CBF

ii. Co-transplantation of CBU and mobilized stem cells from a third party donor.

  1. 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. Fernandez MN, Regidor C, Cabrera R, Garcia-Marco JA, Fores R, Sanjuan I et al. Exp Hematol 2003; 31:535-544.Abstract

To reduce the period of posttransplant neutropenia and related early morbidity and mortality of cord blood transplants, the authors assessed the feasibility of co-infusion of a low number of highly purified peripheral blood CD34+ cells from a related haploidentical donor with a cord blood graft. Seven adult patients with high-risk malignancies received a (low dose) haploidentical peripheral blood graft and a cord blood graft from a sibling (6) or the father (1). The patients had prompt neutrophil engraftment reaching an ANC of 0.5 x 109/L in 9-17 days (median 10 days). Analysis of DNA polymorphisms showed initial predominance of the haploidentical genotype with subsequent progressive replacement by cells of cord blood genotype until final complete cord blood chimerism was achieved by patients who survived for sufficient periods of time. The authors concluded that co-infusion of a cord blood unit and a low number of haploidentical CD34+ cells may result in a shortened period of posttransplant neutropenia.

  1. 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. Magro E, Regidor C, Cabrera R, Sanjuan I, Fores R, Garcia-Marco JA, Ruiz E, Gil S, Bautista G, Millan I, Madrigal A, Fernandez MN. Haematologica. 2006;91:640-648.

The investigators' 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. They theorized that co-infusion of CB cells and selected T-cell-depleted, mobilized hematopoietic stem cells (MHSC) (in a number low enough to carry a total number of T-cells below the threshold for GVHD) from a third party donor (TPD) would be safe in terms of the risks of GVHD and rejection of the CB transplant, and might have the capacity for early engraftment in an intensively immuno-suppressed recipient. For the TPD cells, they chose a level of 104/kg CD3+ cells, a dose that is much lower than the megadose used in transplants from haploidentical donors. They presumed that the CB cells would have a competitive advantage for final chimerism over the third party MHSC. The main role of the third party MHSC would be to provide early neutrophil engraftment during the window period prior to engraftment of the primitive hematopoietic stem cells of the CB transplant.

Twenty-two patients received a preparative regimen containing TBI: the first 3 patients received a 12 Gy dose (lungs shielded at 8 Gy) and did not receive fludarabine. To reduce extra-hematologic toxicity for the other 19 patients, the TBI was reduced to 10 Gy (lungs also shielded at 8 Gy) and fludarabine was introduced. ATG was used in all but two of these patients. Four patients received a busulfan-containing regimen because of myeloproliferative disease or previous irradiation. One patient was conditioned with an individualized regimen.

The 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.

The authors concluded that their 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.

  1. Enhanced in vivo homing of uncultured and selectively amplified cord blood CD34+ cells by cotransplantation with cord blood-derived unrestricted somatic stem cells. Chan SL, Wnendt S, Kraus M, Teng E, Leong HF, Merchav S. Stem Cells. 2007;25:529-36.

Mesenchymal stem cells have been implicated as playing an important role in stem cell engraftment. Recently, a new pluripotent population of umbilical cord blood (UCB) cells, unrestricted somatic stem cells (USSCs), with intrinsic and directable potential to develop into mesodermal, endodermal, and ectodermal fates, has been identified. In this study, the investigators evaluated the capacity of ex vivo expanded USSCs to influence the homing of UCB-derived CD34(+) cells into the marrow and spleen of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice.

USSCs induced a significant enhancement of CD34(+) cell homing to both bone marrow and spleen, with a magnitude similar to that induced by USSCs that had been thawed prior to transplantation. The effect of USSCs was dose-dependent and detectable at USSC:CD34(+) ratios of 1:1 and above. Enhanced marrow homing by USSCs was unaltered by extensive culture passaging of the cells, as similar enhancement was observed for both early-passage (passage 5 [p5]) and late-passage (p10) USSCs. The homing effect of USSCs was also reflected in an increased proportion of NOD/SCID mice exhibiting significant human cell engraftment 6 weeks after transplantation, with a similar distribution of myeloid and lymphoid components. USSCs enhanced the homing of cellular products of ex vivo expanded UCB lineage-negative (lin(-)) cells, generated in 14-day cultures by Selective Amplification. The relative proportion of homing CD34(+) cells within the culture-expanded cell population was unaltered by USSC cotransplantation. Production of stromal-derived factor-1 (SDF-1) by USSCs was detected by both gene expression and protein released into culture media of these cells. Knockdown of SDF-1 production by USSCs using lentiviral-SiRNA led to a significant (p < .05) reduction in USSC-mediated enhancement of CD34(+) homing.

These findings suggest a clinical potential for using USSCs in facilitating homing and engraftment for cord blood transplant recipients.