Transplantation and Cellular Therapy最新文献

Background: Patients with adult T-cell leukemia/lymphoma (ATL) are considered to have worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) than patients with other hematological malignancies, owing to high risk of relapse and immunocompromised status. However, no studies have compared transplant outcomes between patients with ATL and those with other hematological malignancies using a large-scale database.

Objectives: To compare transplant outcomes between patients with ATL and those with other leukemias and to identify factors contributing to worse transplant outcomes in ATL patients.

Study design: Using Japanese registry data, we retrospectively compared transplant outcomes between patients with ATL and those with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). As ATL often develops in patients in their 60s or older, patients with ATL, AML, or ALL aged ≥50 years were included in order to compare patients in the same age group. A total of 7764 patients (ATL, n = 1151; AML, n = 5393; ALL, n = 1220) who underwent their first allo-HSCT between January 1, 2006 and December 31, 2017 were included in this study.

Results: Compared with AML, ATL showed significantly worse overall survival (OS) (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.14 to 1.34; P < .001) and higher risk of relapse (HR, 1.33; 95% CI, 1.2 to 1.47; P < .001), while there were no significant differences between AML and ALL. Among patients in complete remission (CR) at transplantation, ATL showed worse OS (HR, 1.30; 95% CI, 1.08 to 1.56; P = .006), higher risk of relapse (HR, 1.78; 95% CI, 1.48 to 2.14; P < .001), and higher risk of nonrelapse mortality (NRM) (HR, 1.38; 95% CI, 1.14 to 1.33; P = .001) in comparison with AML, whereas there were no significant differences between AML and ALL.

Conclusion: We found that ATL patients have poor transplant outcomes compared with AML or ALL patients. In ATL patients, survival is poor, relapse is more frequent, and NRM is significantly higher, especially in cases of CR. These findings suggest that prevention of relapse and transplant-related complications is important for successful allo-HSCT in ATL.

Background: The relationship between obesity and graft-versus-host disease (GVHD) has been studied in both preclinical and clinical studies with varying results.

Objectives: We aimed to investigate the impact of obesity, as measured by body mass index (BMI), on the incidence, severity, and response to therapy of GVHD in a contemporary cohort.

Study design: We conducted a retrospective study of patients undergoing allogeneic hematopoietic cell transplant (HCT) for acute myelogenous leukemia and myelodysplastic syndrome between January 2010 and December 2021 at the Cleveland Clinic. Incidence, grade, organ involvement, and response to therapy of acute and chronic GVHD were compared between patients with obesity (BMI ≥30) and without obesity. Secondary outcomes included relapse, nonrelapse mortality (NRM), and overall survival (OS).

Results: 531 patients were identified, with a median follow-up of 19 months (range, 7-49). Mean (SD) BMI at time of HCT was 29.1 (6.3) kg/m². There was no significant difference in demographic and HCT characteristics between patients with obesity (N = 199) and without obesity (N = 332). Development of any acute (42% versus 43%) or chronic (29% versus 30%) GVHD was similar in patients with and without obesity. Patients with obesity were less likely to have gastrointestinal involvement from chronic GVHD (28% versus 48%, P = .01). Skin (64% versus 56%), mouth (45% versus 35%) and eye (35% versus 27%) involvements were higher in patients with obesity, although statistically not significant. There were no significant differences in OS, NRM, or relapse.

Conclusion: There were no significant differences in incidence of GVHD among patients with and without obesity. Additional studies are needed to further understand potential differences in organ involvement.

