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1.
Matched unrelated donor transplantation versus haploidentical transplantation with post-transplant cyclophosphamide in children with acute myeloid leukemia: a PDWP-EBMT study
Ruggeri, A., Santoro, N., Galimard, J. E., Kalwak, K., Algeri, M., Zubarovskaya, L., Czyzewski, K., Skorobogatova, E., Sedlacek, P., Besley, C., et al
Haematologica. 2024
Abstract
In children with acute myeloid leukemia (AML) who lack an HLA identical sibling, the donor can be replaced with an HLA matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 and CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globuline (ATG) (n=420) or a haplo HCT with PT-CY (n=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to EBMT. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCTs. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo- HCT recipients, respectively. The risk of grade III-IV aGvHD was significantly higher in the haplo group (HR=2.33, 95%CI1.18-4.58, p=0.03). No significant differences were found in 2 years overall survival (OS; 78.4%vs71.5%; HR 1.39, 0.84-2.31, p=0.19), leukemia-free-survival (LFS; 72.7%vs69.5%; HR1.22, 0.76-1.95, p=0.41), CI of relapse (RI; 19.3%vs19.5%; HR=1.14, 0.62-2.08, p=0.68) non-relapse-mortality (NRM; 8%vs11%; HR=1.39, 0.66-2.93, p=0.39) and graft versus host free-relapse free survival (GRFS; 60.7%vs54.5%, HR=1.38, 0.95-2.02, p=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor.
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2.
Myeloablative Haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide and antithymoglobulin
Fakih, R. E., Nassani, M., Rasheed, W., Hanbali, A., Almohareb, F., Chaudhri, N., Alsharif, F., Alfraih, F., Shaheen, M., Alhayli, S., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Haplo-HSCT with PTCy is now performed on a large scale worldwide. Our patient's outcomes did not completely reflect the results published by other groups. We herein present the results of 60 patients with hematologic malignancies treated homogeneously on a modified version of the standard protocol by adding ATG as an additional GvHD-prophylaxis measure. METHODS Retrospective analysis of 60 haplo-transplanted patients using myeloablative regimen with ATG and PTCy for GvHD prophylaxis. RESULTS At 5-years the OS was 59.2%, the RFS was 48.6% and the CRFS was 40%. The median time to ANC and platelets engraftment was 16 and 28.5 days respectively. The grade II-IV aGvHD and extensive cGvHD were 46.7% and 23.3%. The cumulative incidence of relapse (CIR) was 30%, the NRM was 21.6% and the TRM was 11%. Higher DRI and 50% HLA-match were associated with lower RFS. Female to male donation and higher donor age were associated with higher cGvHD. CONCLUSION The use of PTCy may not yield the same results in different populations. Many remaining questions need to be addressed in randomized trials (optimal graft source and donor, date of CNI initiation, personalized or targeted dose of PTCy, immune reconstitution, etc.).
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3.
Comparison of haploidentical transplantation and single cord blood transplantation for myelofibrosis
Sakatoku, K., Murata, M., Shimazu, Y., Uchida, N., Yoshihara, S., Uehara, Y., Takahashi, S., Kobayashi, H., Tanaka, H., Nakano, N., et al
Bone marrow transplantation. 2024
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4.
Graft CD8 T-cell-based risk system predicts survival in antithymocyte globulin-based myeloablative haploidentical peripheral blood stem cell transplantation
Zhu, P., Yang, L., Wu, Y., Shi, J., Lai, X., Liu, L., Ye, Y., Yu, J., Zhao, Y., Yuan, X., et al
Clinical & translational immunology. 2024;13(1):e1484
Abstract
OBJECTIVE This study investigated the cellular composition of peripheral blood grafts for anti-thymocyte globulin (ATG)-based myeloablative haploidentical haematopoietic stem cell transplantation (haplo-HSCT). METHODS Clinical characteristics were retrospectively evaluated in a training cohort with ATG-based myeloablative haplo-HSCT between January 2016 and February 2020 and confirmed in a validation cohort between March 2020 and June 2021. RESULTS A higher dose of graft CD8(+) T cells (≥ 0.85 × 10(8) kg(-1)) was significantly improved overall survival (OS; hazard ratio [HR], 1.750; P = 0.002) and disease-free survival (DFS; HR, 1.751; P < 0.001) in the training cohort, according to multivariate Cox regression analysis. Higher doses of mononuclear cells (MNCs) demonstrated better OS (HR, 1.517; P = 0.038) and DFS (HR, 1.532; P = 0.027). Older patient age (> 46 years), older donor age (≥ 50 years) and a higher refined disease risk index (rDRI) were also related to OS. A graft CD8(+) T-cell risk system based on graft CD8(+) T-cell dose, donor age and rDRI was constructed using a nomogram model after LASSO Cox regression analysis. It showed acceptable discrimination, with a C-index of 0.62 and 0.63, respectively. Graft CD8(+) T-cell dose was negatively correlated with donor age (P < 0.001) and positively correlated with a higher lymphocyte percentage in the peripheral blood before mobilisation (P < 0.001). CONCLUSION A higher CD8(+) T-cell dose in peripheral blood-derived grafts improves patients' survival with ATG-based myeloablative haplo-HSCT. Younger donors with higher lymphocyte percentages improved patients' survival with an intermediate rDRI risk.
