will build on this concept by evaluating the safety and efficacy of sequential pembrolizumab monotherapy and chemotherapy followed by pembrolizumab consolidation in adult patients with newly diagnosed, early unfavorable, or advanced-stage cHL. Study Design and Methods: Patients must have newly diagnosed, histologically confirmed, untreated (no prior chemotherapy, immunotherapy, or other systemic therapy for cHL), early unfavorable cHL (Ann Arbor stage I/II plus ≥1 National Comprehensive Cancer Network unfavorable risk factor) or advanced-stage cHL (Ann Arbor stage III/IV) and measurable disease per Lugano 2014 classification. Approximately 140 patients will be enrolled. All patients will receive pembrolizumab 200 mg IV every 3 weeks (Q3W) for 3 cycles followed by PET to determine response to pembrolizumab monotherapy. After pembrolizumab induction, all patients will receive 2 cycles of AVD (day 1 and day 15 Q4W) and undergo another assessment by PET (PET 3) to determine the next treatment course. Patients with negative findings on PET 3 (≤3 on the Deauville 5-point scale) will receive 2-4 additional cycles of AVD, depending on stage and bulk of disease; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will proceed to 4 cycles of AVD chemotherapy. Patients who are PET 3+ (≥4 on the FDG-PEG 5-point scale) and aged <60 years will transition to 2-4 cycles of escBEACOPP; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will receive 4 cycles. Patients aged ≥60 years who are PET 3+ will not transition to escBEACOPP and will continue to receive AVD. Finally, all patients will receive 4 cycles of pembrolizumab 400 mg Q6W after the completion of chemotherapy. They will remain on study treatment until disease progression, unacceptable toxicity, illness preventing continuation, investigator's decision, or maximum duration of treatment, which will include 4 cycles of pembrolizumab consolidation. Adverse events will be graded per CTCAE version v5.0. The primary end point is complete response assessed by blinded independent central review (BICR) per Lugano 2014 response criteria. Secondary end points include complete response by investigator per Lugano 2014 response criteria, BICR-assessed PET negativity (score of 1, 2, or 3 per FDG-PET 5-point scale), BICR-assessed duration of complete response per Lugano 2014 response criteria, and safety and tolerability. Exploratory end points include modified progression-free survival and overall survival. The efficacy and safety analysis population will consist of all patients who received ≥1 dose of pembrolizumab. The complete response rate with 95% CI will be reported per the Clopper-Pearson exact binomial method. Duration of complete response, progression-free survival, and overall survival will be evaluated using Kaplan-Meier method. Counts and percentages of patients with adverse events will be provided. Disclosures Winter: Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy; Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria. Nahar: Merck: Current Employment. Kim: Merck: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder.

Hospitalization and Healthcare Resource Use of Omidubicel Vs Cord Blood Transplantation for Hematological Malignancies in a Global Randomized Phase III Clinical Trial

