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1.
Exposure-response analysis of alemtuzumab in pediatric allogeneic HSCT for nonmalignant diseases: the ARTIC study
Achini-Gutzwiller, F., Schilham, M. W., von Asmuth, E. G. J., Jansen-Hoogendijk, A., Jol-van der Zijde, C. M., van Tol, M. J. D., Bredius, R. G., Güngör, T., Lankester, A. C., Moes, D. J.
Blood advances. 2023
Abstract
Alemtuzumab (anti-CD52 antibody) is frequently prescribed to children with non-malignant diseases undergoing allogeneic hematopoietic stem cell transplantation (HSCT) to prevent graft failure (GF) and acute graft-versus-host disease (aGvHD). This multicenter study aimed at the characterization of alemtuzumab population pharmacokinetics to perform a novel model-based exposure-response analysis in 53 children with non-malignant immunological or hematological disease and a median age of 4.4 years (IQR 0.8, 8.7). Median cumulative alemtuzumab dose was 0.6 mg/kg (IQR 0.6-1) administered over 2-7 days. A 2-compartment population pharmacokinetic model with parallel linear and non-linear elimination including allometrically scaled bodyweight [median 17.50 kg (IQR 8.76, 33.00)] and lymphocyte count at baseline [mean 2.24 10*9/L (SD 1.87)] as significant pharmacokinetic predictors was developed using non-linear mixed effects modelling (NONMEM). According to the model estimated median concentration at day of HSCT (0.77 µg/mL, IQR 0.33-1.82), patients were grouped into a low (0.77 µg/mL) exposure group. High alemtuzumab exposure at day of HSCT correlated with delayed CD4+ and CD8+ T-cell reconstitution (p-value <0.0001) and increased risk of graft failure (p-value=0.043). In contrast, alemtuzumab exposure did not significantly influence the incidence of aGvHD ≥ grade II, mortality, chimerism at 1-year, viral reactivations and autoimmunity at a median follow-up of 3.3 years (IQR 2.5-8.0). In conclusion, this novel population PK model is suitable for individualized intravenous precision dosing to predict alemtuzumab exposure in pediatric allogeneic HSCT for non-malignant diseases, aiming at the achievement of early T-cell reconstitution and prevention of graft failure in future prospective studies.
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Posttransplantation Cyclophosphamide-based Graft versus Host Disease Prophylaxis with Non-myeloablative Conditioning for Blood or Marrow Transplantation for Myelofibrosis
Jain, T., Tsai, H. L., DeZern, A. E., Gondek, L. P., Elmariah, H., Bolaños-Meade, J., Luznik, L., Fuchs, E., Ambinder, R., Gladstone, D. E., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
We describe outcomes with posttransplantation cyclophosphamide and non-myeloablative conditioning based allogeneic blood or marrow transplantation for myelofibrosis using matched or mismatched, family or unrelated donors. The conditioning regimen consisted of fludarabine, cyclophosphamide and total body irradiation. Forty-two patients, with a median age of 63 years, were included, of whom 19% had intermediate-1, 60% had intermediate-2, and 21% had high-risk DIPSS-plus disease, and 60% had atleast one high-risk somatic mutation. Over 90% patients engrafted neutrophils at a median of 19.5 days and 7% had graft failure. At 1 and 3-years, respectively, the overall survival was 65% and 60%, relapse-free survival was 65% and 31%, relapse was 5% and 40%, and non-relapse mortality was 30% and 30%. Acute graft versus host disease grade 3-4 was noted in 17% at 1 year and chronic graft versus host disease requiring systemic therapy in 12% patients. Spleen size ≥ 17 cm or prior splenectomy was associated with inferior relapse-free survival (HR 3.50, 95% CI 1.18-10.37, P=0.02) and higher relapse rate (SDHR not calculable, P=0.01). Age > 60 years (SDHR 0.26, 95% CI: 0.08-0.80, P=0.02) and peripheral blood graft (SDHR 0.34, 95% CI 0.11-0.99, P=0.05) was associated with lower risk of relapse. In our limited sample, the presence of a high-risk mutation was not statistically significantly associated with an inferior outcome although ASXL1 was suggestive of inferior survival (SDHR 2.36. 95% CI 0.85-6.6, P=0.09). Overall, this approach shows comparable outcomes as previously reported and underscores the importance of spleen size in evaluation of transplant candidates.