HSCT conditioning regimens cause massive lysis of hematopoietic cells with release of toxic intracellular molecules into the circulation. To describe the response to oxidative stress early after hemopoietic stem cell transplantation (HSCT) and assess the association of early oxidative stress with later transplant outcomes. Key components of in the body's physiological response to oxidative stress were studied in a cohort of 122 consecutive pediatric allogeneic HSCT recipients. Glutathione reductase (GSR), glutathione peroxidase (GPX) and glutathione synthetase protein expression was measured using ELISA and reduced and oxidized glutathione (GSH and GSSG) levels were quantified using mass spectrometry. GSR is an inducible enzyme which catalyzes the regeneration of reduced glutathione (GSH). Levels of GSR increased by more than 5-fold between start of conditioning chemotherapy and day 0 (median 87ng/mL to 459ng/mL, P < .0001). GPX catalyzes removal of toxic reactive oxygen species (ROS) by oxidation of GSH. GPX4 levels fell briskly by day 0 (median 20.3 ng/mL prior to HSCT to 7.4ng/mL at day 0, P < .0001), likely indicating consumption of the enzyme as cell lysis and subsequent oxidative stress occurred. Levels of the antioxidant substrate reduced glutathione stayed stable from pre-HSCT through day 14, likely maintained by increased glutathione synthesis by the enzyme glutathione synthetase, whose median levels increased from 38.8ng/mL before conditioning to 54ng/mL at day 21 (P = .02). GSR levels were associated with patient outcomes. Median GSR levels were significantly elevated through days 0-21 in those who died in the first year after HSCT compared to those who survived. Similarly, patients who developed high risk transplant-associated thrombotic microangiopathy (TA-TMA) and grade 2 and above graft versus host disease (GVHD) also had significantly higher GSR levels early after HSCT. Our data suggest that the body is for the most part able to mount a brisk and effective response to the oxidative stress associated with lysis of the hematopoietic cell system before HSCT. Our data also suggest that early events in the first 21 days of HSCT may set the scene for later clinical events in the first year after HSCT. It is plausible that patients who are unable to effectively overcome this early period of significant oxidative stress may have increased endothelial injury and activation of complement. Potential therapeutics to augment and optimize the body's response to oxidative stress may improve outcomes.

Minimal residual disease (MRD) is the most important prognostic factor for B-cell acute lymphoblastic leukemia (B-ALL) however nearly 20% to 30% of patients relapsed even when they achieved negative MRD, how to identify these patients is less addressed. In this study, we aimed to reassess the prognostic significance of MRD and IKZF1 in adult B-ALL patients receiving pediatric chemotherapy regimens. In the PDT-ALL-2016 cohort (NCT03564470), adult B-ALL patients were treated with a pediatric-inspired regimen; patients were redefined as standard (MRD-negative and IKZF1wild-type), intermediate (MRD-positive or IKZF1 deletion), and high-risk (MRD-positive and IKZF1 deletion) groups by combining IKZF1 deletion status and MRD. Furthermore, the prognostic panel of IKZF1 deletion and/or MRD-positive was confirmed in the independent cohort from the COG-P9906 dataset. In the high- and intermediate-risk groups, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was strongly associated with higher 5-year overall survival (OS), higher leukemia-free survival (LFS), and lower cumulative incidence of relapse (CIR). In the standard-risk group, there was no significant advantage in the 5-year OS, LFS, and CIR of patients who received allo-HSCT versus those who received chemotherapy. Our study demonstrated that combining early MRD response and IKZF1 deletion allows for better risk stratification of patients to identify those who may benefit from allo-HSCT in the context of an intensified pediatric-inspired regimen.

Background: Recurrence of blood malignancy is the major cause of mortality after hematopoietic cell transplantation. NKG2 receptor/HLA-E ligand complexes play a fundamental role in the surveillance and elimination of transformed cells but their role in the control of leukemia in transplantation is unknown.

Objective: We tested the hypothesis that gene variation of patient and/or donor HLA-E ligand and donor NKG2C-NKG2A receptors are associated with the risks of relapse and mortality (primary endpoints) and GVHD and non-relapse mortality (secondary endpoints) after haploidentical transplantation.

Study design: We retrospectively defined donor NKG2 receptor haplotypes and patient HLA-E ligands in 1629 haploidentical related transplantations. HLA-E residue 107 was genotyped in patients and donors. Single nucleotide polymorphisms descriptive of NKG2C and NKG2A haplotypes were characterized in donors. Overall mortality, relapse, nonrelapse mortality and chronic GVHD were studied using Cox regression models. Acute GVHD was studied by logistic regression.

Results: The hazard of relapse for patients transplanted from NKG2C-del/del donors was 51% lower than that from wt/wt donors (hazard ratio, HR, .49 [95% CI, .26 to .89) contributing to a HR for mortality of .62 (95% CI, .38 to 1.02). The HR of mortality among patients transplanted from a donor with 2 vs. 0 copies of the NKG2A rs35909400-rs2734440-rs12824474 CCC haplotype was HR 2.28 (95% CI, 1.34 to 3.86). The HRs of mortality for ArgArg and ArgGly patients compared to GlyGly patients were 1.42 (95% CI, 1.11 to 1.82) and 1.43 (95% CI, 1.13 to 1.81), respectively. Hazard ratios for nonrelapse mortality for patients with ArgGly or ArgArg genotypes compared to patients with GlyGly genotype were HR 1.60 (95% CI, 1.06 to 2.41) and HR 1.79 (95% CI, 1.21 to 2.66), respectively. Assessment of donor receptor/patient ligand pairings showed that among Arg-positive patients, the HR of mortality from donors with any wt-CCC/CCC haplotype was HR 2.52 (95% CI, 1.45 to 4.38) relative to donors with any wt-non CCC/CCC haplotype.

