Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen mismatched donors
This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine and mycophenolate mofetil for GVHD prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched Hematopoietic cell transplantation (HCT). Eligible patients had hematological malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2-3 Gy total body irradiation. GVHD prophylaxis was with cyclosporine, mycophenolate mofetil and sirolimus. The primary objective was to determine whether the cumulative incidence of grade II-IV acute GVHD could be reduced to less than 70%, in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. This study was registered with ClinicalTrials.gov, number NCT01251575. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018 of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94). The cumulative incidence of grade 2-4 acute GVHD at day 100 was 36% (95% CI, 25-46) meeting the primary endpoint. The cumulative incidences of nonrelapse morality, relapse/progression and overall survival were 18% (95% CI, 9-27), 30% (IQR, 19-40) and 62% (95% CI, 50-73%) after 4 years. In conclusion the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into a superior overall survival compared to historical results.
CTLA4Ig Limits Both Incidence and Severity Of Early Cytokine Release Syndrome Following Haploidentical Peripheral Blood Stem Cell Transplantation
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Early and severe cytokine release syndrome (CRS) is a unique complication of T replete haploidentical transplantation, when post-transplant cyclophosphamide (PTCy) is employed as GVHD prophylaxis without preceeding immunosuppression. This phenomenon has been reported with greater frequency and severity following a mobilised peripheral blood stem cell (PBSC) graft. We report on the incidence, severity and outcome of CRS in 157 patients undergoing PTCy-based haploidentical transplantation.
Population Pharmacokinetics and Bayesian Estimators for Intravenous Mycophenolate Mofetil in Haematopoietic Stem Cell Transplant Patients
British journal of clinical pharmacology. 2020
AIMS: Intravenous mycophenolate mofetil (IV MMF), a prodrug of mycophenolic acid (MPA), is used during non-myeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease. The aims of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies, to allow for individual dose adjustment of intravenous mycophenolate mofetil administered by infusion in haematopoietic stem cell transplant patients. METHODS Sixty three MPA concentration-time profiles (median [min-max]=6[4-7] samples) were collected from 34 HCT recipients transplanted for 14[1-45] days and administered IV MMF every 8 hours, concomitantly with cyclosporine. The database was split into development (75%) and validation (25%) datasets. Pharmacokinetic models characterized by a single compartment with first order elimination, combined with two gamma distributions to describe the transformation of MMF into mycophenolic acid, were developed using in parallel, non-parametric (Pmetrics) and parametric (ITSIM) approaches. The performances of the models and the derived Bayesian estimators were evaluated in the validation set. RESULTS The best limited sampling strategy led to a bias [min, max], root-mean-square error between observed and modeled inter-dose area under the curve in the validation dataset of: -11.72% [-31.08%, 5.00%], 14.9% for ITSIM and -2.21% [-23.40%, 30.01%], 12.4% for Pmetrics with 3 samples collected at 0.33, 2 and 3h post dosing. CONCLUSION Population pharmacokinetic models and Bayesian estimators for IV MMF in HCT have been developed and are now available online (https://pharmaco.chu-limoges.fr) for individual dose adjustment based on the interdose area under the curve.
Graft Versus Host Disease Prophylaxis With Abatacept Reduces Severe Acute Graft Versus Host Disease in Allogeneic Hematopoietic Stem Cell Transplant for Beta Thalassemia Major with Busulfan, Fludarabine, and Thiotepa
INTRODUCTION We hypothesized that the addition of 4 doses of abatacept to our standard acute graft versus host disease (GVHD) prophylaxis would reduce the incidence of day+100 severe acute GVHD in children with transfusion dependent beta- thalassemia major undergoing a myeloablative allogeneic hematopoietic stem cell transplant (HSCT), without impacting engraftment. METHODS Twenty-four children with beta-thalassemia major received abatacept at a dose of 10 mg/kg intravenously on days -1, +5, +14 and +28 after HSCT in addition to calcineurin inhibitors and methylprednisolone. Outcomes were compared to 8 beta thalassemia patients who received standard acute GVHD prophylaxis. RESULTS There was no difference in engraftment between the 2 groups. No patient had grades III- IV acute GVHD by day+100 in the abatacept cohort compared to 50% in the standard acute GVHD prophylaxis group (p=0.001). Viral reactivation occurred in 5 children in the standard acute GVHD cohort and in 20 children in the abatacept cohort (p=0.2). Thalassemia-free survival after HSCT was 100% in the abatacept cohort compared to 62.5% in the standard cohort at last follow up (p=0.007). CONCLUSIONS Adding abatacept to our routine GVHD prophylaxis reduced the incidence of day+100 severe acute GVHD without impacting engraftment or survival.
