Allogeneic hematopoietic cell transplantation (allo-HCT) is offered to selected patients after chimeric antigen receptor–modified T-cell (CAR-T) therapy. Lymphodepleting chemotherapy and CAR-T ...therapy have immunosuppressive and immunomodulatory effects that could alter the safety profile of subsequent allo-HCT. We reviewed our experience with 32 adults (acute lymphoblastic leukemia ALL, n = 19; B-cell non-Hodgkin lymphoma NHL/chronic lymphocytic leukemia CLL, n = 13) who received an allo-HCT after CAR-T therapy, with a focus on posttransplant toxicities. Myeloablative conditioning (MAC) was used in 74% of ALL patients and 39% of NHL/CLL patients. The median time from CAR-T therapy to allo-HCT was 72 days in ALL patients and 122 days in NHL/CLL patients. Cumulative incidences of grade 3-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 25% and 10%, respectively. All patients had neutrophil recovery (median, 18.5 days) and all but 3 had platelet recovery (median, 12 days). Twenty-two percent had viral or systemic fungal infection within 100 days after allo-HCT. The 100-day and 1-year cumulative incidences of NRM were 16% and 21%, respectively, for ALL patients and 15% and 33%, respectively, for NHL/CLL patients. In ALL patients, later utilization of allo-HCT after CAR-T therapy was associated with higher mortality. In NHL/CLL patients, MAC was associated with higher mortality. Toxicities did not exceed the expected incidences in this high-risk population.
•The toxicity of allo-HCT in patients with prior CAR-T therapy was not higher than what is expected in these high-risk patients.•In ALL patients, there seems to be a benefit from earlier utilization of allo-HCT after CAR-T therapy.
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A Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was previously developed showing that multiple comorbidities including moderate or greater valvular heart disease to be ...predictors of non-relapse mortality after allogeneic HCT. However, detailed description of the impact of valve disease on outcomes is lacking.
Among a large cohort of patients given allogeneic HCT between 2000 and 2017, we identified 21 patients with moderate or severe valvular disease. We also identified a cohort of 42 controls matched on age and HCT-CI score. The primary outcome was all-cause mortality, with censoring at two years of follow-up. Secondary outcomes included mortality without relapse, duration of index admission, number of readmissions, increase in creatinine and peak troponin.
Non-myeloablative regimens were more common in the valve disease cohort compared to controls (86% vs 54% p = 0.012). Valvular disease was associated with increased all-cause mortality with adjusted hazard ratio of 2.17 (CI 1.08–4.34, p = 0.029) and for non-relapse mortality with adjusted hazard ratio of 2.53 (CI 1.16–5.52, p = 0.020). In the valve disease cohort, creatinine increased by 1.6 vs 0.9 mg/dL (p = 0.003) and peak troponin by 1.6 vs 0.3 ng/mL (p = 0.05) compared to controls. There was no difference in readmissions or length of stay when accounting for outpatient treatment.
Despite having similar pre-procedure risk factors and undergoing less aggressive chemotherapy regimens, patients with moderate valvular disease or greater, most of whom did not meet current guideline recommendations for repair, had worse non-relapse related outcomes with higher mortality, renal and myocardial injury.
•Valve disease increases mortality in stem cell transplantation.•It also increases troponin, creatinine, and pulmonary complications.•Patients may benefit from valve intervention prior to transplantation.
Allogeneic conventional hematopoietic cell transplantation (HCT) can be curative treatment for lymphoid malignancies, but it has been characterized by high nonrelapse mortality (NRM). Here, we ...compared outcomes among patients with lymphoma or chronic lymphocytic leukemia given either nonmyeloablative (n = 152) or myeloablative (n = 68) conditioning. Outcomes were stratified by the HCT-specific comorbidity index. Patients in the nonmyeloablative group were older, had more previous treatment and more comorbidities, more frequently had unrelated donors, and more often had malignancy in remission compared with patients in the myeloablative group. Patients with indolent versus aggressive malignancies were equally distributed among both cohorts. After HCT, patients without comorbidities both in the nonmyeloablative and myeloablative cohorts had comparable NRM (P = .74), overall survival (P = .75), and progression-free survival (P = .40). No significant differences were observed (P = .91, P = .89, and P = .40, respectively) after adjustment for pretransplantation variables. Patients with comorbidities experienced lower NRM (P = .009) and better survival (P = .04) after nonmyeloablative conditioning. These differences became more significant (P < .001 and .007, respectively) after adjustment for other variables. Further, nonmyeloablative patients with comorbidities had favorable adjusted progression-free survival (P = .01). Patients without comorbidities could be enrolled in prospective randomized studies comparing different conditioning intensities. Younger patients with comorbidities might benefit from reduced conditioning intensity.
