Similarities and Differences Between Allogeneic Hematopoietic Cell and Organ Transplantation and What We Can Learn From Each Other to Guide Global Health Strategy

ABSTRACT

Background

Allogeneic hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT) have evolved into successful, curative treatments for many severe congenital and acquired diseases. Both use medical products of human origin and should therefore have overarching regulatory frameworks. Both require critical decisions about donor selection, donor/recipient matching, immunosuppression, and long‐term care, all tasks best performed by a trained, highly specialized multidisciplinary team. Both need committed institutions and governmental support for their success. Whereas the main barrier for performing SOT is the lack of suitable organs, access to a transplant center is the main limitation for HCT, which remains a highly specialized, complex, resource‐intensive, and costly medical procedure.

Methods and Results

Here, we describe the main indications for HCT and SOT, their similarities and differences regarding donor selection, treatment prior to transplant, intensity and duration of immunosuppression after transplantation, their main complications, and consequences of donation for living donors.

Conclusions

Strategies to improve worldwide access to HCT and SOT are discussed, as well as future developments in this highly innovative field of medicine.

Abbreviations

AML

acute myeloid leukemia

ATG

antithymocyte globulin

BKV

BK polyomavirus

BM

bone marrow

CMV

cytomegalovirus

CNI

calcineurin inhibitor

CVD

cardiovascular disease

DD

deceased donor

DSA

donor‐specific antibodies

ESKD

end‐stage kidney disease

FACT

Foundation for the Accreditation of Cellular Therapy

G‐CSF

granulocyte colony‐stimulating factor

GvHD

graft‐versus‐host disease

GvL

graft‐versus‐leukemia effect

GvT

graft‐versus‐tumor effect

HCT

hematopoietic cell transplantation

JACIE

Joint Accreditation Committee of the International Society for Cellular Therapy and the European Society for Blood and Marrow Transplantation

LD

living donor

LMIC

low and middle‐income countries

MAC

myeloablative conditioning

MMF

mycophenolate mofetil

MPHO

medical product of human origin

NMDP

National Marrow Donor Program

PBSC

peripheral blood stem cell

PTCy

post‐transplant cyclophosphamide

RBC

red blood cell

RD

related donor

RIC

reduced‐intensity conditioning

SES

socioeconomic status

SOT

solid organ transplantation

UCB

umbilical cord blood

URD

unrelated donor

WBMT

Worldwide Network for Blood and Marrow Transplantation

WHO

World Health Organization

WMDA

World Marrow Donor Association

1. Introduction

The first clinical successes of allogeneic hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT) occurred in the mid‐20th century, and both have evolved into successful treatments for many congenital and acquired diseases. They involve common elements, including: transfer of medical products of human origin (MPHOs); regulatory frameworks regarding safe and appropriate usage; criteria for donor selection, donor protection, donor/recipient matching, immunosuppression, and long‐term care; plus complex infrastructure involving national or international cooperation. Organ and cell donation and transplantation are variably available within World Health Organization (WHO) regions. Access to life‐enhancing or lifesaving transplants is unavailable for millions of waiting recipients, mostly in low‐and middle‐income countries (LMIC). This contributes to inequitable organ allocation, with the poorest being the least likely to have access to transplantation. Improvements in transplantation during recent years and ongoing challenges to equitable access have prompted WHO Member States to develop a Global Strategy for Donation and Transplantation of Organs, Tissues and Cells, a topic in next year's World Health Assembly. WHO's vision is to integrate cell, tissue, and organ transplantation into healthcare policies that address the needs for treatment of end‐stage diseases or debilitating conditions, and that by 2035, every Member State will be able to address its patients’ needs for life‐saving or life‐enhancing transplantation. The Global Strategy has three key objectives: increased availability of transplants, improved access to transplantation, and enhanced quality, safety, and efficacy in outcomes while protecting living donors (LDs). The Worldwide Network for Blood and Marrow Transplantation (WBMT) supports these goals as a nongovernmental organization collaborating with the WHO. Here, we report similarities and differences between organ and cell transplantation (Table 1). Our aims are to: improve mutual education between practitioners and scientists from each group; highlight areas to limit complications and costs, improve outcomes, and broaden the application of these innovative and highly successful therapies; all in support of the WHO's Global Transplant Strategy. For both, advances in recipient and donor selection, graft preservation, tailored immunosuppression, infection control, and long‐term safety management are continuing. The distinct challenges for each require specialty expertise, multidisciplinary collaboration, and scientific rigor.

