Bronchiolitis obliterans syndrome (BOS) is a highly morbid form of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Several plasma proteins have been identified as biomarkers for BOS after lung transplantation. The relevance of these biomarkers in BOS patients after allogeneic HCT has not been examined. We hypothesized that biomarkers associated with BOS after lung transplantation are also associated with BOS after allogeneic HCT. We tested plasma samples from 33 adult HCT patients who participated in a phase II multicenter study of fluticasone, azithromycin, and montelukast (FAM) treatment for new-onset BOS (NCT01307462), and matched control samples of HCT patients who had non-BOS chronic GVHD (n = 31) and those who never experienced chronic GVHD (n = 29) (NCT00637689 and NCT01902576). Candidate biomarkers included matrix metalloproteinase-9 (MMP-9), MMP-3, and chitinase-3-like-1 glycoprotein (YKL-40). MMP-9 concentrations were higher in the patients with BOS compared with those with non-BOS chronic GVHD (P =.04) or no chronic GVHD (P <.001). MMP-3 concentrations were higher in patients with BOS (P <.001) or non-BOS chronic GVHD (P <.001) compared with those with no chronic GVHD. YKL-40 concentrations did not differ statistically among the 3 groups. MMP-9 concentrations before starting FAM therapy were higher in patients who experienced treatment failure within 6 months compared with those with treatment success (P =.006), whereas MMP-3 or YKL-40 concentrations did not differ statistically between these 2 groups. Patients with an MMP-9 concentration ≥200,000 pg/mL before starting FAM therapy had worse overall survival compared with those with lower MMP-9 concentrations. Our data suggest that plasma MMP-9 concentration could serve as a relevant biomarker at diagnosis of BOS after allogeneic HCT for prognostication of survival and for prediction of treatment response. Further validation is needed to confirm our findings.

Hepatic graft-versus-host disease (HGVHD) contributes significantly to morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Clinical findings and liver biomarkers are neither sensitive nor specific. The relationship between clinical and histologic diagnoses of HGVHD was assessed premortem and at autopsy. Medical records from patients who underwent HSCT at the National Institutes of Health (NIH) Clinical Center between 2000 and 2012 and expired with autopsy were reviewed, and laboratory tests within 45 days of death were divided into 15-day periods. Clinical diagnosis of HGVHD was based on Keystone Criteria or NIH Consensus Criteria, histologic diagnosis based on bile duct injury without significant inflammation, and exclusion of other potential etiologies. We included 37 patients, 17 of whom had a cholestatic pattern of liver injury and two had a mixed pattern. Fifteen were clinically diagnosed with HGVHD, two showed HGVHD on autopsy, and 13 had histologic evidence of other processes but no HGVHD. Biopsy or clinical diagnosis of GVHD of other organs during life did not correlate with HGVHD on autopsy. The diagnostic accuracy of the current criteria was poor (κ = −0.20). A logistic regression model accounting for dynamic changes included peak bilirubin 15 days before death, and an increase from period −30 (days 30 to 16 before death) to period −15 (15 days before death) showed an area under the receiver operating characteristic curve of 0.77. Infection was the immediate cause of death in 68% of patients. In conclusion, liver biomarkers at baseline and GVHD elsewhere are poor predictors of HGVHD on autopsy, and current clinical diagnostic criteria have unsatisfactory performance. Peak bilirubin and cholestatic injury predicted HGVHD on autopsy. A predictive model was developed accounting for changes over time. Further validation is needed.

Bronchiolitis obliterans syndrome (BOS) may develop after either lung or haematopoietic stem cell transplantation (HSCT), with similarities in histopathological features and clinical manifestations. However, there are differences in the contributory factors and clinical trajectories between the two conditions. BOS after HSCT occurs due to systemic graft-versus-host disease (GVHD), whereas BOS after lung transplantation is limited to the lung allograft. BOS diagnosis after HSCT is more challenging, as the lung function decline may occur due to extrapulmonary GVHD, causing sclerosis or inflammation in the fascia or muscles of the respiratory girdle. Treatment is generally empirical with no established effective therapies. This review provides rare insights and commonalities of both conditions, which are not well elaborated elsewhere in contemporary literature, and highlights the importance of cross disciplinary learning from experts in other transplant modalities. Treatment algorithms for each condition are presented, based on the published literature and consensus clinical opinion. Immunosuppression should be optimised, and other conditions or contributory factors treated where possible. When initial treatment fails, the ultimate therapeutic option is lung transplantation (or re-transplantation in the case of BOS after lung transplantation) in carefully selected candidates. Novel therapies under investigation include aerosolised liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies and (in patients with BOS after lung transplantation) B-cell-directed therapies. Effective novel treatments that have a tangible impact on survival and thereby avoid the need for lung transplantation or re-transplantation are urgently required.