Tacrolimus dose modification in patients receiving concomitant isavuconazole after hematopoietic stem cell transplantation
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2020;:1078155220940416
INTRODUCTION Isavuconazole is increasingly being used for antifungal prophylaxis during stem cell transplantation. Isavuconazole is a moderate inhibitor of Cytochrome P4503A4, and tacrolimus levels are anticipated to be elevated when given concomitantly with isavuconazole. We developed and validated a dose-modified tacrolimus regimen to better achieve and maintain target tacrolimus levels.Methods: Allogeneic stem cell transplantation recipients who received concomitant tacrolimus and isavuconazole from September 2017 to September 2018 were included. Tacrolimus was adjusted to achieve a target range 8-12 ng/ml. Intravenous tacrolimus was first initiated at 0.02 mg/kg/day on day 1, and transitioned to oral therapy using a 2:1 conversion ratio (n = 48). Clinical observations showed high interpatient variability. The intravenous dose was then reduced to 0.017 mg/kg/day, and oral:intravenous conversion changed to 3.1:1 (n = 24). RESULTS Interpatient variability was high (lower in the 0.017 mg/kg/day group; P < 0.0217). Patients in the 0.017 mg/kg/day group required fewer dose changes (P < 0.023) and had fewer levels >15 ng/ml (P < 0.021). Median tacrolimus dose declined over time; 0.016, 0.012 and 0.011 on days 1, 7 and 10 for patients receiving 0.02 mg/kg/day and 0.017, 0.014 and 0.013 in the 0.017 mg/kg group. Day 10 tacrolimus accumulation factor was 1.42 Rac(Cmax) in the 0.02 mg/kg/day cohort compared to 1.23 Rac(Cmax) in the 0.017 mg/kg/day cohort (P < 0.015). When transitioned to oral therapy, a oral:intravenous conversion ratio >3.1:1 was shown to improve chances for achieving target levels (P > 0.0744). CONCLUSION We recommend initiating intravenous tacrolimus dose at 0.017 mg/kg/day and using a 3.1:1 oral:intravenous conversion to reduce interpatient variability, drug accumulation and the number of suboptimal tacrolimus levels. Tacrolimus requires frequent drug level monitoring.
Bone marrow haploidentical transplant with post-transplantation cyclophosphamide: does graft cell content have an impact on main clinical outcomes?
We analyzed data relative to cell content in 88 consecutive patients receiving HLA haploidentical bone marrow (BM) transplants with post-transplantation cyclophosphamide (PT-CY). Median age was 54.5 (range, 17-72); diagnoses were acute leukemia (n = 46), lymphoproliferative disorders (n = 24), myelofibrosis (n = 11) and myelodysplastic syndromes (n = 5). Total nucleated cell (TNC) and CD34+, CD3+, CD4+ and CD8+ cell doses were stratified as higher than first, second and third quartile and the dose effect on various clinical outcomes was assessed. Median time to engraftment was 17 days for neutrophils and 24 days for platelets. To receive a dose of TNC ≥3.2 x 10(6)/kg or CD34+ cells ≥2.7 x 10(6)/kg significantly shortened the time to neutrophil and platelet engraftment and reduced the blood product requirements in the 30-day period after transplantation. Overall, TNC and CD34+ cell doses had no effect on acute graft-versus-host disease (GVHD) incidence, whereas patients receiving higher CD3+ and CD8+ cell doses seemed to have less chronic GVHD. No effect on non-relapse mortality, progression-free survival and overall survival was observed at different cell dose thresholds. These data suggest that in HLA haploidentical BM transplant with PT-CY, appropriate cell doses are relevant to the engraftment. The association between low CD3+/CD8+ cells and chronic GVHD deserves further investigation.
Influence of anti-thymocyte globulin plasma levels on outcome parameters in stem cell transplanted children
International immunopharmacology. 2020;83:106371
INTRODUCTION Allogenic hematopoietic stem cell transplantation is a curative option for malignant and non-malignant pediatric diseases. Serotherapy is often employed to avoid graft-versus-host disease (GvHD) on one hand and graft rejection on the other hand. Therapeutic drug monitoring is increasingly used to allow for more precise dosing especially in pediatric patients due to their specific pharmacological characteristics. Application of T-cell directed antibodies is not routinely monitored, but may benefit from more precise dosing regimens. METHODS Two different preparations of rabbit anti-thymocyte globulin (rATG), Thymoglobuline(R) and ATG-F (Grafalon(R)), are frequently used to prevent GvHD in pediatric patients by in vivo T-cell depletion. Total rATG levels and active rATG levels were analyzed prospectively in pediatric patients undergoing HSCT. Clinical and laboratory outcome parameters were recorded. RESULTS rATG levels were measured in 32 patients, 22 received thymoglobuline and 10 received ATG-F. The median total peak plasma level was 419.0 microg/ml for ATG-F and 60.4 microg/ml for thymoglobuline. For ATG-F, exposure could be predicted from the calculated dose more precisely than for thymoglobuline. Active peak plasma levels neither of ATG-F, nor of thymoglobuline correlated significantly with the number of lymphocytes prior to serotherapy. There was no significant difference in incidence of aGvHD, cGvHD, rejection, mixed chimerism or viral infections in the two cohorts. However, in our cohort, patients with high thymoglobuline exposure showed a compromised reconstitution of T cells. CONCLUSIONS ATG-F and thymoglobuline show different pharmacological and immunological impact in children, whose clinical significance needs to be investigated in larger cohorts.
Dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning allo-HSCT results in very low rates of GVHD
Bone marrow transplantation. 2020
The efficacy of posttransplant cyclophosphamide (PTCy) and antithymocyte globulin (ATG) in controlling GVHD has been previously reported. We aim to study the safety and efficacy of the use of dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning regimen allo-HSCT in 270 patients with hematological malignancies. Median follow-up was 12.7 months. Nineteen percent of patients received grafts from a matched related donor, 46% from 10/10 matched unrelated donors (MUD), 16% from 9/10 MUD and 19% from haploidentical donors. Graft failure rate was 9%. CMV and EBV reactivation rates were 58 and 64%. The cumulative incidence of grade II-IV and III-IV acute GVHD at day + 100 was 20.1% and 4.6%, respectively. The CI of moderate/severe chronic GVHD at 1 year was 12.4%. There were no differences in the incidence of GVHD according to donor type. One-year OS, RFS, NRM, CIR, and GVHD-free/RFS respectively were 65.2%, 56.9%, 22.7%, 20.3%, and 47.6%. Higher disease-risk index and worse Karnofsky performance status were significant factors for poor outcomes. In conclusion, the use of T-cell dual depletion with ATG and PTCy results in very low rates of acute and chronic GVHD and acceptable relapse rates and NRM.
ATIR101 administered after T-cell-depleted haploidentical HSCT reduces NRM and improves overall survival in acute leukemia
Overcoming graft-versus-host disease (GvHD) without increasing relapse and severe infections is a major challenge after allogeneic hematopoietic stem-cell transplantation (HSCT). ATIR101 is a haploidentical, naive cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GvHD and provide graft-versus-infection and -leukemia activity. Safety and efficacy of ATIR101 administered after T-cell-depleted haploidentical HSCT (TCD-haplo + ATIR101) without posttransplant immunosuppressors were evaluated in a Phase 2, multicenter study of 23 patients with acute leukemia and compared with an observational cohort undergoing TCD-haplo alone (n = 35), matched unrelated donor (MUD; n = 64), mismatched unrelated donor (MMUD; n = 37), and umbilical cord blood (UCB; n = 22) HSCT. The primary endpoint, 6-month non-relapse mortality (NRM), was 13% with TCD-haplo + ATIR101. One year post HSCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P = 0.008). GvHD-free, relapse-free survival (GRFS) was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P < 0.03; 1-year rates: 56.5%, 27.0%, and 22.7%, respectively) and was not statistically different from MUD (1 year: 40.6%). ATIR101 grafts with high third-party reactivity were associated with fewer clinically relevant viral infections. Results suggest that haploidentical, selective donor-cell depletion may eliminate requirements for posttransplant immunosuppressors without increasing GvHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus posttransplant cyclophosphamide had been initiated.
Role of ATG in patients with hematologic diseases undergoing umbilical cord blood transplantation: A systematic review and meta-analysis
Clinical transplantation. 2020;:e13876
The role of antithymocyte globulin (ATG) in patients with hematologic diseases undergoing umbilical cord blood transplantation (UCBT) remains controversial. This systematic review and meta-analysis were conducted to comprehensively evaluate this issue. PubMed, Embase and the Cochrane Library were systematically searched. Clinical studies reporting the impact of ATG- vs. non-ATG-containing conditioning regimens on transplantation outcomes were identified. Twenty-five studies were included. ATG significantly prevented grades II-IV and III-IV acute graft-versus-host disease (GVHD) (11 studies, 5020 patients, HR: 0.49, 95% CI: 0.42 to 0.56, P < 0.001; 5 studies, 5490 patients, HR: 0.60, 95% CI: 0.46 to 0.80, P < 0.001) but not chronic GVHD (8 studies, 5952 patients, HR: 0.78, 95% CI: 0.51 to 1.20, P = 0.266). However, use of ATG was associated with increased transplantation-related mortality and inferior overall survival (9 studies, 4244 patients, HR: 1.79, 95% CI: 1.38 to 2.33, P < 0.001; 8 studies, 5438 patients, HR: 1.96, 95% CI: 1.56 to 2.46, P < 0.001). Our study did not recommend routine use of ATG in UCBT. Individualizing the ATG timing and dose based on patient characteristics to retain the prophylactic effects of ATG on GVHD without compromising the survival of UCBT recipients may be reasonable.