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Individualized rabbit anti-thymocyte globulin dosing in adult haploidentical hematopoietic cell transplantation with high-risk hematologic malignancy: Exposure-response analysis and population pharmacokinetics simulations
Teramoto, M., Takahashi, T., Matsumoto, K., Jaber, M., Kaida, K., Tamaki, H., Ikegame, K., Yoshihara, S.
American journal of hematology. 2024
Abstract
Hematopoietic cell transplantation (HCT) for hematologic malignancies with non-remission disease and/or prior post-transplant relapse have poor relapse-free survival. We previously demonstrated the efficacy of haploidentical reduced-intensity HCT regimen with glucocorticoid-based graft-versus-host disease (GVHD) prophylaxis. We recently showed a possible association between rabbit antithymocyte globulin (rATG) exposure and acute GVHD (aGVHD) risk, leading to hypothesize that optimization of rATG exposure may further improve this regimen. We retrospectively examined the exposure-response association of rATG and key clinical outcomes post haploidentical HCT. We subsequently developed an individualized rATG dosing that optimizes rATG exposure using a previously developed population pharmacokinetic model. Of the 103 patients analyzed, the median age was 47 years (range: 17-70) and majority had a non-remission disease prior to HCT (88%). rATG concentration on day 0 of HCT (C(day_0) ) was the strongest predictor of Grade 2-4 aGVHD through day +100. Patients with C(day_0) ≥ 20 μg/mL had an approximately 3-fold lower risk of Grade 2-4 aGVHD (hazard ratio [HR]: 0.32, 95% confidence interval [CI]: 0.16, 0.62) and Grade 3-4 aGVHD (HR: 0.33, 95% CI: 0.16, 0.68) as well as an approximately 2-fold lower risk of overall mortality (HR: 0.47, 95% CI: 0.28, 0.77) and relapse (HR: 0.50, 95% CI: 0.26, 0.94). In conclusion, this reduced-intensity haploidentical HCT regimen with exposure-optimized rATG may provide a promising option to patients undergoing high-risk HCT for hematologic malignancy. The developed rATG dosing warrant prospective validation.
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Peripheral blood stem cell transplantation using HLA-haploidentical donor with post-transplant cyclophosphamide versus HLA-matched sibling donor for lymphoma
Nakaya, Y., Nakamae, H., Nishikubo, M., Kondo, E., Fukuda, T., Hiramoto, N., Mori, Y., Nagafuji, K., Eto, T., Onishi, Y., et al
Bone marrow transplantation. 2024
Abstract
Data comparing HLA-haploidentical donors and HLA-matched sibling donors (MSDs) in peripheral blood stem cell transplantation (PBSCT) for lymphoma are scarce. We retrospectively analyzed 465 patients with lymphoma aged 16 years or older who underwent PBSCT using haploidentical donors with post-transplant cyclophosphamide (PTCy-haplo) (n = 166) or MSDs with calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis (n = 299). Two-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) in the PTCy-haplo and MSD groups were 49.2% versus 51.9% (P = 0.64), 38.0% versus 39.9% (P = 0.97), and 27.7% versus 18.5% (P = 0.006), respectively. In multivariable analyses, PTCy-haplo recipients had slower neutrophil recovery (hazard ratio [HR], 0.62; P < 0.001) and platelet recovery (HR, 0.54; P < 0.001), lower risk of chronic GVHD (HR, 0.64; P = 0.038) and extensive chronic GVHD (HR, 0.45; P = 0.008), and better GRFS (HR, 0.66; P = 0.003) than MSD transplant recipients. OS, PFS, relapse or progression, and non-relapse mortality were similar between the groups. The difference might be mainly due to PTCy use rather than donor type; however, the results suggested that PTCy-haplo could be a possible option as an alternative to conventional MSD transplantation for lymphoma in PBSCT.
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3.
