Immune effector cell-associated haematotoxicity after CAR T-cell therapy: from mechanism to management.

Genetically engineered chimeric antigen receptor (CAR) T cells have become an effective treatment option for several advanced B-cell malignancies. Haematological side-effects, classified in 2023 as immune effector cell-associated haematotoxicity (ICAHT), are very common and can predispose for clinically relevant infections. As haematopoietic reconstitution after CAR T-cell therapy differs from chemotherapy-associated myelosuppression, a novel classification system for early and late ICAHT has been introduced. Furthermore, a risk stratification score named CAR-HEMATOTOX has been developed to identify candidates at high risk of ICAHT, thereby enabling risk-based interventional strategies. Therapeutically, growth factor support with granulocyte colony-stimulating factor (G-CSF) is the mainstay of treatment, with haematopoietic stem cell (HSC) boosts available for patients who are refractory to G-CSF (if available). Although the underlying pathophysiology remains poorly understood, translational studies from the past 3 years suggest that CAR T-cell-induced inflammation and baseline haematopoietic function are key contributors to prolonged cytopenia. In this Review, we provide an overview of the spectrum of haematological toxicities after CAR T-cell therapy and offer perspectives on future translational and clinical developments.

Atrial arrhythmias following CAR-chimeric antigen receptor T-cell therapy: Incidence, risk factors and biomarker profile.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain.

T-Cell Malignant Neoplasms After Chimeric Antigen Receptor T-Cell Therapy.

This cohort study assesses the increase in second primary malignant neoplasms and T-cell malignant neoplasm cases associated with chimeric antigen receptor­T cells.

Conventional and novel [18F]FDG PET/CT features as predictors of CAR-T cell therapy outcome in large B-cell lymphoma.

Relapse and toxicity limit the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL), yet biomarkers that predict outcomes and toxicity are lacking. We examined radiomic features extracted from pre-CAR-T 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scans (n = 341) of 180 patients (121 male; median age, 66 years). Three conventional (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG]) and 116 novel radiomic features were assessed, along with inflammatory markers, toxicities, and outcomes. At both pre-apheresis and pre-infusion time points, conventional PET features of disease correlated with elevated inflammatory markers. At pre-infusion, MTV was associated with grade ≥ 2 cytokine release syndrome (odds ratio [OR] for 100 mL increase: 1.08 [95% confidence interval (CI), 1.01-1.20], P = 0.031), and SUVmax was associated with failure to achieve complete response (CR) (OR 1.72 [95% CI, 1.24-2.43], P < 0.001). Higher pre-apheresis and pre-infusion MTV values were associated with shorter progression-free survival (PFS) (HR for 10-unit increase: 1.11 [95% CI, 1.05-1.17], P < 0.001; 1.04 [95% CI, 1.02-1.07], P < 0.001) and shorter overall survival (HR for 100-unit increase: 1.14 [95% CI, 1.07-1.21], P < 0.001; 1.04 [95% CI, 1.02-1.06], P < 0.001). A combined MTV and LDH measure stratified patients into high and low PFS risk groups. Multiple pre-infusion novel radiomic features were associated with CR. These quantitative conventional [18F]FDG PET/CT features obtained before CAR-T cell infusion, which were correlated with inflammation markers, may provide prognostic biomarkers for CAR-T therapy efficacy and toxicity. The use of conventional and novel radiomic features may thus help identify high-risk patients for earlier interventions.

Recruitment and Retention of Hematopoietic Cell Transplantation and Cellular Therapy Physicians: A Report from the ASTCT Talent Acquisition Task Force.