Introduction Umbilical cord blood (UCB) remains an important source of hematopoietic stem cells for patients, where no matched donor is available and for racial minorities. However, cord blood transplants have been associated with delayed hematopoietic recovery, prolonged hospitalization, and higher costs of transplant compared with other donor sources. Omidubicel is an advanced cell therapy that preserves stem cell function to optimize cell homing, engraftment, differentiation, and self-renewal and is manufactured from an appropriately HLA-matched single UCB unit for each patient. A recent phase III clinical trial (NCT02730299) reported that patients who received omidubicel experienced faster time to neutrophil engraftment, faster platelet recovery, reduced rates of infections and shorter hospitalization time than patients who received standard single (33%) or double (67%) UCB transplantation [Horwitz et al, Blood, 2021]. We report on an analysis of resource utilization including hospital length of stay, hospital care setting, visits by provider type, rates of transfusions and readmissions from the Phase III trial. Methods The Phase III clinical trial included patients aged 12-65 with hematological malignancies and eligible for an allogeneic transplant. The primary endpoint was time to neutrophil engraftment, with secondary endpoints of time to platelet engraftment, first grade 2/3 bacterial or fungal infections and days alive and out of hospital in the first 100 days. 125 patients were randomized in the study. We analyzed resource utilization data for patients treated with omidubicel (n=52) or UCB (n=56) ("as-treated population") focusing on resource utilization within the first 100 days of transplantation. Summary statistics were compared between treatment arms, means and medians used to draw comparison and significance testing was performed. Results In the Phase III clinical trial, omidubicel met its primary endpoint and secondary endpoints with statistical significance. The demographics and patient characteristics were overall well-balanced with slightly more males (52% vs 63%) and a lower median age (40 vs 36) in the UCB arm. The study population was diverse with 17.6% Black, 14.8% Asian, 14% Hispanic or Latino and 12% other/unknown. Most patients had AML (45%) or ALL (34.3%), with MDS, CML and lymphomas making up the rest of the study population. The disease risk index was high/very high in 35% of the patients and 24% of the patients had a Karnofsky/Lansky performance score of <90. The rapid hematopoietic recovery was supported by a reduced rate of infections. The rates of acute and chronic GVHD in the two arms were comparable. Within the first 100 days after transplant, omidubicel patients experienced shorter average total length of hospital stay than UCB recipients (mean 41.2 vs 50.8 days; p = 0.027) and more days alive and out of the hospital (mean 55.8 vs 43.7 days; p=0.023). 12% of patients on omidubicel arm died vs 16% on UCB arm before day 100. During the primary hospitalization (transplant to discharge), fewer omidubicel patients required intensive care unit (ICU) stay (9.6% vs 23.2%) and spent fewer days in the ICU (mean 0.4 vs 4.7 days; p =0.028) and the transplant unit (mean 25.3 vs 32.9 days; p =0.022) compared to UCB recipients. Omidubicel patients required fewer outpatient consultant visits and fewer outpatient non-consultant visits (X-rays, scans, biopsies etc.) and required fewer platelet or other transfusions (RBC, albumin, plasma, and factor product) within 100 days from transplant (Table 1). Conclusions This analysis shows that more rapid hematopoietic recovery in patients transplanted with omidubicel was associated with significantly shorter hospital length of stay and reduced healthcare resource use compared to UCB in the clinical trial. Although economic data were not collected as part of the clinical trial, the costs of providing transplantation care during the first 100 days are likely lower with omidubicel compared to UCB in the real-world setting, as hospital stay, outpatient visits, and blood product transfusions are among the major drivers of costs during this time period. Figure 1 Figure 1. Disclosures Majhail: Incyte Corporation: Consultancy; Anthem, Inc: Consultancy. Manghani: Gamida Cell, Inc.: Current Employment; Tricida, Inc.: Ended employment in the past 24 months. Sivaraman: Incyte Corporation: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Gamida Cell, Inc.: Current Employment. Galamidi-Cohen: Gamida Cell, Ltd: Current Employment. Maziarz: Bristol-Myers, Squibb/Celgene,, Intellia, Kite: Honoraria; CRISPR Therapeutics: Consultancy; Artiva Therapeutics: Consultancy; Intellia: Honoraria; Omeros: Research Funding; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties; Incyte Corporation: Consultancy, Honoraria; Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Allovir: Consultancy, Research Funding; Vor Pharma: Other: Data and Safety Monitoring Board.

Pembrolizumab (PEM) Added to ICE Chemotherapy Results in High Complete Metabolic Response Rates in Relapsed/Refractory Classic Hodgkin Lymphoma (cHL): A Multi-Institutional Phase II Trial

