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Infection-related mortality after HLA-identical and haploidentical hematopoietic cell transplantation using reduced-intensity conditioning in an outpatient setting
Jaime-Pérez, J. C., Meléndez-Flores, J. D., Ramos-Dávila, E. M., Gutiérrez-Aguirre, C. H., Cantú-Rodríguez, O. G., Marfil-Rivera, L. J., Áncer-Rodríguez, J., Gómez-Almaguer, D.
Clinical transplantation. 2023;:e14972
Abstract
BACKGROUND Despite the improvements in supportive care for allogeneic-hematopoietic cell transplantation (allo-HCT) recipients, infectious complications and infection-related mortality (IRM) continue to be a major issue for transplantation centers. METHODS We herein report the infectious complications and IRM of 107 and 89 patients that underwent haploidentical (haplo-HCT) or HLA-identical HCT at a tertiary referral center during 2013-2020. Patients in the haplo-HCT group received post-transplant cyclophosphamide (PT-Cy), and all received reduced-intensity conditioning regimens. RESULTS More haplo-HCT recipients presented severe infections in the pre-engraftment period (22.4% vs. 6.7%, p = 0.003). Viral (14.9% vs. 4.5%, p = 0.016) and fungal (12.1% vs. 1.1%, p = 0.003) etiologies were more common in this period in this group. The 100-day and 2-year cumulative incidence of IRM was 15% and 21% for the haplo-HCT and 5.6% and 17% for the HLA-identical group; no significant differences were observed between the groups. Fungal pathogens mainly contributed to IRM (33.3%). Infections were the most common cause of mortality (40/81, 49.4%). There were significant differences in donor/recipient CMV serostatus between transplant groups (0.002). CONCLUSIONS No differences in IRM were observed based on allo-HCT type, with more haplo-HCT patients suffering from severe infections in the pre-engraftment period. Studies to assess future prevention, diagnostic, and treatment strategies to reduce IRM are warranted.
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Unique reduced intensity conditioning haploidentical peripheral blood stem cell transplantation protocol for patients with hematological malignancy
Xu, J., Miao, W., Yuan, H., Liu, Y., Chen, G., Wang, H., Aizezi, G., Qu, J., Duan, X., Yang, R., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
Reduced-intensity conditioning haploid hematopoietic stem cell transplantation (RIC-haplo-HSCT) requires more hematopoietic progenitor and stem cells (HPSCs) to promote engraftment and immune reconstitution and needs stronger graft versus leukemia (GVL) effect. Peripheral blood stem cells (PBSCs) offer more advantages compared to bone marrow (BM). However, higher dose non-T cell depleted (non-TCD) in vitro PBSCs may increase the occurrence of severe graft versus host disease (GVHD). This prospective, single-arm clinical research was performed to investigate high-dose non-TCD in vitro PBSCs as graft, Flu/Ara-C/Bu (FAB) as conditioning regimen, adopting rATG to remove T cells in vivo, and enhancing GVHD prophylaxis with IL-2 receptor antagonist in RIC-haplo-HSCT in patients with hematological malignancies aged 50 to 70 years or < 50 years with comorbidities (HCT-CI scores ≥2) classified as intermediate to higher risk. The primary endpoint was day-100 acute GVHD (aGVHD). A total of 47 patients were enrolled; the median age was 52 years (range: 30-68 years), the median follow-up time was 34 months (range: 2-99), and the medium-infused doses of MNC, CD34+ cells, and CD3+ cells were 15.93 × 10(8)/kg, 8.68 × 10(6)/kg and 5.57 × 10(8)/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day-100 was 30.3% (95% CI: 15.9-44.8), while that of grade III-IV aGVHD was 10.2% (95% CI: 0.6-19.8). The two-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI: 19.0-50.8). The two-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI: 11.80-40.40) and 8.7% (95% CI: 3.26-20.65), respectively. The two-year cumulative incidence of relapse was 17.3% (95% CI: 5.1-29.5). The two-year overall survival and disease-free survival rates were 71.2% (95% CI: 57.9-84.5) and 66.2% (95% CI: 52.1-80.3), respectively. The outcomes showed that the incidence of aGVHD was not high, and the overall efficacy was good. This study demonstrated that this unique RIC-haplo-PBSCT protocol was effective in treating hematological malignancies. Nonetheless, larger prospective multi-center clinical trials and experimental studies should be performed to further confirm our findings.