PICO Summary
Population
Patients with high-risk Dynamic International Prognostic Scoring System (DIPSS)-plus myelofibrosis (n=42)
Intervention
Matched or mismatched allogeneic transplantation with non-myeloablative conditioning, and post-transplant cyclophosphamide
Comparison
None
Outcome
Over 90% patients engrafted neutrophils at a median of 19.5 days and 7% had graft failure. At 1 and 3-years, respectively, the overall survival was 65% and 60%, relapse-free survival was 65% and 31%, relapse was 5% and 40%, and non-relapse mortality was 30% and 30%. Acute graft versus host disease grade 3-4 was noted in 17% at 1 year and chronic graft versus host disease requiring systemic therapy in 12% patients. Spleen size ≥ 17 cm or prior splenectomy was associated with inferior relapse-free survival (HR 3.50, 95% CI 1.18-10.37) and higher relapse rate (SDHR not calculable). Age > 60 years (SDHR 0.26, 95% CI: 0.08-0.80) and peripheral blood graft (SDHR 0.34, 95% CI 0.11-0.99) was associated with lower risk of relapse. In our limited sample, the presence of a high-risk mutation was not statistically significantly associated with an inferior outcome although ASXL1 was suggestive of inferior survival (SDHR 2.36. 95% CI 0.85-6.6).
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Impact of Conditioning Regimen and Graft-versus-Host Disease Prophylaxis on The Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation for High-Risk Severe Aplastic Anaemia in Children and Young Adults: A Report from the Pediatric
Kharya, G., Jaiswal, S. R., Bhat, S., Raj, R., Yadav, S. P., Dua, V., Sen, S., Bakane, A., Badiger, S., Uppuluri, R., et al
Transplantation and cellular therapy. 2022
Abstract
Allogenic hematopoietic cell transplant (HCT) is the best curative approach patients with severe aplastic anemia (SAA). Outcome of HCT from haploidentical family donor (HFD) has improved, making it a feasible option for patients lacking HLA-identical donor. However, data on HFD-HCT for younger patients with SAA is sparse. In multicentre retrospective study, we report outcome of 79 patients undergoing HFD-HCT for SAA. All were heavily pre-transfused, median time to HCT >12 months and 67% had failed previous therapies. Conditioning was based on Flu-Cy-ATG/TBI with or without thiotepa/melphalan (TT/Mel). Post-transplantation cyclophosphamide (PTCy) and CNI/Sirolimus were employed as GvHD prophylaxis with or without abatacept. Primary graft failure (PGF) was 16.43%, less in those conditioned with TT/Mel. Incidence of acute and chronic GVHD were 26.4% and 18.9%. At a median follow-up of 48 months, the overall survival (OS) and event free survival (EFS) were 61.6% and 58.1% respectively. Both OS/EFS were better in TT/Mel group and with abatacept as GVHD prophylaxis. On multivariate analysis, use of Abatacept was found to favourably impact the outcome variables including GVHD and EFS. Our study suggests that PTCy-based HFD-HCT is a reasonable option for young patients with high-risk SAA, where optimisation of conditioning and GVHD prophylaxis might improve outcomes further.
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Assessing the Efficacy of Alkylating Agent Regimens in the Treatment of Infantile Malignant Osteopetrosis: Cyclophosphamide, Busulfan, or Thiotepa
Wagh, H., Arif, A., Reddy, A. J., Tabaie, E., Shekhar, A., Min, M., Nawathey, N., Bachir, M., Brahmbhatt, H.