A shortage of transplant and cellular therapy (TCT) physicians is expected given the expansion of TCT indications and the scope of practice of TCT programs in recent years. American Society of Transplantation and Cellular Therapy (ASTCT) conducted a survey of early career transplant physicians and trainees to assess the factors that prompted them to pursue to career in TCT. This was a cross-sectional survey conducted via emails sent to the ASTCT membership. Fifty-nine respondents completed the survey. The vast majority of respondents decided to pursue a career in TCT during their hematology/oncology fellowship (41%), followed by during residency (25%) or medical school (18%), and a majority of them had some exposure to TCT in their clinical training already. The most common reason for choosing to specialize in TCT was interest in the clinical practice of TCT (81%) closely followed by the scientific allure of the field (75%). Most respondents were extremely committed to remaining in this field of practice. We found that those in the field report high levels of satisfaction despite factors that would otherwise predispose them to burnout. A systematic and sustained effort to promote trainee engagement that could result in improved recruitment and retention in the field of TCT is needed. Professional societies in partnership with educational institutions could conduct outreach and help attract trainees from diverse backgrounds.

ASTCT Committee on Practice Guidelines Survey on Evaluation and Management of Relapsed/Refractory Multiple Myeloma after Failure of Chimeric Antigen Receptor T Cell Therapy.

Chimeric antigen receptor T cell therapy (CAR-T) has revolutionized the management of relapsed and/or refractory multiple myeloma (RRMM). However, CAR-T treatment failure is not uncommon and remains a major therapeutic challenge. There is substantial variability across transplantation and cellular therapy programs in assessing and managing post-CAR-T failures in patients with RRMM. The American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines conducted an online cross-sectional survey between September 2023 and December 2023 to determine myeloma, transplantation, and cellular therapy physicians' practice patterns for the surveillance, diagnosis, and management of CAR-T failure. The intent of this survey was to understand clinical practice patterns and identify areas for further investigation. Email surveys were sent to 1311 ASTCT physician members, of whom 80 (6.1%) completed the survey. The respondents were 58% white and 66% male, and 51% had >10 years of clinical experience. Most (89%) respondents were affiliated with a university/teaching center, and 56% had a myeloma-focused transplantation and/or cellular therapy practice. Post-CAR-T surveillance laboratory studies were commonly done every 4 weeks, and surveillance bone marrow biopsies and/or imaging surveillance were most commonly done at 3 months. Sixty-four percent of the respondents would often or always consider biopsy or imaging to confirm relapse. The most popular post-CAR-T failure rescue regimen was GPRC5D-directed immunotherapy (30%) for relapses occurring ≤3 months and BCMA-directed bispecific therapies (32.5%) for relapse at >3 months. Forty-one percent of the respondents endorsed post-CAR-T prolonged cytopenia as being "often" or "always" a barrier to next-line therapy; 53% had offered stem cell boost as a mitigation approach. Substantial across-center variation in practice patterns raises the need for collaborative studies and expert clinical recommendations to describe best practices for post-CAR-T disease surveillance, optimal workup for treatment failure, and choice of rescue therapies.

Real-World and Clinical Trial Outcomes in Large B-cell Lymphoma with Axicabtagene Ciloleucel Across Race and Ethnicity.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting the use of axi-cel in patients with LBCL, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients with R/R LBCL who received axi-cel between 2017-2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 clinical trials, respectively. Adjusted odds ratio (OR) and hazard ratio (HR) for race and ethnicity groups are reported. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37, [95% CI, 0.22-0.63]) and lower complete response rate (OR, 0.57, [95% CI, 0.33-0.97]) than NH-white patients. NH-Black patients also had a shorter progression-free survival versus NH-white (HR, 1.41, [95% CI, 1.04-1.90]) and NH-Asian patients (HR, 1.67, [95% CI, 1.08-2.59]). NH-Asian patients had a longer duration of response compared with NH-white (HR, 0.56, [95% CI, 0.33-0.94]) and Hispanic patients (HR, 0.54, [95% CI, 0.30-0.97]). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade ICANS were observed in NH-white patients compared with other patients. These results provide important context when treating patients with R/R LBCL with axi-cel across different racial and ethnic groups. ZUMA-1 (NCT02348216) and ZUMA-7 (NCT03391466), both registered on ClinicalTrials.gov.

Second Primary Malignancies After Commercial CAR T Cell Therapy: Analysis of FDA Adverse Events Reporting System (FAERS).

