Dendritic Cell Recovery Impacts Outcomes after Umbilical Cord Blood and Sibling Donor Transplantation for Hematologic Malignancies.

Dendritic cells (DCs) orchestrate immune responses after allogeneic hematopoietic cell transplantation (HCT). We studied the association of donor myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) recovery in the landmark analysis of umbilical cord blood (UCB) and matched related donor (RD) HCT. Eighty patients (42 UCB and 38 RD recipients) with a day 100 blood sample were included in the analysis. Median age was 51 years (range, 20 to 71). Most patients had acute leukemia (50%) or lymphoma (23%) and received reduced-intensity conditioning (75%). After transplantation, UCB recipients had higher DC counts than RD recipients reaching normal levels at day 100 after transplantation (UCB median 4.7 cells/µL versus RD median 1.7 cells/µL). UCB recipients with high day 100 pDCs levels (≥ median) had 2-fold lower risk of relapse compared with those with pDClow (14% versus 28%, P = .29) and a trend to improved 1-year survival in multivariate analysis with hazard ratio of .22 (95% confidence interval, .04 to 1.05; P = .057). Cytomegalovirus (CMV) reactivation had adverse impact on DC reconstitution at day 100 in both UCB and RD groups and almost exclusively affected the mDC subset (CMV reactivation: mDC 3.2 cells/µL versus no CMV reactivation: 7.8 cells/µL; P = .004). Collectively, these data suggest that high levels of circulating pDCs at day 100 after UCB transplantation confer a survival advantage at 1 year.

Busulfan dose intensity and outcomes in reduced-intensity allogeneic peripheral blood stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia.

Comparisons of myeloablative conditioning versus reduced-intensity conditioning (RIC) have demonstrated a tradeoff between relapse and toxicity. Dose intensity across RIC regimens vary and may affect treatment outcomes. In this retrospective analysis, we investigated the effect of i.v. busulfan dosing (total dose 3.2 mg/kg versus 6.4 mg/kg) in RIC regimens that combined fludarabine and busulfan on outcomes in patients who were undergoing hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). A total of 217 consecutive patients with MDS or AML underwent first busulfan and fludarabine RIC peripheral blood stem cell transplantation from well-matched related or unrelated donors at our institutions between 2004 and 2009. Of the 217 patients, 135 patients received Bu1 (3.2 mg/kg of busulfan) and 82 patients received Bu2 (6.4 mg/kg of busulfan), both with daily fludarabine (30 mg/m(2)/day for 4 days). The choice of RIC regimen was based on temporal institutional standard, enrollment on protocols, and physician choice. Patients had similar characteristics with a few notable differences: Patients who received Bu1 were younger (median age 61 versus 64 years, P < . 001), received more single-antigen mismatched unrelated grafts (14.1% versus 1.2%, P < . 001), received more sirolimus-based graft-versus-host disease (GVHD) prophylaxis regimens (63% versus 45%, P < .0001), received less antithymocyte globulin for GVHD prophylaxis (0% versus 22%, P < .001), and had less enrollment on a clinical trial that used prophylactic rituximab for the prevention of chronic GVHD (2.2% versus 11.0%, P = .011). Clinical disease status was similar between the groups. Median follow-up for survivors was 4.4 years for Bu1 and 3.2 years for Bu2. Because of the differences in characteristics, the 2 groups were compared with the adjustment of a propensity score that predicted Bu2 to account for measured differences. The day +200 cumulative incidence rates of grades II to IV acute GVHD (Bu1, 17%, versus Bu2, 8.5%; hazard ratio [HR], .56; 95% confidence interval [CI], .22 to 1.41; P = .22) or grades III to IV acute GVHD (Bu1, 6.7%, versus Bu2, 4.9%) were not different. The 2-year cumulative incidence of chronic GVHD was not significantly different between Bu1 and Bu2 (41.5% versus 28%, respectively; HR, .70; CI, .42 to 1.17; P = .09). Two-year nonrelapse mortality rates were similar for Bu1 and Bu2 (8.9% versus 9.8%, respectively; HR, .80; CI, .29 to 2.21; P = .67). Two-year progression-free survival and overall survival were also similar between Bu1 and Bu2 (progression-free survival: 40.6% versus 39.3%, respectively; HR, .82; CI, .57 to 1.30; P = .33; and overall survival: 47.4% versus 48.8%, respectively; HR, .96; CI, .64 to 1.44; P = .85). Subset analysis defined by clinical disease and cytogenetic risk with the propensity risk score applied suggest that in patients with high clinical disease risk and nonadverse cytogenetics, the higher dose busulfan RIC regimen may be of marginal benefit (2-year progression-free survival: HR, .54; CI, .29 to 1.03; P = .062). For the majority of patients with MDS or AML undergoing busulfan and fludarabine RIC peripheral blood stem cell transplantation, however, the dose of busulfan (3.2 mg/kg versus 6.4 mg/kg) is not associated with significant differences in overall outcomes.