PICO Summary
Population
Adults with haematological malignancies aged 50 to 70 years or less than 50 years but with intermediate or higher risk comorbidities (HCT-CI scores ≥2), from a single centre in China (n=47)
Intervention
Reduced intensity conditioning haploidentical HSCT: high-dose non-T-cell depleted in vitro peripheral blood stem cells as graft, Flu/Ara-C/Bu (FAB) as conditioning regimen, rabbit antithymocyte globulin (rATG) to remove T cells in vivo, and enhanced GVHD prophylaxis with IL-2 receptor antagonist.
Comparison
None
Outcome
The median age was 52 years (range: 30-68 years), the median follow-up time was 34 months (range: 2-99), and the medium-infused doses of MNC, CD34+ cells, and CD3+ cells were 15.93 × 10(8)/kg, 8.68 × 10(6)/kg and 5.57 × 10(8)/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day-100 was 30.3% (95% CI: 15.9-44.8), while that of grade III-IV aGVHD was 10.2% (95% CI: 0.6-19.8). The two-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI: 19.0-50.8). The two-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI: 11.80-40.40) and 8.7% (95% CI: 3.26-20.65), respectively. The two-year cumulative incidence of relapse was 17.3% (95% CI: 5.1-29.5). The two-year overall survival and disease-free survival rates were 71.2% (95% CI: 57.9-84.5) and 66.2% (95% CI: 52.1-80.3), respectively.
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Reduced intensity versus non-myeloablative conditioning regimen for haploidentical transplantation and post-transplantation cyclophosphamide in complete remission acute myeloid leukemia: a study from the ALWP of the EBMT
Devillier, R., Galimard, J. E., Labopin, M., Blaise, D., Raiola, A. M., Pavlu, J., Castagna, L., Socié, G., Chalandon, Y., Martino, M., et al
Bone marrow transplantation. 2022;57(9):1421-1427
Abstract
The optimal conditioning regimen prior haploidentical stem cell transplantation (Haplo-SCT) with post transplantation cyclophosphamide (PT-Cy) for acute myeloid leukemia (AML) remains unknown. A non-myeloablative conditioning (NMAC) regimen (cyclophosphamide + fludarabine + TBI 2 Gy [CyFluTBI]) is a safe approach, but relapse incidence remains high in this setting. Alternatively, a reduced intensity conditioning (RIC) regimen combining thiotepa and reduced-dose busulfan with fludarabine (TBF) may decrease AML relapse. However, an excess of toxicity may counterbalance this potential benefit. We retrospectively compared CyFluTBI vs. TBF in CR AML patients who underwent Haplo-SCT with PT-Cy, in two different populations based on age. We analyzed 490 patients. In patients aged <60 years (n = 203), we observed a higher RI (HR = 3.59, 95% CI = 1.75-7.37, p < 0.01), lower LFS (HR = 1.98, 95% CI = 1.22-3.22, p < 0.01) and lower OS (HR = 1.73, 95% CI = 1.04-2.88, p = 0.04) in the CyFluTBI group, without significant difference in NRM. In older patients (n = 287), we observed that conditioning regimen did not significantly influence LFS (HR = 0.90, 95% CI = 0.56-1.44, p = 0.65), OS (HR = 0.81, 95% CI = 0.49-1.32, p = 0.39) and RI (HR = 1.78, 95% CI = 0.90-3.50, p = 0.10), but showed that CyFluTBI was associated with a significantly lower risk of NRM (HR = 0.48, 95% CI = 0.25-0.92, p = 0.03). Thus, younger patients seem to benefit from conditioning intensification from CyFluTBI to TBF regimens prior PT-Cy Haplo-SCT for CR AML, while older ones do not.
