Chronic graft-versus-host disease: unresolved complication or ancient history?

ABSTRACT: Chronic graft-versus-host disease (cGVHD) is associated with morbidity, mortality, impaired quality of life, prolonged immunosuppressive therapy, and infection risk after allogeneic hematopoietic cell transplantation (HCT). Major strides have occurred in the understanding of cGVHD biology; National Institutes of Health Consensus meetings have refined rigorous approaches to diagnosis, staging, and response criteria; major interventional trials have established standard benchmarks for treatment outcome; and 3 agents to date have been US Food and Drug Administration approved for treating corticosteroid-refractory cGVHD. Promising results from several recent trials have led some, but not others, to conclude that the risk of developing cGVHD is sufficiently low to be considered a major post-HCT complication of the past. We propose that it is time to critically examine the results of contemporary graft-versus-host disease (GVHD) prophylaxis regimens and discuss the state of the science and associated controversies in the spectrum of conclusions reached as to the risk of cGVHD. With these data, the current cGVHD incidence can be most precisely determined, and the present and future burden of cGVHD-affected patients can be accurately modeled. Through review of existing evidence, we highlight unresolved needs and opportunities to refine best GVHD prophylaxis or preemptive therapy approaches and optimize established cGVHD therapy, and make the argument that support of preclinical and clinical research is critical in improving patient outcomes.

HA-1-targeted T-cell receptor T-cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.

ABSTRACT: Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective antileukemic effect post-HCT. We conducted a phase 1 clinical trial using a novel TCR-T product targeting the minor H antigen, HA-1, to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T after HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8 coreceptor were successfully manufactured from HA-1-disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to 9 HCT recipients who had developed disease recurrence after HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, 4 patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with 1 patient still in remission at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T-cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial was registered at ClinicalTrials.gov as #NCT03326921.

An 8-year pragmatic observation evaluation of the benefits of allogeneic HCT in older and medically infirm patients with AML.

We designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients' overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

HLA-DQ heterodimers in hematopoietic cell transplantation.

HLA-DQ heterodimers increase the susceptibility to autoimmune diseases, but their role in hematopoietic cell transplantation is unknown. We tested the hypothesis that outcome after HLA-matched and HLA-DQ-mismatched hematopoietic cell transplantation is influenced by HLA-DQ heterodimers. Heterodimers were defined in 5164 HLA-matched and 520 HLA-DQ-mismatched patients and their transplant donors according to well-established crystallographic criteria. Group 1 (G1) heterodimers are any DQA1*02/03/04/05/06α paired with any DQB1*02/03/04ß. Group 2 (G2) heterodimers are DQA1*01α paired with any DQB1*05/06ß. Multivariable models identified significantly higher relapse risk in G1G2 and G2G2 compared with G1G1 HLA-matched patients with malignant disease; risk increased with an increasing number of G2 molecules. In HLA-DQ-mismatched transplantation for malignant diseases, matching or mismatching for G2 increased relapse risk. G2 lowered disease-free survival after both HLA-matched and HLA-DQ-mismatched transplantation. A paradigm based on HLA-DQ heterodimers provides a functional definition of the hematopoietic cell transplantation barrier and a means to lower risks for future patients.

Craniospinal irradiation for CNS leukemia: rates of response and durability of CNS control.

PURPOSE: Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited. METHODS: We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated. RESULTS: Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18 Gy to the brain and 12 Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12 Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI. CONCLUSION: CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space.

Merkel cell carcinoma recurrence risk estimation is improved by integrating factors beyond cancer stage: A multivariable model and web-based calculator.