Post-transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia
Borovkova, A. S., Paina, O. V., Semenova, E. V., Bykova, T. A., Osipova, A. A., Slesarchuk, O. A., Kozhokar, P. V., Tsvetkova, L. A., Rakhmanova, Z. Z., Kozlov, A. V., et al
Clinical transplantation. 2023;:e15181
Abstract
INTRODUCTION The data on post-transplant cyclophosphamide (PTCy) in pediatric acute leukemia after matched allo-HSCT are limited to case series. The present study aimed to assess the results of PTCy-based GVHD prophylaxis in a large cohort of children with acute leukemia after matched allo-HSCT. METHODS A retrospective analysis of 190 pediatric patients with acute leukemia who had a first allograft between 2008 and 2020 from a matched sibling donor (MSD) or matched unrelated donor (MUD) was carried out. In the MSD setting, GVHD prophylaxis consisted of PTCy alone (n = 28) for the study group, and calcineurin inhibitor (CNI) ± antimetabolite (n = 30) for the control group. In MUD setting, most patients in the study group received GVHD prophylaxis with PTCy+CNI+mycophenolate mofetil (n = 42, 66.7%) or PTCy+CNI+sirolimus (n = 12, 19%). All patients (n = 69) in the control group received ATG+CNI+antimetabolite. RESULTS After MUD allo-HSCT, the incidences of acute GVHD grade III-IV and moderate/severe chronic GVHD were significantly lower in the PTCy group compared to control (6.6% vs. 35.0% and 12.7% vs. 47.1%, respectively, p < .0001). Five-year GVHD-free, relapse-free survival (GRFS) after MUD allo-HSCT was higher in the PTCy group compared to control (35.1% vs. 7.3%, p < .0001). At the same time, there was no significant difference between both groups after MSD allo-HSCT. CONCLUSIONS In pediatric acute leukemia, PTCy-based GVHD prophylaxis for MUD allo-HSCT is a feasible and effective option that results in a low incidence of GVHD. Compared to the ATG-based approach, PTCy provides better control of GVHD in children. In pediatric allo-HSCT from MSD, PTCy demonstrates comparable effectiveness to conventional GVHD prophylaxis.
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Abatacept for graft versus host disease prophylaxis in patients 60 years and older receiving mismatched unrelated donor transplantation for hematologic malignancies
Raghunandan, S., Qayed, M., Watkins, B. K., Graiser, M., Gorfinkel, L., Westbrook, A., Gillespie, S., Bratrude, B., Petrovic, A., Suessmuth, Y., et al
Bone marrow transplantation. 2023
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The role of anti-thymocyte globulin in allogeneic stem cell transplantation (HSCT) from HLA-matched unrelated donors (MUD) for secondary AML in remission: a study from the ALWP /EBMT
Nagler, A., Labopin, M., Kröger, N., Schroeder, T., Gedde-Dahl, T., Eder, M., Franke, G. N., Blau, I. W., Salmenniemi, U., Socie, G., et al
Bone marrow transplantation. 2023
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Full text
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Editor's Choice
Abstract
We compared outcomes, of 1609 patients with secondary acute myeloid leukemia (sAML) undergoing allogeneic transplantation (HSCT) in first complete remission (CR1) from matched unrelated donors (MUD) from 2010 to 2021, receiving or not receiving anti-thymocyte globulin (ATG) (ATG-1308, no ATG-301). Median age was 60.9 (range, 18.5-77.8) and 61.1 (range, 21.8-75.7) years, (p = 0.3). Graft versus host disease (GVHD) prophylaxis was cyclosporin-A with methotrexate (41%) or mycophenolate mofetil (38.2%), without significant differences between groups. Day 28, engraftment (ANC > 0.5 × 10(9)/L) was 92.3% vs 95.3% (p = 0.17), respectively. On multivariate analysis, ATG was associated with lower incidence of grade II-IV and grade III-IV acute GVHD (p = 0.002 and p = 0.015), total and extensive chronic GVHD (p = 0.008 and p < 0.0001), and relapse incidence (RI) (p = 0.039), while non-relapse mortality (NRM) did not differ (p = 0.51). Overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were significantly higher in the ATG vs no ATG group, HR = 0.76 (95% CI 0.61-0.95, p = 0.014) and HR = 0.68 (95% CI 0.57-0.8, p < 0.0001), with a tendency for better leukemia-free survival (LFS), HR = 0.82 (95% CI 0.67-1, p = 0.051). The main causes of death were the original disease, infection, and GVHD. In conclusion, ATG reduces GVHD and improves LFS, OS, and GRFS in sAML patients without increasing the RI, despite sAML being a high-risk disease.