Unrelated cord blood transplants in adults with hematologic malignancies.

BACKGROUND AND OBJECTIVES: We analyzed outcomes and risk factors after unrelated cord blood transplantation (CBT) in adults with hematologic malignancies. DESIGN AND METHODS: One hundred and seventy-one patients were transplanted after 1997. Their median age was 29 years (15-55), and the median follow-up time was 18 months (1-71). Most patients had acute or chronic leukemia (n=142, 83%), 91 (53%) were transplanted in advanced phase and an autologous transplant had failed in 32 (19%). Most patients (87%) received an HLA-mismatched cord blood unit with 1-2 HLA disparities. At infusion, the median number of nucleated cells and CD34(+) cells was 2.1x10(7)/kg and 1x10(5)/kg, respectively RESULTS: The cumulative incidence of neutrophil recovery at day 60 was 72+/-3% with a median of 28 days (11-57). A higher neutrophil count and use of hematopoietic growth factors were independently associated with faster neutrophil recovery. The cumulative incidence of grade II-IV acute graft-versus-host disease was 32+/-4% and this complication was not associated with the number of HLA mismatches. The 2-year cumulative incidence of chronic graft-versus-host disease, transplant related-mortality and relapse were 36+/-10%, 51+/-4% and 22+/-4%, respectively. At 2-years, disease-free-survival for patients transplanted in early, intermediate and advanced phases of disease was 41+/-9%, 34+/-10% and 18+/-4%, respectively. In multivariate analyses, advanced disease status was an adverse factor for relapse and disease-free survival. INTERPRETATION AND CONCLUSIONS: Unrelated CBT is a clear alternative for adults with hematological malignancies lacking an HLA-matched related or unrelated donor. The choice of units containing a higher neutrophil count and a policy of earlier transplantation are likely to provide better results.

Outcomes of unrelated cord blood transplantation in pediatric recipients.

We report results of unrelated cord blood transplants (UCBT) in 29 pediatric recipients in one center and the risk factors associated with survival. Median age: 9 years (0.5-20); diagnosis: ALL (9), AML (4), CML (1), HD (3), HLH (1), NHL (3), NBL (2); B-thal (1), FA (1), FEL (1), Krabbe (1), WAS (1), SAA (1); median follow-up: 11 months; conditioning: total body irradiation (TBI)-ablative (14), chemotherapy-ablative (6) and reduced intensity chemotherapy (9); GVHD prophylaxis: MMF/FK506 (18), cyclosporin A (CsA)+steroids+/-MMF (7) or CsA+methotrexate (MTX) (4); median total nucleated cells (TNC): 3.8 x 10(7)/kg (1.1-11); median CD34+: 2.3 x 10(5)/kg (0.2-9.9); and HLA match: 2 (6/6), 5 (5/6), 22 (4/6). Neutrophil engraftment by cumulative incidence curves 63% (median 28 (95% confidence interval (CI) 18-32)). Probability of >/=grade II acute graft-versus-host disease (aGVHD) by day +60 27%, >/=grade III aGVHD 20% and chronic graft-versus-host disease 3%. Estimated 1-year overall survival (OS) 46% (95% CI 30-71) and standard risk 60% (95% CI 29-100%). Variables associated with improved survival by multivariate analysis include non-TBI-ablative conditioning (P=0.024), CD34+/kg (P=0.038) and gender (P=0.048). These results suggest that CD34/kg cell dose and non-TBI-ablative conditioning may be important variables influencing OS following UCBT in pediatric recipients. Given the small number of patients, these results should be viewed cautiously.

Current issues in living donor nephrectomy.

