Impact of Graft-Versus-Host Disease on Relapse and Nonrelapse Mortality Following Posttransplant Cyclophosphamide-Based Transplantation.

Following conventional graft-versus-host disease (GVHD) prophylaxis, the development of acute and/or chronic GVHD is associated with lower relapse rates. However, the effects of GVHD on relapse and non-relapse mortality following post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis have not been well studied. To this end, we analyzed the impact of acute and chronic GVHD following PTCy-based haploidentical donor transplantation (HIDT). The analysis included 335 consecutive HIDT recipients transplanted at a single institution between 2005 and 2021. Landmark analysis (LA) and time-dependent multivariable analysis (MVA) were utilized to study the impact of GVHD development on transplant outcome. Landmarks were defined as Day +100 for acute GVHD and one-year for chronic GVHD. Recipient characteristics included a median age of 50 (19-80) years, most commonly transplanted for acute leukemia[/MDS [242]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23-207) months. In landmark analysis, development of grade 3 to 4 acute GVHD (versus 0-1) was associated with inferior 3-year overall survival (OS 47% versus 64%, P = .041), due to higher NRM (25% versus 10%, P = .013). In contrast, development of grade 2 acute GVHD had no significant effect on NRM or survival. When restricted to acute leukemia/MDS patients, development of grade II acute GVHD was associated with improved OS (79% versus 58%, P = .027) and a trend towards lower relapse (24% versus 36%, P = .08). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM (15% versus 4%, P = .010), but had no impact on relapse, DFS or OS. In Cox multivariate analysis (MVA), grade 3 to 4 acute GVHD and moderate-to-severe chronic GVHD were both associated with significantly higher NRM (HR 3.38, P < .001 and HR3.35, P < .001, respectively). In addition, grade 3 to 4 acute GVHD predicted worse OS (HR 1.80, P = .007) and DFS (HR 1.55, P = .041). In contrast, relapse was not impacted by acute or chronic GVHD in MVA. Grade 2 acute GVHD was not associated with transplant outcome in MVA. In summary, both grade 3 to 4 acute and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT, without an effect on relapse risk. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed.

Revised HLA-DP TCE-Core Permissiveness Model Better Defines Relapse Risk and Survival following Haploidentical Transplant.

The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT. To this end, we analyzed 242 consecutive HIDT recipients with acute leukemia or myelodysplastic syndrome who underwent transplantation between 2005 and 2021 (median age, 51 years; range, 19 to 80 years). The median follow-up was 62 months (range, 23 to 199 months). Of the 136 HIDTs classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the graft-versus host (GVH) vector (37 were host-versus-graft [HVG] only). Given comparable survival between conventional NPMM and C-NPMM, GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1-matched and PMM (permissive) because of similar outcomes. The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year overall survival (OS) (66% versus 47%) and disease-free survival (DFS) (60% versus 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a higher percentage of nonpermissive transplants (38% versus 23%) and better discriminated outcomes between nonpermissive and permissive status, with a larger difference in survival outcomes using TCE-Core compared to TCE-3 (OS Δ, 18.3% versus 12.7%; DFS Δ, 16.5% versus 8.5%). In multivariable analysis (MVA), a nonpermissive TCE-Core mismatch led to improved OS (hazard ratio [HR], .54; P = .003) and DFS (HR, .62; P = .013), largely due to decreased relapse risk (HR, .63; P = .049). In contrast, nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) outcomes were not significantly impacted. In summary, the presence of nonpermissive TCE-Core HLA-DP mismatch strongly predicts survival following PTCy-based HIDT, owing to a reduction in relapse risk without a corresponding increase in GVHD or NRM. As a donor selection tool, TCE-Core appears to better discriminate HIDT outcomes while at the same time identifying a larger percentage of the potential donor pool.

Phase 2 study of PD-1 blockade following autologous transplantation for patients with AML ineligible for allogeneic transplant.