PICO Summary
Population
Adults with secondary acute myeloid leukemia (sAML) undergoing allogeneic HSCT) in first complete remission from matched unrelated donors and reported to the EBMT registry (n=1609)
Intervention
Anti-thymocyte globulin (ATG) included in GvHD prophylaxis (n=1308)
Comparison
No ATG included in GvHD prophylaxis (n=301)
Outcome
Day 28, engraftment (ANC > 0.5 × 10(9)/L) was 92.3% vs 95.3%, respectively. On multivariate analysis, ATG was associated with lower incidence of grade II-IV and grade III-IV acute GVHD, total and extensive chronic GVHD, and relapse incidence (RI), while non-relapse mortality (NRM) did not differ. Overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were significantly higher in the ATG vs no ATG group, HR = 0.76 (95% CI 0.61-0.95) and HR = 0.68 (95% CI 0.57-0.8), with a tendency for better leukemia-free survival (LFS), HR = 0.82 (95% CI 0.67-1). The main causes of death were the original disease, infection, and GVHD.
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Optimizing cyclosporine A dose post allogeneic hematopoietic stem cell transplantation in paediatric cancer patients
Elnaggar, M., Hafez, H., Abdallah, A., Hamza, M., Khalaf, M. M., El-Haddad, A.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2023;:10781552231192516
Abstract
BACKGROUND/OBJECTIVES Cyclosporine A (CSA) dosing has been complicated by considerable intra-patient and inter-patient variability in pharmacokinetics, which is affected by different factors. We aimed to assess the various factors that might affect the CSA dose and its plasma level. PATIENTS AND METHODS This retrospective study included paediatric cancer patients who underwent allogeneic hematopoietic stem cell transplant at the Children's Cancer Hospital Egypt 57357 from matched related donors with CSA as graft versus host disease prophylaxis. The CSA initial dose was 1.5 mg/kg IV Q12H. Then, it was titrated according to the level and drug toxicity. Cyclosporine A trough levels were assessed two to three times per week using the Emit 2000 cyclosporine-specific assay. Moreover, factors that may affect cyclosporine levels, such as age, sex, weight and the antifungal used, were analyzed to determine their effect on CSA plasma levels. RESULTS There were 119 patients included in the study. The median age was 10 years; and 43% of them used voriconazole as a prophylactic antifungal. The multivariate analysis revealed that female patients, those >9 years or on voriconazole reached the target level at low initial CSA doses. A higher probability (93%) of reaching the desired plasma level with doses 1.5 mg/kg IV Q12H was observed among patients >9 years, and on voriconazole. While those who were ≤9 years and not on voriconazole required doses >1.5 mg/kg IV Q12H, with an 89% probability of reaching the desired level. CONCLUSION This study suggests that the initial CSA dose should consider the patient's age and the antifungal used. Patients >9 years and/or on voriconazole may require lower initial CSA doses and could start with 1.5 mg/kg IV Q12H.
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Population Pharmacokinetics of Total Rabbit Anti-thymocyte Globulin in Non-obese Adult Patients Undergoing Hematopoietic Cell Transplantation for Hematologic Malignancy
Takahashi, T., Teramoto, M., Matsumoto, K., Jaber, M. M., Tamaki, H., Ikegame, K., Yoshihara, S., Kaida, K.
