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Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation
Penack, O., Marchetti, M., Aljurf, M., Arat, M., Bonifazi, F., Duarte, R. F., Giebel, S., Greinix, H., Hazenberg, M. D., Kröger, N., et al
The Lancet. Haematology. 2024
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Editor's Choice
Abstract
Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic haematopoietic stem-cell transplantation (HSCT). In the last 3 years, there has been regulatory approval of new drugs and considerable change in clinical approaches to prophylaxis and management of GVHD. To standardise treatment approaches, the European Society for Blood and Marrow Transplantation (EBMT) has updated its clinical practice recommendations. We formed a panel of one methodologist and 22 experts in the field of GVHD management. The selection was made on the basis of their role in GVHD management in Europe and their contributions to the field, such as publications, presentations at conferences, and other research. We applied the GRADE process to ten PICO (patient, intervention, comparator, and outcome) questions: evidence was searched for by the panel and graded for each crucial outcome. In two consensus meetings, we discussed the evidence and voted on the wording and strengths of recommendations. Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD. The EBMT proposes to use these recommendations as the basis for routine management of GVHD during allogenic HSCT. The current recommendations favour European practice and do not necessarily represent global preferences.
PICO Summary
Population
Panel of 22 experts and one methdologist convened by the European Society for Blood and Marrow Transplantation (EBMT)
Intervention
Update of the EBMT consensus recommendations
Comparison
Outcome
Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD.
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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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A phase 2, prospective, randomized, open-label study of defibrotide added to standard-of-care prophylaxis for the prevention of acute graft-versus-host disease after allogeneic hematopoietic cell transplantation
Hudspeth, M., Mori, S., Nachbaur, D., Perez-Simon, J. A., Stölzel, F., Riches, M., Wu, W., Zhang, P., Agarwal, S., Yakoub-Agha, I.
Haematologica. 2022
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Editor's Choice
Abstract
Acute graft-versus-host disease (aGvHD) is a life-threatening complication typically occurring within 100 days after allogeneic hematopoietic cell transplantation (allo-HCT). This hypothesisgenerating, phase 2, prospective, open-label, randomized study compared defibrotide added to standard-of-care (SOC) GvHD prophylaxis (defibrotide prophylaxis arm) versus SOC alone (SOC arm) to prevent aGvHD post-transplant. This study estimated incidences of aGvHD and was not statistically powered to assess differences among treatment arms. Patients were randomized 1:1 to defibrotide prophylaxis arm (n=79; median age: 57 years, range: 2-69 years) or SOC arm (n=73; median age: 56 years, range: 2-72 years). Patient demographics in the two arms were similar except for conditioning regimen type (myeloablative: defibrotide, 76% vs. SOC, 61%) and stem cell source for allo-HCT (bone marrow: defibrotide, 34% vs. SOC, 26%). In the intent-to-treat primary endpoint analysis, the cumulative incidence of grade B-D aGvHD at Day 100 post-transplant was 38.4% in the defibrotide prophylaxis arm versus 47.1% in the SOC arm (difference: -8.8% [90% confidence interval (CI): -22.5, 4.9]). The difference noted at Day 100 became more pronounced in a subgroup analysis of patients who received antithymocyte globulin (defibrotide: 30.4%, SOC: 47.6%; difference: -17.2% [90% CI: -41.8, 7.5]). Overall survival rates at Day 180 post-transplant were similar between arms, as were the rates of serious treatment-emergent adverse events (defibrotide: 42%, SOC: 44%). While the observed differences in endpoints between the two arms were not substantial, these results suggest defibrotide prophylaxis may add a benefit to currently available SOC to prevent aGvHD following allo-HCT without adding significant toxicities.
PICO Summary
Population
Adults undergoing allogeneic stem cell transplantation, and enrolled in a multicentre randomised controlled trial in 62 centres in North America and Europe (n=152)
Intervention
Defibrotide added to standard-of-care GvHD prophylaxis (n=79)
Comparison
Standard-of-care (SOC) alone (n=73)
Outcome
In the intent-to-treat primary endpoint analysis, the cumulative incidence of grade B-D aGvHD at Day 100 post-transplant was 38.4% in the defibrotide prophylaxis arm versus 47.1% in the SOC arm (difference: -8.8% [90% confidence interval (CI): -22.5, 4.9]). The difference noted at Day 100 became more pronounced in a subgroup analysis of patients who received antithymocyte globulin (defibrotide: 30.4%, SOC: 47.6%; difference: -17.2% [90% CI: -41.8, 7.5]). Overall survival rates at Day 180 post-transplant were similar between arms, as were the rates of serious treatment-emergent adverse events (defibrotide: 42%, SOC: 44%).