Of 96 consecutive renal transplants in 2 years, 50 (52%) were living donor grafts. Donor demographics, treatment plans, length of stay (LOS), charges, and complications were reviewed. Donors included 27 women and 23 men aged 22 to 61 (mean 42.2) years; 33 were living related and 17 living unrelated donors. Racial distribution included 1 Hispanic, 2 Asian, 8 black, and 39 white donors. Pretransplant evaluation defined renal anatomy and function (minimal creatinine clearance 75 cc/min). Hospital admission occurred the morning of donation. Nephrectomy under general anesthesia entailed an anterior flank, extra-retroperitoneal approach (no rib resection); and postoperative epidural pain control was standard. Progressive early ambulation and pulmonary self-care optimized recovery. The 50 donors were hospitalized for 2 (n = 7), 3 (n = 18), 4 (n = 15), 5 (n = 6), and 6-8 (n = 4) days (mean LOS: 3.74 +/- 0.17, range 2-8 days). The mean charge for donor hospitalization was $15,415 +/- $397 (range $10,808-$29,579). One major intraoperative hemorrhage required transfusion; 1 patient was readmitted for wound drainage and pneumonia treated medically. While 40 of 50 patients (80%) were hospitalized for 4 days or less, there was no readmission because of short hospital stay. One early graft loss (3 days) occurred from technical problems; all others gained excellent life sustaining function. Three additional kidneys failed from rejection, noncompliance, and systemic coagulopathy. One recipient died at 8 months (CVA) with normal renal function. Current strategies for successful living kidney donation are thorough patient and family education, ambulatory preoperative testing, morning of surgery admission, and discharge planning beginning before hospitalization. Excellent outcomes may be accompanied by a brief LOS, epidural pain management, and liberal use of willing and healthy related and unrelated living donors.

Thiotepa cyclophosphamide followed by granulocyte colony-stimulating factor mobilized allogeneic peripheral blood cells in adults with advanced leukemia.

Thirty-one patients (median age, 44 years) with advanced hematologic malignancies were given thiotepa 15 mg/kg, and cyclophosphamide 120 (n = 14) or 150 (n = 17) mg/kg followed by unfractionated peripheral blood stem cell transplants (PBSCT) from genotypically identical siblings (n = 28) or one antigen mismatched family donor (n = 3). Donors were mobilized with granulocyte colony-stimulating factor 5 to 10 microgram/kg/d for 6 days and underwent two to three leukapheresis on days +5, +6, +7. The median cell yield per donor expressed/kg of recipients body weight was as follows: nucleated cells 13 x 10(8)/kg; CD34+ cells 6 x 10(6)/kg; colony-forming unit-granulocyte macrophage 38 x 10(4)/kg, and CD3+ cells 449 x 10(6)/kg. The diagnoses were chronic myeloid leukemia (n = 4), acute myeloid (n = 9) or lymphoid leukemia (n = 2), acute myelofibrosis (n = 2), multiple myeloma (n = 1), lymphoma (n = 6), chronic lymphocytic leukemia (n = 1) myelodysplasia (n = 6). Twenty-eight patients had advanced disease, 29 patients were first grafts, and 2 were second transplants 3 and 9 years after the first. Neutrophil counts of 0.5 x 10(9)/L and platelet counts of 30 x 10(9)/L platelets were both achieved on day +14 (median). Engraftment could be proven by sex markers or DNA polymorphism in 29 of 31 patients: one had early leukemia relapse and one patient was unevaluable because of early death. Acute graft-versus-host disease (GVHD) was scored as minimal or absent (grade 0 to 1) in 14 patients, moderate (grade II) in 13, and severe (grade III to IV) in four. Causes of death were leukemia (n = 4), acute GVHD (n = 4, with associated cytomegalovirus infections in three), sepsis (n = 1), liver failure (n = 1), multiorgan failure (n = 1), and hemorrhage (n = 1). The actuarial transplant mortality is 29%, the actuarial relapse rate 22%. Nineteen patients survive with a median follow up of 288 days (100-690). The actuarial 2-year survival is 57%. Three patients received PBSCT from family donors mismatched for one class II antigen: all engrafted, one developed grade I aGVHD; one died of leukemia on day +155; two are alive disease free 267 to 290 days postgraft. This study suggests that thiotepa cyclophosphamide followed by unfractionated PBSC allograft may be an alternative form of transplant for adults with advanced leukemia, also in the setting of one antigen mismatched donor. The engraftment is rapid with acceptable GVHD and relatively low transplant-related mortality.