Adult hematopoietic stem cell transplantation (HSCT) recipients are at a high risk of adverse outcomes after COVID-19. Although children have had better outcomes after COVID-19 compared to adults, data on risk factors and outcomes of COVID-19 among pediatric HSCT recipients are lacking. We describe outcomes of HSCT recipients who were ≤21 years of age at COVID-19 diagnosis and were reported to the Center for International Blood and Marrow Transplant Research between March 27, 2020, and May 7, 2021. The primary outcome was overall survival after COVID-19 diagnosis. We determined risk factors of COVID-19 as a secondary outcome in a subset of allogeneic HSCT recipients. A total of 167 pediatric HSCT recipients (135 allogeneic; 32 autologous HSCT recipients) were included. Median time from HSCT to COVID-19 was 15 months (interquartile range [IQR] 7-45) for allogeneic HSCT recipients and 16 months (IQR 6-59) for autologous HSCT recipients. Median follow-up from COVID-19 diagnosis was 53 days (range 1-270) and 37 days (1-179) for allogeneic and autologous HSCT recipients, respectively. Although COVID-19 was mild in 87% (n = 146/167), 10% (n = 16/167) of patients required supplemental oxygen or mechanical ventilation. The 45-day overall survival was 95% (95% confidence interval [CI], 90-99) and 90% (74-99) for allogeneic and autologous HSCT recipients, respectively. Cox regression analysis showed that patients with a hematopoietic cell transplant comorbidity index (HCT-CI) score of 1-2 were more likely to be diagnosed with COVID-19 (hazard ratio 1.95; 95% CI, 1.03-3.69, P = .042) compared to those with an HCT-CI of 0. Pediatric and early adolescent and young adult HSCT recipients with pre-HSCT comorbidities were more likely to be diagnosed with COVID-19. Overall mortality, albeit higher than the reported general population estimates, was lower when compared with previously published data focusing on adult HSCT recipients.

Patients with hematologic malignancies relapsing after allogeneic blood or marrow transplantation (BMT) have limited response to conventional salvage therapies, with an expected 1-year overall survival (OS) of,20%. We evaluated the safety and clinical outcomes following administration of a novel T-cell therapeutic targeting 3 tumor-associated antigens (TAA-T) in patients with acute leukemia who relapsed or were at high risk of relapse after allogeneic BMT. Lymphocytes obtained from the BMT donor were manufactured to target TAAs WT1, PRAME, and survivin, which are over-expressed and immunogenic in most hematologic malignancies. Patients received TAA-T infusions at doses of 0.5 to 4 3 107/m2. Twenty-three BMT recipients with relapsed/refractory (n 5 11) and/or high-risk (n 5 12) acute myeloid leukemia (n 5 20) and acute lymphoblastic leukemia (n 5 3) were infused posttransplant. No patient developed cytokine-release syndrome or neurotoxicity, and only 1 patient developed grade 3 graft-versus-host disease. Of the patients who relapsed post-BMT and received bridging therapy, the majority (n 5 9/11) achieved complete hematologic remission before receiving TAA-T. Relapsed patients exhibited a 1-year OS of 36% and 1-year leukemia-free survival of 27.3% post–TAA-T. The poorest prognosis patients (relapsed,6 months after transplant) exhibited a 1-year OS of 42.8% postrelapse (n 5 7). Median survival was not reached for high-risk patients who received preemptive TAA-T posttransplant (n 5 12). Although as a phase 1 study, concomitant antileukemic therapy was allowed, TAA-T were safe and well tolerated, and sustained remissions in high-risk and relapsed patients were observed. Moreover, adoptively transferred TAA-T detected by T-cell receptor V-b sequencing persisted up to at least 1 year postinfusion. This trial was registered at clinicaltrials.gov as #NCT02203903.

