Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities

Table 1 Molecules that mediate hematopoietic stem and progenitor cell adhesion and chemotaxis during transplantation

HSPC receptor	Bone marrow ligands	Effect	Ref.
PSGL-1/CD162	Selectins (P and E)	Promote HSPC homing	[10]
β1 integrin	Opn	Contribute to HSC trans-marrow migration toward the endosteal region	[17,18]
VLA-4/α4 β1	VCAM-1, fibronectin	Promote HSPC homing	[7,11]
VLA-5/α5 β1	Fibronectin	Promote HSPC homing and proliferation	[19,20]
LFA-1/αL β2	ICAM-1	Promote HSPC homing	[7,11]
LPAM-1/α4 β7	MAdCAM-1	Promote HSPC homing and engraftment	[21]
Cx43		Participate in the formation of intercellular transmembrane channels, facilitate the transportation of mitochondria or other substances, and promote bone marrow regeneration and HSPC engraftment	[22]
CXCR4	SDF-1	Promote HSPC homing and engraftment and participate in the regulation of HSPC survival and proliferation	[7]
c-kit	SCF	The transmembrane isoform of SCF is critical in the lodgment and detainment of HSCs within the bone marrow niche	[23]
c-MPL	TPO	TPO promotes the survival and proliferation of HSPCs and upregulates SDF-1 in the bone marrow niche, thereby contributing to HSPC homing and engraftment	[24,25]
CD44/Pgp-1	Selectins (P, E and L), HA	CD44 and HA play a key role in SDF-1-dependent transendothelial migration of HSPCs and their final anchorage within the bone marrow niche	[26]
CD82/KAI1		CD82 modulates HSPC bone marrow maintenance, homing, and engraftment	[27]
Anxa2r	Annexin II/Anxa2	Regulate stem cell adhesion, homing, and engraftment	[28]
CaR	Ca2+	Enhance HSC lodgment and engraftment in the bone marrow niche	[29]
N-cadherin	N-cadherin	N-cadherin-mediated cell adhesion is functionally required for the establishment of hematopoiesis in the bone marrow niche after bone marrow transplantation	[30]

Anxa2r: Annexin II receptor; c-kit: Tyrosine-protein kinase kit; c-MPL: Thrombopoietin receptor; Ca²⁺: Calcium; CaR: Calcium-sensing receptor; CD162: cluster of differentiation 162; CD44: Cluster of differentiation 44; CD82: Cluster of differentiation 82; Cx43: Connexin 43; CXCR4: C-X-C chemokine receptor 4; HA: Hyaluronic acid; HSC: Hematopoietic stem cell; HSPC: Hematopoietic stem and progenitor cells; ICAM-1: Intercellular adhesion molecule 1; KAI1: Kangai 1; LFA-1: Lymphocyte function-associated antigen-1; LPAM-1: Lymphocyte Peyer's patch adhesion molecule-1; MAdCAM-1: Mucosal addressin cell adhesion molecule-1; MPL: Myeloproliferative leukemia gene; Opn: Osteopontin; Pgp-1: Phagocytic glycoprotein-1; PSGL-1: P-selectin glycoprotein ligand-1; Ref.: Reference; SCF: Stem cell factor; SDF-1: Stromal cell-derived factor-1; TPO: Thrombopoietin; VCAM-1: Vascular cellular adhesion molecule-1; VLA-4: Very late antigen 4; VLA-5: Very late antigen 5.

Table 2 Main factors for post-transplant immune reconstitution

Factors	Effect	Ref.
Recipient age	Several studies show that immune reconstitution, especially the reconstitution of CD4+ T cells, is inversely related to age. However, some studies report that age has no effect on the reconstitution of any subgroup of lymphocytes	[63,90,91]
Graft source	Immune reconstitution occurs faster after PBSCT than after BMT. This may be because PBSCT grafts are rich in mature lymphocytes. Delayed immune reconstitution after UCBT is related to low lymphocyte count and immature immune cells in umbilical cord blood	[61,92-95]
HLA matching between donor and recipient	HLA mismatch causes delayed reconstitution of neutrophils and T cells
Intensity of preconditioning	Several studies show that compared with MA-SCT, RICSCT reduces thymus damage and promotes immune reconstitution. However, some studies show no significant difference in recipient immune reconstitution between these two transplantation methods	[60,96-98]
GVHD	GVHD damages thymus structure and function and interferes with T cell differentiation at all stages, thereby affecting T cell reconstitution. GVHD also affects the recovery of B cell number and function	[84,99]
GVHD prevention	Donor TCD reduces the risk of GVHD; however, the lack of T cells increases the risk of infection and delayed immune reconstitution	[100]
	The use of ATG or alemtuzumab has a negative effect on the reconstitution of T cells and B cells	[101-103]

ATG: Antithymocyte globulin; BMT: Bone marrow transplantation; CD4: Cluster of differentiation 4; GVHD: Graft-versus-host disease; HLA: Human leukocyte antigen; MA-SCT: Myeloablative stem cell transplantation; PBSCT: Peripheral blood stem cell transplantation; Ref.: Reference; RICSCT: Reduced-intensity conditioning stem cell transplantation; TCD: T cell depletion; UCBT: Umbilical cord blood stem cell transplantation.