BACKGROUND: Merkel cell carcinoma (MCC) recurs in 40% of patients. In addition to stage, factors known to affect recurrence risk include: sex, immunosuppression, unknown primary status, age, site of primary tumor, and time since diagnosis. PURPOSE: Create a multivariable model and web-based calculator to predict MCC recurrence risk more accurately than stage alone. METHODS: Data from 618 patients in a prospective cohort were used in a competing risk regression model to estimate recurrence risk using stage and other factors. RESULTS: In this multivariable model, the most impactful recurrence risk factors were: American Joint Committee on Cancer stage (P < .001), immunosuppression (hazard ratio 2.05; P < .001), male sex (1.59; P = .003) and unknown primary (0.65; P = .064). Compared to stage alone, the model improved prognostic accuracy (concordance index for 2-year risk, 0.66 vs 0.70; P < .001), and modified estimated recurrence risk by up to 4-fold (18% for low-risk stage IIIA vs 78% for high-risk IIIA over 5 years). LIMITATIONS: Lack of an external data set for model validation. CONCLUSION/RELEVANCE: As demonstrated by this multivariable model, accurate recurrence risk prediction requires integration of factors beyond stage. An online calculator based on this model (at merkelcell.org/recur) integrates time since diagnosis and provides new data for optimizing surveillance for MCC patients.

γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial.

BACKGROUND: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. METHODS: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. FINDINGS: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. INTERPRETATIONS: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. FUNDING: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.

Transplantation for myeloid neoplasms with antecedent solid tumor.

BACKGROUND: Definitive treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN) involves allogeneic hematopoietic stem cell transplantation (allo-HSCT), either with myeloablative (MAC) or reduced-intensity conditioning (RIC). These diseases may arise in patients with a prior solid tumor. The impact of antecedent solid tumor on transplantation decision-making and outcomes is not well defined. METHODS: The authors performed a retrospective cohort study to address this question. A total of 1193 patients who underwent allo-HSCT for AML, MDS, or MPN between January 1, 2010 and December 31, 2018 were included, 102 of whom had a history of prior solid tumor. RESULTS: Patients with prior solid tumor were older (median age, 62.5 vs. 54.9 years; p < .00001) and more frequently were conditioned with RIC (52.5% vs. 27.2%; p < .00001). A higher incidence of acute graft-versus-host disease was observed in patients with prior solid tumor (73.5% vs 66.4%; adjusted odds ratio, 1.65; 95% confidence interval, 1.03-2.65; p = .037), yet overall survival and relapse did not significantly differ. Cytogenetic risk was the dominant risk factor for survival. CONCLUSIONS: Analysis by the authors suggests that patients with antecedent solid tumor and respective therapy can be transplanted successfully. Although selection bias is likely to be a factor, the results are encouraging for patients who come to transplantation after surviving a prior cancer.

Dental evaluation and clearance prior to allogeneic hematopoietic cell transplantation.

INTRODUCTION: Dental examination and stabilization are performed prior to allogeneic hematopoietic cell transplantation to decrease infection risk during neutropenia. Burden of dental disease and treatment need is not well characterized in this population. OBJECTIVES: This report describes the dental status of a cohort of patients within the Chronic Graft-versus-Host Disease Consortium and treatment rendered prior to transplant. METHODS: The cohort included 486 subjects (Fred Hutchinson: n = 245; Dana-Farber: n = 241). Both centers have institutional-based dental clearance programs. Data were retrospectively abstracted from medical records by calibrated oral health specialists. RESULTS: The median age at transplant was 55.9 years, 62.1% were male, and 88% were white. Thirteen patients were edentulous (2.7%). The mean teeth among dentate patients before clearance was 26.0 (SD, 4.6). Dental findings included untreated caries (31.2%), restorations (91.6%), endodontically treated teeth (48.1%), and dental implants (5.7%). Pretransplant procedures during clearance included endodontic therapy (3.6%; mean = 0.1 teeth), restorations (25.1%; mean = 0.7), dental prophylaxis (59.2%), scaling/root planing (5.1%), and extraction (13.2%; mean = 0.3). The mean teeth after clearance was 25.6 (SD, 5.0). CONCLUSIONS: Retrospective analysis of pre-AlloHCT dental data in subjects at two large transplant centers identified low levels of dental need. Findings suggest high access to care.

The impact of histological grade on outcomes in follicular lymphoma: An analysis of patients in the SEER database in the context of evolving disease classification and treatment.

