Cyclosporine and mycophenolate mofetil prophylaxis with fludarabine and melphalan conditioning for unrelated donor transplantation: a prospective study of 22 patients with hematologic malignancies

Abstract

Summary:In an attempt to decrease toxicity in high-risk patients undergoing unrelated donor hematopoietic stem cell transplantation (URD HSCT), we tested a combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis with the reduced-intensity conditioning regimen fludarabine/melphalan (Flu/Mel). A total of 22 adult patients with advanced myeloid (n ¼ 15) and lymphoid (n ¼ 7) malignancies were treated. All patients received Flu 25 mg/m 2 for 5 days and Mel 140 mg/m 2 , with CSP 3 mg/kg daily and MMF 15 mg/kg three times a day. The median age was 49 years (range 18-66). Durable engraftment was seen in all but one patient with myelofibrosis. The 1-year nonrelapse mortality was 32%, 27% from GVHD. The cumulative incidence of acute GVHD grade 2-4 and 3-4 was 63 and 41%, respectively. With a median follow-up of 18 months, the disease-free survival (DFS) and overall survival (OS) are 55 and 59%, respectively. For patients with AML and MDS (n ¼ 14), the DFS and OS is 71%. For patients undergoing a second transplant (n ¼ 14), the DFS and OS is 57%. In conclusion, this regimen is associated with acceptable toxicity but high rates of GVHD in high-risk patients undergoing URD HSCT. Encouraging disease control for patients with advanced myeloid malignancies was observed. The applicability of unrelated hematopoietic stem cell transplantation (URD HSCT) for patients with hematological malignancies has been greatly hampered by its early toxicity, with 100-day mortality ranging from 15 to 50%. 1 These statistics have been generated from younger patients (o55 years) with normal organ function, with age and disease status at transplantation largely accounting for the variability in outcome. Older patients and those who have comorbidities or who have failed previous autologous transplants experience even greater toxicity, thus making them extremely high risk or ineligible for this procedure. 2 Reduced-intensity conditioning (RIC) regimens have allowed high-risk patients to undergo allogeneic HSCT with decreased transplant-related toxicity. The RIC regimen fludarabine/melphalan (Flu/Mel), for example, has been used in conjunction with tacrolimus (FK-506) and mini-methotrexate (MTX) as graft-versus-host-disease (GVHD) prophylaxis, for high-risk patients with a variety of hematological malignancies, resulting in a relatively low 100-day nonrelapse mortality (NRM) of 37%. 3 Excellent engraftment was also seen with this regimen (median donor chimerism of 100% at day 30), with an encouraging disease-free survival (DFS) at 1 year of 57 and 49%, for patients with early and advanced disease, respectively. In this series, the probability of grade 2-4 and 3-4 acute GVHD was 0.49 and 0.29, respectively.The combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) has been successfully developed as GVHD prophylaxis, with powerful synergism in animal models, 4 and clinical efficacy in the nonmyeloablative transplant setting. 5,6 In an attempt to further reduce regimen-related toxicity...

Reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation with fludarabine and melphalan is associated with durable disease control in myelodysplastic syndrome

“…26 In the current study focusing on MDS patients, transplant-related mortality and GVHD were comparable to the overall RIC-HCT experience in our institution. The 2-year OS of 53% and DFS of 51% in our case series compare favorably with the results from fullintensity conditioning HSCT including our own historic data with busulfan plus cyclophosphamide conditioning.…”

HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen

“…Therefore, SAHA can augment depletion or inhibition of the anti-CD3-activated host T cells, resulting in facilitation of donor hematopoietic cell engraftment. Donor T cells usually induced GVHD in recipients conditioned with chemotherapy (1,25). However, we observed no clinical signs of GVHD in the recipients conditioned with anti-CD3 and SAHA after infusion of a high dose of CD4 ϩ T-depleted spleen cells.…”

Thymoglobulin, CYA and mycophenolate mofetil as GVHD prophylaxis for reduced-intensity unrelated donor hematopoietic cell transplantation: beneficial effect seen on chronic GVHD

“…2 This beneficial effect on chronic GVHD was seen despite a majority of patients (19/20) receiving PBSC grafts in this study compared with 50% (11/22) in the earlier study. One of the nine patients who received rituximab for EBV reactivation developed chronic GVHD.…”

“…1 However, a study conducted at the City of Hope Cancer Center using CSA and MMF in patients who had undergone reduced-intensity URD hematopoietic cell transplantation showed high rates of both acute and chronic GVHD. 2 In an attempt to improve on our earlier experience, and based on emerging data using thymoglobulin, 3,4 we conducted a prospective clinical trial using thymoglobulin added to CSA/MMF as GVHD prophylaxis.…”

“…CSA and MMF were given as reported earlier. 2 Patients with grade 2 or greater acute GVHD were treated with methylprednisolone 1 mg/kg twice daily. At the discretion of the treating physician, chronic GVHD was treated with either corticosteroids or other immunosuppressive agents.…”