TABLE 1.

Differences between allogeneic hematopoietic cell and organ transplantation.

	Organ transplantation	Allogeneic HCT
Donor status	Deceased or living donors	Only living donors
Recipient/donor HLA matching	HIghly preferable	Critical
Recipient/donor ABO matching	Essential, but may be overcome	Not essential
Recipient myeloablation	No	Yes
Need for organ preservation	Yes	Mainly given fresh
Main complications	Rejection, organ loss Death with adequate function	GvHD, infections
Engraftment by	Acceptance	Tolerance
Immunosuppression‐free	Rare	Common
Ultimate goal	Organ acceptance under IS Tolerance	Complete donor chimerism, off IS without GvHD
Consequences for living donor	Surgical (rare) Long‐term concerns for kidney	None

Abbreviations: HCT, hematopoietic cell transplantation; IS, immunosuppression.

HCT ‐Hematopoietic cell transplantation is a multistep procedure including: (1) donor and graft source selection, (2) recipient treatment with a conditioning regimen for immunosuppression and malignant disease eradication; (3) collection of donor stem cells; and (4) intravenous infusion of stem cells to establish donor‐derived hematopoietic and immune function [1]. Current indications are primarily malignant hematological disorders, most commonly acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndromes (MDS) [2, 3]. Importantly, the donor graft‐derived immune cells contribute to the elimination of malignant disease via the graft‐versus‐leukemia (GvL) or graft‐versus‐tumor (GvT) effect [4]. HCT was the first established curative cellular immune therapy. HCT is also used for curative treatment of nonmalignant hematologic diseases, including aplastic anemia, transfusion‐dependent thalassemia, sickle cell disease, and inherited immunodeficiencies and metabolic syndromes. (Table 2) [2, 3, 5]. Currently, 93,000+ HCT (48% allogeneic) are performed annually, with over 1.5 million completed worldwide [6, 7].

TABLE 2.

Main indications for allogeneic hematopoietic cell transplantation. ^a

Disease	Disease status	HLA‐identical sib	URD
AML	CR1 (favorable risk and MRD+)	S	CO
	CR1 (intermediate risk)	S	CO
	CR1 (adverse risk)	S	S
	CR2	S	S
	APL Molecular CR2	S	CO
	Relapse or refractory	CO	CO
ALL	Ph‐, CR1 (standard risk and MRD+)	S	CO
	Ph‐, CR1 (high risk)	S	S
	Ph+, CR1	S	S
	CR2	S	S
CML	1st CP, failing 2nd or 3rd TKI	S	S
	Accelerated phase, blast crisis or >1st CP	S	S
Myelofibrosis	Primary or secondary with an intermediate‐2 or high DIPSS score	S	S
MDS	IPSS‐R intermediate risk with additional factors	S	S
	IPSS‐R high, very high risk	S	S
	sAML in CR1 or CR2	S	S
CMML	CMML‐2 or MP‐CMML	S	S
	CMML‐0 or CMML‐1 with additional risk factors	S	S
CLL	Richter transformation	S	S
LBCL	Chemosensitive early relapse, ≥CR2	CO	CO
	Chemosensitive late relapse, ≥CR2	CO	CO
	Chemosensitive late relapse after auto‐HCT failure	CO	CO
	Refractory disease	CO	CO
FL	Chemosensitive relapse, >CR2	CO	CO
	≥CR2 after auto‐HCT failure	S	S
	Refractory	CO	CO
MCL	CR/PR≥1, no prior auto‐HCT	CO	CO
	CR/PR≥1, after prior auto‐HCT	CO	CO
	Refractory	CO	CO
WM	Poor risk disease	CO	CO
PTCL	CR1	CO	CO
	Chemosensitive relapse, ≥CR2	S	S
	Refractory	CO	CO
HL	Chemosensitive relapse after auto‐HCT	S	S
MM	Upfront standard risk	CO	CO
	Upfront high risk	S	S
	Chemosensitive relapse, prior auto‐HCT	CO	CO
	Refractory/relapse	CO	CO
Acquired SAA; AA/PNH	Newly diagnosed	S	CO
	Relapsed/refractory	S	S
Constitutional BMF syndromes		S	S

Abbreviations: CO, clinical option; S, standard care.

