Faculty Bibliography

Background: Overall survival (OS) in adults with ALL remains around 40%, but treatment with asparaginase (ASP)-containing pediatric-inspired regimens demonstrated a 3- or 4-year OS of 67-76%, including in patients with T-cell ALL, with manageable toxicities (Geyer 2020, Stock 2019, DeAngelo 2015). Recent studies in adults with reduced pegaspargase (PEG-ASP) doses showed survival outcomes similar to those with standard doses, with reduced toxicities, including pancreatitis, hepatic and thromboembolic events (Derman 2020, Patel 2020). Calaspargase pegol (ASPARLAS; Cal-PEG), similar to PEG-ASP, is an E. coli L-asparaginase covalently conjugated to monomethoxy polyethylene glycol, but with a more chemically stable succinimidyl carbonate linker, providing sustained asparagine depletion with less frequent dosing (every 21 days). The efficacy and safety of Cal-PEG 2500 U/m ², vs PEG-ASP 2500 U/m ², was evaluated in 2 multicenter, randomized clinical trials (AALL07P4 [n=166] and DFCI 11-001 [n=239]) in newly diagnosed patients with ALL <=21 years. Complete remission (CR), minimal residual disease (MRD), event-free survival (EFS), and OS were similar in both arms, with a 94% 5-year OS for Cal-PEG. The safety profile was consistent with that of PEG-ASP, with similar rates of hypersensitivity, pancreatitis, thrombosis, and hyperbilirubinemia (Vrooman 2021). Plasma asparaginase activity (PAA) levels were >=0.1 U/mL 25 days after the induction dose in 95% of patients (Angiolillo 2014). The absence of a standardized treatment and the inadequate outcome of adult treatment regimens, as well as a lack of targeted immunotherapies for T-ALL, highlight a critical unmet need for improved therapeutic approaches. A treatment protocol with less frequent Cal-PEG administration due to a more sustained asparaginase activity as well as age- and weight-based dose adjustments may improve clinical outcomes without added toxicities, and possibly extend the upper age limit of ASP-containing regimen for older adults. Trial Design: We present a clinical trial design of an ongoing, multicenter, phase 2/3 study (NCT04817761) assessing the safety and anti-leukemic activity of Cal-PEG in newly diagnosed patients with Philadelphia-negative B- or T-cell ALL. Patients aged >=22 years are eligible with ECOG performance status 0-2, no known history of pancreatitis, coagulopathy, CNS thrombosis or severe hepatic impairment. This trial comprises two parts: dose confirmation run-in (part 1) and the expansion phase (part 2). Part 1 is open for enrollment and is the focus of this abstract. Starting doses of Cal-PEG are based on the patients' age and BMI, with older patient groups assigned to lower doses (Table 1). A minimum of 4 (initial cohort) and up to 8 patients will be admitted per patient group. A total of 6 Cal-PEG doses will be administered during the treatment period as part of a multiagent chemotherapy regimen based on CALGB 10403 trial (Figure 1; Table 2), with end of treatment visit 1 year after the induction dose, and an additional 2 years of survival follow-up. The primary endpoints in part 1 are 1) the safety of Cal-PEG, including incidence of pre-defined unacceptable toxicities (UT) within 30 days after the induction dose and 2) PAA profiles, including achieving PAA >=0.1 U/mL at pre-specified time points. Secondary endpoints include immunogenicity, CR, end of induction and consolidation MRD, and 1-, 2- and 3-year EFS, disease-free survival, and OS. Bayesian optimal interval design (BOIN) will be used to evaluate UT with specified boundaries for dose confirmation, expansion, or reduction. For each patient group, the observed UT rate at a dose level will be compared with the safety boundary (23.6%) and toxicity boundary (35.8%) to guide safety confirmation. PAA data from previous pediatric studies and each run-in cohort will also be used to confirm the tested dose through population PK modeling-based predictions. The decision to confirm or adjust the dose will be based on the accumulated safety and induction PAA data at end-of-cohort meetings with the investigators, sponsor and in consult with DSMB recommendations. Part 1 started in July 2021 and will enroll =16-32 patients at multiple sites in the US. Part 2 will commence once the safety and PAA data from part 1 are analyzed and the expansion doses are confirmed. Up to 122 patients are expected to be enrolled in both phases of the trial. Clinical trial information: NCT04817761 [Formula presented] Disclosures: Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Park: Kura Oncology: Consultancy; Autolus: Consultancy; Intellia: Consultancy; Affyimmune: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; BMS: Consultancy; PrecisionBio: Consultancy; Minerva: Consultancy; Innate Pharma: Consultancy; Curocel: Consultancy; Servier: Consultancy; Artiva: Consultancy. Emadi: Secura Bio.: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder. Abdul-Hay: Jazz: Other: Advisory Board, Speakers Bureau; Servier: Other: Advisory Board, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Takeda: Speakers Bureau. Cassaday: Kite/Gilead: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Webster: AmGen: Consultancy; Pfizer: Consultancy. Pandya: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Mogul: Servier Pharmaceuticals: Current Employment. Shvenke: Servier Pharmaceuticals: Current Employment. Zhu: Servier Pharmaceuticals: Current Employment. Tessier: Servier: Current Employment. DeAngelo: Abbvie: Research Funding; Incyte Corporation: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Agios: Consultancy; Autolus: Consultancy; Forty-Seven: Consultancy; Blueprint Medicines Corporation: Consultancy; Jazz: Consultancy; GlycoMimetics: Research Funding. OffLabel Disclosure: Calaspargase pegol is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years, with recommended dosage of 2,500 units/m2 intravenously no more frequently than every 21 days
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Introduction. Prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (AHCT) remains a major challenge. The combination of methotrexate (MTX) and a calcineurin inhibitor has been the standard regimen for prophylaxis in patients receiving matched sibling donor (MSD) or matched unrelated donor (MUD) transplants for the past few decades. However, over 50% of patients undergoing AHCT still develop acute or chronic GvHD or even both, causing high rates of morbidity and mortality. Moreover, calcineurin inhibitors also have untoward toxic side effects. High dose post-transplant cyclophosphamide (PTCy), initially introduced for GvHD prevention in the setting of haploidentical transplantation, has now been studied in MSD and MUD transplants. We adopted a novel approach to prevent GvHD using a short course of PTCy and bortezomib. We hypothesized that such combination is safe and effective and omits the need for calcineurin or m-TOR inhibitors. Study Design. We report the outcomes of a prospective cohort of patients who received PTCy and bortezomib for GvHD prevention following MSD or MUD transplants. Twenty-eight patients were treated in a phase I-II trial and their clinical outcomes were previously reported (al-Homsi AS et al, BBMT 2019). Most of the remaining patients were treated on an extension trial. GvHD prevention consisted of PTCy 50 mg/kg IV on day +3 and +4, and bortezomib 1.3mg/m ² IV 6 hours after transplant and again 72 hours after. Patients receiving MUD transplants also received rabbit ATG (thymoglobulin) 5mg/kg total IV fractionated on day -4 to -2. All patients received peripheral blood grafts and standard supportive care as per Institutional policy. G-CSF was administered routinely until neutrophil engraftment. Results. Fifty-eight patients are included in this analysis. Median age was 60 (range 22-78) years. Fifty-three percent of patients were male. Underlying malignancies consisted of myeloid and lymphoid malignancies in 79.3% and 20.6%, respectively. Acute myeloid leukemia (50%) and myelodysplastic syndromes (24.1%) were the most common diseases. At transplant, disease risk index was low, intermediate, high and very high in 19.0%, 48.3%, 31.0% and 1.7% of patients, respectively. Median Pretransplant Assessment of Mortality Score (PAM) was 16.7 (5.4-29.4). Grafts were from MSD in 24.1% or MUD in 75.9% of patients. Recipient (R)/Donor (D) CMV status at transplant was as follows: R+/D+: 43%; R+/D-: 21%; R-/D+: 14% and R-/D-: 22%. Conditioning regimens consisted of reduced intensity fludarabine and busulfan in all but 2 patients who were conditioned with myeloablative fludarabine and busulfan. Overall, the regimen was remarkably well tolerated. Median times to neutrophil and platelet engraftment were 16 (13-28) and 26 (15-57) days respectively. No patient experienced primary graft failure. CMV and EBV reactivation rates were 46.6% and 24%. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35% (95% CI: 22%-47%) and 15% (95% CI: 7%-25%) at day +120, respectively. Cumulative incidence of chronic GvHD was 14% at 1 year. Overall, 34% of patients required immunosuppression with systemic steroids after day +4 either for grade III-IV acute or chronic GvHD. Disease relapse rate was 26%. One-year cumulative incidence of transplant-related mortality was 14% (95% CI: 6%-25%). Median overall survival was 30.7 (95% CI: 15.7-not yet reached) months. One-year overall survival was 72% (95% CI: 57%-82%). One-year composite GvHD (acute and chronic) free and relapse free survival (GRFS) was 41.6% (95% CI: 28.9%-54%). Conclusion. PTCy and bortezomib combination for GvHD prophylaxis following MSD and MUD transplants is well tolerated and effective. It offers an alternative regimen to calcineurin and m-TOR inhibitor-containing regimens and may be preferred in certain settings including patients with limited resources, poor medication compliance, and with impaired renal function. A comparison of this cohort to a matched control group of patients receiving methotrexate and cyclosporine for GvHD prevention is ongoing. Disclosures: Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Other: Advisory Board, Speakers Bureau; Jazz: Other: Advisory Board, Speakers Bureau; Abbvie: Consultancy; Takeda: Speakers Bureau. Al-Homsi: Celyad: Other: Advisory Board; Daichii Sanyko: Consultancy. OffLabel Disclosure: Cyclophosphamide and Bortezomib are used for GvHD prevention
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PURPOSE/UNASSIGNED:The recruitment of underserved patients into therapeutic oncology trials is imperative. The National Institutes of Health mandates the inclusion of minorities in clinical research, although their participation remains under-represented. Institutions have used data mining to match patients to clinical trials. In a public health care system, such expensive tools are unavailable. METHODS/UNASSIGNED:The NYU Clinical Trials Office implemented a quality improvement program at Bellevue Hospital Cancer Center to increase therapeutic trial enrollment. Patients are screened through the electronic medical record, tumor board conferences, and the cancer registry. Our analysis evaluated two variables: number of patients identified and those enrolled into clinical trials. RESULTS/UNASSIGNED:Two years before the program, there were 31 patients enrolled. For a period of 24 months (July 2017 to July 2019), we identified 255 patients, of whom 143 (56.1%) were enrolled. Of those enrolled, 121 (84.6%) received treatment, and 22 (15%) were screen failures. Fifty-five (38.5%) were referred to NYU Perlmutter Cancer Center for therapy. Of the total enrollees, 64% were female, 56% were non-White, and overall median age was 55 years (range: 33-88 years). Our participants spoke 16 different languages, and 57% were non-English-speaking. We enrolled patients into eight different disease categories, with 38% recruited to breast cancer trials. Eighty-three percent of our patients reside in low-income areas, with 62% in both low-income and Health Professional Shortage Areas. CONCLUSION/UNASSIGNED:Prescreening at Bellevue has led to a 4.6-fold increase in patient enrollment to clinical trials. Future research into using prescreening programs at public institutions may improve access to clinical trials for underserved populations.

Background: Autologous chimeric antigen receptor (CAR) T-cells targeting B-cell maturation antigen (BCMA) have shown impressive objective response rates in patients with advanced multiple myeloma (MM). CYAD-211 is a first-in-class, non-gene edited allogeneic anti-BCMA CAR T-cell product that uses an "all-in-one" vector approach to co-express, in addition to the CAR, a single optimized short hairpin RNA (shRNA) to down-regulate the expression of the T-cell receptor (TCR) CD3zeta subunit thus reducing the risk of graft-versus-host disease (GvHD). This non-gene editing technology does not permanently alter the genome integrity, therefore decreasing the potential safety risk associated with "off-target" genome modifications. Preclinical experiments demonstrated that persistence of allogeneic T-cells produced with shRNA technology is superior to cells engineered with gene-editing technologies.
Aim(s): The objective of the open-label Phase I IMMUNICY-1 (NCT04613557) trial is to evaluate the safety and clinical activity of a single infusion of CYAD-211 in relapsed or refractory MM patients.
Method(s): A bank of clinical- grade CYAD-211 cells was generated through a single production run using a portion of a single donor apheresis. The bank generated >1010 CYAD-211 cells suitable for the entire dose escalation segment and expansion cohort of the trial. Patients with relapsed or refractory MM with measurable disease as per the International Myeloma Working Group (IMWG) response criteria are eligible for the trial.