Second primary malignancies (SPMs) were reported in 536 out of 12,394 (4.3%) adverse event reports following CAR T cell therapies in the FDA Adverse Event Reporting System (FAERS). Myeloid and T-cell neoplasms were disproportionately more frequently reported, warranting further follow-up.

Defining and Grading Infections in Clinical Trials Involving Hematopoietic Cell Transplantation: A Report From the BMT CTN Infectious Disease Technical Committee.

The Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) was established in 2001 to conduct large multi-institutional clinical trials addressing important issues towards improving the outcomes of HCT and other cellular therapies. Trials conducted by the network investigating new advances in HCT and cellular therapy not only assess efficacy but require careful capturing and severity assessment of adverse events and toxicities. Adverse infectious events in cancer clinical trials are typically graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). However, there are limitations to this framework as it relates to HCT given the associated immunodeficiency and delayed immune reconstitution. The BMT-CTN Infection Grading System is a monitoring tool developed by the BMT CTN to capture and monitor infectious complications and differs from the CTCAE by its classification of infections based on their potential impact on morbidity and mortality for HCT recipients. Here we offer a report from the BMT CTN Infectious Disease Technical Committee regarding the rationale, development, and revising of BMT-CTN Infection Grading System and future directions as it applies to future clinical trials involving HCT and cellular therapy recipients.

Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies.

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

Immune reconstitution, vaccine responses, and rituximab use after ex-vivo CD34-selected myeloablative allogenic hematopoietic cell transplantation.

Myeloablative T cell depleted (CD34-selected) hematopoietic cell transplantation (HCT) is associated with less acute and chronic graft versus host disease (GVHD). We aimed to examine vaccine responses in relation to immune reconstitution and post HCT rituximab administration in this population. This single center retrospective study included 251 patients with hematological malignancies who received a first CD34-selected HCT between 2012 and 2015. Of 251 patients, 190 were alive 1 year after HCT. Among the entire population, 77 (30.7%) patients were vaccinated. After vaccine administration, 35/44 (80%), 30/75 (40%), 27/36 (75%), 33/65 (51%), 34/51 (51%), 22/28 (79%) and 20/34 (59%) of evaluable patients had protective antibody titers for haemophilus influenzae type B (Hib), Pneumococcus, Tetanus, Diphtheria, Pertussis, hepatitis A (HAV), and hepatitis B (HBV) respectively. Responders to the pneumococcal vaccine had a higher CD45RA T cell count than non responders, with 12/18 patients (66.7%) vs 11/32 (34.4%) p = 0.04. For pneumococcal vaccine, there was also a trend to higher total lymphocyte B cell count in responders vs non responders p = 0.06. Rituximab post HCT was given to 59/251 (23.5%) patients. No difference was found in immune reconstitution patterns for rituximab use between vaccine responders and not. Recipients of CD34-selected HCT may respond to vaccination, and T and B cell subsets could be useful to predict vaccine response.

Outcomes of subsequent anti-lymphoma therapies after second-line axicabtagene ciloleucel or standard of care in ZUMA-7.

In ZUMA-7 (NCT03391466), axicabtagene ciloleucel (axi-cel) significantly improved outcomes versus second-line (2L) standard of care (SOC) for adults with relapsed/refractory large B-cell lymphoma (LBCL). The optimal management of patients after disease progression or lack of response to 2L therapy remains unclear. Here, we report outcomes among patients who received subsequent anti-lymphoma therapy per investigator discretion separately by their randomized 2L arm in ZUMA-7. Progression-free survival (PFS) and overall survival (OS) were calculated from 3L therapy initiation by randomized 2L arm. In the SOC arm, 127/179 randomized patients (71%) received 3L therapy. Median PFS among those who received 3L cellular immunotherapy (n=68) versus those who did not (n=59) was 6.3 versus 1.9 months, respectively; median OS was 16.3 versus 9.5 months, respectively. In the axi-cel arm, 84/180 randomized patients (47%) received 3L therapy. Median PFS among those who received 3L chemotherapy (n=60) versus cellular immunotherapy (n=8) was 1.7 versus 3.5 months, respectively; median OS was 8.1 months versus not reached, respectively. Of the 60 patients who received 3L chemotherapy, 10 underwent stem cell transplantation (SCT; 9 autologous; 1 allogeneic) after salvage chemotherapy. Median PFS was 11.5 versus 1.6 months, and median OS was 17.5 versus 7.2 months for those who did versus those who did not reach SCT, respectively. Eight patients received 3L cellular immunotherapy after 2L axi-cel. Of these, 6 patients received subsequent SCT in any line, and all 6 were alive at data cutoff. These findings help inform subsequent treatment choices after failure of 2L therapy for relapsed/refractory LBCL.