Preventing chronic graft-versus-host disease (GVHD) remains challenging because the unique cellular and molecular pathways that incite chronic GVHD are poorly understood. One major point of intervention for potential prevention of chronic GVHD occurs at the time of transplantation when acute donor anti-recipient immune responses first set the events in motion that result in chronic GVHD. After transplantation, additional insults causing tissue injury can incite aberrant immune responses and loss of tolerance, further contributing to chronic GVHD. Points of intervention are actively being identified so that chronic GVHD initiation pathways can be targeted without affecting immune function. The major objective in the field is to continue basic studies and to translate what is learned about etiopathology to develop targeted prevention strategies that decrease the risk of morbid chronic GVHD without increasing the risks of cancer relapse or infection. Development of strategies to predict the risk of developing debilitating or deadly chronic GVHD is a high research priority. This working group recommends further interrogation into the mechanisms underpinning chronic GVHD development, and we highlight considerations for future trial design in prevention trials.

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome and is related to defects in DNA repair pathways that predispose affected individuals to malignancies.1 Monomorphic posttransplant lymphoproliferative disorder (PTLD) is a rare complication of hematopoietic cell transplantation (HCT) and behaves like an aggressive malignancy, often treated with alkylator-based chemotherapy. The underlying DNA repair defect in FA increases susceptibility to significant HCT treatment-related morbidity and mortality and makes standard monomorphic PTLD therapy challenging. We hypothesized that the novel approach of blinatumomab immunotherapy would have efficacy against PTLD that expresses CD19, with minimal toxicity. A 6-year-old male with FA, FANCA subtype, received an HLA-C 1-allele mismatched unrelated donor bone marrow HCT for progressive pancytopenia without evidence of myelodysplasia that was unresponsive to androgen therapy. On pretransplant evaluation, he was immunoglobulin G (IgG)–negative for Epstein-Barr virus (EBV). The donor’s EBV serologic status was unknown. He was enrolled in a phase 2 clinical trial (registered on ClinicalTrials.gov as #NCT03924401) and, per protocol, received a preparative regimen of thymoglobulin (12 mg/kg), fludarabine (150 mg/m2), and cyclophosphamide (30 mg/kg). Graft-versus-host disease (GVHD) prophylaxis included tacrolimus (serum target level, 8-12 ng/dL), mycophenolate mofetil through day 30, and the study drug abatacept on days −1, +5, +14, +28, +56, +87, +112, and +150. The patient had an uneventful early transplant course, with neutrophil engraftment on day +18. He was discharged on day +30 without evidence of GVHD and was on our institutional standard infectious prophylactic agents: acyclovir, Bactrim, and voriconazole at discharge.

As we pass the nearly 9 month mark of the coronavirus virus disease 2019 (COVID-19) pandemic in the United States, we sought to compile a brief multi-disciplinary compendium of COVID-19 information learned to date. COVID-19 is an active viral pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that confers high morbidity and mortality. COVID-19 has been associated with: pulmonary compromise and acute respiratory distress syndrome, thrombotic events, inflammation and cytokine, and post-infectious syndromes. Mitigation of these complications and expeditious therapy are a global urgency; this is brief summary of current data and management approaches synthesized from publications, experience, cross-disciplinary expertise (Figure 1).

Critically ill pediatric allogeneic hematopoietic cell transplant (HCT) patients may benefit from early and aggressive interventions aimed at reversing the progression of multiorgan dysfunction. Therefore, we evaluated 25 early risk factors for pediatric intensive care unit (PICU) mortality to improve mortality prognostication. We merged the Virtual Pediatric Systems and Center for International Blood and Marrow Transplant Research databases and analyzed 936 critically ill patients ≤21 years of age who had undergone allogeneic HCT and subsequently required PICU admission between January 1, 2009, and December 31, 2014. Of 1532 PICU admissions, the overall PICU mortality rate was 17.4% (95% confidence interval [CI], 15.6% to 19.4%) but was significantly higher for patients requiring mechanical ventilation (44.0%), renal replacement therapy (56.1%), or extracorporeal life support (77.8%). Mortality estimates increased significantly the longer that patients remained in the PICU. Of 25 HCT- and PICU-specific characteristics available at or near the time of PICU admission, moderate/severe pre-HCT renal injury, pre-HCT recipient cytomegalovirus seropositivity, <100-day interval between HCT and PICU admission, HCT for underlying acute myeloid leukemia, and greater admission organ dysfunction as approximated by the Pediatric Risk of Mortality 3 score were each independently associated with PICU mortality. A multivariable model using these components identified that patients in the top quartile of risk had 3 times greater mortality than other patients (35.1% versus 11.5%, P <. 001, classification accuracy 75.2%; 95% CI, 73.0% to 77.4%). These data improve our working knowledge of the factors influencing the progression of critical illness in pediatric allogeneic HCT patients. Future investigation aimed at mitigating the effect of these risk factors is warranted.