Conclusions: The success of haploidentical transplantation may be defined by the cumulative effects of donor NKG2 receptor and patient HLA-E ligand polymorphisms. Patient HLA-E ligand and donor NKG2C-NKG2A receptor haplotypes shed new light on their role in the control of malignancy.

CD19-directed chimeric antigen receptor T cell (CAR-T) therapy is now standard of care for relapsed/refractory large B cell non-Hodgkin lymphoma. Despite good overall response rates, many patients still experience disease progression and therefore it is important to predict those at risk of relapse following CAR-T therapy. We performed a prospective study using a flow cytometry assay at a single treatment center to assess early CAR T cell expansion in vivo 6 to 9 days after CAR T cell infusion. Early CAR T cell expansion was used in conjunction with additional clinical risk factors to identify those at greater risk of relapse or treatment failure. Forty-four patients treated with commercial CD19-directed CAR-T therapy were included in the study, with a median follow-up of 306 days. CAR T cell expansion of >30 cells/μL was associated with a lower risk of disease progression or death (hazard ratio, 0.34; P = .048), but did not correlate with the risk of death alone. Patients who had poor early CAR T cell expansion (<30 cells/μL) in addition to high lactate dehydrogenase (LDH) had significantly lower median progression-free survival and overall survival. High LDH level alone was not a statistically significant risk factor for death or disease progression, and thus the interaction between CAR T cell expansion and this clinical risk factor may be important in predicting response. The mean CAR T cell count was higher in patients with grade 2 to 4 cytokine release syndrome (CRS) compared to those with grade 0 to 1 CRS (54.9 cells/μL versus 25.5 cells/μL; P = .01). The methodology of this assay is easily reproducible outside of a clinical trial, allowing for real-life implementation in clinical settings. This study suggests that early assessment of CAR T cell expansion can assist in identifying patients with poor overall survival who may benefit from early intervention or more intensive monitoring.

Multiple factors have been described to influence the risk of acute or chronic graft-versus-host disease (aGVHD or cGVHD) after allogeneic hematopoietic cell transplantation (HCT), including underlying chronic myeloid leukemia (CML) and high-dose total body irradiation (TBI). However, the impact of the underlying disease or low-dose TBI on the risk of GVHD in the modern era has not been determined. The objective of this study was to determine risk factors for GVHD in the modern era in the setting of antithymocyte globulin (ATG)-based GVHD prophylaxis. This retrospective study included 1219 patients with hematologic malignancy who underwent first peripheral blood allogeneic HCT using myeloablative fludarabine and busulfan conditioning ± low-dose total body irradiation, along with ATG, cyclosporine, and methotrexate as GVHD prophylaxis. The adjusted cumulative incidence of GVHD was compared between patient subgroups using multivariable competing risks regression. When disregarding the underlying disease, risk factors for grade 2-4 aGVHD were donor type other than matched sibling donor (non-MSD) and lack of low-dose TBI (non-TBI). Risk factors for grade 3-4 aGVHD were non-MSD, non-TBI, and CMV donor negative/recipient positive serostatus (D-R+). Risk factors for moderate-severe cGVHD were ≤9/10 HLA match, non-male/male donor/recipient sex, and non-TBI. In models including the underlying disease, additional significant risk factors were chronic lymphocytic leukemia (CLL) for grade 2 to 4 aGVHD (sub-hazard ratio over acute myeloid leukemia [SHR] 3.16, 95% CI 1.97-5.08, P < .001); CLL and acute lymphoblastic leukemia (ALL) for grade 3-4 aGVHD (SHR for CLL 3.54, 95% CI 1.54-8.17, P = .003 and SHR for ALL 2.26, 95% CI 1.26-4.04, P = .006); and myelofibrosis (MF) for moderate-severe cGVHD (SHR 2.14, 95 CI 1.34-3.41, P = .001). In the modern era when using ATG for GVHD prophylaxis, newly identified risk factors include CLL and non-TBI for grade 2-4 aGVHD; CLL, ALL, and non-TBI for grade 3-4 aGVHD; and MF and non-TBI for moderate-severe cGVHD. These findings, if confirmed in a separate cohort, should be taken into consideration when tailoring the prophylaxis and monitoring of GVHD.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potential cure for many hematological malignancies. Historically, older adults were not considered eligible for allo-HCT due to increased toxicity and mortality concerns. This systematic review and meta-analysis aim to explore the outcomes of allo-HCT in patients aged 70 years or older. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a comprehensive literature search was performed on PubMed, Cochrane Register of Controlled Trials, and Clinicaltrials.gov using MeSH terms and keywords for "Hematopoietic Stem Cell Transplantation" AND "Outcome Assessment" from the date of inception to June 30, 2024. Our search produced 102 articles. After excluding irrelevant and review articles during primary and secondary screening, eight original studies reporting outcomes of allo-HCT in patients aged 70 years or older were included. The survival data were retrieved from Kaplan-Meier (KM) curves using an online plot digitizer tool to calculate the overall survival (OS) and disease-free survival (DFS). The pooled KM curves were plotted and analyzed using the "MetaSurvival" package of R software version 4.2.1. Proportions and 95% confidence intervals (CIs) were extracted as well. A total of 2519 patients aged 70 years or older with allo-HCT were included in the analysis. The included patients' age ranged from 70 to 84 years, and 68% were male. Median follow-up was 23.2 (0.4 to 122.5) months. The combined median OS was 14.84 months (95% CI: 11.61 to 19.50), with OS rates at 6, 12, 24, and 36 months of 71.8%, 54.5%, 41.9%, and 34.9%, respectively. The estimated pooled mean OS was 28.62 months (95% CI: 23.41 to 31.44). The pooled median DFS was 10.54 months (95% CI: 7.93 to 14.17), with DFS rates at 6, 12, 24, and 36 months of 61.5%, 47.5%, 37%, and 30.6%, respectively. The estimated pooled mean DFS was 24.45 months (95% CI: 18.30 to 23.74). The relapse rate ranged from 28% to 55.6%, while non-relapsed mortality ranged from 5.6% to 42%. The acute graft versus host disease (GvHD) incidence varied from 9.3% to 32%, while chronic GvHD rates ranged from 10% to 43%. Allo-HCT provides promising outcomes for patients aged 70 or older with transplant-eligible diseases. Disease progression, followed by infections, is the leading cause of mortality, underscoring the need for improved post-transplant care, including optimized GvHD regimens and strategies to reduce infection risk.