Introduction: Approximately 30-35% of patients with classic Hodgkin Lymphoma will prove refractory to frontline therapy or relapse subsequently. Traditional second-line chemotherapy regimens including ifosfamide, carboplatin, and etoposide (ICE) result in complete response rates of ~50%. Achievement of complete metabolic response (CMR) assessed by PET/CT imaging prior to autologous hematopoietic stem cell transplant (AHSCT) predicts favorable progression free survival (PFS) and overall survival (OS). PD-1 blockade is a well-established therapeutic strategy for the treatment of cHL. Pembrolizumab (PEM) is a checkpoint inhibitor targeting PD-1 currently FDA approved as monotherapy in relapsed cHL. We hypothesized that PEM in combination with ICE (PEM-ICE) chemotherapy would be a safe and effective regimen that would yield high CMR rates prior to AHSCT. Methods: This single arm, phase II, multi-institutional clinical trial evaluated the addition of PEM to ICE chemotherapy in AHSCT eligible patients with relapsed and refractory cHL (NCT03077828). The regimen consisted of 21 day cycles of PEM 200 mg IV on day 1 with standard ICE including ifosfamide 5 g/m2 with MESNA as a 24hr continuous infusion on day 2, carboplatin AUC 5 IV (max 800 mg) on day 2, and etoposide 100 mg/m2/day IV on days 1 to 3. Two cycles of PEM-ICE were followed by stem cell mobilization/collection. One cycle of PEM 200 mg IV monotherapy was then administered. Our primary endpoint was the rate of CMR on PET/CT (PET2) imaging defined as a Deauville score of ≤ 3. Images were reviewed centrally. An optional third cycle of PEM-ICE was permitted for patients achieving CMR to allow for appropriate timing of AHSCT. Secondary objectives included clinical outcomes (PFS and OS), safety and tolerability, and transplantation related metrics including ability to collect stem cells and time to engraftment. Results: A total of 42 patients were enrolled with 37 patients evaluable for the primary endpoint. Median age was 34 (19-70) with female predominance (n=27, 64%). 16 patients had primary refractory disease. The CMR rate assessed by PET/CT imaging following 2 cycles of PEM-ICE was 86.5% (95% CI, 71.2-95%), meeting our primary endpoint of improvement over historical outcomes to 70%. The PET2 ORR was 97.3% with 11% PR and 2.7% PD. PET2 scores were Deauville 1 in 45% (n=17), Deauville 2 in 27.0% (n=10), Deauville 3 in 8.1% (n=3), Deauville 4 in 13.5% (n=5), and Deauville 5 in 5.4% (n=2). New areas of PET-positivity in two cases were biopsied showing noncaseating granuloma in one case and EBV but no cHL in another. Five patients received the optional third cycle of PEM-ICE chemotherapy with 35 of the 37 evaluable patients proceeding to AHSCT. Seven patients had radiation as part of the conditioning regimen with an additional 4 patients receiving consolidative radiation following transplant. After a median follow up of 27 months, the median PFS was 26.9 months with survival probability at 24 months of 88.2% (Figure 1). Median OS was not reached with too few events but remained 95.1% at 27 months. The addition of PEM to ICE did not impair stem cell mobilization and all patients successfully collected, with 35 (87%) within 2 apheresis sessions (range 1-7). No patients had engraftment delays or failure. Of the 42 patients, all received at least one dose of PEM and were therefore eligible for toxicity analyses. 34 patients (81%) experienced adverse events (AEs) attributed to PEM and 22 patients (52.3%) had grade 3-4 AEs comprised of cytopenias, elevated AST/ALT, hyponatremia, hypophosphatemia, and fatigue. Five patients had severe AEs attributed to PEM which included anemia, back pain, decreased EF, fever, and thrombocytopenia. There were no significant PEM-related autoimmune events that delayed a patient's treatment on protocol. There were two grade 5 toxicities on the protocol including a patient with cardiac arrest during stem cell collection and a patient with acute respiratory distress syndrome attributed to engraftment syndrome. Both were judged "possibly" related to PEM. Conclusions: Pembrolizumab with ICE chemotherapy is a tolerable and efficacious regimen with high CMR rate as assessed by PET/CT. Despite short follow up, patients had excellent PFS and OS in the post-transplant setting. The results support further investigation of PEM-ICE as second-line treatment for AHSCT eligible patients with relapsed and refractory classical Hodgkin lymphoma. Figure 1 Figure 1. Disclosures Casulo: BMS: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Allen: Kyowa Kirin: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy, Honoraria; Secure Bio: Consultancy, Honoraria. Karmali: Epizyme: Consultancy; AstraZeneca: Speakers Bureau; Roche: Consultancy; Genentech: Consultancy; EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; Karyopharm: Consultancy; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Winter: Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy. OffLabel Disclosure: new combination of study agent with standard of care chemotherapy regimen

Phase I Study of Novel SYK Inhibitor TAK-659 in Combination with R-CHOP for Front-Line Treatment of High Risk Diffuse Large B-Cell Lymphoma