Clinical pharmacokinetics. 2023
Abstract
BACKGROUND AND OBJECTIVES Rabbit anti-thymocyte globulin (rATG), a therapeutic polyclonal antibody against human T cells, is commonly used in conditioning therapy prior to allogeneic hematopoietic cell transplantation (HCT). Previous studies successfully developed an individualized rATG dosing regimen based on "active" rATG population PK (popPK) analysis, while "total" rATG can be a more logistically favorable alternative for early HCT outcomes. We conducted a novel popPK analysis of total rATG. METHODS Total rATG concentration was measured in adult human-leukocyte antigen (HLA) mismatched HCT patients who received a low-dose rATG regimen (total 2.5-3 mg/kg) within 3 days prior to HCT. PopPK modeling and simulation was performed using nonlinear mixed effect modeling approach. RESULTS A total of 504 rATG concentrations were available from 105 non-obese patients with hematologic malignancy (median age 47 years) treated in Japan. The majority had acute leukemia or malignant lymphoma (94%). Total rATG PK was described by a two-compartment linear model. Influential covariate relations include ideal body weight [positively on both clearance (CL) and central volume of distribution], baseline serum albumin (negatively on CL), CD4(+) T cell dose (positively on CL), and baseline serum IgG (positively on CL). Simulated covariate effects predicted that early total rATG exposures were affected by ideal body weight. CONCLUSIONS This novel popPK model described the PK of total rATG in the adult HCT patients who received a low-dose rATG conditioning regimen. This model can be used for model-informed precision dosing in the settings with minimal baseline rATG targets (T cells), and early clinical outcomes are of interest.
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Graft-versus-Host Disease Prophylaxis with Post Transplant Cyclophosphamide in Chronic Myeloid Leukemia patients undergoing Allogeneic Hematopoietic Cell Transplant from either an Unrelated or Mismatched Related Donor: a comparative study from the Chr
Ortí, G., Gras, L., Koster, L., Kulagin, A., Byrne, J., Apperley, J. F., Halaburda, K., Blau, I. W., Clark, A., Kröger, N., et al
Transplantation and cellular therapy. 2023
Abstract
Outcomes following allogeneic hematopoietic cell transplant (allo-HCT) for Chronic Myeloid Leukemia (CML) with post-transplant cyclophosphamide (PTCy) utilising an unrelated donor (UD) or mismatched related donor (MMRD) remain unknown. We report on a retrospective comparison of PTCy based allo-HCT from an UD, non-PTCy allo-HCT from an UD and PTCy allo-HCT from a MMRD. Inclusion criteria were adult patients with CML undergoing first allo-HCT between 2012 to 2019 from an UD with either PTCy or non-PTCy GvHD prophylaxis and MMRD using PTCy. Primary endpoint was GvHD relapse-free survival (GRFS). A total of 1341 patients were included (82% in the non-PTCy UD cohort). With a median follow-up of 34.9 months, the 3-year GRFS was 43%, 37% and 39% in the non-PTCy UD, PTCy-UD and PTCy MMRD cohorts, respectively (p=0.15). In multivariable analyses, there were no significant differences between the three cohorts regarding OS, PFS, RI and NRM. Factors independently associated with worse OS in the overall cohort were KPS<90 (HR 1.86, 95%CI, 1.41-2.45; p<0.001), older age (HR 1.24, 95%CI, 1.11-1.38; p<0.001) and disease stage (compared to CP1) blast phase HR 2.25, 95% CI, 1.60-3.16; p<0.001, accelerated phase HR 1.63, 95% CI, 1.05-2.54; p=0.03 and CP>2 HR 1.58, 95% CI, 1.15-2.17; p=0.005. These results suggest that allo-HCT in CML utilizing either an UD or MMRD with a PTCy GvHD-based prophylaxis are feasible transplant platforms and that the disease stage at allo-HCT remains a major prognostic factor, highlighting the importance to closely monitor CML patients and propose transplantation when indicated, when still in CP1.
