Unrelated Donor Cord Blood Transplantation for Children with Severe Sickle Cell Disease: Results of One Cohort from the Phase II Study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)

Abstract

The Sickle Cell Unrelated donor Transplant trial (SCURT trial) of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a phase II study of the toxicity and efficacy of unrelated donor hematopoietic cell transplantation in children with severe sickle cell disease (SCD) using a reduced intensity conditioning regimen. Here we report the results for the cord blood cohort of this trial. Eight children with severe SCD underwent unrelated donor cord blood transplantation (CBT) following alemtuzumab, fludarabine and melphalan. Cyclosporine or tacrolimus and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis. Donor/recipient HLA match status was 6/6 (n=1) or 5/6 (n=7), based on low/intermediate resolution molecular typing at HLA -A, -B, and high resolution typing at -DRB1. Median recipient age was 13.7 years (range 7.4 to 16.2 years), and median weight was 35.0 kg (range 25.2 to 90.2 kg). The median pre-cryopreservation total nucleated cell dose was 6.4 × 107 /kg (range 3.1 to 7.6) and the median post-thaw infused CD34 cell dose was 1.5 × 105 /kg (range 0.2 to 2.3). All patients achieved neutrophil recovery (ANC>500/mm3) by day 33 (median 22 days). Three patients who engrafted had 100% donor cells by day 100, which was sustained and five patients had autologous hematopoietic recovery. Six of eight patients had a platelet recovery to > 50,000/mm3 by day 100. Two patients developed grade II acute GVHD. Of these, one developed extensive chronic GVHD and died of respiratory failure 14 months post-transplant. With a median follow up of 1.8 years (range 1 – 2.6), 7 patients are alive with a 1-year survival of 100% and 3 of 8 are alive without graft failure or disease recurrence. Conclusion Based upon the high incidence of graft rejection after unrelated donor CBT, enrollment onto the cord blood arm of the SCURT trial was suspended. However, since this reduced intensity regimen has demonstrated a favorable safety profile, this trial remains open to enrollment for unrelated marrow donor transplants. Novel approaches aimed at improving engraftment will be needed before unrelated CBT can be widely adopted for transplanting patients with severe SCD.

Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel

“…Analyses showed that OS, DFS, acute and chronic GvHD were 95%, 88%, 20%, and 12%, respectively for BM recipients (n=389), and 96%, 81%, 10%, and 5%, respectively for CB recipients (n=70). In this cohort, the cell dose (median 3.9x10 7 /kg) did not influence outcome of patients given cord blood. 21 …”

“…So far, a total of 32 patients with SCD transplanted with an UCB unit have been published, 18 of them following an RIC regimen, with an overall survival of 91%, but a diseasefree survival of only 50% because of rejection. 7,45,83,84 The Sickle Cell Unrelated Donor Transplant Trial (SCURT trial) of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) was a phase II study on the toxicity and efficacy of UCB or BMT in children with severe SCD using RIC. Eight children with severe SCD underwent unrelated donor CB-transplantation following alemtuzumab, fludarabine, and melphalan.…”

“…However, because this RIC has demonstrated a favorable safety profile, the trial remains open to enrolment for unrelated BMT. 7 Another concern to be considered is the high incidence of chronic GvHD in the context of unrelated CBT. 85 Recently, promising results from haploidentical HSCT following an RIC regimen have been published.…”

“…4,5 There are a number of possible reasons for this difference, including a lack of consensus about the indications and time point for HSCT in SCD, and the low chance of identifying an unrelated donor for SCD patients. 6,7 Table 1 shows the principal differences between TM and SCD from the transplant perspective.…”

β-globin gene transfer to human bone marrow for sickle cell disease

“…Transplantation of allogeneic cells carries the risk of graft-versushost disease (GvHD), which can be a cause of extensive morbidity. HSCT using UCB from matched unrelated donors holds reduced risk of acute or chronic GvHD compared with using BM; however, there is a higher probability of engraftment failure using UCB as a result of its lower cell dose and immunologic immaturity (8,9).…”