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5.
Phase I study of zoledronic acid combined with escalated doses of interleukine-2 for early in vivo generation of Vγ9Vδ2 T-cells after haploidentical stem cell transplant with posttransplant cyclophosphamide
Jullien, M., Guillaume, T., Le Bourgeois, A., Peterlin, P., Garnier, A., Eveillard, M., Le Bris, Y., Bouzy, S., Tessoulin, B., Gastinne, T., et al
American journal of hematology. 2024
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Editor's Choice
Abstract
The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (h-HSCT) has been associated with improved disease-free survival. These cells kill tumor cells in a non-MHC restricted manner, do not induce graft-versus-host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin-2 (IL-2). This monocentric phase I, open-label, dose-escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T-cells early after h-HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low-doses of IL-2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T-cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h-HSCT recipients. Twenty-six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h-HSCT only. At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T-cells was observed during IL-2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T-cells is feasible after h-HSCT by using a combination of ZA and repeated IL-2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.
PICO Summary
Population
Adults with haematological malignancy, eligible for haploidentical transplant from a single centre in France (n=26)
Intervention
Increasing low-doses of IL-2 (5 days per week, 4 weeks) in combination with a single dose of zoledronic acid (ZA) to generate Vγ9Vδ2 T-cells early after h-HSCT (n=16)
Comparison
Haploidentical HSCT only (n=7)
Outcome
At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. Maximum tolerated dose was not reached.
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6.
Galectin-9 alleviates acute graft-versus-host disease after haplo-hematopoietic stem cell transplantation by regulating regulatory T cell/effector T cell imbalance
Pang, N., Tudahong, S., Zhu, Y., He, J., Han, C., Chen, G., Wang, W., Wang, J., Ding, J.
Immunity, inflammation and disease. 2024;12(2):e1177
Abstract
BACKGROUND Acute graft-versus-host disease (aGVHD) arises from the imbalance of host T cells. Galectin-9 negatively regulates CD4 effector T cell (Th1 and Th17) function by binding to Tim-3. However, the relationship between Galectin-9/Tim-3 and CD4(+) T subsets in patients with aGVHD after Haplo-HSCT (haploidentical peripheral blood hematopoietic stem cell transplantation) has not been fully elucidated. Here, we investigated the role of Galectin-9 and CD4(+) T subsets in aGVHD after haplo-HSCT. METHODS Forty-two patients underwent Haplo-HSCT (26 without aGVHD and 16 with aGVHD), and 20 healthy controls were included. The concentrations of Galectin-9, interferon-gamma (IFN-γ), interleukin (IL)-4, transforming growth factor (TGF)-β, and IL-17 in the serum and culture supernatant were measured using enzyme-linked immunosorbent assay or cytometric bead array. The expression levels of Galectin-9, PI3K, p-PI3K, and p-mTOR protein were detected by western blot analysis. Flow cytometry was used to analyze the proportions of CD4(+) T cell subsets. Bioinformatics analysis was performed. RESULTS In patients with aGVHD, regulatory T (Treg) cells and Galectin-9 decreased, and the Th1, Th17, and Treg cells were significantly imbalanced. Moreover, Treg and Galectin-9 were rapidly reconstituted in the early stage of patients without aGVHD after Haplo-HSCT, but Th17 cells were reconstituted slowly. Furthermore, Tim-3 upregulation on Th17 and Th1 cells was associated with excessive activation of the PI3K/AKT pathway in patients with aGVHD. Specifically, in vitro treatment with Galectin-9 reduced IFN-γ and IL-17 production while augmenting TGF-β secretion. Bioinformatics analysis suggested the potential involvement of the PI3K/AKT/mTOR pathway in aGVHD. Mechanistically, exogenous Galectin-9 was found to mitigate aGVHD by restoring the Treg/Teffs (effector T cells) balance and suppressing PI3K. CONCLUSION Galectin-9 may ameliorate aGVHD after haplo-HSCT by modulating Treg/Teffs balance and regulating the PI3K/AKT/mTOR pathway. Targeting Galectin-9 may hold potential value for the treatment of aGVHD.
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7.
Haploidentical bone marrow transplantation for AML in remission following TBF conditioning: a long-term follow up
Raiola, A. M., Di Grazia, C., Dominietto, A., Bregante, S., Giammarco, S., Varaldo, R., Sorà, F., Metafuni, E. Md, Limongiello, M. A., Laudisi, A., et al
Blood advances. 2024
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8.
