Novel strategies for improving hematopoietic reconstruction after allogeneic hematopoietic stem cell transplantation or intensive chemotherapy

Abstract

Introduction: High-dose conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT) as well as intensive poly-chemotherapy for acute myeloid leukemia (AML) induce prolonged periods of neutropenia. The duration of the neutropenia is particularly long following umbilical cord blood transplantation (UCBT). Areas covered: After briefly reviewing the impact of hematopoietic growth factors administration to hasten hematologic reconstitution after allo-HCT or intensive AML chemotherapy, this article summarizes recent approaches that have been investigated to prompt hematologic reconstruction after UCBT or intensive AML chemotherapy. Expert opinion: In the allo-HCT setting, administration of G-CSF or GM-CSF shortened the duration of the neutropenia but failed to decrease infection-related mortality or to improve survival. Novel approaches to hasten hematological reconstruction after UCBT such as double UCBT with expansion of one of the 2 UCB units with Notch ligand, mesenchymal stromal cells, nicotinamide, or StemRegenin 1, co-transplanting a single UCB unit with HLA-haploidentical CD34+ cells, or increasing UCB HSC homing to marrow niches via direct intra bone UCB administration, pulse treatment with dmPGE2 or enforced fucosylation are promising and deserve further investigations in prospective phase III studies. In the AML setting, G-CSF or GM-CSF administration after intensive chemotherapy decreased the duration of the neutropenia without improving survival. ARTICLE HISTORY

Reconstitution of adaptive immunity after umbilical cord blood transplantation: impact on infectious complications

“…Several other approaches have been assessed to improve both thymo-dependent and thymo-independent pathways of T-cell reconstitution after UCBT. These include, ex vivo expansion of hematopoietic stem cells [reviewed in (88,89)], modulation of thymic niche accessibility by lymphoid progenitors (90), enhancement of thymic function (i.e., through stimulation of the GH pathway or through sex steroid blockade) and treatments with recombinant IL-7 and IL-15 [reviewed in (89,91)]. Posttransplant adoptive transfer of donor-derived T-cell progenitors or virusspecific mature T cells was also used to boost immunity against infections.…”

Cord Haploidentical Non-In Vitro T Cell Depletion Allogeneic Hematopoietic Stem Cell Transplantation Reduces Relapse of Refractory Acute Leukemia

“…Conventional allogeneic hematopoietic stem cell transplantation (HSCT) yields long-term survival in only 7% to 24% of patients with refractory acute lymphoblastic leukemia and in only 10% to 40% of those with late-stage acute myelogenous leukemia (AML) [1][2][3][4][5][6]. Although several recent studies of allogeneic HSCT using 2 grafts (ie, double-umbilical cord blood [UCB] transplantation [dUCBT]) and haploidentical cord blood (haplo-cord) HSCT have shown an enhanced graft-versus-leukemia (GVL) effect along with a graft-versus-graft (GVG) response [4,[7][8][9][10][11][12][13][14][15][16][17], this finding remains controversial [9,14,18,19]. The outcomes of previous studies were strongly influenced by the extent of HLA mismatching and patient selection [20,21].…”

Effects and Predictive Factors of Immunosuppressive Therapy Combined with Umbilical Cord Blood Infusion in Patients with Severe Aplastic Anemia

“… 31 32 3) UCBI offers a large amount of G-CSF, GM-CSF, and CFU-F to increase the recovery of SAA. 21 22 23 24 25 26 27 It was noteworthy that intervals from first diagnosis to IST at baseline was longer in the UCBI+IST group than the IST group. The detailed reasons were as follows.…”

“… 6 2) UCB brings plentiful hematopoietic factors, such as Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), that could stimulate proliferation and differentiation of hematopoietic progenitors, consequently promoting hematopoiesis. 21 22 23 24 3) Colony forming unit-fibroblastic (CFU-F) in UCB, which plays a critical role in hematopoietic microenvironment, improves the recovery of hematopoiesis. 25 26 27 4) HSCs from UCB are characterized by weak antigenicity that decreases the risk of GVHD.…”