We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at ...reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.
Summary
It is not known whether obesity has a differential effect on allogeneic haematopoietic cell transplantation outcomes with alternative donor types. We report the results of a retrospective ...registry study examining the effect of obesity body mass index (BMI) > 30 on outcomes with alternative donors (haploidentical related donor with two or more mismatches and receiving post‐transplant cyclophosphamide haplo and cord blood (CBU) versus matched unrelated donor (MUD). Adult patients receiving haematopoietic cell transplantation for haematologic malignancy (2013–2017) (N = 16 182) using MUD (n = 11 801), haplo (n = 2894) and CBU (n = 1487) were included. The primary outcome was non‐relapse mortality (NRM). The analysis demonstrated a significant, non‐linear interaction between pretransplant BMI and the three donor groups for NRM: NRM risk was significantly higher with CBU compared to haplo at BMI 25–30 hazard ratio (HR) 1.66–1.71, p < 0.05 and MUD transplants at a BMI of 25–45 (HR, 1.61–3.47, p < 0.05). The results demonstrated that NRM and survival outcomes are worse in overweight and obese transplant recipients (BMI ≥ 25) with one alternative donor type over MUD, although obesity does not appear to confer a uniform differential mortality risk with one donor type over the other. BMI may serve as a criterion for selecting a donor among the three (MUD, haplo and CBU) options, if matched sibling donor is not available.
Summary
The haematopoietic cell transplantation‐specific comorbidity index (HCT‐CI) was developed in a single centre as a weighted scoring system to predict risks of non‐relapse mortality (NRM) ...following allogeneic haematopoietic cell transplantation. Information on the performance of the HCT‐CI in multi‐centre studies is lacking in the literature. To that end, a collaborative multicentre retrospective study was initiated. Comorbidity data from 2523 consecutive recipients of human leucocyte antigen‐matched grafts from five different US institutions were analysed. Among all patients, HCT‐CI scores of 0 vs. 1–2 vs. ≥3 were associated with 2–year NRM rates of 14%, 23% and 39% (P < 0·0001), respectively, and 2–year overall survival (OS) rates of 74%, 61% and 39%, respectively (P < 0·0001). Using regression models, increasing HCT‐CI scores were independently associated with increases in hazard ratios for NRM and worse survival within individual institutions. The HCT‐CI retained independent capacity for association with outcomes within different age as well as conditioning intensity groups. C‐statistic estimates for the prognostic power of the HCT‐CI for NRM and OS were 0·66 and 0·64, respectively. The estimates within each institution were overall similar. The HCT‐CI is a valid tool for capturing comorbidities and predicting mortality after haematopoietic cell transplantation across different institutions.
Abstract Prospective validation of the hematopoietic cell transplantation–comorbidity index (HCT-CI) using contemporary patients treated with hematopoietic cell transplantation (HCT) across the ...Unites States is necessary to confirm its widespread applicability. We performed a prospective observational study including all patients (8115 recipients of allogeneic and 11,652 recipients of autologous HCT) who underwent a first HCT that was reported to the Center for International Blood and Marrow Transplant Research between 2007 and 2009. In proportional hazards models, increased HCT-CI scores were independently associated with increases in hazard ratios for nonrelapse mortality (NRM) ( P < .0001) and overall mortality ( P < .0001) among recipients of allogeneic HCT. HCT-CI scores of ≥3 were uniformly associated with higher risks for outcomes in both allogeneic and autologous HCT and in all subgroups, regardless of diagnoses, age, and conditioning intensity. Recipients of allogeneic HCT with scores of 1 and 2 who were ages < 18 years or were treated with lower intensity conditioning regimens had similar outcomes compared with those with a score of 0. Higher risks for overall mortality, but not for NRM, were observed among recipients of autologous HCT with scores of 1 and 2 versus 0. Our results confirm the validity the HCT-CI in both allogeneic and autologous HCT. The index should be used as a valid standard-of-care health measure in counseling patients for HCT, in clinical trial design, and in adjusting outcome analyses.
•Among 1067 critically ill pediatric patients with HCT, survival to ICU discharge was 85%, but half of patients required ICU readmission.•For pediatric patients with HCT, overall survival 1-year ...after ICU admission was only 52% and survivors had excess long-term mortality risk.
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Allogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in intensive care unit (ICU) use and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6995 pediatric patients with HCT aged ≤21 years who underwent first allogeneic HCT between 2008 and 2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years after HCT), and was linked to demographic background, pretransplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7%, but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pretransplant organ function, and alloreactivity risk factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (P<.001). Thus, although ICU management is common and survival to ICU discharge is high, ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in select patients who are at high risk.
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