Allogeneic transplant remains the best postremission therapy for patients with nonfavorable risk acute myeloid leukemia (AML). However, some patients are ineligible because of psychosocial barriers, such as lack of appropriate caregiver support. We hypothesized that immune checkpoint inhibition after autologous transplant might represent effective postremission therapy in such patients. We conducted a phase 2 study of autologous transplantation followed by administration of pembrolizumab (8 cycles starting day +1). Twenty patients with nonfavorable AML in complete remission were treated (median age, 64 years; CR1, 80%); 55% were non-White and adverse-risk AML was present in 40%. Treatment was well tolerated, with only 1 nonrelapse death. Immune-related adverse events occurred in 9 patients. After a median follow-up of 80 months, 14 patients remain alive, with 10 patients in continuous remission. The estimated 2-year LFS was 48.4%, which met the primary end point of 2-year LFS >25%; the 2-year overall survival (OS), nonrelapse mortality, and cumulative incidences of relapse were 68%, 5%, and 46%, respectively. In comparison with a propensity score-matched cohort group of patients with AML receiving allogeneic transplant, the 3-year OS was similar (73% vs 76%). Patients in the study had inferior LFS (51% vs 75%) but superior postrelapse survival (45% vs 14%). In conclusion, programmed cell death protein-1 blockade after autologous transplant is a safe and effective alternative postremission strategy in patients with nonfavorable risk AML who are ineligible for allogeneic transplant, a context in which there is significant unmet need. This trial was registered at www.clinicaltrials.gov as #NCT02771197.

Improved access to HCT with reduced racial disparities through integration with leukemia care and haploidentical donors.

Few patients with nonfavorable risk (NFR) acute leukemia and myeloid dysplasia syndrome (AL/MDS) undergo allogeneic transplantation (HCT). We assessed whether this could be improved by integrating HCT/leukemia care and the use of haploidentical donors. Of 256 consecutive patients aged <75 years who received initial therapy at our center for NFR AL/MDS from 2016 to 2021, 147 (57%) underwent planned HCT (70% for patients aged <60 years). In the logistic regression analysis, age (OR 1.50 per 10-year increment; P < .001) and race (Black vs White [OR 2.05; P = .023]) were significant factors for failure to receive HCT. Reasons for no HCT included comorbidities (37%), poor KPS, lack of caregiver support, refractory malignancy (19% each), and patient refusal (17%). Lack of donor or insurance were rarely cited (3% each). In older patients (≥60 years), comorbidities (49 vs 15%; P < .001) and KPS (25% vs 10%; P = .06) were more common, and lack of caregivers was less common (13% vs 30%; P = .031). In Black vs White patients, lack of caregivers (37% vs 11%; P = .002) was more frequent. The median time from initial treatment to HCT was 118 days and was similar for Black and White patients. Landmark analysis showed that HCT within 6 months of the initial treatment produced better survival. Multivariable analysis showed that HCT resulted in a significant survival benefit (HR 0.60; P = .020). With the above approach, most of the currently treated patients aged <75 years can access planned HCT. Black patients remain at greater risk of not receiving HCT.

Elevated LDH greater than 400 U/L portends poorer overall survival in diffuse large B-cell lymphoma patients treated with CD19 CAR-T cell therapy in a real world multi-ethnic cohort.

Anti-CD19 chimeric antigen receptor T-cell therapies have shown striking clinical activity in diffuse large B-cell lymphoma but robust biomarkers predictive of responsiveness are still needed. We treated a multi-ethnic cohort of 31 diffuse large B-cell lymphoma patients with axicabtagene ciloleucel with an overall response rate of 71%. Analysis of various biomarkers identified a significant decrease in overall survival with elevated lactate dehydrogenase, measured both at time of cell infusion and before lymphodepletion. Lactate dehydrogenase was prognostic in a multivariate analysis [HR = 1.47 (1.1-2.0)] and a value of 400 U/L at time of infusion and a value of 440 U/L before lymphodepletion provided the best prognostic cutoffs for overall survival in our cohort. These data demonstrate efficacy of anti-CD19 chimeric antigen receptor T-cell therapy in a diverse inner city population and demonstrate novel lactate dehydrogenase cutoffs as prognostic biomarkers.

Patterns of leukocyte recovery predict infectious complications after CD19 CAR-T cell therapy in a real-world setting.