Result(s): As of the data cutoff of February 24, 2021, enrollment in the DL1 was completed (Table). Clinical activity evaluation was performed on Day (D) 22 and D36 for the first two patients with one confirmed partial response (PR) and one stable disease (SD). No dose-limiting toxicity nor Grade >= 3 treatment-related adverse events (AE) were reported. No immune effector cell-associated neurotoxicity syndrome (ICANS) nor GvHD were observed. One cytokine release syndrome (CRS) grade 1 was observed in the patient presenting the PR. CYAD-211 cells were detected by PCR-based method in the peripheral blood of the PR patient. Summary/Conclusion: The IMMUNICY-1 clinical trial seeks to provide the proof-of-principle that single shRNA-mediated knockdown can generate safe and functional allogeneic CAR T-cells in humans. The observed clinical activity at such low DL of 30x106 cells is encouraging in the allogeneic setting. Clinical and cell kinetics data from the completed first DLs will be presented at the time of the congress.The early stages of this trial continue to support the development of allogeneic CAR T-cell therapy as a feasible approach that may overcome many of the hurdles associated with autologous CAR-T cells

Graft-versus-host disease (GvHD) in its acute and chronic forms continues to represent a significant barrier to the success and wide-applicability of blood and marrow transplantation as a potentially curative treatment modality for a number of benign and malignant blood conditions. Presently, calcineurin inhibitor (CNI)-based regimens remain the most commonly used prevention strategy, although post-transplant cyclophosphamide is emerging as an alternative approach, and is providing a backbone for innovative CNI-free combinations. In this paper, we review the current strategies used for the prevention of GvHD, and highlight some of the developing and promising combinations.

Following allogeneic blood and marrow transplantation (BMT), graft-versus-host disease (GvHD) continues to represent a significant cause of treatment failure, despite the routine use of conventional, mainly calcineurin inhibitor-based prophylaxis. Recently, post-transplant cyclophosphamide (PTCy) has emerged as a safe and efficacious alternative. First, omitting the need for ex vivo T-cell depletion in the setting of haploidentical transplantation, growing evidence supports PTCy role in GvHD prevention in matched-related and matched-unrelated transplants. Through improved understanding of GvHD pathophysiology and advancements in drug development, PTCy emerges as a unique opportunity to design calcineurin inhibitor-free strategies by integrating agents that target different stages of GvHD development.

CYAD-01 cells are engineered T-cells expressing a chimeric antigen receptor (CAR) based on the natural full-length human natural killer group 2D (NKG2D) receptor fused to the intracellular domain of CD3zeta. NKG2D binds to 8 ligands (MICA, MICAB, and ULBP1-6) over-expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Phase I DEPLETHINK study (NCT03466320) evaluates the safety and preliminary efficacy of a single CYAD-01 infusion (inf.) after lymphodepletion with cyclophosphamide and fludarabine in patients with relapsed or refractory (r/r) AML and MDS. A second cycle of 3 CYAD-01 infusions without preconditioning could be administered in absence of progressive disease (PD) following the 1XX infusion. Three dose-levels (DLs; 1x10XX and 1x10XX cells/inf.) are evaluated in the dose escalation segment. The first DL is also evaluated at two different intervals between preconditioning and CYAD-01 infusion (T7: seven days interval; T3: three days interval) in order to mitigate for any potential increased toxicity due to the administration of lymphodepletion. As of end of July 2019, 6 patients (4 AML and 2 MDS) were enrolled in the first 2 cohorts which evaluated DL1 (1x10XX cells/inf. at T3 or T7) and 3 patients (3 AML) were enrolled in the cohort 3 evaluating DL2 (3x10XX cells/inf. at T3). The blasts in the bone marrow of 8 out of 9 patients ranged between 3% and 48% at baseline. Of the 6 patients treated at DL1 (with lymphodepletion administered up to 7 or 3 days before first CYAD-01 infusion), 3 patients experienced grade (G) 1 toxicity (cytokine release syndrome or CRS and diarrhea), or G2 CRS (uncleaned database). The patient with G2 CRS following the first infusion also experienced G4 CRS and G3 CAR T-cell-related encephalopathy syndrome (CRES) during the second inf. at 3x10XX cells/inf. One other patient experienced G1 CRS during the second cycle. At DL2, only 1 patient experienced G1 related AEs (diarrhea and CRS) after the first CYAD-01 infusion. Another patient experienced G3 CRS during the second