Background: Post-transplant cyclophosphamide (PTCy) is a commonly used graft-vs-host disease (GVHD) prophylaxis, particularly in the setting of haploidentical (haplo) hematopoietic cell transplantation (HCT). The rate of graft failure has been reported to be as high as 12% to 20% in haplo-HCT recipients using PTCy. The objective of this study was to determine whether donor type influenced the risk of late graft failure following reduced-intensity conditioning (RIC) HCT using PTCy-based GVHD prophylaxis.

Study design: A retrospective cohort analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database among adult patients who underwent first RIC haplo or 8/8 matched unrelated donor (MUD) HCT between 2011 and 2018 for acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS) with PTCy GVHD prophylaxis. The primary outcome was incidence of late graft failure, defined as secondary graft loss in the absence of relapse or poor graft function requiring a cellular therapy intervention.

Results: A total of 1336 patients met the eligibility criteria (1151 haplo, 185 MUD). Patients in the MUD group were older (65 vs. 61 years), less ethnically diverse (95% vs. 72% White), received fewer bone marrow grafts (45% vs. 16%), and had younger donors (median age, 28 vs. 37 years old). Conditioning regimens were predominately fludarabine, cyclophosphamide, and total body irradiation (TBI; 87% haplo and 38% MUD). At 2 years, the adjusted probabilities of late graft failure for the haplo group was 6.5% (95% confidence interval [CI], 5.2-8.0) versus 5.9% (95% CI, 2.7%-10.9%) for the MUD group (P = .79). Multivariate analysis for risk factors associated with late graft failure found associations with a diagnosis of MDS (HR, 1.98; 95% CI, 1.22-3.20; P = .005), and earlier year of HCT (2015-2018 vs. 2011-2014; HR, 0.39; 95% CI, 0.24-0.64; P = .0002). A post-hoc sensitivity analysis was performed to evaluate the effect of donor age and use of peripheral blood stem cell (PBSC) grafts. Graft failure did not differ between haplo and MUD HCT (HR, 1.19; P = .67) when adjusted for donor age nor when restricted to PBSC grafts only (HR, 0.85; P = .70).

Conclusion: In this registry-based analysis of patients undergoing RIC HCT for AML, ALL, or MDS using GVHD prophylaxis with PTCy, there was no significant difference in late graft failure rates between haplo and MUD donors. Overall rates of late graft failure were high.