scholarly journals Comparative Study of Mizoribine and Mycophenolate Mofetil Combined with a Calcineurin Inhibitor-Based Immunosuppressive Regimen in Patients with Alternative Donor Hematopoietic Cell Transplantation

2020 ◽  
Vol 26 (9) ◽  
pp. 1663-1669
Author(s):  
Yong Huang ◽  
Mingzhe Han ◽  
Donglin Yang ◽  
Rongli Zhang ◽  
Qiaoling Ma ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Comparative Study ◽  
Cell Transplantation ◽  
Calcineurin Inhibitor ◽  
Hematopoietic Cell Transplantation ◽  
Immunosuppressive Regimen ◽  
Hematopoietic Cell ◽  
Alternative Donor

Gvhd Prophylaxis With Mycophenolate Mofetil and Calcineurin Inhibitor In Allogeneic Hematopoietic Cell Transplantation From HLA-Matched Siblings Or 7–8/8 HLA-Matched Unrelated Volunteer Donors: A Japanese, Multicenter, Phase II Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4586-4586
Author(s):  
Takahiko Nakane ◽  
Hirohisa Nakamae ◽  
Saiko Kurosawa ◽  
Atsuo Okamura ◽  
Michihiro Hidaka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mycophenolate Mofetil ◽  
Cell Transplantation ◽  
Primary Endpoint ◽  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Gvhd Prophylaxis ◽  
Neutrophil Engraftment

Background In allogeneic hematopoietic cell transplantation (allo-HCT), graft versus host disease (GVHD) remains a major cause of non-relapse mortality. Although methotrexate (MTX) combined with a calcineurin inhibitor (CI) is the current standard for GVHD prophylaxis, several recent studies have also reported the utility of mycophenolate mofetil (MMF) combined with CI, in terms of earlier hematological recovery and less mucositis with a similar incidence of GVHD. In Asian populations, however, there have been few prospective studies with MMF and CI as GVHD prophylaxis, and we thus carried out this Japanese multicenter prospective trial of allo-HCT with MMF and CI. Methods From April 2010 to September 2012, we prospectively registered patients with hematological malignancy who received their first T cell-replete allo-HCT from HLA-matched related donors (MRD group) or 8/8 or 7/8 matched unrelated volunteer donors (URD group). The primary endpoint was the cumulative incidence of grade II to IV acute GVHD at day 100. The expected and threshold incidences were 30% and 60% in MRD group, and 40% and 65% in URD group, respectively. With a statistical power of 80% and a one-sided, type I error of 5%, the each number of eligible patients required for these studies was calculated to be 17 and 25 in MRD and URD groups, respectively, and the each maximal number of registerable patients was set to be 30 and 45, respectively. As of June 2013, the primary endpoint for evaluation of all patients has been attained. As GVHD prophylaxis, MMF (500mg three times/day) and cyclosporine were used in MRD group, and MMF (1000mg three times/day) and tacrolimus were used in URD group. The MMF dose was tapered according to plan, starting on day 30–40 with cessation by day 100. The cyclosporine and tacrolimus were continued until days 60 and 100 and then tapered and stopped on days 150 and 180, respectively, unless GVHD developed. Results There were 20 patients (median age:47.5) in the MRD group and 31 patients (median age:45) in the URD group (HLA 8/8 matches:23, HLA 7/8 matches:8). In the MRD and URD groups, acute leukemia was present in 90% and 65%, and standard risk disease comprised 90% and 65%, respectively. In the MRD and URD groups, 75% (15/20) and 55% (17/31) received standard myeloablative conditioning (BuCy or CyTBI), and the remainder received reduced intensity conditioning (FluBu±TBI or FluMel±TBI). In the MRD group, peripheral blood stem cells and bone marrow were used in seven and 13 patients, respectively. In the URD group, all 31 patients received allo-HCT from a bone marrow donor. The cumulative incidences of grades II to IV and III to IV acute GVHD on day 100 were 45% (90% confidence interval [CI]:26.9-63.1) and 15% in the MRD group, respectively. The primary endpoint was not achieved in the MRD group, although the dose of MMF in the MRD group (1.5g/day) was lower than the URD group (3g/day). In contrast, the cumulative incidences of grades II to IV and III to IV acute GVHD on day 100 were 19.4% (90%CI:8.0-30.8) and 6.5% in the URD group, respectively. The primary endpoint was achieved in the setting of allo-HCT form URD. In the MRD and URD groups, cumulative incidences of neutrophil engraftment were 94.7% and 96.8%, and the median times to neutrophil engraftment were 12 days (range:10–13) and 13 days (range:8–26), respectively. Although one patient in the MRD group and 3 patients in the URD group experienced secondary graft failure, all of them recovered with dose adjustment of myelosuppressive drugs including MMF. Grade 3 stomatitis occurred only in 10% of the MRD group and 13% of the URD group, and there was no grade 4 stomatitis in either group. The cumulative incidences of late onset acute GVHD and chronic GVHD at one year were 12.5% and 37.5% in the MRD group, and 7.4% and 29.6% in URD group, respectively. With a median follow-up of 589 days in surviving patients, 1-year overall survival was 89.1% in the MRD group and 86.0% in the URD group. The 1-year cumulative incidences of non-relapse mortality and relapse were 10.9% and 11.9% in the MRD group, and 6.5% and 31.6% in URD group, respectively. Conclusion Our study confirmed that GVHD prophylaxis with MMF plus CI was associated with earlier hematological recovery and less mucositis. The use of MMF (3g/day) plus tacrolimus was a feasible and effective option as GVHD prevention in allo-HCT from 7/8 or 8/8 HLA-matched URD. Further studies will be needed to clarify the optimal dose of MMF in allo-HCT from MRD. Disclosures: Nakane: Chugai Pharma: Travel/accommodations/meeting expenses Other. Off Label Use: CellCept (mycophenolate mofetil). This drug was a primary drug to be evaluated for GVHD prophylaxis in this study. Nakamae:Chugai Pharma: Travel/accommodations/meeting expenses Other. Hino:Chugai Pharma: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other.

