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Post-transplant cyclophosphamide versus anti-thymocyte globulin after reduced intensity peripheral blood allogeneic cell transplantation in recipients of matched sibling or 10/10 HLA matched unrelated donors: final analysis of a randomized, open-label, multicenter, phase 2 trial
Brissot, E., Labopin, M., Labussière, H., Fossard, G., Chevallier, P., Guillaume, T., Yakoub-Agha, I., Srour, M., Bulabois, C. E., Huynh, A., et al
Blood cancer journal. 2024;14(1):31
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Editor's Choice
Abstract
The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679.
PICO Summary
Population
Adults with haematological malignancies undergoing transplant from a matched related or 10/10 HLA-matched unrelated donor with reduced intensity conditioning, recruited from eleven centres in France (n=89)
Intervention
Post-transplantation cyclophosphamide 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis (PTCy, n=44)
Comparison
Anti-thymocyte globulin 5 mg/kg plus standard GVHD prophylaxis (ATG, n=45)
Outcome
At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group. Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group. The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups.
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Low-dose PTCy plus low-dose ATG as GVHD prophylaxis after UD-PBSCT for hematologic malignancies: a prospective, multicenter, randomized controlled trial
Zu, Y., Gui, R., Li, Z., Wang, J., Zhang, Y., Yu, F., Zhao, H., Zhan, X., Wang, Z., Xing, P., et al
Blood Cancer Journal. 2023;13(1):10
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Single Center Randomized Trial of T-reg graft alone versus T-reg graft Plus Tacrolimus for the Prevention of Acute GVHD
Bader, C. S., Pavlova, A., Lowsky, R., Muffly, L., Shiraz, P., Arai, S., Johnston, L. J., Rezvani, A. R., Weng, W. K., Miklos, D. B., et al
Blood advances. 2023
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Editor's Choice
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies for which graft-versus-host disease (GVHD) remains a major complication. The use of donor T regulatory cells (Tregs) to prevent GVHD appears promising, including in our previous evaluation of an engineered graft product (T-reg graft) consisting of the timed, sequential infusion of CD34+ hematopoietic stem cells and high-purity Tregs followed by conventional T cells. However, whether immunosuppressive prophylaxis can be removed from this protocol remains unclear. We report the results of the first stage of an open-label single-center phase 2 study (NCT01660607) investigating T-reg graft in myeloablative HCT of HLA-matched and 9/10 matched recipients. Twenty-four patients were randomized to receive T-reg graft alone (n=12) or T-reg graft plus single-agent GVHD prophylaxis (n=12) to determine if T-reg graft alone was non-inferior in preventing acute GVHD. All patients developed full donor myeloid chimerism. Patients with T-reg graft alone versus with prophylaxis had an incidence of grade II-IV acute GVHD of 58% versus 8% (p=0.005) and grade III-IV of 17% versus 0% (p=0.149), respectively. The incidence of moderate to severe chronic GVHD was 28% in the T-reg graft alone arm versus 0% with prophylaxis (p=0.056). Among patients with T-reg graft and prophylaxis, CD4+ T cell:Treg ratios were reduced after transplantation, gene-expression profiles showed reduced CD4+ proliferation, and the achievement of full donor T cell chimerism was delayed. This study indicates that T-reg graft with single-agent tacrolimus is preferred to T-reg graft alone for the prevention of acute GVHD. Clinical Trial #: NCT01660607.
PICO Summary
Population
Adults with haematological disorders, scheduled for allogeneic transplantation with a 9/10 or matched donor, and suitable for myeloablative conditioning, from a single centre in USA (n=24)
Intervention
An engineered graft product (T-reg) graft alone (n=12)
Comparison
An engineered graft product (T-reg) graft plus single-agent GVHD prophylaxis (n=12)
Outcome
All patients developed full donor myeloid chimerism. Patients with T-reg graft alone versus with prophylaxis had an incidence of grade II-IV acute GVHD of 58% versus 8% and grade III-IV of 17% versus 0%, respectively. The incidence of moderate to severe chronic GVHD was 28% in the T-reg graft alone arm versus 0% with prophylaxis. Among patients with T-reg graft and prophylaxis, CD4+ T cell:Treg ratios were reduced after transplantation, gene-expression profiles showed reduced CD4+ proliferation, and the achievement of full donor T cell chimerism was delayed.