Cureus. 2022;14(7):e26600
Abstract
Infantile malignant osteopetrosis is a debilitating disease that requires total bone marrow irradiation and transplant procedures for patients to survive. The major complication of this procedure is graft vs host disease (GVHD), followed by infections and end organ toxicity. Therefore, current research efforts into treatment mainly aim to reduce GVHD while limiting infections and organ toxicity. Different regimens of alkylating agents have been used to try to reduce GVHD. The most common regimen is cyclophosphamide (Cy) with busulfan (Bu), followed by Cy with Bu and thiotepa (Thio). This meta-analysis aimed to evaluate the efficacy of different treatments by comparing mortality and morbidity causes and rates across groups. The mean one-year survival rate for the Cy, Bu, Thio regimen studies in the human leukocyte antigen (HLA) unmatched group (45.01%) was statistically lower than the one-year survival rate for the studies using just a Cy, Bu regimen (70.8%) in the HLA unmatched studies (p<0.00142). The one-year survival in the studies which had HLA-matched donors was 80.56%, which is statistically higher (p<0.001) than the one-year survival in the HLA-unmatched studies (53.96%), indicating a benefit of finding HLA-matched donors. It seems that price and availability could be a factor in the widespread use of Cy.
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Comparison of porcine ALG and rabbit ATG on outcomes of HLA-haploidentical hematopoietic stem cell transplantation for patients with acquired aplastic anemia
Chen, J., Zhang, Y., Chen, X., Pang, A., Zhao, Y., Liu, L., Ma, R., Wei, J., He, Y., Yang, D., et al
Cancer cell international. 2022;22(1):89
Abstract
OBJECTIVE To evaluate the efficacy and safety of P-ALG (porcine anti-lymphocyte globulin) and R-ATG (rabbit anti-thymocyte globulin) in the conditioning regime for patients with acquired aplastic anemia who underwent HLA-haploidentical hematopoietic stem cell transplantation (halpo-HSCT). METHODS A total of 91 patients with acquired aplastic anemia who received haplo-HSCT at our center between January 2014 and December 2020 were retrospectively reviewed. Twenty-eight patients were in the P-ALG group while sixty-three patients were in the R-ATG group. RESULTS The median time was 11 versus 13 days (P = 0.294) for myeloid engraftment and 12.5 versus 15 days (P = 0.465) for platelet engraftment in the P-ALG and R-ATG groups, respectively. There were no significant difference in 5-year overall survival (74.83% ± 8.24% vs 72.29% ± 6.26%, P = 0.830), GVHD-free, failure-free survival (71.05% ± 8.65% vs 62.71% ± 6.22%, P = 0.662), failure-free survival (74.83% ± 8.24% vs 66.09% ± 5.84%, P = 0.647) and transplantation-related mortality (25.17% ± 8.24% vs 26.29% ± 6.22%, P = 0.708) between the two groups. The incidence of aGVHD (acute graft versus host disease) (65.39% ± 9.33% vs 62.71% ± 6.30%, P = 0.653), II-IV aGVHD (38.46% ± 9.54% vs 35.64% ± 6.24%, P = 0.695), III-IV aGVHD (19.23% ± 7.73% vs 10.53% ± 4.07%, P = 0.291), cGVHD (chronic graft versus host disease) (22.22% ± 12.25% vs 22.31% ± 6.30%, P = 0.915), and moderate to severe cGVHD (5.56% ± 5.40% vs 9.28% ± 4.46%, P = 0.993) were not significantly different. Similar outcomes were observed between the P-ALG and R-ATG groups for severe bacterial infection (17.9% vs 25.4%, P = 0.431), invasive fungal diseases (3.6% vs 9.5%, P = 0.577) and graft rejection (0% vs 9.5%, P = 0.218). However, the incidence of cytomegalovirus infection and Epstein-Barr virus infection was significantly lower in the P-ALG group (46.4% vs 71.4%, P = 0.022; 3.6% vs 25.4%, P = 0.014). CONCLUSION The efficacy and safety of P-ALG were similar with R-ATG in the setting of haplo-HSCT for patients with acquired aplastic anemia patients. P-ALG could be an alternative for R-ATG.
