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Efficacy of PTCy after mismatched unrelated donor (MMUD) HCT is unknown. In this pilot clinical trial, we enrolled 38 patients with hematologic malignancies scheduled to undergo MMUD-HCT (≥6/8 HLA-matched donors) onto 1 of 2 conditioning strata: myeloablative using fludarabine and fractionated total body irradiation (n = 19) or reduced intensity with fludarabine/melphalan (n = 19). Graft source was peripheral blood stem cells (PBSCs), and GVHD prophylaxis was PTCy, tacrolimus, and mycophenolate mofetil. Patients’ median age was 53 years (range, 21-72 years). Median number of HLA mismatches was 2 (range, 1-4) of 12 loci. Twenty-three patients (61%) were considered racial (n = 12) or ethnic (n = 11) minorities. Median time to neutrophil engraftment was 16 days (range, 13-35 days). With a median follow-up of 18.3 months (range, 4.3-25.0 months) for surviving patients, 1-year overall survival (OS) and GVHD-free/relapse-free survival (GRFS) were 87% (95% confidence interval [CI]: 71-94) and 68% (95% CI: 51-81), respectively. Cumulative incidence of nonrelapse mortality at 100 days and 1 year were 0% and 11% (95% CI: 4-27), respectively, whereas relapse/progression was 11% (95% CI: 4-27). Cumulative incidence of 100-day acute GVHD grades 2-4 and 3-4 and 1-year chronic GVHD were 50% (95% CI: 36-69), 18% (95% CI: 9-36), and 48% (95% CI: 34-68), respectively. The rate of moderate/severe chronic GVHD was 3% in the entire cohort. We showed highly promising OS/GRFS rates with an acceptable risk profile after PBSC-MMUD-HCT with PTCy. This trial was registered at www.clinicaltrials.gov as #NCT03128359.

Background: In November 2020, the U.S. Food and Drug Administration (FDA) issued emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild to moderate COVID-19 who are at high risk for disease progression. These mAbs reduce the risk of hospitalization in the general population. However, its efficacy and safety in immunocompromised hematology patients are not known. Methods: From November 9th, 2020, until February 28th, 2021, all adult hematology patients with mild to moderate COVID-19 disease who received monoclonal antibodies within 10 days of symptoms onset were included. Patients who were asymptomatic, had severe or critical COVID-19 disease, or were hospitalized at the time of COVID-19 diagnosis were excluded. Baseline demographic, clinical outcomes, and hematologic-related data were extracted. All statistical analysis was performed using SAS statistical software. Results: Thirty-eight hematology patients with mild to moderate COVID-19 disease who received mAb therapy under EUA were included in this study. Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Baseline characteristics prior to mAB administration include: 53% female, median age of 51 years (range: 21-80), with 18% above 65 years old. Twenty-eight (74%) patients received cellular therapy: 18 (47%) had undergone allogeneic hematopoietic cell transplantation (HCT), 9 (24%) autologous HCT, and 1 (3%) chimeric antigen receptor T-cell (CAR T) therapy. Among the 17 patients who had COVID-19 disease after HCT, the median time to COVID-19 diagnosis was 22.8 months (range: 2.6-274.4) from HCT to COVID-19 diagnosis. Twelve out of 17 (71%) alloHCT patients were being managed for active graft-vs-host disease (GvHD) at the time of COVID-19 diagnosis (chronic GVHD: n=11 [mild: 4, moderate: 4, severe: 3], acute GVHD (grade 2): n=1). Ten (59%) alloHCT patients were on immunosuppressant therapy at the time of COVID-19 diagnosis. Fifteen (39%) patients were on active treatment for their hematologic malignancy (HM) at the time of COVID-19 diagnosis with a mean of 3 previous lines of treatment (range: 1-6). Additional patient characteristics are shown in Table 1. mAb therapy under EUA was well tolerated in this patient population with only 1 (3%) patient having experienced an adverse reaction characterized as headache. Four (11%) patients were hospitalized due to COVID-19, and 2 (5%) progressed to severe disease. All four patients had received bamlanivimab. The median time for hospitalization from diagnosis of COVID-19 to admission date was 8 days (range: 1-20) while median time from mAB infusion to hospitalization was 7.5 days (range: 0-17). One patient (3%) died within 30 days of COVID-19 diagnosis; the cause of death was COVID-19 disease. Most patients (n=34, 89%) ultimately tested negative for SARS-CoV-2 by PCR after mAb infusion. 34% of patients (n=13) cleared the virus within 2 weeks of receiving mAb infsuion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients (10/15; 67%) who were previously on active treatment for HM prior to diagnosis of COVID-19 resumed therapy for their HM with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization was amongst patients who received a HCT vs. non-HCT (0%, 0/26 and 36%, 4/11 respectively; p Conclusion: This study demonstrates that SARS-COV2 specific mAb use in malignant hematology patients under EUA was safe and may reduce hospitalization as reported in the literature amongst those at high risk for disease progression. Thus, the access to SARS-COV2 mAb in this population who is at increased risk for complications from SARS-COV2 infection is critical in reducing progression to severe COVID-19 disease and hospitalization. Figure 1 Figure 1. Disclosures Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Aribi: Seagen: Consultancy. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Koller: Novartis: Consultancy. Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Shouse: Beigene: Honoraria; Kite Pharma: Speakers Bureau. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Marcucci: Abbvie: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Dadwal: AlloVir: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Speakers Bureau; Shire/Takeda: Research Funding; Aseptiscope: Consultancy; Janssen: Other: Investigator; Karius: Other: Investigator. Al Malki: CareDx: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Neximmune: Consultancy; Hansa Biopharma: Consultancy.

Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation.

Acute lymphoblastic leukemia (ALL) with high-risk features has a poor prognosis in adults despite aggressive chemotherapy. Reduced-intensity conditioning (RIC) is a lower toxicity alternative for high-risk patients requiring hematopoietic cell transplantation (HCT); however, it has not been widely used for ALL. We conducted a retrospective study of 24 high-risk adult ALL patients who received an RIC regimen of fludarabine (Flu)/melphalan (Mel) prior to allogeneic peripheral blood stem cell transplantation (PBSCT) between 6/14/02 and 6/15/07 at the City of Hope. Indications for the RIC regimen were: (1) aged 50 years or older (42%), (2) compromised organ function (54%), or (3) recipient of a previous HCT (37.5%). Patients had a median age of 47.5 years and the median follow-up was 28.5 months for living patients. Both overall survival (OS) and disease-free survival (DFS) at 2 years was 61.5%. Relapse incidence was 21.1% and nonrelapse mortality (NRM) was 21.5% at 2 years. Chronic graft-versus-host (cGVHD) developed in 86% of evaluable patients. In this series, no significant correlations were made between outcomes and patient age, presence of Philadelphia chromosome, relatedness of donor source, or prior HCT. These high survival rates for high-risk ALL patients following RIC HCT may offer a promising option for patients not eligible for a standard myeloablative transplant.

Patients with peripheral T cell lymphoma (PTCL) have a poor prognosis with current treatment approaches. We examined the outcomes of high-dose therapy (HDT) and autologous hematopoietic cell transplant (AHCT) on the treatment of PTCL and the impact of patient/disease features on long-term outcome. Sixty-seven patients with PTCL–not otherwise specified (n = 30), anaplastic large cell lymphoma (n = 30), and angioimmunoblastic T cell lymphoma (n = 7) underwent HDT/AHCT at the City of Hope. The median age was 48 years (range: 5-78). Twelve were transplanted in first complete remission (1CR)/partial remission (PR) and 55 with relapsed or induction failure disease (RL/IF). With a median follow-up for surviving patients of 65.8 months (range: 24.5-216.0) the 5-year overall survival (OS) and progression-free survival (PFS) were 54% and 40%, respectively. The 5-year PFS was 75% for 1CR/PR compared to 32% for RL/IF patients (P = .01). When the Prognostic Index for PTCL unspecified (PIT) was applied at the time of transplant, patients in the PIT 3-4 group had 5-year PFS of only 8%. These results show that HDT/AHCT can improve long-term disease control in relapsed/refractory PTCL and that HDT/AHCT should ideally be applied either during 1CR/PR, or as part of upfront treatment. More effective and novel therapies are needed for patients with high-risk disease (PIT 3-4 factors) and allogeneic HCT should be explored in these patients.