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4.
Posttransplant Cyclophosphamide for Prevention of Graft-versus-Host Disease: The Prospective Randomized HOVON-96 Trial
Broers, A. E. C., de Jong, C. N., Bakunina, K., Hazenberg, M. D., van Marwijk Kooy, M., de Groot, M., van Gelder, M., Kuball, J., van der Holt, B., Meijer, E., et al
Blood advances. 2022
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Editor's Choice
Abstract
Graft versus host disease (GVHD) is the most important complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). We performed a prospective randomized, multicenter, phase III trial to study whether posttransplant cyclophosphamide (PT-Cy) combined with a short course of cyclosporine A (CsA) would result in a reduction of severe GVHD and improvement of GVHD-free, relapse free survival (GRFS) as compared to the combination of CsA and mycophenolic acid (MPA) after non-myeloablative (NMA) matched related and unrelated peripheral blood alloHSCT. Between October 2013 and June 2018, 160 patients diagnosed with a high-risk hematological malignancy and having a matched related or at least 8 out of 8 HLA matched unrelated donor were randomized and allocated in a 1:2 ratio to CsA/MPA or PT-Cy/CsA. A total of 151 patients was transplanted (52 versus 99 patients). The cumulative incidence of grade II-IV acute GVHD at six months was 48% in recipients of CsA/MPA versus 30% following PT-Cy/CsA (Hazard ratio (HR): 0.48, 95% confidence interval (CI): 0.29-0.82, p=0.007). The two-year cumulative incidence of chronic extensive GVHD was 48% versus 16% (HR: 0.36, 95%CI: 0.21-0.64, p<0.001). The one-year estimate of GRFS was 21% (11%-32%) versus 45% (35%-55%), p<0.001. With a median follow-up of 56.4 months, relapse incidence, progression-free and overall survival were not significantly different between the two treatment arms. PT-Cy combined with a short course of CsA after NMA matched alloHSCT significantly improves GRFS due to a significant reduction in severe acute and chronic GVHD. The trial was registered as number NL2128 in the Dutch trial registry (www.trialregister.nl).
PICO Summary
Population
Patients with haematological malignancy due to undergo non-myeloablative allogeneic stem cell transplant with a matched related or at least 8/8 HLA matched unrelated donor, in six centres in the Netherlands (n=151)
Intervention
Posttransplant cyclophosphamide combined with a short course of cyclosporine A (PT-Cy/CsA, n=99)
Comparison
Cyclosporine A and mycophenolic acid (CsA/MPA, n=52)
Outcome
The cumulative incidence of grade II-IV acute GVHD at six months was 48% in recipients of CsA/MPA versus 30% following PT-Cy/CsA (Hazard ratio (HR): 0.48, 95% confidence interval (CI): 0.29-0.82). The two-year cumulative incidence of chronic extensive GVHD was 48% versus 16% (HR: 0.36, 95%CI: 0.21-0.64). The one-year estimate of GRFS was 21% (11%-32%) versus 45% (35%-55%), p<0.001. With a median follow-up of 56.4 months, relapse incidence, progression-free and overall survival were not significantly different between the two treatment arms.
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Mycophenolate Mofetil: A Friend or a Foe with PTCy and Tacrolimus Prophylaxis in HLA-Matched donors?