Background: DLBCL is highly heterogeneous in underlying biology and clinical behavior. Several high-risk disease features and poor prognostic factors are associated with a higher propensity for refractory disease or relapse after standard R-CHOP therapy; these subset patients require novel strategies to improve upon outcomes. Single-agent TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pre-treated DLBCL (Gordon et al., Clin Cancer Res, 2020). We report results of a phase I single institution, single arm dose escalation study that assessed safety of 1 st line treatment with R-CHOP and adjunctive TAK-659 for treatment naïve high-risk DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage I-IV DLBCL with high-risk features defined as, ABC/non-GCB subtype, high-intermediate or high-risk NCCN-IPI (score ≥4), MYC gene rearranged by FISH including double hit lymphoma (DHL), double expressing DLBCL (DEL; overexpression of MYC ≥40% AND BCL2 ≥50% by IHC respectively), or previously treated transformed low-grade lymphoma without prior exposure to anthracycline, were eligible. Patients were treated with R-CHOP for 1 cycle on or off study followed by combined treatment with R-CHOP and TAK-659 for an additional 5 cycles on study. TAK-659 was dosed daily with dosing escalated from 60mg (dose level 1), to 80mg (dose level 2) to 100mg (dose level 3) based on a 3+3 design. The primary objective was to determine the safety and establish the maximum tolerated dose of TAK-659 when combined with R-CHOP in the front-line treatment of high-risk DLBCL. Secondary objectives were to assess preliminary efficacy of this combination as determined by overall response rate (ORR) by PET-CT (Lugano 2014 criteria), progression free survival (PFS), overall survival (OS) and establish the pharmacokinetics of TAK-659 according to dose. Results: 12 pts were enrolled from Dec 2019 to Nov 2021. The median age was 64 yrs (range 25-75); 8 (67%) had stage III/IV disease, 4 (33%) with high risk NCCN-IPI ≥ 4. Histology included 7 (58%) with de novo DLBCL (4 GCB, 3 non-GCB subtype DLBCL) including 7 (58%) with DEL, 3 (25%) with transformed FL, 1 (8%) with Richter's and 1 (8%) with DHL. Dose level 3 (100 mg) was established as the MTD. PKs were measured pre- and post-dose D1 and D15 of cycle 2; Cuzick's test signaled an increase in AUC by dose level on D1 (p = 0.01) but not on D15 (Fig 1). ORR was 100% (CR 92%; Fig 2). With a median follow-up of 14.2 months, 1 pt had primary refractory disease (ABC and DEL), 2 pts with CR subsequently progressed (1 non-GC DLBCL, 1 Richter's) and 1 died of cardiogenic shock unrelated to study drug. The 12-month PFS and OS rates were 82% and 90% respectively with estimated 18-month PFS and OS rates of 68% and 90% respectively. The most common treatment related adverse events (TRAEs) attributed to TAK-659 were lymphopenia (n=12, 100%), infection (6=, 50%), AST elevation (n = 12, 100%) and ALT elevation (n = 10, 83%) (Table). Incidence and severity of transaminitis was consistent with prior reports for this agent. Most common grade 3/4 toxicities were hematologic. Median number of cycles of TAK-659 delivered was 5 (range 3-5). TRAEs led to TAK-659 dose modifications in 8 (67%) pts, though none at dose level 1: 2 (17%) required permanent dose reductions (both for lung infections), while 5 (42%) required discontinuation (4 for infection, and 1 for febrile neutropenia). R-CHOP administration was delayed in 2 pts because of TAK-659 related TRAEs. Aside from dose modifications of vincristine for peripheral neuropathy, no additional dose modifications for R-CHOP were needed. Infections encountered included bacterial and opportunistic infections (1 each for PJP, CMV and aspergillosis) and 1 case of COVID. Growth factor prophylaxis and anti-fungal therapy were not mandated; PJP prophylaxis was advised for CD4 counts < 200 at initial diagnosis. Conclusion: TAK-659, a novel SYK inhibitor combined with R-CHOP in pts with newly diagnosed high-risk DLBCL including DLBCL transformed from follicular lymphoma and DEL produces high CR rates; survival at 12 months appears promising. A dose of 60 mg was well tolerated, did not require dose modifications and maintained a similar AUC to the MTD of 100 mg with ongoing treatment. Opportunistic infections were noted with this treatment combination suggesting that patients should receive aggressive anti-microbial prophylaxis with future evaluation of this combination. Figure 1 Figure 1. Disclosures Karmali: BeiGene: Consultancy, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding; Karyopharm: Consultancy; EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; AstraZeneca: Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; Roche: Consultancy. Ma: Beigene: Research Funding, Speakers Bureau; Juno: Research Funding; AstraZeneca: Honoraria, Research Funding, Speakers Bureau; Loxo: Research Funding; Janssen: Research Funding, Speakers Bureau; Abbvie: Honoraria, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Actinium Pharma: Consultancy; Janssen: Other: Husband: Consultancy; Epizyme: Other: Husband: Data and Safety Monitoring Board; Gilead: Other: Husband: Consultancy; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. OffLabel Disclosure: TAK-659 will be discussed for the treatment of DLBCL (not FDA approved for this indication)