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Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis in HLA-matched and haploidentical donor transplants for patients with Hodgkin lymphoma: a comparative study of the LWP EBMT.: GVHD prophylaxis for patients with Hodgkin lymphoma
Montoro, J., Boumendil, A., Finel, H., Bramanti, S., Castagna, L., Blaise, D., Dominietto, A., Kulagin, A., Yakoub-Agha, I., Tbakhi, A., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCy) has emerged as a promising approach for preventing graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is a lack of studies examining the impact of this GVHD prophylaxis when different donor types are used in patients with Hodgkin lymphoma (HL). OBJECTIVE To compare the outcomes of patients with HL undergoing HSCT from both HLA-matched donors, which include matched sibling donors (MSD) and matched unrelated donors (MUD), and haploidentical donors, using PTCy as GVHD prophylaxis approach in all cohorts. STUDY DESIGN We retrospectively compared transplant outcomes of allo-HSCT from 166 HLA-matched donors (96 siblings and 70 unrelated) and 694 haploidentical donors using PTCy-based GVHD prophylaxis in patients with HL registered in the EBMT database from 2010 to 2020. RESULTS Haploidentical transplantation showed significantly lower platelet engraftment (86% vs 94%, p<0.001) and higher rates of grades II-IV acute GVHD (24% vs 34%, p=0.01) compared to HLA-matched transplantation. The 2-year cumulative incidence of non-relapse mortality (NRM) was significantly lower in the HLA-matched cohort compared to haploidentical cohort (10% vs 18%, p=0.02), resulting in a higher overall survival (OS) rate (82% vs 70%, p=0.002). There were no significant differences observed in terms of relapse, progression-free survival, or GVHD-free relapse-free survival between the groups. In multivariable analysis, haploidentical transplantation was associated with an increased risk of grades II-IV acute GVHD, NRM, and worse OS compared to HLA-matched transplantation. CONCLUSIONS Our findings suggest that, in the context of PTCy-based GVHD prophylaxis, transplantation from HLA-matched donors appears to be a more favorable option compared to haploidentical transplantation.
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10.
Post-transplant cyclophosphamide and early mixed donor Chimerism in myeloid malignancies; a single-center experience
Hoff, F. W., Chung, S. S., Patel, P. A., Premnath, N., Khatib, J., Tadic-Ovcina, M., AhmedRabie, A., Helton, D., Yohannes, S., Shahan, J., et al
Transplant immunology. 2023;77:101808
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for high-risk myeloid malignancies. Post-transplant cyclophosphamide (PT-Cy) has proven to be effective for graft versus host disease (GVHD) prophylaxis. Given that graft-versus-tumor (GVT) effect plays a major role in reducing the risk of disease relapse, the application of PT-Cy must balance the risk of relapse. Mixed chimerism (MC) refers to a state of concurrent presence of recipient and donor cells post allo-HSCT which may precede relapse disease. OBJECTIVE We investigated the impact of PT-Cy on early MC (EMC) and disease relapse in patients with a myeloid malignancy post allo-HSCT. STUDY DESIGN This retrospective single-center study included patients that underwent allo-HSCT between 2015 and 2021. Patient and disease characteristics were collected from the electronic health records. EMC was defined as <95% donor cells at day 90-120 post allo-HSCT. RESULTS A total of 144 patient that received an allo-HSCT were included in the study. One hundred and eight (75%) patients received PT-Cy as part of the GVHD prophylaxis regimen. The majority underwent allo-HSCT for acute myeloid leukemia (62%) or myelodysplastic syndrome (31%). Sixty-five percent received allo-HSCT from a matched unrelated donor transplant and 65% received a myeloablative conditioning regimen. A lower rate of chronic GVHD (p = 0.03) and a higher rate of EMC (p = 0.04) were observed in patients that received PT-Cy. PT-Cy was not associated with overall survival (OS) and relapse-free survival (RFS). Multivariable analysis identified measurable residual disease status (p = 0.003), hematopoietic cell transplantation-specific comorbidity index (p = 0.012) and chronic GVHD (p = 0.006) as independent prognostic variables for OS. AML-adverse risk (p = 0.004) and EMC (p = 0.018) were independently prognostic for RFS. While EMC overall was not significantly associated with higher risk of relapse, EMC was associated with shorter RFS within adverse-risk AML patients. CONCLUSION Our study shows that PT-Cy was associated with an increased risk of EMC. The predictive value of EMC for relapse remains unclear and may depend on the underlying disease, which should be validated in a larger cohort.