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Mesenchymal Stem Cells for Prophylaxis of Chronic Graft-vs-Host Disease After Haploidentical Hematopoietic Stem Cell Transplant: An Open-Label Randomized Clinical Trial
Huang, R., Chen, T., Wang, S., Wang, J., Su, Y., Liu, J., Zhang, Y., Ma, X., Wen, Q., Kong, P., et al
JAMA oncology. 2023
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Abstract
IMPORTANCE Chronic graft-vs-host disease (GVHD) limits the long-term benefit of haploidentical hematopoietic stem cell transplant (HSCT). This clinical trial evaluated repeated infusions of umbilical cord mesenchymal stem cells (MSCs) during the early stage (45 days and 100 days) after haplo-HSCT to prevent chronic GVHD. OBJECTIVE To determine whether repeated infusions of MSCs during the early stage after haplo-HSCT decreases the incidence of severe chronic GVHD. DESIGN, SETTING, AND PARTICIPANTS This open-label, multicenter, parallel randomized clinical trial was conducted from April 2016 to January 2022. Eligibility criteria included a diagnosis of acute leukemia and having a haploidentical, suitable related donor for HSCT. The median (range) follow-up time was 39.0 (1.5-67.0) months. INTERVENTIONS The enrolled patients with a haploidentical relative for HSCT received the modified busulfan/cyclophosphamide + antithymocyte globulin modified regimen and standard GVHD prophylaxis. Patients were randomly chosen to receive MSCs (the MSC group) (1 × 106 cells/kg, every 2 weeks, starting from 45 days after transplant, 4 times total) or regular prophylaxis (control group). MAIN OUTCOME AND MEASURE The cumulative incidence of severe chronic GVHD. RESULTS Of 158 patients, 58 (36.7%) were female individuals; the median (range) age for the MSC and control groups was 28 (18-60) years and 28 (18-56) years, respectively. A total of 158 patients were screened, and 148 patients were randomly assigned to the MSC group (n = 74) or control group (n = 74) 1 day before MSCs infusion. The estimated 2-year cumulative incidence of severe chronic GVHD was 5.4% (95% CI, 1.8%-14.0%) in the MSC group and 17.4% (95% CI, 10.1%-28.5%) in the control group (hazard ratio [HR], 0.29; 95% CI, 0.10-0.88; P = .03). There was no difference between the MSC and control groups in the cumulative incidence of leukemia relapse (HR, 1.17; 95% CI, 0.55-2.47; P = .68). The cumulative incidence of stage II to IV acute GVHD in the MSC group was significantly lower than that in the control group (HR, 0.25; 95% CI, 0.09-0.67; P = .01). The MSC group had better GVHD-free and relapse-free survival rates than the control group (HR, 0.62; 95% CI, 0.39-0.98; P = .04). CONCLUSIONS AND RELEVANCE The results of this randomized clinical trial show that early repeated infusions of MSCs decreased the incidence and severity of chronic GVHD, and the incidence and severity of acute GVHD manifested as a better GVHD-free and relapse-free survival rate for patients after haplo-HSCT. TRIAL REGISTRATION Chinese Clinical Trial Registry: ChiCTR-IIR-16007806.
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A Phase 2 Trial of CD24Fc for Prevention of Graft-vs-Host Disease
Magenau, J. M., Jaglowski, S. M., Uberti, J., Farag, S. S., Mansour Riwes, M., Pawarode, A., Anand, S., Ghosh, M., Maciejewski, J., Braun, T. M., et al
Blood. 2023
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Editor's Choice
Abstract
Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-vs-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This Phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at Day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P=0.03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as NCT02663622.