SARS-CoV-2 vaccination in the first year after hematopoietic cell transplant or chimeric antigen receptor T cell therapy: A prospective, multicenter, observational study (BMT CTN 2101).

Background: The optimal timing of vaccination with SARS-CoV-2 vaccines after cellular therapy is incompletely understood. Objective: To describe humoral and cellular responses after SARS-CoV-2 vaccination initiated <4 months versus 4-12 months after cellular therapy. Design: Multicenter prospective observational study. Setting: 34 centers in the United States. Participants: 466 allogeneic hematopoietic cell transplant (HCT; n=231), autologous HCT (n=170), or chimeric antigen receptor T cell (CAR-T cell) therapy (n=65) recipients enrolled between April 2021 and June 2022. Interventions: SARS-CoV-2 vaccination as part of routine care. Measurements: We obtained blood prior to and after vaccinations at up to five time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T cell receptors (TCRs), in a subgroup. Results: Anti-S IgG and neutralizing antibody responses increased with vaccination in HCT recipients irrespective of vaccine initiation timing but were unchanged in CAR-T cell recipients initiating vaccines within 4 months. Anti-S IgG ≥2,500 U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T cell recipients, respectively. SARS-CoV-2-specific T cell responses were attained in 57%, 83%, and 58%, respectively. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months vs 4-12 months after cellular therapy. Pre-cellular therapy SARS-CoV-2 infection or vaccination were key predictors of post-cellular therapy anti-S IgG levels. Limitations: The majority of participants were adults and received mRNA vaccines. Conclusions: These data support starting mRNA SARS-CoV-2 vaccination three to four months after allogeneic HCT, autologous HCT, and CAR-T cell therapy. Funding: National Marrow Donor Program, Leukemia and Lymphoma Society, Multiple Myeloma Research Foundation, Novartis, LabCorp, American Society for Transplantation and Cellular Therapy, Adaptive Biotechnologies, and the National Institutes of Health.

A multicenter study of posttransplantation low-dose inotuzumab ozogamicin to prevent relapse of acute lymphoblastic leukemia.

ABSTRACT: The curative potential of allogeneic hematopoietic transplantation (allo-HCT) in patients with acute lymphoblastic leukemia (ALL) is hampered by relapse. Inotuzumab ozogamicin (INO) is an anti-CD22 monoclonal antibody bound to calicheamicin, which has significant activity against ALL. We hypothesized that low-dose INO would be safe and feasible after allo-HCT. Therefore, we conducted a phase 1 study to determine the dose and safety in this setting. Patients were eligible if they were aged 16 to 75 years, had undergone allo-HCT for CD22+ ALL, were in complete remission (CR) after allo-HCT, had high risk of recurrence, were between day 40 and 100 after allo-HCT with adequate graft function, and did not have a history of sinusoidal obstruction syndrome (SOS). The objectives of this trial were to define INO maximum tolerated dose (MTD), to determine post-allo-HCT INO safety, and to measure 1-year progression-free survival (PFS). The trial design followed a "3+3" model. The treatment consisted of INO given on day 1 of 28-day cycles. Dose levels were 0.3 mg/m2, 0.4 mg/m2, 0.5 mg/m2, and 0.6 mg/m2. Median age was 44 years (range, 17-66 years; n = 18). Disease status at transplantation was first CR (n = 14) or second CR or beyond (n = 4). Preparative regimen was of reduced intensity in 72% of patients who received transplantation. Most common toxicity was thrombocytopenia. There were no instances of SOS; the MTD was 0.6 mg/m2. One-year nonrelapse mortality was 5.6%. With a median follow-up of 18.1 months (range, 8.6-59 months) 1-year post-allo-HCT PFS and overall survival is 89% and 94%, respectively. Low-dose INO has a favorable safety profile and was associated with high rates of 1-year PFS. This trial was registered at www.clinicaltrials.gov as #NCT03104491.

