mycophenolic-acid and Hemoglobinuria--Paroxysmal

The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft-rejection/failure, unmanipulated G-CSF mobilized PBPCs obtained from an HLA-identical or single HLA-antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA-alloimmunization (41%) and a heavy prior transfusion burden, graft-failure did not occur with all patients having sustained donor lympho-hematopoietic engraftment. The cumulative incidence of grade II-IV acute-GVHD and chronic-GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow-up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T-cell engraftment (≥95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic-GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine-based PBPC transplantation overcomes the risk of graft-failure in patients with BMFS, although rapid donor T-cell engraftment associated with this approach appears to increase the risk of chronic-GVHD. (Clinicaltrials.gov identifier: NCT00003838).

Topics: Adult; Aged; Anemia, Aplastic; Antilymphocyte Serum; Antineoplastic Agents; Bone Marrow Diseases; Bone Marrow Failure Disorders; Child; Chronic Disease; Cyclosporine; Female; Graft Rejection; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Hemoglobinuria, Paroxysmal; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Risk Factors; Salvage Therapy; T-Lymphocytes; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult

We evaluated the safety and efficacy of high-dose, posttransplantation cyclophosphamide (Cy) to prevent graft rejection and graft-versus-host disease (GVHD) after outpatient nonmyeloablative conditioning and T cell-replete bone marrow transplantation from partially HLA-mismatched (haploidentical) related donors. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received Cy 50 mg/kg i.v. on day 3 (n = 28) or on days 3 and 4 (n = 40) after transplantation. The median times to neutrophil (>500/microL) and platelet recovery (>20,000/microL) were 15 and 24 days, respectively. Graft failure occurred in 9 of 66 (13%) evaluable patients, and was fatal in 1. The cumulative incidences of grades II-IV and grades III-IV acute (aGVHD) by day 200 were 34% and 6%, respectively. There was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttransplantation Cy (P = .05), the only difference between these groups. The cumulative incidences of nonrelapse mortality (NRM) and relapse at 1 year were 15% and 51%, respectively. Actuarial overall survival (OS) and event-free survival (EFS) at 2 years after transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies had an improved EFS compared to those with myelogenous malignancies (P = .02). Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD.

Topics: Adult; Aged; Blood Component Transfusion; Bone Marrow Transplantation; Cyclophosphamide; Disease-Free Survival; Drug Administration Schedule; Female; Filgrastim; Graft Survival; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hemoglobinuria, Paroxysmal; Histocompatibility; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Recombinant Proteins; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Post-transplantation cyclophosphamide (PTCy) demonstrated effectiveness to prevent GVHD after haploidentical hematopoietic cell transplantation (HCT). Reducing toxicities with a maximized efficacy is still challenging in HCT. In this retrospective study, we analyzed the safety and efficacy of transplantation from a 1-antigen HLA-mismatched unrelated donor (9/10 MMUD) in 80 patients with hematological disorders between 2010 and 2018; 22 patients received PTCy with a reduced dose of 40 mg/kg, cyclosporine A, and mycophenolate mofetil (MMF); 58 patients received anti-thymocyte globulin (ATG), cyclosporine A, and either methotrexate or MMF for GVHD prophylaxis. Cumulative incidence (CI) of acute GVHD grades II-IV in the PTCy group was significantly lower (15% vs. 50%, p = 0.006); however, CI of chronic GVHD was (not significantly) lower in the PTCy group (26% vs. 35%, p = 0.137). One-year OS was significantly longer (p = 0.008) in the PTCy group with a similar 1-year PFS (p = 0.114) in both groups. Rates of 1-year relapse and non-relapse mortality were similar. Median time to neutrophil engraftment was comparable in both GVHD prophylaxis groups (14 days vs. 16 days, respectively, p = 0.107). Our results show that a lower dose of PTCy-based prophylaxis is an effective and safe strategy to prevent acute GVHD in HCT with 9/10 MMUD compared to ATG.

Topics: Adult; Aged; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Diseases; Bone Marrow Failure Disorders; Cyclophosphamide; Cyclosporine; Drug Evaluation; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hemoglobinuria, Paroxysmal; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Retrospective Studies; T-Lymphocytes; Tissue Donors

To evaluate the outcomes of allogeneic hematopoietic stem cell transplantation（allo-HSCT）for paroxysmal nocturnal haemoglobinuria（PNH）and aplastic anemia（AA）- PNH syndrome.. The clinical data of 18 PNH or AA-PNH patients, including 4 classic PNH and 14 AA-PNH, received allo-HSCT from Dec 2007 to Feb 2015 were analyzed retrospectively. Nine patients received HLA-haploidentical donor HSCT（1 patient received salvage HLA-haploidentical donor HSCT after the graft failure of double cord blood transplantation）, 7 patients received HLA-identical sibling donor HSCT, and 2 HLA-identical unrelated donor HSCT. The conditioning regimens were as follow: 13 patients received modified BU/CY- based regimens, 5 non- myeloablative regimens ［fludarabine （Flu） + antithymocyte globulin（ATG）+ cyclophosphamide（CY）or busulfan（BU）］. Prophylaxis for graft- versushost disease（GVHD）: the patients with HLA-identical sibling donor received cyclosporine（CsA）plus short-term methotrexate（MTX）, the patients with HLA -haploidentical donor or HLA-identical unrelated donor received CsA or tacrolimus（FK506）+ mycophenolate mofetil（MMF）+ short- term methotrexate （MTX）.. All patients were engrafted successfully（1 patient engrafted by haploidentical donor after the graft failure of double cord blood transplantation）. The median days of neutrophils（ANC）above 0.5 × 109/L and platelets （PLT） more than 20 × 10⁹/L were 11（10- 26）days and 15（11- 120）days, respectively. Three patients（17.6%）developed acute GVHD（aGVHD）, 2 for grade Ⅱ aGVHD, 1 for grade Ⅳ aGVHD. Of 16 patients, 2 occurred limited chronic GVHD（cGVHD）. After a median follow-up of 14.6（2.0-86.7）months, 3 patients（17.6%）died, out of which one died of severe aGVHD, one died of severe pulmonary infection, one pulmonary infection with transplant- associated thrombotic microangiopathy. The 5- year estimated disease free survival was（80.5 ± 10.2）%. No patient relapsed.. Allo-HSCT is an effective and curable therapy for PNH or AA-PNH with improved prognosis, and offers a valid therapeutic option for these patients before humanized monoclonal antibody against C5 are widely used clinically.

Topics: Anemia, Aplastic; Antilymphocyte Serum; Busulfan; Cyclophosphamide; Cyclosporine; Disease-Free Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hemoglobinuria, Paroxysmal; Humans; Methotrexate; Mycophenolic Acid; Retrospective Studies; Siblings; Tacrolimus; Transplantation Conditioning; Treatment Outcome; Unrelated Donors; Vidarabine