PICO Summary
Population
Adults up to 70 years undergoing myeloablative allogeneic HSCT for hematologic malignancies from four centres in USA (RCT n=24; Expansion cohort n=112)
Intervention
Dose escalation cohorts of CD24Fc, a novel human CD24 fusion protein, in combination with tacrolimus and methotrexate as GvHD prophylaxis (RCT n=18; Expansion cohort n=20)
Comparison
Placebo plus tacrolimus and methotrexate (RCT n=6; Expansion cohort n=92)
Outcome
A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at Day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT.
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Tacrolimus/methotrexate vs tacrolimus/reduced-dose methotrexate/mycophenolate for graft-vs-host disease prevention
Hamilton, B. K., Rybicki, L. A., Li, H., Lucas, T., Corrigan, D., Kalaycio, M. E., Sobecks, R. M., Hanna, R., Rotz, S. J., Dean, R. M., et al
Blood advances. 2023
Abstract
Tacrolimus (Tac)/methotrexate (MTX) is standard graft-versus-host disease (GVHD) prophylaxis, however, associated with several toxicities. Tac, reduced dose ("mini")-MTX, mycophenolate mofetil (MMF) has been used, but never compared to standard MTX. We performed a randomized trial comparing Tac/MTX (Full-MTX) to Tac/mini-MTX/MMF (Mini-MTX/MMF) for GVHD prevention after allogeneic hematopoietic cell transplantation (HCT). Patients (pts) receiving first myeloablative HCT using an 8/8 HLA-matched donor were eligible. Primary endpoints were incidence of acute (a)GVHD, mucositis, and engraftment. Secondary endpoints included chronic (c)GVHD, organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). Ninety-six pts were randomized to Full-MTX (N=49) or Mini-MTX (N=47). The majority (86%) used bone marrow grafts. There was no significant difference in day 100 grade 2-4 aGVHD (28% Mini-MTX/MMF vs 27% Full-MTX, P=0.41), however higher grade 3-4 aGVHD (13% vs 4%, P=0.07) with Mini-MTX/MMF. Mini-MTX/MMF pts had lower grade 3-4 mucositis (57% vs 82%, P=0.010), and faster neutrophil engraftment (median 15 vs 17 days, P<0.001). There were no significant differences in moderate-severe cGVHD at 1 year (23% vs 20%, P=0.14) or infections. Mini-MTX/MMF pts experienced less nephrotoxicity (2% vs 26%, P<0.001) and less respiratory failure (6% versus 18%, P=0.03). There was no difference in 1-year relapse (19% vs 21%, P=0.89) or OS (72% vs. 71%, P=0.08), and Mini-MTX/MMF was associated with lower but non-significant NRM (11% vs 22%), P=0.06. Compared to Full-MTX, Mini-MTX/MMF was associated with no difference in grade 2-4 aGVHD and a more favorable toxicity profile. The higher severe aGVHD warrants additional study to further optimize this regimen.