Outcomes and Management of the SARS-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy.

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell therapy (CAR-T) recipients who develop Coronavirus disease 2019 (COVID-19) can have decreased overall survival (OS), likely due to disease-inherent and therapy-related immunodeficiency. The availability of COVID-19-directed therapies and vaccines have improved COVID-19-related outcomes, but immunocompromised individuals remain vulnerable. Specifically, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infections, including Omicron and its sublineages, particularly in HCT recipients, remain to be defined. The aim of this study was to compare the impact of SARS-CoV-2 Omicron infections in HCT/CAR-T recipients with outcomes previously reported for ancestral SARS-CoV-2 infections early in the pandemic (March to June 2020). This was a retrospective analysis of adult HCT/CAR-T recipients diagnosed with COVID-19 at Memorial Sloan Kettering Cancer Center between July 2021 and July 2022. We identified 353 patients (172 autologous HCT recipients [49%], 152 allogeneic HCT recipients [43%], and 29 CAR-T recipients [8%]), with a median time from HCT/CAR-T to SARS-CoV-2 infection of 1010 days (interquartile range, 300 to 2046 days). Forty-one patients (12%) were diagnosed with COVID-19 during the delta wave, and 312 patients (88%) were diagnosed during the Omicron wave. Risk factors associated with increased odds of COVID-19-related hospitalization were the presence of 2 or more comorbidities (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4 to 10.7; P < .001), CAR-T therapy compared to allogeneic HCT (OR, 7.7; 95% CI, 3.0 to 20.0; P < .001), hypogammaglobulinemia (OR, 2.71; 95% CI, 1.06 to 6.40; P = .027), and age at COVID-19 diagnosis (OR, 1.03; 95% CI, 1.0 to 1.05; P = .04). In contrast, infection during the Omicron variant BA5/BA4-dominant period compared to variant BA1 (OR, .21; 95% CI, .03 to .73; P = .037) and more than 3 years from HCT/CAR-T therapy to COVID-19 diagnosis compared to early infection at <100 days (OR, .31; 95% CI, .12 to .79; P = .011) were associated with a decreased odds for hospitalization. The OS at 12 months from COVID-19 diagnosis was 89% (95% CI, 84% to 94%), with 6 of 26 deaths attributable to COVID-19. Patients with the ancestral strain of SAR-CoV-2 had a lower OS at 12 months, with 73% (95% CI, 62% to 84%) versus 89% (95% CI, 84% to 94%; P < .001) in the Omicron cohort. Specific COVID-19 treatment was administered in 62% of patients, and 84% were vaccinated with mRNA COVID-19 vaccines. Vaccinated patients had significantly better OS than unvaccinated patients (90% [95% CI, 86% to 95%] versus 82% [95% CI, 72% to 94%] at 12 months; P = .003). No significant difference in OS was observed in patients infected with the Omicron and those infected with the Delta variant (P = .4) or treated with specific COVID-19 treatments compared with those not treated (P = .2). We observed higher OS in HCT and CAR-T recipients infected with the Omicron variants compared to those infected with the ancestral strain of SARS-CoV2. The use of COVID-19 antivirals, mAbs, and vaccines might have contributed to the improved outcomes.

Incidence and Impact of Fungal Infections in Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis and Haploidentical Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis.