Mehta, R. S., Saliba, R. M., Hayase, E., Jenq, R. R., Abraham, S., Rashid, A., Rondon, G., Al-Atrash, G., Bashir, Q., Hosing, C. M., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
Adapted from the haploidentical literature, post-transplantation cyclophosphamide (PTCy) is increasingly being used with HLA-matched donors, generally with a calcineurin inhibitor, such as tacrolimus (Tac) with or without mycophenolate mofetil (MMF). Owing to its immunosuppressive, potentially antitumor, and antimicrobial properties, MMF is an attractive drug; however, it remains unclear how much benefit is gained when used with PTCy/Tac. To assess that, we compared PTCy/Tac (n=242) to PTCy/Tac/MMF (n= 144) in recipients of HLA-matched donors. In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD; hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.6-2.8, p<0.001), and steroid-refractory/dependent acute GVHD (HR 4.8, 95% CI 2.4-9.6, p<0.001), yet a significantly lower risk of relapse (HR 0.5, 95% CI, 0.3-0.9, p=0.009) and better progression-free survival (PFS; HR 0.7, 95% CI 0.5-0.9, p=0.04). There was no difference in the risk of grade III-IV acute GVHD, chronic GVHD, non-relapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days, and a higher risk of bacterial infections. In an exploratory stool microbiome analysis (n=16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD. Our data suggest that the addition of MMF to PTCy/Tac for HLA-matched donor HCT does not provide any advantage for GVHD prevention. Further studies are needed to decipher this mechanism, and understand its role with PTCy-based prophylaxis.
PICO Summary
Population
Adults with haematological malignancy who had first transplant with HLA-matched donor (n=386)
Intervention
Post-transplant cyclophosphamide with tacrolimus and mycophenalate mofetil (PTCy/Tac/MMF, n= 144)
Comparison
Post-transplant cyclophosphamide with tacrolimus only (PTCy/Tac, n=242)
Outcome
In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD; hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.6-2.8), and steroid-refractory/dependent acute GVHD (HR 4.8, 95% CI 2.4-9.6), yet a significantly lower risk of relapse (HR 0.5, 95% CI, 0.3-0.9) and better progression-free survival (PFS; HR 0.7, 95% CI 0.5-0.9). There was no difference in the risk of grade III-IV acute GVHD, chronic GVHD, non-relapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days, and a higher risk of bacterial infections. In an exploratory stool microbiome analysis (n=16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD.
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A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention
Perez, L., Fernandez, H., Kharfan-Dabaja, M., Khimani, F., Betts, B., Mishra, A., Ayala, E., Locke, F. L., Ochoa-Bayona, L., Nieder, M., et al
Blood advances. 2021;5(13):2740-2750
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Editor's Choice
Abstract
Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day -5 (5 mg orally 3 times a week) with tacrolimus initiated on day -3 plus sirolimus on day -1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8-matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor-stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.
PICO Summary
Population
Patients undergoing 8/8 matched related or unrelated transplantation (n=38)
Intervention
Panobinostat (PANO) administered over 26 weeks, starting on day -5 (5 mg orally 3 times a week) with tacrolimus initiated on day -3 plus sirolimus on day -1
Comparison
None
Outcome
Cumulative incidence of chronic GVHD at 1 year was 31.6%. Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5%, relapse-free survival was 78.9%, nonrelapse mortality was 2.6%, and GVHD relapse-free survival was 60.5%. PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs.
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7.
Low-dose antithymocyte globulin inhibits chronic graft-versus-host disease in peripheral blood stem cell transplantation from unrelated donors
Shiratori, S., Sugita, J., Fuji, S., Aoki, J., Sawa, M., Ozawa, Y., Hashimoto, D., Matsuoka, K. I., Imada, K., Doki, N., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
Antithymocyte globulin (ATG) has been shown to reduce chronic graft-versus-host disease (GVHD) particularly in allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors; however, anti-GVHD effects of lower doses of ATG remains to be elucidated. We conducted a nationwide retrospective study to compare the outcomes of unrelated PBSCT with or without rabbit ATG (thymoglobulin) in 287 patients. A median ATG dose was 2.0?mg/kg. The primary endpoint, the cumulative incidence of moderate-severe chronic GVHD at 2 years was 22.1% in the ATG group, which was significantly less than that in the non-ATG group (36.3%, P?=?0.025). The ATG group had a higher incidence of immunosuppressant discontinuation, GVHD-free, relapse-free survival, and moderate-severe chronic GVHD-free, relapse-free survival at 2 years compared to the non-ATG group. The incidences of grade III-IV aGVHD and moderate-severe chronic GVHD were significantly higher in patients with high absolute lymphocyte count (ALC) before the administration of ATG, whereas relapse rate was significantly higher in patients with low ALC before ATG. In conclusion, low-dose ATG effectively suppresses chronic GVHD in unrelated PBSCT, and ALC before ATG may be a potential predictor for GVHD and relapse.