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Comparisons Between modified PTCY and G-CSF/ATG Regimens for Haploidentical Transplantation in Patients with Aplastic Anemia
Li, Y., Lu, X., Wang, N., Zhang, X., Cao, Y., Xiao, Y., Meng, F., Zhang, D., You, Y., Zou, L., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Haploidentical transplantation has become an alternative treatment option for aplastic anemia patients without matched sibling donors or matched unrelated donors. Recently, the post-transplantation cyclophosphamide (PTCY) regimen and granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG) regimen have become the most common protocols used worldwide. OBJECTIVE We designed this retrospective study to compare the outcomes of patients receiving a modified post-transplantation cyclophosphamide (mPTCY) regimen versus the G-CSF/ATG regimen. STUDY DESIGN We retrospectively reviewed and analyzed the clinical data of 130 aplastic anemia patients who underwent haplo-HSCT and received the mPTCY regimen (n=55) or G-CSF/ATG regimen (n=75) between Jan 2013 and Jun 2021 across seven transplant centers. RESULTS Neutrophil engraftment was successful in all patients within 30 days in the G-CSF/ATG group. The cumulative neutrophil engraftment rate in the mPTCY group was 96.36% (95% CI, 94.57-97.57, P=0.010). The median time of neutrophil engraftment in the G-CSF/ATG group was 10 (7-28) days, which was more rapid than that observed in the mPTCY group (P <0.001). There were no significant differences in the incidence of graft versus host disease (GVHD) between the two groups. The cumulative incidence of II-IV acute GVHD was 18.40% (95% CI, 4.27-40.31) in the mPTCY group and 19.32% (95% CI, 5.86-38.58) in the G-CSF/ATG group, while the cumulative incidence of III-IV acute GVHD was 7.31% (95% CI, 0.09-37.48) in the mPTCY group and 7.57% (95% CI, 0.20-34.19) in the G-CSF/ATG group. Similarly, no significant difference was observed between the two groups in terms of overall survival (OS), failure-free survival (FFS), and GVHD relapse-free survival (GRFS). The 2-year OS, FFS and GRFS rates were 95.91% (95% CI, 84.59-98.96), 92.25% (95% CI, 80.59-97.03) and 86.68% (95% CI, 73.98-93.44), respectively, in the mPTCY group and 86.67% (95% CI, 76.64-92.59), 81.28% (95% CI, 70.45-88.46) and 77.20% (95% CI, 65.89-85.16), respectively, in the G-CSF/ATG group. The transplantation-related mortality (TRM) rate was significantly higher in the G-CSG/ATG group than in the mPTCY group (13.33% in the G-CSG/ATG group versus 1.96% in the mPTCY group, P=0.022). In multivariate analysis, female donors, a higher hematopoietic cell transplantation comorbidity index (HCT-CI) and III-IV aGVHD were associated with worse survival outcomes. CONCLUSIONS In conclusion, the mPTCY and G-CSF/ATG regimens led to similar outcomes in AA patients, but quicker engraftment was observed with the ATG/G-CSF regimen, and a lower incidence of TRM was observed with the mPTCY regimen.