Fungal infection (FI) after allogeneic hematopoietic cell transplantation (HCT) is associated with increased morbidity and mortality. Neutropenia, HLA mismatch, graft-versus-host disease (GVHD), and viral infections are risk factors for FI. The objectives of this Center for International Blood and Marrow Transplant Research registry study were to compare the incidence and density of FI occurring within 180 days after HCT in matched sibling (Sib) transplants with either calcineurin inhibitor (CNI)-based or post-transplantation cyclophosphamide (PTCy)-based GVHD prophylaxis and related haploidentical transplants receiving PTCy, and to examine the impact of FI by day 180 on transplantation outcomes. METHODS: Patients who underwent their first HCT between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome and received a related haploidentical transplant with PTCy (HaploCy; n = 757) or a Sib transplant with PTCy (SibCy; n = 403) or CNI (SibCNI; n = 1605) were analyzed. The incidence of FI by day 180 post-HCT was calculated as cumulative incidence with death as the competing risk. The associations of FI with overall survival, transplant-related mortality, chronic GVHD, and relapse at 2 years post-HCT were examined in Cox proportional hazards regression models. Factors significantly associated with the outcome variable at a 1% level were kept in the final model. RESULTS: By day 180 post-HCT, 56 (7%) HaploCy, 24 (6%), SibCy, and 59 (4%) SibCNI recipients developed ≥1 FI (P < .001). The cumulative incidence of yeast FI was 5.2% (99% confidence interval [CI], 3.3% to 7.3%) for HaploCy, 2.2% (99% CI, .7% to 4.5%) for SibCy, and 1.9% (99% CI, 1.1% to 2.9%) for SibCNI (P = .001), and that of mold FI was 2.9% (99% CI, 1.5% to 4.7%), 3.7% (99% CI, 91.7% to 6.6%), and 1.7% (99% CI, 1.0% to 2.6%), respectively (P = .040). FI was associated with an increased risk of death, with an adjusted hazard ratio (HR) of 4.06 (99% CI, 2.2 to 7.6) for HaploCy, 4.7 (99% CI, 2.0 to 11.0) for SibCy, and 3.4 (99% CI, 1.8 to 6.4) for SibCNI compared with SibCNI without FI (P < .0001 for all). Similar associations were noted for transplantation-related mortality. FI did not impact rates of relapse or chronic GVHD. CONCLUSIONS: Rates of FI by day 180 ranged between 1.9% and 5.2% for yeast FI and from 1.7% to 3.7% for mold FI across the 3 cohorts. The use of PTCy was associated with higher rates of yeast FI only in HaploHCT and with mold FI in both HaploHCT and SibHCT. The presence of FI by day 180 was associated with increased risk for overall mortality and transplant-related mortality at 2 years regardless of donor type or PTCy use. Although rates of FI were low with PTCy, FI is associated with an increased risk of death, underscoring the need for improved management strategies.

Reduced-Intensity Compared to Nonmyeloablative Conditioning in Patients with Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens in RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. We performed a retrospective single-center analysis to determine outcomes of adult patients with B cell and T cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 and December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4 Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4 Gy-total body irradiation (Flu-Cy-4Gy-TBI), and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen comprised fludarabine-cyclophosphamide-2 Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), nonrelapse mortality (NRM), and the incidence of acute and chronic graft-versus-host-disease (GVHD). Of 279 transplants recipients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up post-allo-HCT, there was no significant difference in OS between the NMA and RIC groups (median, not reached [NR] versus 103 months; P = .1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky Performance Status [KPS], Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI], and disease histology), the regression analysis showed no significant difference in PFS with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% confidence interval [CI], .92 to 2.09; P = .24). On univariable analysis, there was no significant difference in NRM between the RIC and NMA arms (100-day estimate, 10.0% versus 1.8%; P = .5). After adjustment for age, ethnicity, KPS, HCT-CI, GVHD prophylaxis, and donor source, RIC conditioning was associated with a significantly higher incidence of NRM compared to NMA conditioning (HR, 2.61; 95% CI, 1.04 to 6.52; P = .039). On multivariable analysis, compared with the NMA arm, the RIC arm had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 to 3.86; P = .002) and grade III-IV acute GVHD (HR, 5.62; 95% CI, 2.03 to 15.6; P < .001). The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.