^a Modified according to Snowden et al., BMT 2022.[7]

Initially, HCT grafts used bone marrow (BM), but peripheral blood stem cells (PBSCs) or umbilical cord blood (UCB) became alternative sources during the 1990s. Subsequently, advances in graft manipulation and cellular addback posttransplant help limit toxicities and improve engraftment while enhancing the antineoplastic potency of the HCT [8, 9, 10]. Gene‐engineered chimeric antigen receptor‐T cells (most often autologous) may be an alternative to HCT for selected lymphoid malignancies [11].

SOT—The main indication for SOT is irreversible loss of organ function. In the case of liver, heart, or lung failure, transplantation is the only available life‐saving approach, while in kidney failure, dialysis is an alternative, though an inferior treatment option. Compared with dialysis, transplant improves survival and quality of life (QoL). Published data also support its cost‐effectiveness [12]. SOT has evolved as therapy for multiple congenital and acquired conditions using newer immunosuppressive agents and surgical techniques for liver, pancreas, heart, lung, intestine for short bowel syndromes, uterine transplantation for infertility, and face and limb transplantation for tissue damage and loss [13, 14]. Combined kidney/pancreas transplantation is increasingly utilized for patients with either type 1 or type 2 diabetes. “SOT” now includes cellular therapy, with pancreatic islet transplantation as a less invasive alternative to whole organ pancreas transplant [15].

2. Donor Source and Matching

HCT—The processes for all HCTs are relatively similar. All hematopoietic graft cells come from LDs that can be: (a) BM aspirated from the posterior iliac crests; (b) peripheral blood stem and progenitor cells (PBSC) mobilized by granulocyte‐colony stimulating factor (G‐CSF, filgrastim) and collected by leukapheresis; or c) cryopreserved UCB units [1, 16]. Use of PBSCs has largely replaced the use of BM grafts due to the ease of collection, avoidance of general anesthesia for the donor, more rapid engraftment rates, and reduced risk of graft failure [17, 18, 19]. However, compared with marrow, PBSCs are associated with an increased risk of chronic graft‐versus‐host disease (GvHD) [17, 18, 19].

Due to the self‐replenishing nature of hematopoietic stem cells, donor graft collection does not compromise the donor's hematopoietic reserve. Usually, the preferred donor is an HLA‐identical sibling, unless the HCT is performed for an inherited condition that might be present or partially manifest in the donor [20, 21]. Yet only a minority of patients have an available sibling (approximately 1 in 4 are HLA‐identical) and thus require an alternative donor. While identical twin (syngeneic) donors yield no GvHD risk, they also provide no allogeneic anti‐neoplastic GvL effect, thus limiting their utility for some malignant or inherited conditions.

For patients lacking HLA‐identical siblings, HLA‐A, ‐B, ‐C, ‐DRB1 (and possibly DQB1) matched adult volunteer unrelated donors (URD) are a widely used donor source [16, 21]. National Marrow Donor Program (NMDP) in the US, Anthony Nolan in the UK, the World Marrow Donor Association (WMDA), and other registries maintain secure, real‐time databases that provide access to potential donors for cellular therapy worldwide. Donor registries from over 57 countries execute daily uploads of their donor and UCB inventory, permitting multinational donor searches with up‐to‐date donor and UCB data (Accessible online at NMDP.org; Anthony Nolan.org; https://searchmatch.wmda.info). For HCT, it is possible to find an HLA‐matched URD despite enormous HLA diversity [22] and stringent matching requirements (i.e., consideration of additional HLA loci, advancing to high‐resolution HLA matching, permissive DP mismatches) [21]. Obviously, patients from a population with many registered and available donors and lower intra‐population HLA diversity have better chances to find an HLA‐matched URD. Regions with high donor matching probabilities include Japan [23] and Northern and Western Europe, while other world regions or patients of mixed ethnic backgrounds have a lower likelihood of a well‐matched URD [24].