Table 3 Strategies to separate graft-versus-host disease and graft-versus-leukemia

Separation strategies	Approaches	Brief description	Ref.
GVHD risk prediction	GVHD biomarker testing	Contributes to GVHD diagnosis and provides evidence for the early use of anti-GVHD drugs	[123]
	Cytokine gene polymorphism testing	Helps to identify patients with a high risk of severe GVHD and take preventive measures	[124]
Modification of donor graft cells	Donor T cell depletion	Donor T cell depletion reduces GVHD while increasing the risk of infections, graft rejection, and disease relapse	[109]
	Graft-specific cell population depletion	Removing specific cell populations such as naïve T cells in the graft that consistently cause severe GVHD	[118]
	DLI to treat relapse	DLI is very effective in the treatment of relapsed slow-growing hematopoietic malignancies such as CML; however, the mechanism is unknown	[122]
	Application of CAR T cell	The combination of scFv that identifies leukemia-specific antigens and the activating domain of T cells enhances specific identification and killing of leukemia cells	[125,126]
	Suicide gene transduced donor lymphocyte infusion	A genetically modified suicide gene is introduced. Donor lymphocytes expressing this gene are sensitive to prodrugs, a feature that can be used when needed to regulate GVHD through the drug clearance of transduced cells	[127]
	Selecting memory T cells	Memory T cells cause mild or no GVHD and have critical graft-versus-tumor functions	[118]
	Enhancing activated γδ T cells	γδ T cells have the ability to kill leukemic blasts, and allogeneic TCR γδ T cells are not alloreactive and do not cause GVHD	[113]
	Selecting Tregs	Tregs suppress the activation and proliferation of effector T cells and downregulate the body’s response to foreign antigens or autoantigens	[86]
	Modifying/selecting other cells in the grafts	Selecting mesenchymal cells, NK cells, and manipulating dendritic cells and dendritic cell subsets	[79,122,129]
Drug intervention	Application of immunosuppressants	Various immunosuppressants suppress T cells and reduce GVHD via different mechanisms	[130]
	Application of HDACis	HDACis, such as vorinostat, downregulate inflammatory cytokines and increase the number of Tregs, thereby reducing the occurrence of GVHD, without effecting the GVL effect of donor CTLs	[131,132]
	Suppression of cytokines related to the occurrence of GVHD	Th1 cytokines such as TNF-α, IFN-γ, and IL-6 are related to aGVHD; Th2 cytokines such as IL-4, IL-5, and IL-10 are related to cGVHD. Appropriate regulation of these cytokines facilitates GVHD management	[122]
	Enhancing cytokines that suppress GVHD	Various cytokines such as IL-11 and keratinocyte growth factor reduce GVHD while preserving the GVL effect	[122]
	Targeting MiHAs on hematopoietic cells	CTLs targeting MiHAs such as HA-1 and HA-2 (expressed on hematopoietic cells only) promote the GVL effect	[121]
	Development and application of tumor vaccines	Vaccines targeting MiHAs on hematopoietic cells and leukemia-specific antigens improve GVL specificity	[133]

aGVHD: Acute GVHD; CAR: Chimeric antigen receptor; cGVHD: chronic GVHD; CML: Chronic myeloid leukemia; CTLs: Cytotoxic T lymphocytes; DLI: Donor lymphocyte infusion; GVHD: Graft-versus-host disease; GVL: Graft versus leukemia; HA-1: Histocompatibility antigens 1; HA-2: Histocompatibility antigens 2; HDACis: Histone deacetylase inhibitors; IFN-γ: Interferon-γ; IL-10: Interleukin 10; IL-4: Interleukin 4; IL-5: Interleukin 5; IL-6: Interleukin 6; MiHAs: Minor histocompatibility antigens; NK: Natural killer; Ref.: Reference; scFv: Single-chain variable fragment; TCR: T cell receptor; Th2: T-helper 2; TNF-α: Tumor necrosis factor α; Tregs: Regulatory T cells.

Table 4 Main factors for post-hematopoietic stem cell transplantation relapse

Factors	Brief description	Ref.
Disease type	The relapse rate is highest in ALL patients, followed by AML patients and CML patients	[161]
Pretransplant disease status	The risk of relapse is significantly higher in nonremission patients and patients with a high level of residual leukemia cells before transplantation	[151]
Risk stratification	The level of risk is positively correlated with the relapse rate and negatively correlated with the disease-free survival rate	[162]
Stem cell source	Peripheral blood stem cells contain more lymphocytes with a more potent GVL effect; as a result, the relapse rate of BMT is higher than that of PBSCT	[163,164]
Preconditioning	Myeloablative preconditioning is more effective in reducing post-transplant relapse than reduced intensity conditioning and nonmyeloablative preconditioning; T cell depletion is associated with increased relapse rates in CML and AML	[164,165]
GVHD	Post-transplant GVHD, especially cGVHD, is associated with a significantly lower relapse rate and a higher survival rate	[166,167]

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; BMT: Bone marrow transplantation; cGVHD: Chronic GVHD; CML: Chronic myeloid leukemia; GVHD: Graft versus host disease; GVL: Graft versus leukemia; PBSCT: Peripheral blood stem cell transplantation; Ref.: Reference.