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Allogeneic haematopoietic cell transplants as dynamical systems: influence of early-term immune milieu on long-term T-cell recovery
Zelikson, V., Sabo, R., Serrano, M., Aqeel, Y., Ward, S., Al Juhaishi, T., Aziz, M., Krieger, E., Simmons, G., Roberts, C., et al
Clinical & translational immunology. 2023;12(7):e1458
Abstract
OBJECTIVES Immune recovery following haematopoietic cell transplantation (HCT) functions as a dynamical system. Reducing the duration of intense immune suppression and augmenting antigen presentation has the potential to optimise T-cell reconstitution, potentially influencing long-term outcomes. METHODS Based on donor-derived T-cell recovery, 26 patients were adaptively randomised between mycophenolate mofetil (MMF) administered for 30-day post-transplant with filgrastim for cytokine support (MMF30 arm, N = 11), or MMF given for 15 days with sargramostim (MMF15 arm, N = 15). All patients underwent in vivo T-cell depletion with 5.1 mg kg(-1) antithymocyte globulin (administered over 3 days, Day -9 through to Day -7) and received reduced intensity 450 cGy total body irradiation (3 fractions on Day -1 and Day 0). Patients underwent HLA-matched related and unrelated donor haematopoietic cell transplantation (HCT). RESULTS Clinical outcomes were equivalent between the two groups. The MMF15 arm demonstrated superior T-cell, as well as T-cell subset recovery and a trend towards superior T-cell receptor (TCR) diversity in the first month with this difference persisting through the first year. T-cell repertoire recovery was more rapid and sustained, as well as more diverse in the MMF15 arm. CONCLUSION The long-term superior immune recovery in the MMF15 arm, administered GMCSF, is consistent with a disproportionate impact of early interventions in HCT. Modifying the 'immune-milieu' following allogeneic HCT is feasible and may influence long-term T-cell recovery.
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The MAGIC algorithm probability (MAP)-guided preemptive therapy of acute graft versus host disease with methylprednisolone: A randomized controlled trial
Zeng, Q., Zhang, H., Kuang, P., Li, J., Chen, X., Dong, T., Wu, Q., Zhang, C., Chen, C., Niu, T., et al
American journal of hematology. 2023
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Editor's Choice
Abstract
Acute graft versus host disease (aGvHD) is a severe complication that arises in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and remains the primary cause of nonrelapse mortality (NRM). The MAGIC algorithm probability (MAP) has been proposed to identify patients at intermediate and high risk of developing aGvHD. The levels of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (Reg3α) were assessed, and MAP was calculated on days 7, 14, 21, and 28 after allo-HSCT. Based on the MAP results, patients were classified into low-, intermediate-, or high-risk groups for the development of aGvHD. Random assignment was performed to allocate intermediate- or high-risk patients to receive preemptive therapy with methylprednisolone or not. The 100-day cumulative incidences of grade 2 or higher (35.5% ± 8.6%) and grade 3 or higher (12.9% ± 6.0%) aGvHD in the methylprednisolone group were significantly lower than those in the control group (66.7% ± 7.9%, p = .01; 42.9% ± 8.4%, p = .01), and similar to those observed in the low-risk group (31.7% ± 7.3%, p = .75; 2.4% ± 2.4%, p = .08). The 6-month cumulative incidences of NRM were 14.1% ± 6.6%, 22.7% ± 7.1%, and 2.4% ± 2.4% in the methylprednisolone, control, and low-risk groups, respectively, with no significant difference between the methylprednisolone and control groups (p = .29). Methylprednisolone did not increase infections (p = .34). The 100-day cumulative incidences of cytomegalovirus (CMV) reactivation were 67.7% ± 8.4%, 65.6% ± 8.4%, and 46.3% ± 7.8% (p = .08), and those of grade 2 or higher hemorrhagic cystitis were 29.0% ± 8.2%, 45.2% ± 8.9% and 22.0% ± 6.5% (p = .11) in the methylprednisolone, control, and low-risk groups, respectively. MAP-guided preemptive therapy for aGvHD is promising. The long-term efficacy and safety remain to be investigated.