Efficacy and Reliability of T-Cell-Depleted Haploidentical Stem Cell Transplantation in Hematologic Disorders: A Retrospective Study
Deveci, B., Kublashvili, G., Oztekin, A. T., Ertugrul, M. A., Veske, H., Celikbilek, G., Dosemeci, L., Salim, O., Ozdemir, Y., Toptas, T., et al
Transplantation proceedings. 2024
Abstract
BACKGROUND A promising recent strategy for haploidentical transplantation is the depletion of T lymphocytes based on the selective elimination of T cells by manipulation, which enables a very low incidence of nonrelapse mortality and graft-vs-host disease. It is more expensive than conventional unmanipulated methods and requires dedicated transplant centers and sufficient stem cell processing facilities. This retrospective study aimed to evaluate the relapse, survival, and clinical data of the patients and to analyze the outcomes of the technique. METHODS The study included 56 adult patients who underwent haploidentical stem cell transplantation via αβ T-cell depletion. RESULTS The median age of the patients at the time of hematopoietic stem cell transplantation was 41.5 years (range, 20-70 years); 22 patients (39.3%) were women. After the transplantation, half of the patients (50.0%) needed immunosuppressive drugs, and 17.9% of the patients experienced a post-transplant relapse. The mortality rate was 55.4%, and nonrelapse mortality was 25.0%. The 100-day mortality rate was 19.6%. The median overall days was 1101 days (142-3813 days), whereas the median progression-free overall was 302.5 days (11-2479 days). Being older (age >40), having hypertension, having acute liver graft-vs-host disease, and having systemic fungal infection were found as risk factors that significantly increased mortality (with 3.5-, 2.8-, 3.7-, and 2.7-fold increases, respectively). CONCLUSION To conclude, T-cell-depleted hematopoietic stem cell transplantation is an effective and reliable technique that has the potential to decrease morbidity and improve relapse-free survival, especially for young patients requiring haploidentical donor transplantation for hematologic malignancy.
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A comparison of long-term outcomes by donor type in the era of post-transplantation cyclophosphamide for aggressive adult T-cell leukemia/lymphoma
Hirose, A., Koh, H., Nakamae, M., Nakashima, Y., Nishimoto, M., Okamura, H., Makuuchi, Y., Kuno, M., Takakuwa, T., Ido, K., et al
Bone marrow transplantation. 2024
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10.
The Impact of NK Cell-Associated Factors on Acute Leukemia Outcomes after Haplo-HSCT with αβ T Cell Depletion in Pediatric Cohort
Glushkova, S., Shelikhova, L., Voronin, K., Pershin, D., Vedmedskaya, V., Muzalevskii, Y., Kazachenok, A., Kurnikova, E., Radygina, S., Ilushina, M., et al
Transplantation and cellular therapy. 2024
Abstract
INTRODUCTION αβ T cell-depletion (αβTCD) is a well-established method of HSCT for children with acute leukemia due to the low rate of graft-versus-host disease and non-relapse mortality. The graft-versus-leukemia effect is generally ascribed to the NK cells, conserved within the graft. However, it is not known whether NK-related factors affect the outcome of αβTCD HSCT. OBJECTIVES The aim of this retrospective study is to explore the impact of NK-alloreactivity (based on donor-recipient KIR mismatch), graft NK-cell dose, and blood NK-cell recovery on day +30 after HSCT on the incidence of leukemia relapse and non-relapse mortality (NRM). STUDY DESIGN The pediatric acute leukemia cohort includes 295 patients first transplanted from haploidentical donors in complete remission. During post hoc analysis, the total cohort was divided into subcohorts by diagnosis (ALL/AML), NK alloreactivity prediction (KIR match/KIR mismatch), graft NK cell dose (less vs. greater than the median value), and blood NK cell recovery on day +30 after HSCT (less vs. greater than the median value). We also investigated the influence of serotherapy (ATG group) versus abatacept + tocilizumab combination (aba+toci group) on relapse risk in the context of KIR mismatch. The relapse and NRM risk were calculated by the cumulative risk method, and groups were compared by Gray's test. Multivariate analysis was provided. RESULTS There was no apparent impact of predicted NK alloreactivity, or other studied NK-related factors for the total cohort. For patients with AML, a significantly higher relapse risk associated with high NK graft content on the background of no predicted KIR mismatch (p=0.002) was shown. Multivariate analysis confirmed this finding (p=0.018); on the other hand, for KIR mismatch cohort, there was a trend towards lower relapse risk associated with high NK-cell dose. The use of ATG was associated with a trend of reduced relapse risk (p=0.074) for AML cohort. There was no significant impact of NK-related factors among ALL patients. CONCLUSIONS Overall, the evaluated NK-related factors did not show a clear and straightforward correlation with the key outcomes of HSCT in the total cohort of children with acute leukemia. In practice, the data support prioritization of KIR-mismatched donors for patients with AML. Importantly, a potential interaction of KIR ligand mismatch and NK cell content in the graft was identified. Indirect evidence suggests that additional cellular constituents of the graft could influence the function of NK cells after HSCT and affect their role as GVL effectors.