Currently, there is no convincing evidence that the grade of follicular lymphoma (FL) impacts patient outcome. We correlated grades in 33 925 patients with nodal FL during 1992-2018 in the SEER database with disease-specific survival (DSS) and overall survival (OS). Patients with FL grade 3 had lower DSS and OS as compared to FL grades 1-2. During 1992-2005, the 10-year DSS for patients with FL grades 3 and grades 1-2 were 68.6%, and 71.4%, respectively, and in 2006-2018, they were 77.7% and 82.6%, respectively. The 10-year OS estimates in 1992-2005 were 49.9% and 54.2% for grade 3 and grades 1-2 respectively, and in 2006-2018, they were 59.1% and 63.5% for grade 3 and grades 1-2, respectively. After adjustment for stage and age, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 during 1992-2005 were 1.09 (1.02-1.16) and 1.07 (1.02-1.12), respectively, compared to FL grades 1-2; and during 2006-2018, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 were 1.34 (1.22-1.45) and 1.16 (1.10-1.23), respectively compared to FL grades 1-2. The grade of FL is an important determinant of disease biology.

The impact of B-cell-directed therapy on SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia.

Prior reports evaluating SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia (CLL) used semiquantitative measurements of anti-S to evaluate immunity; however, neutralization assays were used to assess functional immunity in the trials leading to vaccine approval. Here, we identified decreased rates of seroconversion in vaccinated CLL patients and lower anti-S levels compared to healthy controls. Notably, we demonstrated similar results with the Roche anti-S assay and neutralization activity. Durable responses were seen at six months; augmentation with boosters was possible in responding patients. Absence of normal B cells, frequently seen in patients receiving Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors, was a strong predictor of lack of seroconversion.

HLA-B leader and survivorship after HLA-mismatched unrelated donor transplantation.

Hematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B-mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1-mismatched MM patients compared with HLA-DQB1-mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1-mismatched MM or MT patients compared with HLA-DRB1-mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.

Immune Checkpoint Inhibitor Use in Solid Organ Transplant Recipients: A Systematic Review.

Chronic immunosuppression in solid organ transplant recipients (SOTRs) leads to an increased risk of a wide variety of cancers. Immune checkpoint inhibitor (ICI) therapy is indicated for many of these; however, the risks and benefits of ICI use in the SOTR population have not been well characterized. We performed a systematic literature review identifying 119 reported cases of ICI use among SOTRs. Treatments used included PD-1 inhibition (75.6%), CTLA-4 inhibition (12.6%), PD-L1 inhibition (1.7%), and combination and/or sequential ICI therapy (10.1%). The most common cancers included cutaneous melanoma (35.3%), hepatocellular carcinoma (22.7%), and cutaneous squamous cell carcinoma (18.5%). The overall objective response rate (ORR) was 34.5%, with a median duration of response of 8.0 months. Ongoing response was seen in 21.0%. Cutaneous squamous cell carcinoma had significantly better ORR compared with other cancer types (68.2% vs 26.8%; odds ratio [OR], 5.85; P =.0006). Factors associated with improved ORR included increasing time from transplant to ICI (OR, 1.09; P =.008) and preemptive reduction in intensity of the graft maintenance immunosuppressive regimen (50.0% vs 18.5%; OR, 4.40; P =.0088). Rejection occurred in 41.2%, graft failure in 23.5%, and immune-related adverse events in 18.5%. Factors significantly associated with allograft rejection included allograft PD-L1 positivity (100% vs 0%; P<.0001) and absence of tacrolimus in the immunosuppressive regimen (48.7% vs 25.6%; OR, 0.36; P =.019). The most common cause of death was progressive malignancy (64.0%), followed by graft failure (24.0%). Our analysis provides current benchmark data to help inform management of SOTRs with advanced cancers that are reflected by our patient cohort. Biomarker development, more robust datasets, and prospective study of concomitant immunosuppression management may help refine decision-making in this complex scenario in the future. Close coordination of care between the medical oncologist and transplant specialist is encouraged to help optimize treatment outcomes.

Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy.

Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease-negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/µL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells.

Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T-cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors affecting response and progression-free survival (PFS) in patients with aggressive NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by 2 × 106 CD19-directed CAR T cells/kg. The best overall response rate was 51%, with 40% of patients achieving complete remission. The median PFS of patients with aggressive NHL who achieved complete remission was 20.0 months (median follow-up, 26.9 months). Multivariable analysis of clinical and treatment characteristics, serum biomarkers, and CAR T-cell manufacturing and pharmacokinetic data showed that a lower pre-lymphodepletion serum lactate dehydrogenase (LDH) level and a favorable cytokine profile, defined as serum day 0 monocyte chemoattractant protein-1 (MCP-1) and peak interleukin-7 (IL-7) concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion, and higher intensity of cyclophosphamide and fludarabine lymphodepletion was associated with higher probability of a favorable cytokine profile. PFS was superior in patients who received high-intensity lymphodepletion and achieved a favorable cytokine profile compared with those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH levels above normal, a favorable cytokine profile after lymphodepletion was associated with a low risk of a PFS event. Strategies to augment the cytokine response to lymphodepletion could be tested in future studies of CD19 CAR T-cell immunotherapy for aggressive B-cell NHL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

Use of the HLA-B leader to optimize cord blood transplantation

Cord-blood transplantation (CBT) can cure life-threatening blood disorders. The HLA-B leader affects the success of unrelated donor transplantation but its role in CBT is unknown. We tested the hypothesis that the HLA-B leader influences CBT outcomes in unrelated single-unit cord-blood transplants performed by Eurocord/European Blood and Marrow Transplant (EBMT) centers between 1990 and 2018 with data reported to Eurocord. Among 4822 transplants, 2178 had one HLA-B mismatch of which 1013 were HLA-A and HLA-DRB1-matched. The leader (M or T) was determined for each HLA-B allele in patients and units to define the genotype. Among single HLA-B-mismatched transplants, the patient/unit mismatched alleles were defined as leader-matched if they encoded the same leader, or leader-mismatched if they encoded different leaders; the leader encoded by the matched (shared) allele was determined. The risks of GVHD, relapse, non-relapse mortality and overall mortality were estimated for various leaderdefined groups using multivariable regression models. Among the 1013 HLA-A, -DRB1- matched transplants with one HLA-B mismatch, increasing numbers of cord-blood unit M-leader alleles was associated with increased risk of relapse (hazard ratio [HR] for each increase in one M-leader allele 1.30, 95% confidence interval [CI] 1.05 to 1.60, P 0.02). Furthermore, leader mismatching together with an M-leader of the shared HLA-B allele lowered non-relapse mortality (HR 0.44, 95% CI 0.23 to 0.81; P 0.009) relative to leader-matching and a shared T-leader allele. The HLA-B leader may inform relapse and non-relapse mortality risk after CBT. Future patients might benefit from the appropriate selection of units that consider the leader.

Survival, Nonrelapse Mortality, and Relapse-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: Comparing 2003-2007 Versus 2013-2017 Cohorts.

Background: Allogeneic hematopoietic cell transplantation is indicated for refractory hematologic cancer and some nonmalignant disorders. Survival is limited by recurrent cancer and organ toxicity. Objective: To determine whether survival has improved over the past decade and note impediments to better outcomes. Design: The authors compared cohorts that had transplants during 2003 to 2007 versus 2013 to 2017. Survival outcome measures were analyzed, along with transplant-related complications. Setting: A center performing allogeneic transplant procedures. Participants: All recipients of a first allogeneic transplant during 2003 to 2007 and 2013 to 2017. Intervention: Patients received a conditioning regimen, infusion of donor hematopoietic cells, then immunosuppressive drugs and antimicrobial approaches to infection control. Measurements: Day-200 nonrelapse mortality (NRM), recurrence or progression of cancer, relapse-related mortality, and overall mortality, adjusted for comorbidity scores, source of donor cells, donor type, patient age, disease severity, conditioning regimen, patient and donor sex, and cytomegalovirus serostatus. Results: During the 2003-to-2007 and 2013-to-2017 periods, 1148 and 1131 patients, respectively, received their first transplant. Over the decade, decreases were seen in the adjusted hazards of day-200 NRM (hazard ratio [HR], 0.66 [95% CI, 0.48 to 0.89]), relapse of cancer (HR, 0.76 [CI, 0.61 to 0.94]), relapse-related mortality (HR, 0.69 [CI, 0.54 to 0.87]), and overall mortality (HR, 0.66 [CI, 0.56 to 0.78]). The degree of reduction in overall mortality was similar for patients who received myeloablative versus reduced-intensity conditioning, as well as for patients whose allograft came from a matched sibling versus an unrelated donor. Reductions were also seen in the frequency of jaundice, renal insufficiency, mechanical ventilation, high-level cytomegalovirus viremia, gram-negative bacteremia, invasive mold infection, acute and chronic graft-versus-host disease, and prednisone exposure. Limitation: Cohort studies cannot determine causality, and current disease severity criteria were not available for patients in the 2003-to-2007 cohort. Conclusion: Improvement in survival and reduction in complications were substantial after allogeneic transplant. Relapse of cancer remains the largest obstacle to better survival outcomes. Primary Funding Source: National Institutes of Health.