PICO Summary
Population
Patients aged 16-65 years undergoing allo-HSCT and assessed as intermediate- or high-risk using the MAGIC algorithm (n=67)
Intervention
Pre-emptive therapy with methylprednisolone (n=31)
Comparison
Control: no methylprednisolone therapy (n=36)
Outcome
The 100-day cumulative incidences of grade 2 or higher (35.5% ± 8.6%) and grade 3 or higher (12.9% ± 6.0%) aGvHD in the methylprednisolone group were significantly lower than those in the control group (66.7% ± 7.9%, p = .01; 42.9% ± 8.4%), and similar to those observed in the low-risk group (31.7% ± 7.3%, p = .75; 2.4% ± 2.4%). The 6-month cumulative incidences of NRM were 14.1% ± 6.6%, 22.7% ± 7.1%, and 2.4% ± 2.4% in the methylprednisolone, control, and low-risk groups, respectively, with no significant difference between the methylprednisolone and control groups. Methylprednisolone did not increase infections. The 100-day cumulative incidences of cytomegalovirus (CMV) reactivation were 67.7% ± 8.4%, 65.6% ± 8.4%, and 46.3% ± 7.8%, and those of grade 2 or higher hemorrhagic cystitis were 29.0% ± 8.2%, 45.2% ± 8.9% and 22.0% ± 6.5% in the methylprednisolone, control, and low-risk groups, respectively.
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Low-dose post-transplant cyclophosphamide with low-dose antithymocyte globulin for prevention of graft-versus-host disease in first complete remission undergoing 10/10 HLA-matched unrelated donor peripheral blood stem cell transplants: a multicentre, randomized controlled trial
Zu, Y., Li, Z., Gui, R., Liu, Y., Zhang, Y., Yu, F., Zhao, H., Fu, Y., Zhan, X., Wang, Z., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
The most widely used regimens of graft-versus-host disease (GVHD) prophylaxis in HLA-matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT) are based on anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). To improve the efficiency of GVHD prophylaxis, a novel regimen, composed of low-dose PTCy (20 mg/kg on day +3 and +4) and low-dose ATG (6 mg/kg), was evaluted in patients with hematological malignancies ungoing 10/10 HLA MUD-PBSCT in first remission (CR1). In our prospective, multicenter study, 104 patients were randomly assigned one-to-one to low-dose PTCy-ATG (n = 53) or standard-dose ATG (10 mg/kg, n = 51). Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; P = 0.017; 14.1% vs. 33.3%; P = 0.013). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%; P = 0.049) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%; P = 0.032). The low-dose PTCy-ATG based GVHD prophylaxis is a promising strategy for patients in CR1 after 10/10 HLA MUD-PBSCT.
PICO Summary
Population
Participants aged 12-69 years with haematological malignancies receiving 10/10 matched unrelated donor (MUD) transplantation in three transplant centres in China (n=104)
Intervention
Post-transplant cyclophosphamide, 20 mg/kg on day +3 and +4 and low-dose (6mg/kg) antithymocyte globulin (low-dose PTCy-ATG, n=53)
Comparison
ATG 2.0 mg/kg/day on days −5 through -1 (standard-dose ATG, n=51)
Outcome
Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; 14.1% vs. 33.3%). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%).
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Are We Making PROGRESS in Preventing Graft-versus-Host Disease and Improving Clinical Outcomes? Impact of BMT CTN 1301 Study Results on Clinical Practice
Hamilton, B. K., Cutler, C., Divine, C., Juckett, M., LeMaistre, C., Stewart, S., Wilder, J., Horowitz, M., Khera, N., Burns, L. J.
Transplantation and cellular therapy. 2022
Abstract
The need for prospective randomized clinical trials investigating novel graft-versus-host disease (GVHD) prevention strategies which include other clinical outcomes impacted by GVHD has been highlighted as a priority for the field of hematopoietic cell transplantation. A recently completed study through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1301) comparing CD34+ selection and post-transplant cyclophosphamide to tacrolimus/methotrexate (Tac/MTX) for GVHD prevention demonstrated no significant differences in the primary endpoint of Chronic GVHD-Relapse-Free Survival (CRFS) among the three approaches. The trial did not demonstrate a superior approach compared to Tac/MTX; however, it highlights several challenges in determining the best and most relevant approaches to clinical trial design, particularly in the context of current and ongoing changes in real world practices. Here, we review BMT CTN 1301 results and implications for clinical practice and future clinical trial design.