PICO Summary
Population
Patients undergoing peripheral blood stem cell transplantation from unrelated donors (n=287)
Intervention
Rabbit antithymocyte globulin (ATG) as GvHD prophylaxis (ATG group, n=97)
Comparison
No ATG prophylaxis (non-ATG group, n=190)
Outcome
A median ATG dose was 2.0mg/kg. The primary endpoint, the cumulative incidence of moderate-severe chronic GVHD at 2 years was 22.1% in the ATG group, which was significantly less than that in the non-ATG group (36.3%). The ATG group had a higher incidence of immunosuppressant discontinuation, GVHD-free, relapse-free survival, and moderate-severe chronic GVHD-free, relapse-free survival at 2 years compared to the non-ATG group. The incidences of grade III-IV aGVHD and moderate-severe chronic GVHD were significantly higher in patients with high absolute lymphocyte count (ALC) before the administration of ATG, whereas relapse rate was significantly higher in patients with low ALC before ATG. In conclusion, low-dose ATG effectively suppresses chronic GVHD in unrelated PBSCT, and ALC before ATG may be a potential predictor for GVHD and relapse.
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A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation
Bejanyan, N., Pidala, J. A., Wang, X., Thapa, R., Nishihori, T., Elmariah, H., Lazaryan, A., Khimani, F., Davila, M. L., Mishra, A., et al
Blood advances. 2021;5(5):1154-1163
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Editor's Choice
Abstract
The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (=18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.
PICO Summary
Population
Adult patients who received a haploidentical stem cell transplant (n=32)
Intervention
Post-transplant cyclophosphamide (PTCy) and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis
Comparison
None
Outcome
At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8%. There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8%, nonrelapse mortality was 18.8%, relapse was 22.2% , disease-free survival was 59.0%, GVHD-free relapse-free survival was 49.6% and overall survival was 71.7% for the entire cohort.
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Comparison of immune reconstitution between anti-T-lymphocyte globulin and post-transplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation
Massoud, R., Gagelmann, N., Fritzsche-Friedland, U., Zeck, G., Heidenreich, S., Wolschke, C., Ayuk, F., Christopeit, M., Kröger, N.
Haematologica. 2021
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Editor's Choice
Abstract
Anti T-cell lymphocyte globulin (ATLG) and post-transplant cyclophosphamide (PTCy) are now widely used strategies to prevent graft-versus-host disease after allogeneic stem cell transplantation. Data comparing immune reconstitution (IR) between ATLG and PTCy is scarce. This retrospective study conducted at the University Medical-Center Hamburg- Eppendorf (UKE) compares after myeloablative PBSC allogeneic stem cell transplant between PTCy (n=123) and ATLG (n=476). Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 100 and 180 posttransplant. Incidence of infections, viral reactivations graft-versus-host disease and relapse were collected. Neutrophil engraftment was significantly delayed in the PTCy group (median day 12 vs. 10, p < 0.001) with a high incidence of infection before day+100 in the PTCy arm but a higher EBV reactivation in the ATLG arm and comparable CMV reactivation. Overall incidence of acute GVHD was similar but moderate/severe chronic GVHD was more seen after PTCy (44% vs. 38%, p = 0.005). ATLG resulted in a faster reconstitution of CD8+ T-cells, NK cells, NKT cells, and ?dT cells while CD4 T-cells and B-cells reconstituted faster after PTCy. Similar reconstitution was observed for T-regulatory cells and B-cells. NRM, relapse incidence, DFS, and overall survival did not differ significantly between both arms. Even though difference in IR have been translated into decreased incidence of infections and moderate/severe cGVHD in the ATLG group they had no impact on any of the other longterm outcomes. However, it remains undetermined which regimen is better as graft-versushost disease prophylaxis.
