Phase I-II study of clofarabine-melphalan-alemtuzumab conditioning for allogeneic hematopoietic cell transplantation.

We conducted a phase I-II study of transplantation conditioning with clofarabine-melphalan-alemtuzumab for patients with advanced hematologic malignancies. Ten patients were accrued to the phase I portion, which utilized an accelerated titration design. No dose-limiting toxicity was observed, and clofarabine 40 mg/m(2) × 5, melphalan 140 mg/m(2) × 1, and alemtuzumab 20 mg × 5 was adopted for the phase II study, which accrued 72 patients. Median age was 54 years. There were 44 patients with acute myelogenous leukemia or myelodysplastic syndromes, 27 with non-Hodgkin lymphoma, and nine patients with other hematologic malignancies. The largest subgroup of 35 patients had American Society for Blood and Marrow Transplantation high-risk, active disease. All evaluable patients engrafted with a median time to neutrophil and platelet recovery of 10 and 18 days, respectively. The cumulative incidence of treatment-related mortality was 26% at 1 year. Cumulative incidence of relapse was 29% at 1 year. Overall survival was 80% (95% confidence interval [CI], 71-89) at 100 days and 59% (95% CI, 47-71) at 1 year. Progression-free-survival was 45% (95% CI, 33-67) at 1 year. Rapid-onset renal failure was the main toxicity in the phase II study and more frequent in older patients and those with baseline decrease in glomerular filtration rate. Grade 3-5 renal toxicity was observed in 16 of 74 patients (21%) treated at the phase II doses. Clofarabine-melphalan-alemtuzumab conditioning yields promising response and duration of response, but renal toxicity poses a considerable risk particularly in older patients.

Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions.

We conducted a 45 patient prospective study of reduced-intensity conditioning (RIC) and transplantation of unrelated umbilical cord blood (UCB) and CD34(+) stem cells from a haploidentical family member. Median age was 50 years; weight was 80 kg. Fifty-eight percent had active disease. Neutrophil engraftment occurred at 11 days (interquartile range [IQR], 9-15) and platelet engraftment at 19 days (IQR, 15-33). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB by 100 days, with regular persistence of minor host and/or haplo-hematopoiesis. Percentage of haplochimerism at day 100 correlated with the haplo-CD34 dose (P = .003). Cumulative incidence of acute GVHD (aGVHD) was 25% and chronic GVHD (cGVHD) was 5%. Actuarial survival at 1 year was 55%, progression-free survival (PFS) was 42%, nonrelapse mortality (NRM) was 28%, and relapse was 30%. RIC and haplo-cord transplantation results in fast engraftment of neutrophils and platelets, low incidences of aGVHD and cGVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay, and promising long-term outcomes. UCB cell dose had no impact on time to hematopoietic recovery. Therefore, UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. This study is registered at http://clinicaltrials.gov as NCI clinical trial no. NCT00943800.

Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease.

Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 µmol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late-occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 µmol-min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUC(max)) rather than with the average cumulative AUC (AUC(avg)). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 µmol-min/L-higher than that achieved by current standard busulfan regimens-was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning.

Methodological and logistical considerations to study design and data collection in racial/ethnic minority populations evaluating outcome disparity in hematopoietic cell transplantation.

Outcome disparity associated with race or ethnicity in the United States has been observed in hematopoietic cell transplantation (HCT). The underlying reasons for such disparity are not known. In the United States, an optimal study of health care disparity by race or ethnicity involves consideration of both biologic and psychosocial determinants, which requires an adequately powered, prospective cohort study design. To better characterize the nature and quantify the magnitude of the many impediments relevant to conducting a successful prospective study involving racial or ethnic minorities in HCT, we conducted a feasibility study to help guide planning of a larger scale outcome and disparity study in HCT. The primary questions to be addressed in the study were: (1) can we establish a racially or ethnically diverse patient sample that will respond to a survey focused on sociodemographic, economic, health insurance, cultural, spiritual, and religious well-being, and social support information? (2) What is the retention rate in the study over time? (3) What is the quality of the data collected from the patients over time? The challenges we faced in conducting this multicenter feasibility study are summarized in this report. Despite the difficulty in conducting disparity studies in racial and ethnic minorities, such studies are essential to ensure that people of all ethnic and racial backgrounds have the best chance possible of benefiting from HCT.