cycle. All patients recovered with treatment including tocilizumab and, when indicated, steroids. At DL1, two out of 5 evaluable patients reached a stable disease (SD) at day (d) 36, allowing the initiation of the 2XX cycle. At DL2, one patient out of 3 reached SD. The DEPLETHINK study is currently enrolling at DL3 (T3). Preliminary correlative studies show that the area under the curve at d36 (AUC XX) after a single infusion of CYAD-01 with prior lymphodepletion is better than without preconditioning. Furthermore, the T3 interval between the preconditioning and CYAD-01 provides better engraftment than the T7 interval. In conclusion, to date, the results demonstrate the safety and tolerability for CYAD-01 doses 1x10XX cells/infusion with a prior lymphodepletion in patients with r/r AML and MDS. The T3 interval was therefore chosen for further CYAD-01 evaluations. The improved persistence of CYAD-01 with lymphodepletion, in particular 3 days before infusion, could lead to improved clinical responses. The study is ongoing and further data will be provided at the meeting. Disclosures: Al-Homsi: Celyad: Membership on an entity's Board of Directors or advisory committees. Abdul-Hay: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pollyea: Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lequertier: Celyad: Employment. Alcantar-Orozco: Celyad: Employment. Borghese: Celyad: Employment. Lonez: Celyad: Employment. Braun: Celyad: Employment. Renard: Celyad: Employment. Flament: Celyad: Employment.XXCopyright

Importance/UNASSIGNED:Anti-PD-1 (anti-programmed cell death 1) and anti-PD-L1 (anti-programmed cell death ligand 1) regimens are preferred therapies for many cancers, including cancers associated with HIV. However, patients with HIV were excluded from most registered trials. Objective/UNASSIGNED:The primary objective was to evaluate the safety of pembrolizumab in people with HIV and advanced cancer; the secondary objective was to evaluate tumor responses. Design, Setting, and Participants/UNASSIGNED:Open-label, nonrandomized, phase 1 multicenter study conducted at 7 Cancer Immunotherapy Trials Network sites. Patients with HIV and advanced cancer as well as a CD4 count greater than or equal to 100 cells/μL, antiretroviral therapy (ART) for 4 or more weeks, and an HIV viral load of less than 200 copies/mL were eligible. Exclusion criteria included uncontrolled hepatitis B or C infection, active immunosuppressive therapy, or a history of autoimmune disease requiring systemic therapy. Interventions/UNASSIGNED:Pembrolizumab, 200 mg, administered intravenously every 3 weeks for up to 35 doses in 3 CD4 count-defined cohorts. Participants continued ART. Main Outcomes and Measures/UNASSIGNED:Safety and tolerability were assessed using current NCI Common Terminology Criteria for Adverse Events. Immune-related adverse events grade 2 or higher were considered immune-related events of clinical interest (irECI). Tumor responses were evaluated using standard tumor-specific criteria. Results/UNASSIGNED:Thirty participants (28 men and 2 women; median [range] age, 57 [39-77] years) were enrolled from April 2016 through March 2018; 6 had Kaposi sarcoma (KS), 5 had non-Hodgkin lymphoma (NHL), and 19 had non-AIDS-defining cancers. Safety was observed over 183 cycles of treatment with pembrolizumab. Most treatment-emergent adverse events at least possibly attributed to pembrolizumab were grade 1 or 2 (n = 22), and 20% (n = 6) were grade 3. The irECI included hypothyroidism (6 participants), pneumonitis (3 participants), rash (2 participants), an elevated aminotransferase/alanine aminotransferase level (1 participant), and a musculoskeletal event (1 participant). One participant with pretreatment KS herpesvirus (KSHV) viremia developed a polyclonal KSHV-associated B-cell lymphoproliferation and died. HIV was controlled in all participants. Increases in CD4 count were not statistically significant (median increase, 19 cells/μL; P = .18). Best tumor responses included complete response (lung, 1 patient), partial response (NHL, 2 patients), stable disease for 24 weeks or more (KS, 2 patients), stable disease for less than 24 weeks (15 patients), and progressive disease (8 patients); 2 patients were not evaluable. Conclusions and Relevance/UNASSIGNED:Pembrolizumab has acceptable safety in patients with cancer, HIV treated with ART, and a CD4+ T-cell count of greater than 100 cells/μL but may be associated with KSHV-associated B-cell lymphoproliferation. Clinical benefit was noted in lung cancer, NHL, and KS. Anti-PD-1 therapy is appropriate for US Food and Drug Administration-approved indications and clinical trials in this population. Trial Registration/UNASSIGNED:ClinicalTrials.gov identifier: NCT02595866.