Charles D. Bolan

Allogeneic Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease

BACKGROUND Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease. METHODS Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward. RESULTS All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean (+/-SE) donor-recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3+/-8.6% and 83.3+/-10.3%, respectively, in the nine patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0+/-0.3 and 12.6+/-0.5 g per deciliter, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient. CONCLUSIONS A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor-recipient chimerism and reverse the sickle cell phenotype. (ClinicalTrials.gov number, NCT00061568.)

Massive immune haemolysis after allogeneic peripheral blood stem cell transplantation with minor ABO incompatibility

Immune haemolysis as a result of minor ABO incompatibility is an underappreciated complication of haematopoietic transplantation. The increased lymphoid content of peripheral blood stem cell (PBSC) transplants may increase the incidence and severity of this event. We observed massive immune haemolysis in 3 out of 10 consecutive patients undergoing HLA‐identical, related‐donor PBSC transplants with minor ABO incompatibility. Non‐ablative conditioning had been given in 9 of these 10 cases, including two with haemolysis. Cyclosporin alone was used as prophylaxis against graft‐vs.‐host disease (GVHD). Catastrophic haemolysis of 78% of the circulating red cell mass led to anoxic death in the first case seen, but severe consequences were avoided by early, vigorous donor‐compatible red cell transfusions in the subsequent two cases. Haemolysis began 7–11 d after PBSC infusion and all patients with haemolysis had a positive direct antiglobulin test (DAT), with eluate reactivity against the relevant recipient antigen. However, neither the intensity of the DAT, the donor isohaemagglutinin titre, nor other factors could reliably be used to predict the occurrence of haemolysis. Our data indicate that haemolysis may be frequent and severe after transplantation of minor ABO‐incompatible PBSCs when utilizing cyclosporin alone to prevent GVHD. Meticulous clinical monitoring and early, vigorous donor‐compatible red cell transfusions should be practiced in all instances.

Twenty Years of Unrelated Donor Hematopoietic Cell Transplantation for Adult Recipients Facilitated by the National Marrow Donor Program

For more than 20 years the National Marrow Donor Program has facilitated unrelated donor hematopoietic cell transplants for adult recipients. In this time period, the volunteer donor pool has expanded to nearly 12 million adult donors worldwide, improvements have occurred in the understanding and technology of HLA matching, there have been many changes in clinical practice and supportive care, and the more common graft source has shifted from bone marrow (BM) to peripheral blood stem cells (PBSCs). The percentage of older patients who are receiving unrelated donor transplants is increasing; currently over 1 in 10 adult transplant recipients is over the age of 60 years. Chronic myelogenous leukemia (CML) was previously the most common diagnosis for unrelated donor transplantation, but it now comprises less than 10% of transplants for adult recipients. Transplants for acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and myelodysplastic syndromes (MDS) all outnumber CML. Treatment-related mortality (TRM) has declined significantly over the years, particularly in association with myeloablative transplant preparative regimens. Correspondingly, survival within each disease category has improved. Particularly gratifying are the results in severe aplastic anemia (AA) where 2-year survival has doubled in just 10 years.

Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population

A reliable estimate of peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF) may identify donors at risk for poor mobilization and help optimize transplantation approaches. We studied 639 allogeneic PBSC collections performed in 412 white, 75 black, 116 Hispanic, and 36 Asian/Pacific adult donors who were prescribed G-CSF dosed at either 10 or 16 microg/kg per day for 5 days followed by large-volume leukapheresis (LVL). Additional LVL (mean, 11 L) to collect lymphocytes for donor lymphocyte infusion (DLI) and other therapies was performed before G-CSF administration in 299 of these donors. Day 5 preapheresis blood CD34(+) cell counts after mobilization were significantly lower in whites compared with blacks, Hispanics, and Asian/Pacific donors (79 vs 104, 94, and 101 cells/microL, P < .001). In addition, donors who underwent lymphapheresis before mobilization had higher CD34(+) cell counts than donors who did not (94 vs 79 cells/microL, P < .001). In multivariate analysis, higher post-G-CSF CD34(+) cell counts were most strongly associated with the total amount of G-CSF received, followed by the pre-G-CSF platelet count, pre-G-CSF mononuclear count, and performance of prior LVL for DLI collection. Age, white ethnicity, and female gender were associated with significantly lower post-G-CSF CD34(+) cell counts.