A Phase 1 Trial of Regorafenib in Advanced Myeloid Malignancies

BACKGROUND: Angiogenesis is increasingly known to play a role in pathogenesis of hematologic malignancies, including myeloid neoplasms. Regorafenib is a multikinase inhibitor that targets angiogenic, stromal and oncogenic kinases including VEGF- 1, 2, 3, TIE-2, PDGFR-β,c-KIT, rRET, RAF-1, FGFR-1, BRAF and p38 MAP kinase. As a result of regorafenib's broad inhibition of kinases and its effects on angiogenesis, this drug has the potential to overcome the limitations of more selective kinase inhibitors and may be associated with efficacy in various myeloid neoplasms, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). METHODS: We conducted a single-center, open-label, dose-escalation and expansion phase I trial in patients with relapsed/refractory AML, MPN, or MDS to assess the safety, tolerability, and preliminary efficacy of regorafenib and identify the recommended phase 2 dose (RP2D). A 3+3 dose escalation design was used with 2 planned dose levels (120 mg or 160 mg daily in 28-day cycles), as well as 1 de-escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. RESULTS: Six patients were enrolled during the dose escalation phase (3 at 120 mg daily followed by 3 at 160 mg daily), with no DLTs, as defined by a Grade >3 toxicity occurring within the first 28 days after initiation of treatment, and unrelated to the myeloid neoplasm. Therefore, the RP2D of regorafenib was identified as 160 mg daily. Ten additional patients were enrolled on this dose during the expansion phase. The median age was 74 (range 36-84), and 13 (81%) patients were male. Diagnoses included 7 AML, 6 MDS, and 3 MPN patients (Table 1). Dose modifications and delays occurred in 5 and 4 patients, respectively. The median duration of treatment was 56 days or 2.5 cycles (range: 5-410 days, 1-15 cycles). Of the 16 patients, the best overall disease response as measured by IWG criteria included partial remission (in 1 patient with AML), stable disease in 12 (2 de novo AML, 2 secondary AML, 3 MPN, and 5 MDS) patients, and progressive disease in 3 (1 MDS and 2 secondary AML) patients. An initial improvement in absolute neutrophil count and/or hemoglobin was observed in the 6 MDS patients, although this did not meet criteria for hematologic improvement by IWG criteria. All patients have discontinued off treatment. The most frequent Grade 3-4 adverse effects (AEs) included liver function test abnormalities (5.1%), fatigue (4.3%), thrombocytopenia (3.4%), and neutropenia (3.4%) (Table 2). The majority of AEs were grades 1-2. CONCLUSIONS: Regorafenib demonstrates an acceptable safety profile in relapsed/refractory myeloid malignancy patients, a population where few treatment options exist. The majority of patients achieved stable disease. Modest improvements in cell counts were observed in MDS patients, and we are performing correlative studies to clarify regorafenib's mechanism of action and identify populations which may benefit from treatment. Disclosures Amrein: AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Brunner:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Fathi:Kura Oncology: Consultancy; Trillium: Consultancy; Boston Biomedical: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Blueprint: Consultancy; Kite: Consultancy; Trovagene: Consultancy; Forty Seven: Consultancy; Newlink Genetics: Consultancy; Novartis: Consultancy; BMS/Celgene: Consultancy, Research Funding. Narayan:Sanofi-Genzyme: Other: Current Spouse employment ; Takeda: Other: Prior Spouse employment within 24 months; Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months. Neuberg:Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Celgene: Research Funding. Chen:Takeda: Consultancy; Magenta: Consultancy; Equillium: Other: Data and Safety Monitoring Board Member; AbbVie: Other: Data and Safety Monitoring Board Member; Incyte Corporation: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Kiadis: Consultancy. Hobbs:Merck: Research Funding; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Jazz: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Bayer: Research Funding. OffLabel Disclosure: Regorafenib was used to assess safety and preliminary efficacy in advanced myeloid malignancies

Utilization of Telemedicine for Comprehensive Visits in Patients with Inherited Bleeding Disorders during the COVID-19 Pandemic

Standard of care for individuals with inherited bleeding disorders includes an annual in person multi-disciplinary comprehensive visit at the Hemophilia Treatment Center (HTC). During the COVID-19 pandemic in person visits were restricted, with mandates to only schedule in person urgent visits and to "stay at home." In order to provide annual visits to as many patients as possible, we developed a quality improvement (QI) project to conduct annual visits via telemedicine (TM), including nursing (RN), physician (MD), social work (SW), and physical therapy (PT) assessments. Our aim was to increase annual comprehensive clinic visits conducted by TM for eligible patients from 0 to 50% between April 1 and June 30, 2020, extended through July 31, 2020 due to the prolonged pandemic. Patients due for an annual visit were contacted by medical assistants (MA) to schedule either a TM (through EPIC MyChart) or an in person visit. MAs were trained on which patients were eligible for a TM visit and how to set-up MyChart remotely. Prior to the visit patients were provided verbal, written, and video instructions on how to attend the TM visit. Quantitative and qualitative data were collected at the time of scheduling and during the visit. Forty-eight patients were scheduled for an annual visit during the QI timeframe. TM visits were not offered to 28 patients for a variety of reasons (first comprehensive clinic visit, need to re-establish or transfer care, need for required laboratory testing, or joint disease requiring in person PT evaluation). Out of the 20 patients who were eligible for a TM visit, 14 (70%) accepted. The two main reasons for declining TM visits were personal preference for an in person visit and preference to not use/activate MyChart. Table 1 compares the characteristics of patients who completed their annual visit via TM versus in person. Of the 14 patients who accepted TM visits, 11 completed the visit and 3 were no-shows. All four adolescent patients who attended their TM completed their annual transition questionnaire online prior to the visit. Of the 11 patients who completed TM visits, 4 (36.3%) saw the same providers during both their TM visit and in person visit the year prior. Of those who saw fewer providers during the TM visits, the most commonly missed providers were the dietician and genetic counselor. TM visits were primarily conducted through two-way audio and video communication within MyChart, while 1 was through Zoom and the other by audio only. Eight of the 11 (72.7%) TM visits had technical issues, including difficulty connecting to MyChart and poor internet connection requiring the remainder of the visit to be completed by audio only. Despite the technical issues, the majority of patients (81.8%) stated that they would prefer in person visits over TM visits in the future. The most common reasons for preference of TM visits in the future were convenience and ability to avoid the clinic during the pandemic. The HTC team members also perceived that TM visits ran more efficiently than the in person visits despite the technical issues during the visits. For in person visits, families were pre-screened by phone and at the time of arrival for symptoms of COVID-19, exposures, and travel outside of US. Two patients only reported potential exposure/travel to the providers in the HTC clinic, which required isolation and use of additional personal protective equipment (PPE). Overall, we increased the number of annual comprehensive clinic visits conducted by TM from 0 to 70% for eligible patients between April 1 and July 31, 2020 during the COVID-19 pandemic. Although there were technical difficulties with the TM visits, the majority of patients found the TM visit to be convenient and expressed a preference for TM for future visits. TM visits reduced potential exposures and use of PPE. Future interventions to improve TM visits include promoting MyChart utilization, additional education for patients regarding logistics of connecting to a TM visit, and additional education for providers regarding the troubleshooting of technical issues. Future QI measures may include patient satisfaction, duration of TM compared to in person visits, and need for additional care coordination post TM visit. In addition, impact on patient outcomes (such as need for return visits or bleeds) should also be evaluated. Disclosures Thornburg: Bluebird Bio: Consultancy; Biomarin: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; NovoNordisk: Research Funding; Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; Spark Therapeutics: Consultancy; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharmaceuticals: Research Funding; American Thrombosis and Hemostasis Network: Research Funding.

