Shelly L. Carter

Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors

BACKGROUND Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. METHODS We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). RESULTS The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. CONCLUSIONS We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).

Alternative donor transplantation after reduced intensity conditioning: Results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts

The Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603).

Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803.

Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies

Outcomes of unrelated donor cord blood transplantation in 191 hematologic malignancy children (median age, 7.7 years; median weight, 25.9 kg) enrolled between 1999 and 2003 were studied (median follow-up, 27.4 months) in a prospective phase 2 multicenter trial. Human leukocyte antigen (HLA) matching at enrollment was 6/6 (n = 17), 5/6 (n = 58), 4/6 (n = 111), or 3/6 (n = 5) by low-resolution HLA-A, -B, and high-resolution (HR) DRB1. Retrospectively, 179 pairs were HLA typed by HR. The median precryopreservation total nucleated cell (TNC) dose was 5.1 x 10(7) TNC/kg (range, 1.5-23.7) with 3.9 x 10(7) TNC/kg (range, 0.8-22.8) infused. The median time to engraftment (absolute neutrophil count > 500/mm(3) and platelets 50 000/muL) was 27 and 174 days. The cumulative incidence of neutrophil engraftment by day 42 was 79.9% (95% confidence interval [CI], 75.1%-85.2%); acute grades III/IV GVHD by day 100 was 19.5% (95% CI, 13.9%-25.5%); and chronic GVHD at 2 years was 20.8% (95% CI, 14.8%-27.7%). HR matching decreased the probability of severe acute GVHD. The cumulative incidence of relapse at 2 years was 19.9% (95% CI, 14.8%-25.7%). The probabilities of 6-month and 2-year survivals were 67.4% and 49.5%. Unrelated donor cord blood transplantation from partially HLA-mismatched units can cure many children with leukemias. The study was registered at www.clinicaltrials.gov as #NCT00000603.

Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II–III trial

BACKGROUND Graft-versus-host disease (GVHD) reduces the efficacy of unrelated donor bone marrow transplantation in patients with lymphohaemopoietic malignancy. A multi-centre, randomised trial was undertaken to determine the effects of ex-vivo T-cell depletion versus methotrexate and cyclosporine immunosuppression on 3-year disease-free survival. METHODS Between Mar 1, 1995, and Oct 31, 2000, 405 patients with lymphohaemopoietic malignancy, from 15 participating centres, were randomly assigned to undergo transplantation with either T-cell depleted marrow and cyclosporine A (TCD arm; n=201) or methotrexate and cyclosporine A after transplantation of T-replete marrow (M/C arm; n=204). The primary outcome was 3-year disease-free survival and was analysed by intention to treat. FINDINGS Five patients died before transplantation. Seven in the TCD arm received T-replete grafts. Disease-free survival at 3 years was 27% (95% CI 21-33) and 34% (27-40) in recipients of TCD and M/C, respectively (p=0.16). TCD was associated with significantly more rapid neutrophil recovery (15 days vs 20 days, p<0.0001), less grade III-IV acute GVHD (18%vs 37%, p<0.0001), reduced grade III-IV toxicities (19%vs 29%, p=0.017), reduced duration of initial hospitalisation, but higher risk of chronic myelogenous leukaemia relapse (20%vs 7%, p=0.009) and cytomegalovirus infection (28%vs 17%, p=0.023) than was M/C. INTERPRETATION Disease-free survival at 3 years did not differ between TCD and M/C groups. Relapse and opportunistic infection are important obstacles to successful unrelated donor bone marrow transplantation, irrespective of the method of GVHD prophylaxis used.

Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network

Acute graft-versus-host disease (aGVHD) is the primary limitation of allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard initial therapy, yet only 25% to 41% of patients completely respond. This randomized, 4-arm, phase 2 trial was designed to identify the most promising agent(s) for initial therapy for aGVHD. Patients were randomized to receive methylprednisolone 2 mg/kg per day plus etanercept, mycophenolate mofetil (MMF), denileukin diftitox (denileukin), or pentostatin. Patients (n = 180) were randomized; their median age was 50 years (range, 7.5-70 years). Myeloablative conditioning represented 66% of transplants. Grafts were peripheral blood (61%), bone marrow (25%), or umbilical cord blood (14%); 53% were from unrelated donors. Patients who received MMF for prophylaxis (24%) were randomized to a non-MMF arm. At randomization, aGVHD was grade I to II (68%), III to IV (32%), and (53%) had visceral organ involvement. Day 28 complete response rates were etanercept 26%, MMF 60%, denileukin 53%, and pentostatin 38%. Corresponding 9-month overall survival was 47%, 64%, 49%, and 47%, respectively. Cumulative incidences of severe infections were as follows: etanercept 48%, MMF 44%, denileukin 62%, and pentostatin 57%. Efficacy and toxicity data suggest the use of MMF plus corticosteroids is the most promising regimen to compare against corticosteroids alone in a definitive phase 3 trial. This study is registered at http://www.clinicaltrials.gov as NCT00224874.

One-Unit versus Two-Unit Cord-Blood Transplantation for Hematologic Cancers

BACKGROUND Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation. METHODS Between December 1, 2006, and February 24, 2012, a total of 224 patients 1 to 21 years of age with hematologic cancer were randomly assigned to undergo double-unit (111 patients) or single-unit (113 patients) cord-blood transplantation after a uniform myeloablative conditioning regimen and immunoprophylaxis for graft-versus-host disease (GVHD). The primary end point was 1-year overall survival. RESULTS Treatment groups were matched for age, sex, self-reported race (white vs. nonwhite), performance status, degree of donor-recipient HLA matching, and disease type and status at transplantation. The 1-year overall survival rate was 65% (95% confidence interval [CI], 56 to 74) and 73% (95% CI, 63 to 80) among recipients of double and single cord-blood units, respectively (P=0.17). Similar outcomes in the two groups were also observed with respect to the rates of disease-free survival, neutrophil recovery, transplantation-related death, relapse, infections, immunologic reconstitution, and grade II-IV acute GVHD. However, improved platelet recovery and lower incidences of grade III and IV acute and extensive chronic GVHD were observed among recipients of a single cord-blood unit. CONCLUSIONS We found that among children and adolescents with hematologic cancer, survival rates were similar after single-unit and double-unit cord-blood transplantation; however, a single-unit cord-blood transplant was associated with better platelet recovery and a lower risk of GVHD. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00412360.).

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)

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 of 6 (n = 1) or 5 of 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: 7.4-16.2 years), and median weight was 35.0 kg (range: 25.2-90.2 kg). The median pre-cryopreservation total nucleated cell dose was 6.4 × 10(7) /kg (range: 3.1-7.6), and the median postthaw infused CD34 cell dose was 1.5 × 10(5) /kg (range: 0.2-2.3). All patients achieved neutrophil recovery (absolute neutrophil count >500/mm(3)) by day 33 (median: 22 days). Three patients who engrafted had 100% donor cells by day 100, which was sustained, and 5 patients had autologous hematopoietic recovery. Six of 8 patients had a platelet recovery to >50,000/mm(3) by day 100. Two patients developed grade II acute GVHD. Of these, 1 developed extensive chronic GVHD and died of respiratory failure 14 months posttransplantation. 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. 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, because 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.

Total Colony-Forming Units Are a Strong, Independent Predictor of Neutrophil and Platelet Engraftment after Unrelated Umbilical Cord Blood Transplantation: A Single-Center Analysis of 435 Cord Blood Transplants

Graft failure occurs in approximately 20% of patients after unrelated umbilical cord blood transplantation (UCBT). This could be because of inadequate potency of the cord blood unit (CBU). To this end, we investigated the impact of graft characteristics on engraftment and survival of 435 primarily pediatric (median age: 5.3 years) patients receiving a single-unit unrelated UCBT after myeloablative conditioning from 2000 to 2008. Pre-cryopreservation (pre-cryo) graft characteristics were provided by the banks. Post-thaw parameters were measured on dextran/albumin-washed grafts. Post-thaw recovery of the colony-forming unit (CFU), a biological assay reflecting functional viability of the cord blood cells was the lowest percent age (median 21.2%, mean 36.5%) of the pre-cryo value, regardless of the bank of origin. The cumulative incidences of neutrophil and platelet engraftment were 76.9% (95%, confidence interval [CI], 71.3%-82.5%) and 55% (95% CI, 49.3%-60.7%), respectively. Univariate and separate multivariate models using pre-cryo and post-thaw datasets including clinical parameters identified predictors of engraftment and survival. In multivariate modeling, higher CFU dosing was the only pre-cryo graft characteristic predictive of neutrophil (P = .0024) and platelet engraftment (P = .0063). In the post-thaw model, CFU dose best predicted neutrophil and platelet engraftment (both P < .0001). Comparatively, CD34(+) and total nucleated cell (TNC) were only weakly predictive in post-thaw neutrophil and platelet engraftment models, respectively. In conclusion, CFU dose is a strong independent predictor of engraftment after unrelated UCBT and should be used to assess potency when selecting CBUs for transplantation.

Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation

Sirolimus is an effective agent used in graft-versus-host disease (GVHD) prophylaxis after allogeneic transplantation. It also has antiproliferative effects on vascular endothelium when used to coat coronary artery stents. We noted an excess of veno-occlusive disease (VOD) in a clinical trial, and retrospectively reviewed the records of 488 patients to determine the association between sirolimus and VOD. When used with cyclophosphamide/total body irradiation (Cy/TBI) conditioning, sirolimus is associated with an increased incidence of VOD (OR 2.35, P = .005). The concomitant use of methotrexate further increased this rate (OR 3.23, P < .001), while sirolimus without methotrexate was not associated with an increased risk of VOD (OR 1.55, P = .33). Mortality after VOD diagnosis was unaffected, and overall treatment-related mortality was lowest when sirolimus was used without methotrexate. Similar findings were noted in matched, related, and unrelated as well as mismatched donor subgroups. When used with busulfan-based conditioning, sirolimus use was associated with an even higher rate of VOD (OR 8.8, P = .008). Our findings suggest that sirolimus use is associated with VOD after TBI-based transplantation when used with methotrexate after transplantation. Sirolimus-based GVHD prophylaxis without methotrexate is associated with the greatest overall survival. Myeloablative doses of busulfan should not be used with sirolimus-based immunosuppression.