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T-cell Depleted Peripheral Blood versus Unmanipulated Bone Marrow in Matched Sibling Transplantation for Aplastic Anemia
Chorão, P., Montoro, J., Balaguer-Roselló, A., Guerreiro, M., Villalba, M., Facal, A., Solves, P., Gómez-Segui, I., Pasquini, M. C., Granados, P., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Bone marrow (BM) is the recommended stem cell source for hematopoietic stem cell transplantation (HSCT) from matched sibling donor (MSD) in severe aplastic anemia (SAA) for its superior survival and lower graft-versus-host disease (GVHD) outcomes compared to unmanipulated peripheral blood (PB). Nevertheless, studies comparing BM with ex vivo T-cell depleted (TCD) PB have not been reported so far. OBJECTIVES The aim of this study was to compare the transplant outcomes of MSD-HSCT in SAA using PB (with partial ex vivo TCD targeted cell dose grafts) with those using unmanipulated BM. STUDY DESIGN We performed a matched-pair analysis of MSD-HSCT using TCD PB in a single institution with unmanipulated BM transplants in the United States between 2013 and 2019 who were reported to CIBMTR. RESULTS We compared 23 recipients of TCD PB HSCT for SAA (cases) to 69 recipients of unmanipulated BM grafts (controls) who were matched for age, Karnofsky performance status, HSCT-specific comorbidity, time from diagnosis to transplant and recipient CMV serostatus. Here, we found a significantly faster neutrophil and platelet recovery in the TCD PB cohort (P < 0.001 and P = 0.03, respectively), as well as a lower incidence of grade II-IV acute GVHD (0% versus 17%; P = 0.05) and similar overall survival (96% vs 97% at 3 years; P = 0.8). CONCLUSIONS Our study shows that TCD PB can be considered as a safe source for MSD-HSCT in SAA, with potential advantages in engraftment and GVHD that could challenge the standard with BM. These findings provide further insights for future research in a prospective controlled clinical trial.
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Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy
Lauer, A., Speroni, S. L., Choi, M., Da, X., Duncan, C., McCarthy, S., Krishnan, V., Lusk, C. A., Rohde, D., Hansen, M. B., et al
Nature communications. 2023;14(1):1900
Abstract
Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.
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Impact of cytoreduction and remission status on hematopoietic cell transplantation outcomes in pediatric myelodysplastic syndrome and related disorders
Wachter, F., Hebert, K., Pikman, Y., Yang, J., Shah, B., Bledsoe, J., Shimamura, A., Neuberg, D. S., Pollard, J. A., Lehmann, L. E.
Pediatric blood & cancer. 2023;:e30530
Abstract
BACKGROUND The role of cytoreduction prior to hematopoietic cell transplant (HCT) for patients with pediatric myelodysplastic syndrome (MDS) and related disorders remains unclear. PROCEDURE We performed a single-center retrospective analysis of pre-transplant disease management and subsequent HCT outcome for pediatric patients with MDS and related disorders who underwent HCT between 2010 and 2020. RESULTS Total 62 patients (median age 11 years) with idiopathic MDS (n = 16), MDS secondary to an underlying germline condition (n = 11), secondary acute myeloid leukemia (n = 9), myeloproliferative neoplasms (n = 8), and treatment-related myeloid neoplasms (n = 18) received an allogeneic HCT. Cytoreduction prior to HCT was performed in 30/62 (48%) patients; this subset of patients had higher risk disease characteristics, including a higher blast count on presentation. In the overall cohort, use of cytoreduction before HCT was associated with higher rates of relapse (cumulative incidence of relapse 24 months post HCT: 48.1% [27.5%-66.1%]) for those who received cytoreduction versus 16.6% (5.9%-32.1%) for those who did not (p = .03). There was a trend toward decreased overall survival (OS) for those patients who received cytoreduction (24 months post HCT 57.1% vs. 75.3%, respectively; p = .06). OS for patients who received cytoreduction and attained measurable residual disease (MRD) negativity prior to HCT was superior compared to those with persistent disease (24 months post HCT 63.9% [36%-81.2%] vs. 33.3% [7.8%-62.3%], respectively; p = .04). CONCLUSION Cytoreduction did not provide survival benefit in our overall cohort, but its increased use in children with higher risk disease impacted the analysis. Patients receiving cytoreduction and achieving MRD-negative status before HCT demonstrated improved OS compared to those with persistent disease.
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Impact of in vivo T-cell depletion in patients with myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplant: a registry study from the Chronic Malignancies Working Party of the EBMT
Forcade, E., Chevret, S., Finke, J., Ehninger, G., Ayuk, F., Beelen, D., Koster, L., Ganser, A., Volin, L., Sengeloev, H., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N = 168; ATG N = 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p < 0.00017); and CI of relapse was 23% vs 25% vs 39% (p < 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p = 0.009) respectively; and GRFS was 21% vs 28% and 20% (p = 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease.
PICO Summary
Population
Patients with myelodysplastic syndromes undergoing allogeneic transplant and reported to the EBMT registry (n=1284)
Intervention
In vivo T-cell depletion (TCD, n=814: receiving alemtuzumab n=168 or ATG n=646)
Comparison
No in vivo T-cell depletion (No-TCD, n=470).
Outcome
At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51%; and CI of relapse was 23% vs 25% vs 39% for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% respectively; and GRFS was 21% vs 28% and 20% respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS
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Alpha-beta T and B-cell depleted HLA-haploidentical HSCT in children with myelodysplastic syndromes
Merli, P., Pagliara, D., Mina, T., Bertaina, V., Li Pira, G., Lazzaro, S., Biagini, S., Galaverna, F., Strocchio, L., Carta, R., et al
Haematologica. 2022
Abstract
Not available.
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6.
Hematopoietic Cell Transplantation with Cryopreserved Grafts for Severe Aplastic Anemia
Eapen, M., Zhang, M. J., Tang, X. Y., Lee, S. J., Fei, M. W., Wang, H. L., Hebert, K. M., Arora, M., Chhabra, S., Devine, S. M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P=.01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P=.0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.
PICO Summary
Population
Patients with severe aplastic anaemia, who underwent HSCT and were reported to CIBMTR registry
Intervention
Cryopreseverved graft (n=52)
Comparison
Matched controls who received non-cryopreserved grafts (n=194)
Outcome
. We recorded higher 1-year rates of graft failure and of 1-year overall after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% in the cryopreserved graft group and 91% in the noncryopreserved graft group.