Pharmacokinetics and Safety of KRN7000 Following Intravenous Infusion of RGI-2001 in Allogeneic Transplant Patients

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an important therapeutic option, and, in some indications, the only potentially curative therapy, for the treatment of a variety of hematologic malignancies. The success of myeloablative alloHSCT derives both from the ability to treat subjects with intensive chemo radiotherapy and from potent graft-versus-leukemia (GvL) effects mediated by donor immunity. Donor T cells in the infused stem cell graft are used to attack malignant cells, but may also strike normal host tissues and organs, resulting in graft versus host disease (GvHD). Despite the use of immunosuppressive agents, GvHD, acute or chronic, is one of the leading causes of morbidity and mortality from alloHSCT. RGI-2001 is a liposomal formulation which contains the active pharmaceutical ingredient, KRN7000. KRN7000 is the first synthetic derivative of α-galactosylceramide (α-GalCer) compound isolated originally from the marine sponge Agelas mauritianus, which is a representative ligand for invariant natural killer (iNKT) cells. RGI-2001 activates a tolerogenic cellular pathway via iNKT cell activation, which ultimately leads to the activation of cellular cascades including regulatory dendritic cells (DCreg) and Tregs. Tregs are upregulated via an IL-4 dependent mechanism produced by iNKT cells. These antigen-specific Tregs have been shown to down regulate the immune response directed toward specific antigens without causing generalized immunosuppression while preserving graft-versus-leukemia effect (GvL). RGI-2001 is being evaluated for the potential to reduce or prevent GvHD post allogeneic transplantation. The aim of this analysis was to characterize the pharmacokinetic (PK) profile of RGI-7000 following weekly intravenous infusions of RGI-2001. Methods: RGI-2001-003 is an open label, multi-center phase 2b study to evaluate the safety and efficacy of RGI-2001 for the prevention of acute GvHD in subjects following alloHSCT. Blood samples were collected for quantification of plasma concentrations of RGI-7000 predose and 0.5, 2, 4, 6, 8, 24, and 48 h after the first dose and predose, 0.5, and 4 h post dose on Day 14. Maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), area under the concentration time curve (AUC) and terminal half-life (T1/2) we calculated by non-compartmental analysis. Results: A total of 6 subjects were evaluated in this safety phase of the study. All subjects received RGI-2001 100 µg/kg as a 30-minute IV infusion weekly for a total of 6 doses post alloHSCT. Subjects were 66.7% male, 33.3% white, 66.7% not-Hispanic or Latino. Mean age was 44 years (range 25-61 years), matched unrelated donors 83.3%. All subjects received donor PBSCT. Dose limiting toxicities (DLT) was evaluated for each subject on day 30. Mean preliminary and interim pharmacokinetic parameters (%CV) are shown in Table 1. Repeat weekly infusion of RGI-2001 lead to generally similar exposure on the first dose and Day 14. There were no deaths, no serious adverse events and no discontinuations related to study drug. There were no DLT reported. The most common treatment emergent adverse events were mucositis, pruritis/rash or erythema, decreased appetite. One infusion-related reaction (Grade 2) was reported in 1 subject and event resolved. Conclusions: Intravenous administration of RGI-2001 resulted in quantifiable levels of RGI-7000 in all patients. Plasma levels of RGI-7000 were similar after the first dose and multiple doses. Its plasma half-life was approximately 36 hours. Disclosures Chen: AbbVie: Other: Data and Safety Monitoring Board Member; Actinium: Other: Data and Safety Monitoring Board Member; Kiadis: Consultancy; Magenta: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy; Equillium: Other: Data and Safety Monitoring Board Member. Lane:Nanoscope Therapeutics: Consultancy; Regimmune Corporation: Consultancy; Revolution Medicines: Consultancy; Star Therapeutics: Consultancy; Valitor: Consultancy; Viewpoint Therapeutics: Ended employment in the past 24 months; Cleave Therapeutics: Consultancy.

