D. Umbilical Cord Blood Transplantation

1. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Locatelli F, Rocha V, Reed W, Bernaudin F, Ertem M, Grafakos S et al. Blood 2003; 101:2137-2143.

Forty-four children with hemoglobinopathies (thalassemia, n = 33; sickle cell disease, n = 11) received cord blood transplants from related donors (most receiving full matched grafts; three were 1-locus mismatched grafts). The median number of nucleated cells infused was 4.0 X 10⁷/kg. Engraftment was obtained in 86.4% of transplants; median time to neutrophil and platelet engraftments were 23 and 39 days, respectively. No patient died, and 36 of 44 children remain free of disease, with a median follow-up of 24 months (range 4-76 months). No grade III-IV acute GVHD occurred; 2 of 36 patients at risk developed limited chronic GVHD. The authors concluded that related cord blood transplantation offers a good probability of success and is associated with a low risk of GVHD.

(NOTE: Laughlin indicates that the low incidence of GVHD in this study compares favorably with the 15-25% incidence of chronic GVHD observed in children receiving HLA-matched sibling allogeneic bone marrow grafts. Thalassemia and sickle cell disease are among the most common genetic disorders, affecting several million children and young adults worldwide. UCB allogeneic transplantation for hemoglobinopathies. Laughlin M. Blood 2003;101: 2077-2078.)

2. Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease. Adamkiewicz TV, Mehta PS, Boyer MW, Kedar A, Olson TA, Olson E, Chiang KY, Maurer D, Mogul MJ, Wingard JR, Yeager AM. Bone Marrow Transplant. 2004;34:405-11.

The authors evaluated unrelated placental blood cell transplantation (UPBCT) after a preparative regimen of busulfan, cyclophosphamide and antithymocyte globulin in three children with sickle cell disease (SCD). All three patients (ages 12.5, 6 and 3 years) had apparent ischemic cerebrovascular accidents at ages 5, 5, and 2 years, respectively, and all patients had residual hemipareses with evidence of brain infarction on magnetic resonance imaging and cerebral arterial occlusions on magnetic resonance angiography. All 3 patients had additional complications of SCD such as recurrent pain crises, seizures, recurrent TIAs, and splenic sequestration crisis. The placental blood cell units were matched with the recipients at four of six HLA-A, HLA-B and HLA-DRB1 antigens. The TNC doses were 2.7, 7.1 and 10.3 x 10(7) cells/kg at cryopreservation. Neutrophil engraftment at levels above 0.5 x 10(9)/l occurred at 23, 38 and 42 days after UPBCT, and platelet levels above 50 x 10(9)/l without transfusions occurred at 62, 81 and 121 days after UPBCT. All patients developed acute graft-versus-host disease which resolved after methylprednisolone therapy, and the oldest child developed extensive chronic GVHD of skin and liver which resolved after treatment after approximately 28 months. One patient had graft failure and complete autologous hematopoietic recovery at 4.5 months posttransplant. Two patients have complete donor hematopoietic chimerism without detectable hemoglobin S or symptoms of SCD. All patients are alive and off all immunosuppressive agents at 40, 44 and 61 months, respectively. The two patients who remained 100% donor chimeras have play-performance scores of 100%. The authors suggest that further studies of UPBCT for SCD are needed but should be restricted to pediatric patients with high-risk manifestations of SCD.

(Comment: The authors offer very conservative recommendations regarding transplantation of SCD patients, that is, they limited their study to children with SCD-associated cerebrovascular accidents (CVAs). All patients in this report had residual hemipareses with evidence of brain infarction on magnetic resonance imaging and cerebral arterial occlusions on magnetic resonance angiography. One patient who was cured of his SCD is receiving special education because of his initial cerebral ischemic events.
Is the sickle cell disease community best served by waiting until irreversible complications of SCD occur prior to being considered a candidate for cure by transplantation? Is waiting until brain infarcts develop the optimal approach to transplantation in SCD? For a discussion of this aspect of transplantation in sickle cell disease, go to the Home page, click on Interactive Forums, Medical Professionals, or click here.