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Retrospective Comparison of Efficacy and Safety of Rabbit Anti-Thymocyte Globulin and Porcine Anti-Lymphocyte Globulin in Patients With Acquired Aplastic Anemia Undergoing Hematopoietic Stem Cell Transplantation From Matched Sibling Donors
Zhang, Y., Chen, X., Li, L., Li, Y., Lin, L., Cao, Y., Wang, N., Yang, D., Pang, A., Zhang, R., et al
Frontiers in immunology. 2022;13:889784
Abstract
We compared the efficacy and safety of porcine anti-lymphocyte globulin (pALG) (n=140) and rabbit anti-thymocyte globulin (rATG) (n=86) in patients with acquired aplastic anemia (AA) receiving hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD) in two transplantation centers in China ranging from 2005 to 2020. The groups had similar baseline characteristics except for a higher number of infused mononuclear cells (P<0.001) and a higher proportion of peripheral blood stem cells as graft sources (P=0.003) in the pALG group. The rates of neutrophil engraftment at day 28 (P=1), platelet engraftment at day 28 (P=0.228), bloodstream infection before engraftment (P=0.867), invasive fungal diseases (P=0.362), cytomegalovirus viremia (P=0.667), and graft rejection (P=0.147) were similar in the two groups. A higher cumulative incidence of grades II-IV acute graft versus host disease (aGvHD) at 100 days occurred in the pALG group (19% vs. 8%, P=0.035) while no significant differences in grades III-IV aGvHD (P=0.572), mild to severe chronic GvHD (cGvHD) (P=0.181), and moderate to severe cGvHD (P=0.586) were observed. The actuarial 5-year overall survival (OS), failure-free survival (FFS), and GvHD-free, FFS rates of the pALG group were 87% (95% confidence interval [CI], 82-93), 85% (95% CI, 80-92), and 78% (95% CI, 72-92) versus 91% (95% CI, 86-99) (P=0.33), 88% (95% CI, 82-97) (P=0.428), and 79% (95% CI, 72-90) (P=0.824) in the rATG group, respectively. A busulfan-containing conditioning regimen was the only adverse risk factor for OS and FFS in multivariate analysis. In conclusion, pALG is an alternative to rATG in patients with severe AA receiving MSD-HSCT. A prospective, large-sample study is needed to explore this therapy further.
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8.
Influential Factors and Efficacy Analysis of Tacrolimus Concentration After Allogeneic Hematopoietic Stem Cell Transplantation in Children with ß-Thalassemia Major
Li, C., Lu, J., Zhou, S., Wei, Y., Lv, C., Liu, T., Wu, Y., Wu, D., Qi, J., Cai, R.
Pharmacogenomics and personalized medicine. 2021;14:1221-1237
Abstract
PURPOSE To analyze factors influencing tacrolimus (TAC) trough concentration (C(0)) in ß-thalassemia major (ß-TM) pediatric patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and to investigate the effects of genotype polymorphism and drug-drug interactions on TAC trough concentration in children with ß-TM. Furthermore, to analyze the correlation between TAC C(0) and efficacy and adverse reactions. PATIENTS AND METHODS Prospectively collection of demographic information and details of combined treatment of patients with ß-TM receiving HSCT, and genotypes of CYP3A4, CYP3A5, and ABCB1 (rs1045642, rs1128503, rs2032582) were obtained for each patient. Univariate analysis and multiple linear regression analysis were used to investigate influencing factors on TAC C(0). The impact of different genotypes and the co-administration of azole antifungal drugs on ß-TM patients receiving TAC were evaluated, together with the correlation between acute graft-versus-host disease (aGVHD), infection, and liver injury of TAC C(0). RESULTS A total of 46 patients with 587 concentration data were included. The multiple linear regression results showed that the patient's sex, weight, postoperative time, hemoglobin, platelet count, serum cystatin C, and combined voriconazole were independent influencing factors of the infusion trough concentration/daily dose, C(0)/D(iv). Age, body surface area, postoperative time, co-administration of voriconazole, and CYP3A4*18B are independent influencing factors of C(0)/D(po). Group comparisons showed that voriconazole can affect TAC C(0) administered intravenously (IV) and orally in ß-TM pediatric patients, while patient genotype can affect TAC C(0) during oral administration. TAC C(0) does not correlate with aGVHD or liver injury, but infection may be associated with TAC C(0). CONCLUSION The concentration of TAC should be closely monitored when co-administered with voriconazole. It is worth considering that the influence of genotype on the trough concentration of oral TAC and individualized drug administration warrant investigation. Finally, this study indicated that C(0) is not suitable as an indicator of the efficacy of TAC.
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9.
Haploidentical Peripheral Stem Cell Transplantation for Young Patients with Severe Aplastic Anemia Using Post-Transplantation Cyclophosphamide and Methotrexate
Yang, K., Gong, S., Jiang, T., Liang, X., Hu, J., Zhu, P., Nie, L., Xu, Y., Fu, B.