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A modified conditioning regimen based on low-dose cyclophosphamide and fludarabine for haploidentical hematopoietic stem cell transplant in severe aplastic anemia patients at risk of severe cardiotoxicity
Lin, F., Zhang, Y., Han, T., Cheng, Y., Mo, X., Wang, J., Chen, Y., Wang, F., Tang, F., Han, W., et al
Clinical transplantation. 2022;36(1):e14514
Abstract
Severe cardiotoxicity is a fatal complication during high-dose cyclophosphamide (Cy)-based conditioning in hematopoietic stem cell transplant (HSCT) for severe aplastic anemia (SAA). This study aimed to evaluate the feasibility and efficacy of a modified conditioning regimen in haploidentical HSCT (haplo-HSCT) for severe-cardiotoxic-risk SAA patients. This BuCy(low) Flu conditioning utilized busulfan (Bu, 3.2 mg/kg for 2 days), low-dose Cy (100 mg/kg), fludarabine (150 mg/m(2) ), and rabbit antithymocyte globulin (rATG, 10 mg/kg). Compared to BuCy conditioning using high-dose Cy of 200 mg/kg, Bu of 3.2 mg/kg for 2 days, and rATG of 10 mg/kg, the incidence of severe cardiotoxicity of BuCy(low) Flu conditioning was significantly decreased (2.17% vs 12.80%, p = .032). The engraftment rates (100% for neutrophil and 84.44% for platelet) were favorable. The probabilities of 100-day transplant-related mortality were similar in the BuCy(low) Flu and the BuCy group (8.75% vs 10.53%, p = .671). Both 1-year overall survival (88.79% vs 84.66%, p = .357) and 1-year failure-free survival (84.78% vs 81.70%, p = .535) were comparable. The BuCy(low) Flu group had higher rates of cytomegalovirus and Epstein-Barr virus reactivation. In conclusion, the BuCy(low) Flu provided reduced severe cardiotoxicity, and achieved favorable engraftment and survival. Our results suggest BuCy(low) Flu conditioning can be a feasible alternative for haplo-HSCT recipients at risk of severe cardiotoxicity.
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A Phase II Trial of Melphalan Based Reduced-Intensity Conditioning for Transplantation of T-Replete HLA-Haploidentical Peripheral Blood Stem Cells with Posttransplant Cyclophosphamide in Patients with Hematologic Malignancies
Solh, M. M., Hinojosa, G., Laporte, J., Solomon, S. R., Morris, L. E., Zhang, X., Holland, H. K., Bashey, A.
Advances in hematology. 2021;2021:8868142
Abstract
T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30?mg/m(2)/day?×?5 days and Melphalan 140?mg/m(2) on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50?mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML (n?=?11), ALL (n?=?4), MDS/MPD (n?=?6), NHL/CLL (n?=?3), and MM (n?=?1). Using the refined Disease Risk Index (DRI), patients were low (n?=?1), intermediate (n?=?13), and high/very high (n?=?11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II-IV and III-IV was seen in 20% (95% CI 8%-37%) and 8% (95% CI 2%-22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%-33%) (moderate-severe 12% (95% CI 3%-27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33-74%), 44% (95%CI 23%-64%), 20% (95% CI 8%-37%), and 36% (95% CI 17%-55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p=0.75 and DFS at 44% vs. 46% p=0.65.
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Comparison of myeloablative and reduced intensity conditioning regimens in haploidentical peripheral blood stem cell transplantation
Modi, D., Kim, S., Deol, A., Ayash, L., Ratanatharathorn, V., Uberti, J. P.
Bone marrow transplantation. 2021;56(3):741-744
Abstract
Limited information is available on the impact of intensity of conditioning regimens in haploidentical peripheral blood stem cell transplant (haploPBSCT) with post-transplant cyclophosphamide (PTcy). We retrospectively compared outcomes of haplo-PBSCT between myeloablative (MAC) (n = 24) and reduced intensity conditioning (RIC) regimens (n = 65). Propensity score-based multivariable analyses were performed to adjust confounding effects of baseline characteristics between both groups. Eighty-nine patients underwent haplo-PBSCT between January 2012 and June 2019. For MAC and RIC, the cumulative incidences of grade III--IV acute GVHD were 4.2% and 3.1%, respectively (p = 0.92), and chronic GVHD were 18.9% and 36.5%, respectively (p = 0.08). Median follow-up for overall survival (OS) after MAC and RIC was 1.86 and 2.2 years, respectively. For MAC and RIC, one-year OS was 68.8% and 67.4%, respectively (p = 0.85); one-year relapse rate was 22.4% and 18.3%, respectively (p = 0.74); one-year relapse-free survival (RFS) was 56% and 59.7%, respectively (p = 0.87); and one-year non-relapse mortality (NRM) was 22% and 21.9%, respectively (p = 0.58). Using propensity score-based multivariable analyses, no difference in OS (HR 0.72, p = 0.51), relapse (SHR 0.63, p = 0.42), RFS (HR 0.74, p = 0.49) and NRM (SHR 1.11, p = 0.87) was noted between RIC and MAC. Our study shows no difference in outcomes between MAC and RIC regimens in haplo-PBSCT.