BACKGROUND: Adoptive immunotherapy using CD19-targeted Chimeric antigen receptor T cells (CAR-T) has revolutionized the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Data is limited on the propensity of infections and lymphohematopoietic reconstitution after Day 30 (D30) following CAR-T cell therapy. In this study, we evaluated the prevalence and nature of infectious complications in an expanded cohort of DLBCL patients treated with CD19 CAR-T therapy and its association with the dynamics of leukocyte subpopulation reconstitution post-CAR-T cell therapy. METHODS: We conducted a retrospective study including 19 patients who received axicabtagene ciloleucel and investigated associations between cytopenia and infectious complications after D30. RESULTS: Nineteen patients were included, consisting of 42% Hispanic, 32% Caucasian, 21% African-American, and 5% Asian subjects. Post-D30 of CAR-T infusion, 47% patients (n=9) developed an infection and 53% (n=10) remained infection-free. The most common infection type observed was viral (7 patients) followed by bacterial (5 patients) and fungal (3 patients). Of 25 total infectious events, 56% were grade 1 or 2 and 44% were grade 3 with 10 being viral in etiology. To determine the kinetics of lymphohematopoietic reconstitution and its association with infection risk, we evaluated the relationship between cytopenias and rates of infection after D30. Notably, compared to non-infection group, infection group had a higher median absolute lymphocyte count (ALC) (1,000/µL vs. 600/µL, P<0.05), a lower median absolute neutrophil count (ANC)/ALC ratio (1.6 vs. 3.1, P<0.05) and a lower median AMC/ALC at D30 (0.37 vs. 1.67, P<0.05). In addition, we observed that only 22% of patients had recovered ANC >1,500/µL in the infection group as opposed to 70% in the non-infection group at D90 (P<0.05). Fifty-eight percent of the patients (11/19) with relapsed refractory DLBCL achieved a complete response with a median follow-up of 233 days (7.7 months). CONCLUSIONS: Although CAR-T cell therapy is highly effective, infectious complications remain an important cause of morbidity and mortality. Low ANC/ALC and AMC/ALC ratios at D30 are potential novel predictors of infection and can be considered in future prophylactic strategies.

Seroconversion rates following COVID-19 vaccination among patients with cancer.

As COVID-19 adversely affects patients with cancer, prophylactic strategies are critically needed. Using a validated antibody assay against SARS-CoV-2 spike protein, we determined a high seroconversion rate (94%) in 200 patients with cancer in New York City that had received full dosing with one of the FDA-approved COVID-19 vaccines. On comparison with solid tumors (98%), a significantly lower rate of seroconversion was observed in patients with hematologic malignancies (85%), particularly recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%). Patients receiving immune checkpoint inhibitor therapy (97%) or hormonal therapies (100%) demonstrated high seroconversion post vaccination. Patients with prior COVID-19 infection demonstrated higher anti-spike IgG titers post vaccination. Relatively lower IgG titers were observed following vaccination with the adenoviral than with mRNA-based vaccines. These data demonstrate generally high immunogenicity of COVID-19 vaccination in oncology patients and identify immunosuppressed cohorts that need novel vaccination or passive immunization strategies.

Axicabtagene ciloleucel CD19 CAR-T cell therapy results in high rates of systemic and neurologic remissions in ten patients with refractory large B cell lymphoma including two with HIV and viral hepatitis.

Axicabtagene ciloleucel (Axi-cel) is a CD-19 Chimeric Antigen Receptor T cell therapy approved for the treatment of relapsed/refractory diffuse large B cell lymphoma. We treated ten patients with DLBCL post-FDA approval in an inner-city tertiary center in the Bronx. Eight patients (80%) had received ≥ 3 lines of therapy, six patients had received prior radiation, and seven had recurrent disease after prior autologous hematopoietic stem cell transplant (AHCT). Our cohort included one patient with HIV, two patients with hepatitis B, and two patients with CNS involvement of lymphoma. Axi-cel treatment led to significant responses with 8/10 patients achieving a complete remission at 3 months, including both patients with prior CNS involvement. The treatment was generally well tolerated with 20% of patients experiencing grade ≥ 2 CRS. One patient each with HIV and hepatitis B responded without significant toxicities. In conclusion, Axi-cel led to significant efficacy with manageable toxicity in DLBCL in a real-world setting.

Outcomes of Autologous Hematopoietic Cell Transplantation Compared With Chemotherapy Consolidation Alone for Non-High-Risk Acute Myeloid Leukemia in First Complete Remission in a Minority-Rich Inner-City Cohort With Limited Access to Allografts.