BTK and/or PLCG2 Mutations in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Ibrutinib: Characteristics and Outcomes at the Time of Progression

INTRODUCTION Mutations in BTK and PLCG2 have been reported to occur in ~80% of CLL patients (pts) who have progression of disease on ibrutinib therapy (Woyach, JCO 2017; Ahn, Blood 2017). These mutations are described as appearing months before actual relapse and thus considered as a potential predictive biomarker for future relapse (Quinquenel, Blood 2019). However, the outcomes of these pts after disease progression are not well described. In this study, we seek to investigate time to next therapy and overall survival (OS) following progression among CLL pts on ibrutinib therapy with and without these resistance mutations. METHODS Between 10/2012 and 6/2019, we identified 34 pts in the Mayo Clinic clinical CLL resource who progressed while receiving ibrutinib therapy and also had testing for BTK and PLCG2 mutation performed as part of routine clinical practice at either NeoGenomics Laboratories or The Ohio State University. OS was calculated from time of ibrutinib progression to last known alive or death date; OS was plotted using Kaplan Meier methods and was compared using the log-rank test between various groups (e.g., mutation positive vs negative; CLL progression vs Richter's). Cumulative incidence of time to next treatment in those who had a treatment after progression was adjusted for the competing risk of death. RESULTS Of 34 pts who progressed while receiving ibrutinib, 26 pts experienced CLL progression and 8 pts had Richter's transformation; baseline characteristics in Table 1A. The presence of a BTK or PLCG2 mutation was found in 20/34 (59%) pts (specific mutations in Table 1B). BTK mutation alone was present in 9 pts, 7 pts had PLCG2 mutation alone, and 4 pts had both mutations. Median time between a positive test and start of next therapy was 4 months (range 1-19 months) and did not vary between BTK vs PLCG2 mutations. Among the 26 pts with CLL progression, 18 (69%) pts had a mutation present: BTK alone (n=8), PLCG2 alone (n=6), both (n=4). Therapy following progression on ibrutinib in these pts was as follows: venetoclax (n=16; 11 pts who continued ibrutinib in combination), idelalisib (n=4), investigational treatments (n=2), continued ibrutinib alone (n=2), dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; n=1), and unknown (n=1). Twelve of the 26 pts with CLL progression on ibrutinib, including 8 pts with a prior resistance mutation detected, had subsequent progression of disease on the aforementioned next line therapy. Treatment of these patients consisted of the following: restarted ibrutinib in addition to current treatment of venetoclax (n=5), venetoclax (n=2), pembrolizumab (n=2; 1 pt with continued ibrutinib), obinutuzumab with continued ibrutinib (n=1), gemcitabine and vinorelbine with continued ibrutinib (n=1), and no further treatment (n=1). Among the 8 pts with Richter's transformation as the initial progression event on ibrutinib after mutation testing, 1 pt had a BTK mutation and 1 pt had a PLCG2 mutation. Treatments following progression on ibrutinib included multi-agent chemoimmunotherapy (n=3; 2 pts received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP] with continued ibrutinib and 1 pt received doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD] alone), pembrolizumab (n=3; 1 pt in combination with continued ibrutinib), venetoclax in combination with continued ibrutinib (n=1), and venetoclax and obinutuzumab (n=1). The median time to next treatment (second line of treatment beyond ibrutinib) for the 31 pts who started another therapy following progression on ibrutinib was 16.7 months (95% CI 9.6-NE; Figure 1A) and was not significantly different for pts with or without a resistance mutation (p=0.57). Median OS for all 26 pts with CLL progression was 28.7 month and there was no difference according to presence or absence of a resistance mutation (median 28.7 months vs 18.2 months, p=0.53; Figure 1B). The 8 pts with Richter's transformation had a median OS of 7.1 months (95% CI 2.0-NE). CONCLUSION Approximately 60% of pts tested in this progression cohort had a BTK or PLCG2 mutation at time of or preceding progression on ibrutinib therapy. OS and time to next therapy did not differ statistically between pts with mutated vs non-mutated clones; however, caution should be applied with the conclusions given the limited sample size. Disclosures Ding: DTRM Biopharma: Research Funding; Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Parikh:Ascentage Pharma: Research Funding; Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding.