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Multicenter Phase II Study on Haploidentical Bone Marrow Transplantation Using a Reduced-Intensity Conditioning Regimen and Posttransplantation Cyclophosphamide in Patients with Poor-Prognosis Lymphomas
Castagna, L., Dodero, A., Patriarca, F., Onida, F., Olivieri, A., Russo, D., Giordano, L., Majolino, I., Bramanti, S., Mariotti, J., et al
Transplantation and cellular therapy. 2021;27(4):328.e1-328.e6
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Editor's Choice
Abstract
Allogeneic stem cell transplantation from haploidentical donors using unmanipulated bone marrow and posttransplantation cyclophosphamide has been largely employed to cure high-risk lymphomas. However, the increased incidence of relapse associated with the use of a nonmyeloablative conditioning regimen is still considered a concerning issue. The aim of our study was to prospectively evaluate the efficacy and feasibility of a reduced-intensity conditioning regimen, including thiotepa, cyclophosphamide, and fludarabine, in high-risk lymphoma patients. This was a prospective multicenter study. We enrolled 49 patients, of whom 47 were evaluable. Graft source (bone marrow) and graft-versus-host disease (GVHD) prophylaxis were the same for all patients. The primary endpoint was the proportion of patients free of disease progression at 1 year. The primary endpoint was met, as 29 out of 47 patients were alive and free of disease at 1 year (1-year progression-free survival, 60%). Forty-five recipients engrafted and achieved full donor chimerism at day 100. The cumulative incidences (CIs) of ANC engraftment at 30 days and platelet engraftment at 60 days were 89% and 83%, respectively. Two patients experienced graft failure. The CIs of day 100 grades 2 to 4 acute GVHD and 2-year moderate-to-severe chronic GVHD were 26% and 16%, respectively. With a median follow-up of 47.5 months (range, 22 to 74), the 4-year progression-free survival and overall survival were 54% and 64%, respectively. The 4-year CI of relapse was 28%, and the 4-year nonrelapse mortality was 15%. Thiotepa-based reduced-intensity conditioning was well tolerated with encouraging survival in a cohort of patients with poor-prognosis lymphoma. Both the incidence of relapse and nonrelapse mortality were acceptable.
PICO Summary
Population
Patients with high-risk lymphoma (n=47)
Intervention
Haploidentical stem cell transplantation with a reduced intensity conditioning regimen, including thiotepa, cyclophosphamide, and fludarabine
Comparison
None
Outcome
The primary endpoint was met, as 29 out of 47 patients were alive and free of disease at 1 year (1-year progression-free survival, 60%). Forty-five recipients engrafted and achieved full donor chimerism at day 100. The cumulative incidences (CIs) of ANC engraftment at 30 days and platelet engraftment at 60 days were 89% and 83%, respectively. Two patients experienced graft failure. The CIs of day 100 grades 2 to 4 acute GVHD and 2-year moderate-to-severe chronic GVHD were 26% and 16%, respectively. With a median follow-up of 47.5 months (range, 22 to 74), the 4-year progression-free survival and overall survival were 54% and 64%, respectively. The 4-year CI of relapse was 28%, and the 4-year nonrelapse mortality was 15%.
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Outpatient haploidentical hematopoietic stem cell transplant using post-transplant cyclophosphamide and incidence of hemorrhagic cystitis
Gutiérrez-Aguirre, C. H., Esparza-Sandoval, A. C., Palomares-Leal, A., Jaime-Pérez, J. C., Gómez-Almaguer, D., Cantú-Rodríguez, O. G.
Hematology, transfusion and cell therapy. 2020
Abstract
INTRODUCTION Hemorrhagic cystitis (HC) is a common complication of haploidentical hematopoietic stem cell transplantation (haplo-HSCT), characterized by irritative symptoms of the urinary tract and a higher morbidity and mortality rate. The worldwide incidence is reported between 10% and 70%. The use of alkylating agents and BK viral infection are the most frequent etiologies. The aim of this study was to report the HC incidence in an outpatient haplo-HCST program with a reduced intensity-conditioning (RIC) regimen, cataloguing risk factors, complications and final outcomes. METHODS The medical database of patients who received a haplo-HSCT between January 2012 and November 2017 was retrospectively analyzed. Demographic variables, general characteristics and HC incidence were included. RESULTS One hundred and eleven patients were included, 30 (27%) of whom developed HC, most of them (70%) being grade II, with a 30-day (7-149) median time of post-transplant HC onset. The BK virus was detected in 71% of the urine samples analyzed. All HC patients responded to treatment, except two (6.6%), who died due to HC complications. CONCLUSIONS There was no difference in the HC incidence or severity, compared to that reported when performing haplo-HSCT in hospitalized patients, although the donor-recipient sex mismatch did relate to a higher HC incidence.
