Tacrolimus and Mycophenolate Mofetil as Post-Grafting Immunosuppression After Conditioning with Fludarabine and Low-Dose Total Body Irradiation for Recipients of HLA-Matched Sibling or Unrelated Donor Hematopoietic Cell Transplants in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder of hematopoiesis that results in bone marrow failure and myelodysplasia. Hematopoietic cell transplantation is the only curative therapy. The success of allogeneic stem cell transplantation has been limited, in part, by regimen-related toxicity associated with high-dose preparative regimens. Nonrandomized studies suggest that long-term remissions are achievable when using allogeneic SCT as treatment for PNH. Mikolajewska, et al. reported treatment of 7 patients with high risk PNH with a reduced intensity conditioning regimen of fludarabine and total body irradiation (TBI). Mycophenolate mofetil (MMF) and cyclosporine were utilized as graft versus host disease (GvHD) prophylaxis (2008 ASH Annual Meeting Abstracts, 4407). The objective of this study is to evaluate the combination of tacrolimus and MMF as GvHD prophylaxis after conditioning with fludarabine and low dose TBI in PNH patients who are not candidates for conventional ablative allografting. This is a novel approach to immunosuppression incorporating an early but extended taper of tacrolimus on day +80.

Four patients with PNH underwent allogeneic SCT after a reduced intensity regimen. Patients received fludarabine (30mg/m²/day) on days -4 to -2 and low dose TBI (200 or 400 cGy at 6-7 cGy/min from a linear accelerator) on day 0. Two patients received TBI 200 cGy and three received 400 cGy. One patient failed to engraft with TBI 200 cGy and was transplanted again with TBI 400 cGy. GvHD prophylaxis was with tacrolimus (0.06mg/kg PO BID) starting on day -3 and MMF (15mg/kg PO BID for related and TID for unrelated donors) starting from day 0. All patients received filgrastim-mobilized peripheral blood stem cells from either from an HLA-matched sibling (n=1) or matched unrelated (n=4) donor.

The median follow up was 20 (range 3 to 36) months after SCT. One patient who received TBI at 200 cGy failed to engraft after an unrelated transplant. She underwent a second transplant from a different unrelated donor with TBI with 400 cGy with engraftment after the second procedure. The patients engrafted reaching a neutrophil count ≥ 500 a median of 16 (range 15 to 18) days post-transplant. Each achieved eradication of their PNH clone based on subsequent marrow and blood chimerism studies together with absence of clinical signs of PNH. Acute GvHD (grades II-IV) occurred in three patients. Chronic GvHD occurred in two patients. Day 100 mortality was 0% and all four patients are alive with an EGOG status of 0-1.

A reduced intensity conditioning regimen consisting of fludarabine and TBI at 200 cGy or 400 cGy with tacrolimus and MMF as post grafting immunosuppression appears well tolerated for performing allogeneic transplants in PNH. Donor cell engraftment with eradication of the PNH clone was observed with this approach. The higher dose of TBI (400 cGy) might be more effective in overcoming graft rejection and warrants further investigation.

No relevant conflicts of interest to declare.