INTRODUCTION: In the United States, autologous hematopoietic cell transplantation (autoHCT) has fallen out of favor over chemotherapy consolidation for non-high-risk acute myeloid leukemia (AML) when allogeneic hematopoietic cell transplantation (alloHCT) is unfeasible, which is common in racial minorities because of donor registry under-representation and socioeconomic challenges. We compared autoHCT consolidation outcomes with chemotherapy alone in a minority-rich cohort in the Bronx. PATIENTS AND METHODS: We identified adults with favorable or intermediate cytogenetic risk AML in first complete remission after induction at Montefiore Medical Center from 1999 to 2015, and analyzed 81 patients who received consolidation with ≥2 cycles of chemotherapy, of whom 28 received autoHCT. RESULTS: The cohort predominantly consisted of ethnic/racial minorities (69%). Age, sex, race, presenting white cell count, and cytogenetic risk were similar between groups. The autoHCT group had longer relapse-free (RFS; 43 vs. 11 months; P = .003) and overall (OS) survival (not reached vs. 36 months; P = .043). Adjusted multivariable analysis showed significant benefit of autoHCT over chemotherapy alone for RFS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.37-0.75; P < .001) and OS (HR, 0.61; 95% CI, 0.40-0.95; P = .027). CONCLUSION: In this inner-city non-high-risk AML cohort, autoHCT provided OS and RFS benefit compared with chemotherapy alone. AutoHCT might constitute a valuable option for ethnic/racial minorities affected by significant barriers to alloHCT, whereas integration of measurable residual disease can help select patients more likely to benefit.

Prophylactic rituximab prevents EBV PTLD in haplo-cord transplant recipients at high risk.

Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD) are common and potentially fatal complications after allogeneic transplantation with mismatched donors and T-cell depletion. Haplo-cord transplantation combines a mismatched UCB graft with third-party cells. Conditioning involves thymoglobulin. EBV reactivation and PTLD were common in initial patients. As of March 2017, we administered a prophylactic dose of rituximab 375 mg/m2 pre-transplant. Among 147 patients who did not receive rituximab, the cumulative incidence of post-transplant EBV reactivation and of EBV PTLD was 13% and 8%, respectively. Among 51 who received pre-transplant rituximab, the incidences were 2% (p = .0017) and 0% (p = .04), respectively. There was no difference in time to hematopoietic recovery, in the incidence of CMV reactivation, of invasive blood stream infections or of proven or probable invasive fungal infections. Pre-transplant administration of rituximab is an effective and nontoxic intervention that drastically reduces EBV reactivation and PTLD in high-risk patients.

Barriers to Allogeneic Hematopoietic Stem Cell Transplantation for Human T Cell Lymphotropic Virus 1-Associated Adult T Cell Lymphoma-Leukemia in the United States: Experience from a Large Cohort in a Major Tertiary Center.

In the United States adult T cell lymphoma-leukemia (ATLL) carries a dismal prognosis and mainly affects immigrants from human T cell lymphotropic virus 1 endemic areas. Allogeneic hematopoietic stem cell transplant (alloHSCT) can be effective and is recommended as an upfront treatment in the National Comprehensive Cancer Network guidelines. We studied the barriers to alloHSCT in one of the largest ATLL populations in the United States. Comprehensive chart and donor registry reviews were conducted for 88 ATLL patients treated at Montefiore Medical Center from 2003 to 2018. Among 49 patients with acute and 32 with lymphomatous subtypes, 48 (59.5%) were ineligible for alloHSCT because of early mortality (52%), loss to follow-up (21%), uninsured status (15%), patient declination (10%), and frailty (2%). Among 28 HLA-typed eligible patients (34.6%), matched related donors were identified for 7 (25%). A matched unrelated donor (MUD) search yielded HLA-matched in 2 patients (9.5%), HLA mismatched in 6 (28.5%), and no options in 13 (62%). Haploidentical donors were identified for 6 patients (46%) with no unrelated options. There were no suitable donors for 7 (25%) alloHSCT-eligible patients. The main limitation for alloHSCT after donor identification was death from progressive disease (82%). AlloHSCT was performed in 10 patients (12.3%) and was associated with better relapse-free survival (26 versus 11 months, P = .04) and overall survival (47 versus 10 months, P = .03). Early mortality and progressive disease are the main barriers to alloHSCT, but poor follow-up, uninsured status, and lack of suitable donor, including haploidentical, are also substantial limitations that might disproportionally affect this vulnerable population. AlloHSCT can achieve long-term remissions, and strategies aiming to overcome these barriers are urgently needed to improve outcomes in ATLL.