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Impact of CD34+ Cell Dose on Reduced Intensity Conditioning Regimen Haploidentical Hematopoietic Stem Cell Transplantation
Salas, M. Q., Atenafu, E. G., Bautista, M. R., Prem, S., Lam, W., Law, A. D., Shaibani, Z. A., Kim, D. D. H., Michelis, F. V., Lipton, J. H., et al
European journal of haematology. 2019
Abstract
OBJECTIVES Haploidentical hematopoietic stem cell transplant (haplo-SCT) has been associated with higher rates of graft rejection and a higher dose of CD34+ cell dose is frequently requested. We aim to explore the impact of CD34+ cell dose in peripheral blood stem cell (PBSC) grafts using reduced intensity conditioning (RIC) in haplo-SCT. METHODS sixty-eight consecutive haplo-SCT in adult patients were included. Graft versus disease (GVHD) prophylaxis consisted on ATG, PTCy and CsA. The cohort was divided in two groups using CD34+ dose of ≥9x10^6 CD34+/Kg as cut-off point. Median follow-up was 8.9 months. RESULTS Median cell dose infused was 9.32 X10^6 CD34+/Kg. Forty (58.8%) recipients received grafts with CD34+ cells ≥9x10^6/kg. The infusion ≥9X10^6 CD34+/Kg cell dose had a negative impact in overall survival (p=0.03) after adjusting for age at transplant. The cumulative incidence of acute GVHD and graft failure were not significantly influenced per CD34+ cell dose. Only 4 recipients had grade III aGVHD, and all of them received grafts with a CD34+ cell dose ≥9X10^6. CONCLUSION In RIC haplo-SCT, recipients may not benefit from PBSC grafts with a CD34+/kg cell dose higher than 9x10^6 cells/kg, as it can have an adverse impact in post-transplant outcome.
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Safety and Efficacy of Haploidentical Peripheral Blood Stem Cell Transplantation for Myeloid Malignancies Using Post-transplantation Cyclophosphamide and Anti-thymocyte Globulin as Graft-versus-Host Disease Prophylaxis
Salas, M. Q., Law, A. D., Lam, W., Al-Shaibani, Z., Loach, D., Kim, D. D. H., Michelis, F. V., Thyagu, S., Kumar, R., Lipton, J. H., et al
Clinical hematology international. 2019;1(2):105-113
Abstract
Haploidentical stem cell transplantation (haploSCT) has greatly improved access to curative treatment for myeloid malignancies in patients without suitable matched sibling/unrelated donors. We investigated the safety and efficacy of haploSCT after reduced intensity conditioning (RIC) with anti-thymocyte globulin (ATG), post-transplant cyclophosphamide (PTCy), and cyclosporine to prevent rejection and graft-versus-host disease (GVHD). In this study, 47 patients received RIC using fludarabine, busulfan, and total body irradiation (200 cGy). Unmanipulated peripheral blood grafts were used. GVHD prophylaxis included ATG (4.5 mg/kg day-3 to -1), PTCy (50 mg/kg/day day +3, +4), and cyclosporine from day +5. The median follow-up was 15 months (range 3-27). Thirty one (66%) patients had acute myeloid leukemia (AML), 10 (21%) had high-risk myelodysplastic syndrome, and 6 (13%) had a myeloproliferative neoplasia. Median age was 60 years (range 22-73). The d+100 cumulative incidences of grade II-IV and III-IV acute GVHD were 17% (95% confidence interval (CI) 7.9-29.1) and 6.4% (1.6-15.9), respectively. The cumulative incidence of moderate-severe chronic GVHD at 1 year was 15.2% (95% CI 6.5-27.1). Overall survival (OS) and relapse-free survival (RFS) were 55.2% (95% CI 39.5-68.4) and 49.5% (95% CI 34.2-63), respectively. Nonrelapse mortality (NRM) for all patients at 1 year was 37.1% (95% CI 23.2-51.1). Infection was the main cause of death (26%). For AML, 1-year OS, RFS, and NRM were 64.1% (95% CI 43.3-78.9), 54.5 (95% CI 34.6-70.7), and 26.8% (95% CI 12.3-43.6), respectively. In conclusion, unmanipulated haploidentical peripheral blood stem cells (PBSC) transplantation following RIC and dual in vivo T-cell depletion results in a low incidence of acute and chronic GVHD for patients diagnosed with myeloid malignancies.