Recovery and Safety Profiles of Marrow and PBSC Donors: Experience of the National Marrow Donor Program

The National Marrow Donor Program (NMDP) has been facilitating hematopoietic cell transplants since 1987. Volunteer donors listed on the NMDP Registry may be asked to donate either bone marrow (BM) or peripheral blood stem cells (PBSC); however, since 2003, the majority of donors (72% in 2007) have been asked to donate PBSC. From the donors perspective these stem cell sources carry different recovery and safety profiles. The majority of BM and PBSC donors experienced symptoms during the course of their donation experience. Pain is the number 1 symptom for both groups of donors. BM donors most often reported pain at the collection site (82% back or hip pain) and anesthesia-related pain sites (33% throat pain; 17% post-anesthesia headache), whereas PBSC donors most often reported bone pain (97%) at various sites during filgrastim administration. Fatigue was the second most reported symptom by both BM and PBSC donors (59% and 70%, respectively). PBSC donors reported a median time to recovery of 1 week compared to a median time to recovery of 3 weeks for BM donors. Both BM and PBSC donors experienced transient changes in their WBC, platelet, and hemoglobin counts during the donation process, with most counts returning to baseline values by 1 month post-donation and beyond. Serious adverse events are uncommon, but these events occurred more often in BM donors than PBSC donors (1.34% in BM donors, 0.6% in PBSC donors) and a few BM donors may have long-term complications. NMDP donors are currently participating in a randomized clinical trial that will formally compare the clinical and quality-of-life outcomes of BM and PBSC donors and their graft recipients.

Persistence of recipient plasma cells and anti-donor isohaemagglutinins in patients with delayed donor erythropoiesis after major ABO incompatible non-myeloablative haematopoietic cell transplantation.

Delayed donor erythropoiesis and pure red‐cell aplasia (PRCA) complicate major‐ABO mismatched non‐myeloablative allogeneic stem‐cell transplantation. To characterize these events, we analysed red‐cell serology and chimaerism in lymphohaematopoietic lineages, including plasma cells and B cells, in 12 consecutive major‐ABO incompatible transplants following cyclophosphamide/fludarabine‐based conditioning. Donor erythropoiesis was delayed to more than 100 days in nine (75%) patients including six (50%) who developed PRCA. During PRCA, all patients had persistent anti‐donor isohaemagglutinins and recipient plasma cells (5–42%), while myeloid and T cells were completely donor in origin. In contrast, B‐cell chimaerism was frequently full‐donor when significant anti‐donor isohaemagglutinins persisted. Four patients with early mixed haematopoietic chimaerism and the prolonged presence of anti‐donor isohaemagglutinins and recipient plasma cells developed delayed‐onset (>100 days post‐transplant) red cell transfusion dependence and PRCA after myeloid chimaerism converted from mixed to full donor. These findings confirm that donor‐erythropoiesis is impacted by temporal disparities in donor immune‐mediated eradication of recipient lymphohaematopoietic cells during major‐ABO incompatibility and suggest that plasma cells are relatively resistant to graft‐versus‐host haematopoietic effects.

Controlled study of citrate effects and response to IV calcium administration during allogeneic peripheral blood progenitor cell donation

BACKGROUND: Leukapheresis procedures are generally performed at citrate anticoagulation rates extrapolated from shorter plateletpheresis procedures. However, neither the metabolic effects nor the management of associated symptoms have been critically evaluated during leukapheresis in healthy donors.

The National Marrow Donor Program 20 Years of Unrelated Donor Hematopoietic Cell Transplantation

In the 20 years since the National Marrow Donor Program (NMDP) facilitated the first unrelated donor transplant, the organization has grown to include almost 7 million donors, and has facilitated over 30,000 transplants on 6 continents. This remarkable accomplishment has been facilitated by the efforts of over 600 employees, and an extensive international network including 171 transplant centers, 73 donor centers, 24 cord blood banks, 97 bone marrow collection centers, 91 apheresis centers, 26 HLA typing laboratories, and 26 Cooperative Registries. In this article, we review the history of the NMDP, and cite the major trends in patient demographics, graft sources, and conditioning regimens over the last 20 years.

Comprehensive analysis of citrate effects during plateletpheresis in normal donors

BACKGROUND: Although plateletpheresis procedures are generally well tolerated, the clinical and metabolic consequences associated with rapid infusion of up to 10 g of citrate are underappreciated, and a comprehensive description of these events is not available.

Analysis of PBPC cell yields during large‐volume leukapheresis of subjects with a poor mobilization response to filgrastim

BACKGROUND: The circulating CD34 count is a reliable predictor of peripheral blood progenitor cell (PBPC) yields in subjects with a vigorous mobilization response to G‐CSF, however, the value of this parameter in poor mobilizers is uncharacterized.