Results of a pilot study on the use of third-party donor mesenchymal stromal cells in cord blood transplantation in adults.

BACKGROUND AIMS: Cord blood (CB) transplants with co-infusion of third-party donor (TPD) mobilized hematopoietic stem cells (MHSC) have been shown to result in 'bridge' engraftment with prompt neutrophil recovery and high final rates of CB engraftment and full chimerism. This strategy overcomes the limitation posed by low cellularity of CB units for unrelated transplants in adults. Enhancement of adaptive immunity reconstitution without increasing risks of graft-versus-host disease (GvHD) is required to optimize results further. Our objectives were to evaluate co-infusion of mesenchymal stromal cells (MSC) from the same TPD regarding tolerance, CB engraftment and effects on acute (a)GvHD, both preventive and therapeutic. METHODS: Ex vivo-expanded bone marrow MSC were infused at the time of the transplant or the in case of refractory aGvHD. RESULTS: Nine patients received 1.04 - 2.15 x 10(6)/kg (median 1.20) MSC immediately after CB and TPD MHSC. Neither immediate adverse side-effects nor significant differences regarding CB engraftment or aGvHD development were observed. Four patients developed grade II aGvHD, refractory to steroids in two. These reached complete remission after therapeutic infusions of MSC. CONCLUSIONS: In recipients of 'dual CB/TPD MHSC transplants', MSC infusions were therapeutically effective for severe aGvHD but no significant differences in CB engraftment and incidence of severe aGvHD were observed following their prophylactic use. Although results of this study alone cannot conclusively determine the application of MSC in CB transplantation, we believe that, in this setting, the best use of MSC could be as pre-emptive treatment for aGvHD.

Early hematopoietic recovery after single unit unrelated cord blood transplantation in adults supported by co-infusion of mobilized stem cells from a third party donor.

BACKGROUND AND OBJECTIVES: Our objective was to improve the outcome of cord blood (CB) transplantation in adults, by overcoming the limitations imposed by the low number of stem cells present in CB units. DESIGN AND METHODS: We combined single CB units and co-infusion of third party donor (TPD)-derived peripheral blood mobilized hematopoietic stem cells (MHSC) following myeloablative conditioning with reduced extra-hematologic toxicity. RESULTS: Twenty-seven eligible patients with high-risk hematologic malignancies (age 16-60 years, median 29, weight 43-78 Kg, median 67) received CB units (median nucleated cell count 2.37x10(7)/Kg, median CD34+ cells 0.11x10(6)/Kg) co-infused with TPD-derived MHSC (2.30x10(6)/Kg CD34+ cells; <1x10(4)/Kg CD3+ cells). Neutrophil engraftment (>0.5x10(9)/L) occurred 10 days (9-36) post-transplant and was initially of TPD-origin in all patients except for four who received maternal MHSC, and then became of stable CB-origin. Median times to CB-derived neutrophil count >0.5x10(9)/L and full CB-chimerism were 22 and 55 days, respectively. The maximum cumulative incidence for engraftment, CB-engraftment and full CB-chimerism was 0.93 (95%CI: 0.83-1.00). The median time to reach unsupported platelet counts >20x10(9)/L was 33 days, with a maximum cumulative incidence of 0.74 (95%CI: 0.59-0.93). Transplant-related morbidity was associated primarily with non-neutropenic phase infections. Co-infusion of TPD-cells was well tolerated, with only 14.8% of recipients developing acute graft-versus-host disease (grade III-IV) and 20% developing a chronic (limited) form. The predicted 4-year overall survival was 69% for the whole group and 77% for the 23 patients receiving non-maternal TPD. INTERPRETATION AND CONCLUSIONS: Our strategy offers prompt engraftment with a low rate of complications in a feasible alternative protocol that overcomes the current limitations of a single CB-transplant in adults.

Unrelated umbilical cord blood transplants in adults: Early recovery of neutrophils by supportive co-transplantation of a low number of highly purified peripheral blood CD34+ cells from an HLA-haploidentical donor.