Transplantation and cellular therapy. 2021;27(5):429.e1-429.e7
Abstract
Severe aplastic anemia (SAA) is a serious bone marrow failure disorder that is often cured with hematopoietic stem cell transplantation (HSCT). The absence of a matched related donor is common, however, and thus novel approaches are needed to safely expand the donor pool to include alternative donors, especially haploidentical related donors, for patients with SAA. This study aimed to explore a novel approach to HSCT for patients with SAA without an available HLA-identical sibling or a matched unrelated donor, termed haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), using a conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine (CBF) and a graft-versus-host disease (GVHD) prophylaxis regimen with post-transplantation cyclophosphamide (PTCy), low-dose methotrexate (LD-MTX), and calcineurin inhibitors. This prospectively designed nonrandomized study included 29 patients with SAA who underwent haplo-PBSCT between November 2017 and May 2020. The median patient age was 17 years (range, 14 to 30 years), and the median time to neutrophil recovery was 13 days (range, 13 to 15 days). There was 1 primary graft failure (GF) in the group receiving PTCy at a dose of 50 mg/kg and no GFs in the group receiving PTCy at a dose of 100 mg/kg. The median duration of follow-up was 736 days (95% confidence interval, 512 to 879 days). The estimated 1-year overall survival and disease-free survival were 91.7 ± 5.7% and 89.7 ± 5.7%, respectively. Only 1 of the 27 patients developed grade II acute GVHD. Four patients developed limited and mild chronic GVHD, involving only the skin or/and oral mucosa. Haplo-PBSCT following CBF and followed by PTCy and LD-MTX represents a novel approach for safely expanding the donor pool to include alternative donors for young patients with SAA.
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10.
Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?-a systematic review and meta-analysis
Li, R., Tu, J., Zhao, J., Pan, H., Fang, L., Shi, J.
Stem cell research & therapy. 2021;12(1):106
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) are an emerging prophylaxis option for graft-versus-host disease (GVHD) in haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) recipients with severe aplastic anemia (SAA), but studies have reported inconsistent results. This systematic review and meta-analysis evaluates the efficacy of MSCs as prophylaxis for GVHD in SAA patients with haplo-HSCT. METHODS Studies were retrieved from PubMed, EMBASE, Cochrane, Web of Science, and http://clinicaltrials.gov from establishment to February 2020. Twenty-nine single-arm studies (n?=?1456) were included, in which eight (n?=?241) studies combined with MSCs and eleven (n?=?1215) reports without MSCs in haplo-HSCT for SAA patients. The primary outcomes were the incidences of GVHD. Other outcomes included 2-year overall survival (OS) and the incidence of cytomegalovirus (CMV) infection. Odds ratios (ORs) were calculated to compare the results pooled through random or fixed effects models. RESULTS Between MSCs and no MSCs groups, no significant differences were found in the pooled incidences of acute GVHD (56.0%, 95% CI 48.6-63.5% vs. 47.2%, 95% CI 29.0-65.4%; OR 1.43, 95% CI 0.91-2.25; p?=?0.123), grade II-IV acute GVHD (29.8%, 95% CI 24.1-35.5% vs. 30.6%, 95% CI 26.6-34.6%; OR 0.97, 95% CI 0.70-1.32; p?=?0.889), and chronic GVHD (25.4%, 95% CI 19.8-31.0% vs. 30.0%, 95% CI 23.3-36.6%; OR 0.79, 95% CI 0.56-1.11; p?=?0.187). Furtherly, there was no obvious difference in 2-year OS (OR 0.98, 95% CI 0.60-1.61; p?=?1.000) and incidence of CMV infection (OR 0.61, 95% CI 0.40-1.92; p?=?0.018). CONCLUSIONS Our meta-analysis indicates that the prophylactic use of MSC co-transplantation is not an effective option for SAA patients undergoing haplo-HSCT. Hence, the general co-transplantation of MSCs for SAA haplo-HSCT recipients may lack evidence-based practice.