Sirolimus and Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis in Myeloablative, Matched Related Donor Hematopoietic Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4348-4348
Author(s):  
Laura Johnston ◽  
Mareike Florek ◽  
Randall Armstrong ◽  
Jeannine S McCune ◽  
Sally Arai ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Cd4 Cells ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Preparative Regimen ◽  
Grade Ii

Abstract We investigated a novel graft-versus-host disease (GVHD) prophylactic regimen, sirolimus and mycophenolate mofetil (MMF), in patients with advanced hematologic malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from matched related donors (MRD). The sirolimus and MMF combination was chosen based on intriguing evidence of sirolimus, and less dramatically MMF, conserving the inhibition of T cell proliferation compared to cyclosporine (CSP) in an AGVHD murine model as well as multiple reports supporting sirolimus’ preservative or augmentative effects on the T regulatory cell population (CD4+CD25+, FoxP3+) in animals and humans in comparison to cyclosporine (CSP) and a theoretical reduction in the incidence and severity of AGVHD. In addition, this regimen may cause less severe toxicities compared with standard methotrexate and/or calcineurin inhibitor (CI)-containing GVHD prophylactic regimens. Sirolimus was begun as an oral medication on day -3 with a 12 mg loading dose followed by 4 mgs daily, dose adjusted to maintain serum trough levels of 3–12 ng/ml. MMF was begun on D0 at 15 mg/kg IV every 12 hours. Mycophenolic acid (MPA) pharmacokinetics were conducted on days 2 and 21 post-HCT. Sirolimus and MMF were scheduled to be tapered simultaneously beginning 100 days post-HCT. FoxP3+ cell populations in the peripheral blood (PB) were analyzed before and after HCT in the patients receiving sirolimus and MMF GVHD prophylaxis as well as in 15 control patients with similar disease categories and preparative regimens receiving CI-containing GVHD prophylaxis. Based on pre-study stopping rules of expected grade II–IV AGVHD incidence, the trial was closed to accrual after enrollment of 11 patients. The median age of the 11 patients was 51 years (26–59). The diagnoses of the study patients included myelodysplasia (5), acute myelogenous leukemia (3) and nonhodgkin lymphoma (3). Seven patients received busulfan, etoposide and cyclophosphamide (CY); three patients received carmustine, etoposide and CY and one patient received total body irradiation, etoposide and CY as the preparative regimens. Sirolimus was discontinued in 4 patients due to concern for toxicity-related events including severe sinusoidal obstructive syndrome (1), altered mental status (1), portal vein thrombosis (1) and risk of poor wound healing after abdominal exploratory surgery (1) 9 days, 9 days, 61 days and 39 days post-HCT, respectively. Six of 11 patients developed grade II-IV AGVHD a median of 15.5 days post-HCT (range 11–25 days), 3 of the 6 with grade IV AGVHD. Two of the 3 patients with grade IV AGVHD required discontinuation of sirolimus 9 days post-HCT due to toxicity. Five of the 6 AGVHD patients had skin-only and one had liver, gut and skin involvement. All patients responded to AGVHD therapy and there were no AGVHD-related deaths. One patient died 54 days post-HCT due to complications of colonic ulceration believed related to oral MMF therapy. Two patients died of relapsed disease at 103 and 304 days post-HCT. At a median follow-up of 416 days (328–652 days), 8 of 11 patients were alive without disease, 5 with active chronic GVHD. The median MPA area under the curve (AUC) on day 2 was 12.8 mcg*hr/mL (6.4–17.4) and day 21 was 17.9 mcg*hr/mL (8–26.6). We measured a statistically significant increase in the percentage of CD4+FoxP3+ cells per total CD4+ cells in the sirolimus/MMF study group compared to the CI historical control group with a mean of the individual patient means over the first 100 days post-HCT of 16% versus 6%, respectively (p.0005). Despite the increased percentage of CD4+FoxP3+ cells per total CD4+ cells identified in the PB of the sirolimus/MMF cohort, the incidence of grade II-IV AGVHD was similar to the CI cohort (6 of 11 versus 7 of 15, respectively). However, all but one patient had skin-only AGVHD and there were no GVHD-related deaths in the sirolimus/MMF group. All patients requiring early withdrawal of sirolimus had received the busulfan-containing preparative regimen with two of these patients developing severe AGVHD. In a subsequent GVHD prophylaxis trial including sirolimus and MMF, the busulfan-containing preparative regimen will be eliminated to optimize sirolimus and MMF administration with the continued goal of reducing the incidence and severity of AGVHD.

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