UNLABELLED: OBJECTIVE, METHODS, AND RESULTS: To reduce the period of posttransplant neutropenia and related early morbidity and mortality of cord blood (CB) transplants, we assessed the feasibility of co-infusion of a low number of highly purified peripheral blood CD34+ cells from a related haploidentical donor with a CB graft. Between March 1999 and May 2002, 11 patients with high-risk hematologic malignancies were transplanted using this strategy. The seven patients who received a haploidentical peripheral blood graft and a CB graft from a sibling (6) or the father (1) had prompt recovery (9-17 days, median 10) of the absolute neutrophil count (ANC) to greater than 0.5 x 10(9)/L. Analysis of DNA polymorphisms showed initial predominance of the haploidentical genotype both in granulocytes and in mononuclear cells, and subsequent progressive replacement by cells of CB genotype until final complete CB chimerism was achieved by patients who survived for sufficient periods of time. The four patients who received maternal haploidentical cells had no significant contribution of these to blood leukocytes, although complete CB chimerism was achieved by three of them and two reached engraftment of the CB on days +20 and +36. Morbidity due to early bacterial or fungal infections was remarkably low in patients with prompt ANC recovery. CONCLUSION: Our data show that co-infusion of a CB unit and a low number of haploidentical CD34+ cells may result in a shortened period of posttransplant neutropenia. This is likely the result of prompt and transient engraftment of the haploidentical hematopoietic stem cells that may provide the patient antimicrobial protection until the later engraftment of the CB hematopoietic stem cells.

Second mobilization and collection of peripheral blood progenitor cells in healthy donors is associated with lower CD34(+) cell yields.

We have retrospectively evaluated the results of two cycles of mobilization and collection of peripheral blood progenitor cells (PBPC) from 46 healthy donors included in the Spanish National Donor Registry. Mobilization involved the administration of granulocyte colony-stimulating factor (G-CSF) at a median dose of 10 microg/kg per day, and apheresis was begun after the fourth dose of G-CSF in both cycles. The median interval between both mobilizations was 187 days (range, 7-1428 days). The incidence and types of side-effects were similar after both donations, with 25 and 26 donors developing some toxicity after the first and second donations, respectively. The median number of CD34(+) cells collected was higher after the first mobilization than after the second (5.15 versus 3.16 x 10(6)/kg, respectively; p = 0.05), and 29 donors yielded fewer CD34(+) cells after the second mobilization (p = 0.018). A lower proportion of donors yielded CD34(+) cell counts >4 x 10(6)/kg after the second cycle than after the first (52% versus 76%, respectively; p = 0.057). Our study shows that second rounds of PBPC collection from normal donors are well tolerated but are associated with a significantly reduced number of CD34(+) cells collected when the same mobilization scheme is used.

Analysis of factors associated with low peripheral blood progenitor cell collection in normal donors.

BACKGROUND: Predictive factors of the response to rHuG-CSF in normal donors have not been extensively studied. STUDY DESIGN AND METHODS: We analyzed factors influencing CD34+ cell yield in the 1st day of collection in 261 healthy donors from the Spanish National Donor Registry. The median age was 38 years (range, 2-72). The median dose of rHuG-CSF was 10 microg per kg per day (range, 5-20) over 4 days. In 103 donors (40%), <4 x 10(6) per kg CD34+ cells were collected. The variables that were analyzed included age, sex, weight, basal complete blood cell count, dose, type of rHuGCSF and schedule of administration, and maximum WBC count before apheresis. RESULTS: By univariate analysis, the maximum WBC count (<50 vs. >or=50 x 10(9)/L, p = 0.004), advanced age (p = 0.008), and number of daily rHuG-CSF doses (one vs. two; p = 0.01) correlated with the number of CD34+ cells collected. By multivariate analysis, donors age (<38 vs. >or=38 years; p = 0.014) and a single daily dose of rHuG-CSF (p = 0.005) were the two variables that significantly predicted a low CD34+ cell yield. CONCLUSION: Donors' age, with a threshold of 38 years or more, and the rHuG-CSF schedule are the factors that significantly affected CD34+ cell mobilization and collection in healthy donors.