Haploidentical HSCT shows promise in adolescent anemia

Edward Gordon-Smith, MD, MSc, FRCPath

Im and colleagues from the department of pediatrics at the University of Ulsan College of Medicine in Seoul have reported an update on previous encouraging results (Koh KN. Br J Haematol. 2012;157:139-142) for the treatment of children and young adults (median age, 13.5 years; range, 3.8-21.7 years) with acquired aplastic anemia using T-cell–depleted haploidentical stem cells from related donors.

They report clinical outcomes of 12 patients with acquired aplastic anemia, nine of whom had failed immunosuppressive treatment previously and all of whom had received multiple transfusions, transplanted with T-cell–depleted haploidentical peripheral blood stem cells mobilized with granulocyte colony-stimulating factor (G-CSF).

The conditioning regimens included fludarabine 150 mg/m2, cyclophosphamide 120mg/m2 and rabbit antithymocyte globulin 7.5 mg/kg. Six patients received an additional 400 cGy of total body irradiation.

Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitors (cyclosporine or tacrolimus plus mycophenolate mofetil). Eleven of the 12 patients had prompt engraftment; two had subsequent graft rejection and one patient had primary graft failure. All three graft failure patients received a second haploidentical graft, two from a different haploidentical family donor from the first graft. Three patients developed steroid-responsive severe acute GVHD.

Natural killer cell recovery was swift, but T and B cells did not recover fully for up to year post transplant, and reactivation of cytomegalovirus (six patients), lymphoproliferative disorder (one patient) and hemorrhagic cystitis (BK virus, five patients) were problems that responded to appropriate anti-viral management. All 12 patients are alive and transfusion independent (median follow up, 14.3 months; range, 4.1-40.7 months).

Stem cell transplants from haploidentical family members have long been considered a possible way of expanding the donor pool for patients without HLA-matched family or unrelated donors. The great majority of attempts to use these donors were made for patients with otherwise untreatable hematologic malignancies. Not surprisingly. Transplant-related mortality was high due primarily to GVHD and graft failure. Very large stem cell doses improved engraftment of haploidentical grafts. Efficient T-cell depletion (CD3+) reduced GVHD but at the cost of slow immune reconstitution, increased infections and higher relapse rates.

Recently there has been considerable interest in the use of unmanipulated grafts using bone marrow from donors primed with G-CSF for malignant disorders (Di Bartolomeo P. Blood. 2013;121:849-857). There has been much less information about the use of haploidentical stem cells in nonmalignant disorders, and this publication adds significantly to available information. As is usually the case in early trials of novel methods in transplantation, the modifications of the conditioning regimens during the trial — together with relatively small numbers of patients — make it difficult to assess results for general use. The authors intend to start a formal continuation study using a standard conditioning regimen, which is to be welcomed.

T-cell depletion is a complex process (not available to all centers) that is essential when peripheral blood mobilized with G-CSF, containing high numbers of T-cells, is used as the source of stem cells. The work of Im and colleagues supports the concept that haploidentical donors are a potential source of stem cells for patients with aplastic anemia who have failed immunosuppression who do not have a suitable matched donor (to be compared with cord blood donations). Particularly for aplastic anemia, it would be useful to know if unmanipulated G-CSF–primed  marrow stem cells would be equally effective.