Early Post-Transplantation Spirometry Is Associated with the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation.

Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (allo-HCT) is often diagnosed at a late stage when lung dysfunction is severe and irreversible. Identifying patients early after transplantation may offer improved strategies for early detection that could avert the morbidity and mortality of BOS. This study aimed to determine whether a decline in lung function before and early after (days +80 to +100) allo-HCT are associated with a risk of BOS beyond 6 months post-transplantation. In a single-center cohort of 2941 allo-HCT recipients, 186 (6%) met National Institutes of Health criteria for BOS. Pretransplantation and post-transplantation day +80 spirometric parameters were analyzed as continuous variables and included in a multivariable model with other factors, including donor source, graft source, conditioning regimen, use of total body irradiation, and immunoglobulin levels. Pre-transplantation forced expiratory flow between 25% and 75% of maximum (FEF25-75), day +80 forced expiratory volume in 1 second (FEV1), and day +80 FEF25-75 had the strongest associations with increased risk of BOS. Assessment of the multivariable model showed that a decline in day +80 FEF25-75 added additional risk to the day +80 FEV1 model (P = .03), whereas FEV1 decline at day +80 added no additional risk to the day +80 FEF25-75 model (P = .645). Moreover, day +80 FEF25-75 conferred additional risk when considered with pretransplantation FEF25-75. These results suggest that day +80 FEF25-75 may be more important than FEV1 in predicting the development of BOS. This study highlights the importance of obtaining early post-transplantation pulmonary function tests for the potential risk stratification of patients at risk for BOS.

Azithromycin Use and Increased Cancer Risk among Patients with Bronchiolitis Obliterans after Hematopoietic Cell Transplantation.

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematologic relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of patients with BOS from 2 large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio (HR) in patients exposed to azithromycin versus unexposed was 1.51 (95% confidence interval [CI], 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR, 0.54; 95% CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.

Yttrium-90-labeled anti-CD45 antibody followed by a reduced-intensity hematopoietic cell transplantation for patients with relapsed/refractory leukemia or myelodysplasia.

Outcomes of patients with persistent high-risk leukemia or myelodysplasia prior to allogeneic hematopoietic cell transplantation are dismal. We therefore conducted a phase I trial evaluating the use of CD45-targeted radiotherapy preceding hematopoietic cell transplantation with the goal of improving outcomes for this high-risk scenario. Fifteen patients, median age 62 (range 37-76) years, were treated: ten with advanced acute myeloid leukemia, five with high-risk myelodysplastic syndrome. All patients had evidence of disease prior to treatment including nine with marrow blast counts ranging from 7-84% and six with minimal residual disease. Patients received escalating doses of yttrium-90-labeled anti-CD45 antibody followed by fludarabine and 2 Gy total body irradiation prior to human leukocyte antigen-matched, related or unrelated hematopoietic cell transplantation. Although a maximum dose of 30 Gy was delivered to the liver, no dose-limiting toxicity was observed. Therefore, the maximum-tolerated dose could not be estimated. Treatment led to complete remission in 13 patients (87%). All patients engrafted by day 28. Six patients relapsed, median of 59 (range 6-351) days, after transplantation. The 1-year estimate of relapse was 41%. Eight patients (53%) are surviving with median follow up of 1.8 (range 0.9-5.9) years. Estimated overall survival at one and two years was 66% and 46%, respectively, with progression-free survival estimated to be 46% at each time point. In conclusion, the combination of 90Y-DOTA-BC8 with an allogeneic hematopoietic cell transplantation regimen was feasible and tolerable. This approach appears promising in this high-risk leukemia/myelodysplasia patient population with active disease. (Trial registered at clinicaltrials.gov identifier: NCT01300572).