Characterizing the Use of Direct Oral Anticoagulants in Children Using the American Thrombosis and Hemostasis Network Dataset (ATHNdataset)

Background: The incidence of venous thromboembolism (VTE) in children has risen significantly. (Raffini, Huang et al. 2009) There are currently four direct oral anticoagulants (DOACs) - apixaban, dabigatran, edoxaban, and rivaroxaban - approved for the acute treatment and prevention of VTE in adults. Advantages of these medications over the traditionally used anticoagulants, enoxaparin and warfarin, include fixed dosing, no need for routine laboratory monitoring, few drug interactions and no dietary restrictions. Despite lack of information on the safety and efficacy of these agents in children, pediatric hematologists across the United States are using DOACs in their patients based on extrapolated data from adult studies. The American Thrombosis and Hemostasis Network (ATHN) is a nonprofit network of over 140 federally funded Hemophilia Treatment Centers (HTCs) which provides the infrastructure for clinical and surveillance-based research. ATHN maintains the ATHNdataset (ADS), a "limited dataset" free of protected health information, with data collected on patients with bleeding and clotting disorders at participating HTCs within the Human Resources and Services Administration (HRSA)-supported regional hemophilia networks across the US. The authors acknowledge ATHN, the ATHN-affiliated U. S. Hemophilia Treatment Centers and their 39,000+ patients who have contributed their demographic, clinical, and genetic information to the ATHNdataset. Methods: The objective of this study was to describe the characteristics of pediatric patients diagnosed with VTE in the ADS, focusing on those patients who received a DOAC. Data were abstracted for patients in the ADS who had acute VTE at age <21 years from January 2010 to March 2019. Data extraction included basic demographics and information about VTE and treatment. Results : A total of 1,094 pediatric VTE cases were captured in the ADS. 577 (52.7%) were male. Caucasians were the most prevalent racial group (n = 809; 74%), followed by African-Americans (n = 203; 18.6%).14.9% (n = 163) were Hispanic. Deep venous thrombosis (DVT) was the most prevalent pediatric VTE reported in the ADS (n=889, 81.3%), followed by pulmonary embolism and cerebral venous thrombosis (n=130, 11.9% and n=40, 3.7% respectively). VTE location by age group is listed in Table 1. The most common DVT location was the lower extremities or pelvis, comprising 37.5% (n = 333) of all reported DVTs. Upper extremities or upper thorax DVT occurred less often (n = 211; 23.8 %). 345 (38.8 %) cases were reported only as "DVT" without a specific thrombus location. We reviewed 1,051 anticoagulant prescriptions for 650 VTE patients (mean 1.6 prescriptions per person). Enoxaparin was the most commonly prescribed anticoagulant (n = 676 prescriptions; 64.3%) followed by warfarin (n = 178 prescriptions, 16.9%). Interestingly, 116 (11%) patients, from 21 HTCs, had a DOAC prescribed as their anticoagulant regimen. Anticoagulant prescription by anticoagulant starting age is shown in Table 2. Further analysis of the DOAC subgroup showed that rivaroxaban was the most prescribed DOAC with 77.6% (n = 90/116) of the patients using this agent. Apixaban and dabigatran use was also reported (n= 23, 19.8% and n= 3, 2.6% respectively). The majority of DOACs were prescribed for patients older than 13 years of (111/116, 95.7 %). In children between 3 to 6 years of age (n = 3), rivaroxaban was the only DOAC prescribed. DOACs were primarily used to treat DVT of the extremities (84/116 patients). Other scenarios in which DOACs were also prescribed were PE and abdominal venous thrombosis patients (26, and 4 patients, respectively). Anticoagulant prescription by anticoagulant starting age is shown in Table 2. Conclusion: DVT of the lower extremities and pelvis is the most prevalent pediatric VTE in the ADS. Enoxaparin and warfarin remain the main anticoagulant agents used for pediatric VTE treatment. Despite lack of an FDA-approved pediatric indication, hematologists in US-based HTCs are already using DOACs in pediatric patients with VTE. As further characterization of DOAC use in children is needed, the authors, in collaboration with ATHN, are currently building a multi-institutional retrospective and prospective registry, ATHN 15. This registry will serve as a resource for pediatric hematologists to collect real-world use of DOACs in children, as we await the results of prospective clinical trials. Disclosures Davila: Octapharma: Other: Grant to attend VWD meeting ; Genentech: Other: Advisory board; Spire Learning: Speakers Bureau. Raffini:Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board; Roche: Other: Advisory Board. Thornburg:Sanofi Genzyme: Research Funding; Bluebird bio: Other: Data Safety Monitoring Board; Genentech: Speakers Bureau; NovoNordisk: Research Funding; Ironwood: Other: Data Safety Monitoring Board; Sanofi Genzyme: Other: Data Safety Monitoring Board. Corrales-Medina:Octapharma: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding.