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Abstract: Haploidentical hematopoietic stem cell transplantation (HSCT) provides an opportunity for nearly all patients to benefit from HSCT when a human leukocyte antigen (HLA) genotypically matched sibling is not available. Initial results with the use of mismatched allografts led to limited enthusiasm because of graft-versus-host disease (GVHD) and infectious complications, resulting in an unacceptable treatment-related morbidity and mortality. Recent advances with effective T cell depletion, the use of a “megadose” of stem cells, earlier detection of severe infections, combined with better antimicrobial therapy and reduced-intensity conditioning (RIC) has significantly decreased the early transplant-related mortality and GVHD, whereas enabling prompt engraftment, hence advancing the therapeutic benefit of haploidentical transplantation. However, the cardinal problems related to delayed immune reconstitution allowing posttransplant infectious complications and relapse remain, limiting the efficacy of haploidentical HSCT. Preliminary data has demonstrated the potential for use of adoptive cellular immunity and selective allodepletion in rapidly reconstituting immunity without GVHD. The encouraging reports from haploidentical transplant using noninherited maternal antigen (NIMA)-mismatched or natural killer (NK) alloreactive donors may greatly increase the donor availability and open the way to more appropriate donor selection in HLA-haploidentical HSCT. Future challenges remain in determining the safest approach for haploidentical transplant to be performed with minimal risk of GVHD, whereas preserving effective graft-versus-leukemia activity and promoting prompt immune reconstitution. [Copyright &y& Elsevier]

Abstract: The development of nonmyeloablative (NM) hematopoietic cell transplantation (HCT) has extended the potential curative treatment option of allografting to patients in whom it was previously contraindicated because of advanced age or comorbidity. Acute and chronic graft versus host disease (GVHD) and its consequent nonrelapse mortality (NRM), remains the major limitation of NM HCT. In this report, we analyzed the outcome of 67 patients (median age, 45 years) with hematologic diseases receiving NM conditioning with fludarabine 90 mg/m2 and total body irradiation (TBI) 200-cGy, followed by filgrastim-mobilized peripheral blood stem cell transplant from HLA identical (n = 61), 5/6 antigen-matched related (n = 1), 6/6 antigen-matched unrelated (n = 3), and 5/6 antigen-matched unrelated (n = 2) donors. The first cohort of 21 patients were given cyclosporine (CSP) and mycophenolate mofetil (MMF) as postgrafting immunosuppression, whereas the subsequent cohort was given additional methotrexate (MTX) and extended duration of CSP/MMF prophylaxis in an attempt to reduce graft-versus-host disease (GVHD). Sixty-four (95%) patients engrafted and 3 (5%) had secondary graft failure. Myelosuppression was moderate with neutrophil counts not declining below 500/μL in approximately 25% of patients, and with more than half of the patients not requiring any blood or platelet transfusion. The 2-year cumulative interval (CI) of grade II-IV, grade III-IV acute GVHD and chronic GVHD were 49%, 30%, and 34%, respectively. The 2-year probability of NRM, overall (OS), and progression-free (PFS) survival were 27%, 43%, and 28%, respectively. GVHD-related death accounted for 85% of NRM. Compared with patients receiving CSP/MMF, patients receiving extended duration of CSP/MMF with additional MTX in postgrafting immunosuppression had a significantly lower risk of grade III-IV acute GVHD (CI 20% versus 52%; P = .009) and NRM (CI at 2 years: 11% versus 62%; P < .001), without any significant adverse impact on the risk of relapse (CI at 2 years: 59% versus 33%; P = .174) Subgroup analysis of a cohort of patients given MTX/CSP/MMF showed that patients with “standard risk” diseases (n = 21) had a 3-year OS and PFS of 85% and 65%, respectively. This compares favorably to the 41% (P = .02) and 23% (P = .03) OS and PFS, respectively, in patients with “high-risk” diseases (n = 25). In conclusion, the addition of MTX onto the current postgrafting immunosuppression regimen with extended CSP/MMF prophylaxis duration provides more effective protection against severe GVHD, and is associated with more favorable outcome in patients receiving NM fludarabine/TBI conditioning than in patients receiving fludarabine/TBI conditioning with CSP and MMF without MTX. [Copyright &y& Elsevier]

We report the outcome of 13 patients with advanced malignancies who underwent nonmyeloablative conditioning therapy followed by infusion of partially matched unrelated cord blood cells. The median age of these patients was 49 years, and their median weight was 65.7 kg. The median nucleated cell dose infused was 2.07 × 107/kg. Eight of the 13 patients demonstrated donor chimerism between 4 weeks and 6 months, and subsequent conversion to full donor chimerism was achieved in 5 patients. Three patients were alive and free of disease at 158 to 1054 days, with a median survival of 288 days after transplantation. The 100-day event-free survival is 69%, and overall survival is 77%. At 1 year, the event-free and overall survival was 43%. Treatment-related mortality observed within the first 100 days after transplantation was low: 1 previously extensively pretreated patient died of multiorgan failure. This result provides a basis for further exploring this potentially curative approach to selected patients who lack matched related or unrelated hematopoietic stem cell donors. [Copyright &y& Elsevier]

Unrelated umbilical cord blood (UCB) transplantation has recently been explored in an increasing number of adult patients. The relative ease of procurement and the lower-than-anticipated risk of severe acute graft-versus-host disease has made UCB transplantation an appealing alternative to bone marrow-derived hematopoietic stem cells. The use of reduced-intensity or nonmyeloablative preparative regimens to allow engraftment of UCB broadens the scope of patients who may benefit from allogeneic immunotherapy, including elderly and medically infirm patients with no matched sibling donor. This review summarizes the available data on the use of UCB as an alternative source of hematopoietic stem cell transplantation in adult patients. [Copyright &y& Elsevier]

The successful expansion of hematopoietic stem and progenitor cells (HSPCs) from umbilical cord blood (UCB) for transplantation could revolutionize clinical practice by improving transplantation-related outcomes and making available UCB units that have suboptimal cell doses for transplantation. New cytokine combinations appear able to promote HSPC growth with minimal differentiation into mature precursors and new agents, such as insulin-like growth factor–binding protein 2, are being used in clinical trials. Molecules that simulate the HSPC niche, such as Notch ligand, have also shown promise. Further improvements have been made with the use of mesenchymal stromal cells, which have made possible UCB expansion without a potentially deleterious prior CD34/CD133 cell selection step. Chemical molecules, such as copper chelators, nicotinamide, and aryl hydrocarbon antagonists, have shown excellent outcomes in clinical studies. The use of bioreactors could further add to HSPC studies in future. Drugs that could improve HSPC homing also appear to have potential in improving engraftment times in UCB transplantation. Technologies to expand HSPC from UCB and to enhance the homing of these cells appear to have attained the goal of accelerating hematopoietic recovery. Further discoveries and clinical studies are likely to make the goal of true HSPC expansion a reality for many applications in future. [ABSTRACT FROM AUTHOR]

Abstract: Several studies have compared the results of unrelated donor bone marrow transplantation (UBMT) and unrelated donor cord blood transplantation (UCBT). To objectively analyze these data, we performed a systematic review and meta-analysis of pooled data on comparative studies of UCBT and UBMT in patients requiring hematopoietic stem cell transplantation. Combining the studies, 161 children and 316 adults undergoing UCBT (mostly 1 or 2 antigen-mismatched), along with 316 children and 996 adults undergoing UBMT (almost entirely fully matched with the recipient), were analyzed. T-cell–depleted UBMT was excluded; where data were available, only fully matched UBMT was used in the analysis. Pooled comparisons of studies of UCBT and UBMT in children found that the incidence of chronic graft-versus-host disease (GVHD) was lower with UCBT (relative risk [RR] = 0.26; 95% confidence interval [CI] = 0.12–0.57; P = .16), but the incidence of grade III–IV acute GVHD did not differ (RR = 1.46; 95% CI = 0.42–5.03; P = .55). There was no difference in 2-year OS in children when studies were pooled (RR = 0.76; 95% CI = 0.31–1.87; P = .55). For adults, transplantation-related mortality (pooled estimate, 1.04; 95% CI = 0.52–2.08; P = .91) and disease-free survival (DFS) (pooled estimate, 0.59; 95% CI = 0.18–1.96; P = .39) were not statistically different. Because of the unavailability of randomized controlled trials, pooled analysis of nonrandomized comparative studies was performed. Thus, our meta-analysis confirmed that UCBT in children and adults had consistently equivalent survival outcomes compared with UBMT despite greater donor–recipient HLA disparity with UCBT. [Copyright &y& Elsevier]

Abstract: We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m2 every 12 hours × 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours × 16 doses, followed by etoposide of 60 mg/kg × 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d × 2 days in lieu of etoposide). PBPCs purged with 4HC were infused following this induction. Toxicities included grade 3 or 4 skin rashes, stomatitis/mucositis, and delay in time to hematopoietic recovery. The maximum tolerated dose of 4HC used to purge PBPCs in this trial was 20 μg/mL, which resulted in an average of 18 days for white blood cells and 28 days for platelet recovery. With a median follow-up of 2.25 years in surviving patients, the 3-year disease free survival rate is 44% and the overall survival rate is 89%. These data suggest that autologous PBPCs are more sensitive than marrow purged with 4HC, tolerating less intense purging, although a survival advantage may still be seen and should be assessed in larger studies. Approaches to minimize stomatitis and protect normal stem cells from the toxicity of 4HC may improve the tolerance and efficacy of this approach. © 2003 American Society for Blood and Marrow Transplantation Biology of Blood and Marrow Transplantation 9:183-188 (2003) [Copyright &y& Elsevier]