PICO Summary
Population
Patients undergoing myeloablative peripheral blood stem cell transplantation (n=599)
Intervention
Post-transplant cyclophosphamide (PTCy, n=123)
Comparison
Anti T-cell lymphocyte globulin (ATLG, n=476)
Outcome
Neutrophil engraftment was significantly delayed in the PTCy group (median day 12 vs. 10) with a high incidence of infection before day+100 in the PTCy arm but a higher EBV reactivation in the ATLG arm and comparable CMV reactivation. Overall incidence of acute GVHD was similar but moderate/severe chronic GVHD was more seen after PTCy (44% vs. 38%). ATLG resulted in a faster reconstitution of CD8+ T-cells, NK cells, NKT cells, and dT cells while CD4 T-cells and B-cells reconstituted faster after PTCy. Similar reconstitution was observed for T-regulatory cells and B-cells. NRM, relapse incidence, DFS, and overall survival did not differ significantly between both arms. Even though difference in IR have been translated into decreased incidence of infections and moderate/severe cGVHD in the ATLG group they had no impact on any of the other longterm outcomes.
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10.
A Phase 3 Double-Blind Study of the Addition of Tocilizumab versus Placebo to Cyclosporin/Methotrexate GvHD Prophylaxis
Kennedy, G., Tey, S. K., Buizen, L., Varelias, A., Gartlan, K. H., Curley, C., Olver, S., Chang, K., Butler, J., Misra, A., et al
Blood. 2021
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Editor's Choice
Abstract
We determined the efficacy of tocilizumab (TCZ) in preventing grade II-IV acute GVHD (aGVHD) in patients with acute-leukemia or myelodysplasia undertaking matched-related-sibling (MSD) or volunteer-unrelated-donor (VUD) allogeneic-SCT after myeloablative or reduced-intensity conditioning across five Australian centers. 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day-1. All patients received T-cell-replete PBSC grafts and GVHD-prophylaxis with cyclosporin/methotrexate. A planned sub-study analyzed the VUD cohort. With a median follow up of 746 days, the incidence of grade II-IV aGVHD at day 100 for the entire cohort was 36% versus 27% for placebo versus TCZ (HR 0.69; CI:0.38-1.26, p=0.23) and 45% versus 32% (HR 0.61; CI:0.31-1.22, p=0.16) for the VUD subgroup. The incidence of grade II-IV aGVHD at day 180 for the entire cohort was 40% versus 29% for placebo versus TCZ (HR 0.68; CI:0.38-1.22, p=0.19) and 48% versus 32% (HR 0.59; CI:0.30-1.16, p=0.13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade II disease. A trend to improved aGVHD-free survival (aGVHD-FS) was noted in the TCZ-treated VUD subgroup, 52% versus 68% for placebo versus TCZ (p=0.13). For the entire cohort, transplant-related-mortality occurred in 8% versus 11% of placebo versus TCZ-treated patients respectively (p=0.56) and overall-survival was 79% versus 71% (p=0.27). Median day to neutrophil and platelet engraftment was delayed by 2-3 days in TCZ-treated patients while liver toxicity and infectious complications were similar between groups. In this phase-3 randomized, double-blind trial (ACTRN12614000266662), tocilizumab showed non-significant trends to reduced incidence of grade II-IV aGVHD and improved aGVHD-FS in recipients of HLA-matched VUD donors, but no improvements in long term-survival.
PICO Summary
Population
Patients with acute-leukemia or myelodysplasia undertaking matched-related-sibling (MSD) or volunteer-unrelated-donor (VUD) allogeneic-SCT (n=145)
Intervention
Tocilizumab on day -1
Comparison
Placebo on day-1
Outcome
With a median follow up of 746 days, the incidence of grade II-IV aGVHD at day 100 for the entire cohort was 36% versus 27% for placebo versus TCZ (HR 0.69) and 45% versus 32% (HR 0.61) for the VUD subgroup. The incidence of grade II-IV aGVHD at day 180 for the entire cohort was 40% versus 29% for placebo versus TCZ (HR 0.68) and 48% versus 32% (HR 0.59) for the VUD subgroup. Reductions in aGVHD were predominantly in grade II disease. A trend to improved aGVHD-free survival (aGVHD-FS) was noted in the TCZ-treated VUD subgroup, 52% versus 68% for placebo versus TCZ. For the entire cohort, transplant-related-mortality occurred in 8% versus 11% of placebo versus TCZ-treated patients respectively and overall-survival was 79% versus 71%. Median day to neutrophil and platelet engraftment was delayed by 2-3 days in TCZ-treated patients while liver toxicity and infectious complications were similar between groups.