Other options include haploidentical related or partially HLA‐matched, related (RD) or URD. With advances in peri‐HCT immunosuppression (particularly post‐transplant cyclophosphamide [PTCy]), a suitable donor is now available for nearly all potential recipients. Advantages of haploidentical HCT include lower procurement costs and rapid graft availability. Potential disadvantages may include increased risks of graft failure and GvHD compared with HLA‐matched HCT [25]. Recent studies have shown generally comparable outcomes with each of these donor and graft sources, and thus, haploidentical HCTs have greatly increased in numbers [2, 3].

Recent data suggest that for older patients, use of younger (<36 years old) URD may yield reduced rates of relapse and improved disease‐free survival (DFS), though this reduction in relapse risk may depend on leukemia phenotype, conditioning regimen intensity, and other HCT components [26, 27]. Donor‐recipient ABO matching is generally not important for HCT. For some cytomegalovirus (CMV)‐seronegative recipients, a CMV‐seronegative donor may be preferred, though some data link immune responses to CMV and other pathogens to augmented anti‐neoplastic potency of the graft [28].

Criteria for HCT donor acceptance include normal blood counts, absence of serious chronic illnesses, and no markers of transmissible pathogens (e.g., HIV, hepatitis, others) [29]. Donors must agree to the chosen graft collection procedure: either PBSC or BM harvest. Since filgrastim‐stimulated leukapheresis for PBSC collection or a marrow harvest (under anesthesia) is generally safe, healthy older donors can be accepted, including RDs up to 65–70 years and URD up to age 60 [29, 30]. Donor mortality is exceedingly rare (2 deaths/>350,000 donations from the WMDA). Late effects following donation are also rare. The URD registries report prompt recovery and few late effects after donation [31, 32, 33]. All donations, both related and unrelated, should be altruistic with no coercion involved.

SOT—In contrast to HCT, organs for SOT can come from either LDs or deceased donors (DDs). Similar to HCT, the ideal living kidney donor is an HLA‐matched sibling, though with improvements in immunosuppression, LD outcomes from RD and URD are similar and surpass those from DDs [14, 34, 35]. In some countries, either by choice or due to a lack of a DD program, most kidney transplants are from LDs. LD liver transplantation is also a frequent option [13]. Results of LD liver transplantation are similar to DD transplantation [36], but the use of LDs expands the donor pool and reduces the chance of mortality while waiting [37].

Donor/recipient matching for both LD and DD SOT, in the absence of special protocols, requires blood type compatibility. In addition, HLA matching is a selection criterion for both [38]. Recent developments in SOT have shown that HLA antibodies bind to specific epitopes not present on self‐HLA antigens, and that each epitope may bind a number of antibodies [35]. Therefore, an antibody, once thought to be HLA‐specific, can bind to a similar epitope on more than one HLA antigen. Studies in kidney transplantation to date suggest that epitope matching results in better outcomes than HLA matching [39]. This may also be applicable for HCT [40].

In SOT, for either LD or DDs, donor‐recipient paired characteristics, including size, weight, sex, and age matching, have important influences on outcomes [41, 42, 43]. For liver, heart, and lung transplants, nonimmunologic matching (e.g., size) is essential. In addition, for the heart and liver, priority is given to the sickest patients on the list. In the lung, allocation is more nuanced and is based on a number of factors, including risk of waitlist mortality, likelihood of long‐term survival, and biological characteristics of candidates that impact their access to transplant, including ABO blood type, height, and calculated panel reactive antibodies (PRA) [44]. For liver transplants, only blood group compatibility is considered in organ allocation [36].

A recent major advance in living donation, first used in South Korea, has been the sharing of organs when donor‐recipient pairs are incompatible [37, 45]. In this situation, called ^„paired exchange^‘’, the incompatible donor (donor 1) may match another recipient (recipient 2) who has an incompatible donor (donor 2), but who matches recipient 1. (Figure 1A) With the development of powerful computer algorithms, paired exchange has been expanded into a chain of transplants, serving multiple donor‐ recipient pairs (Figure 1B) [46].

FIGURE 1.

(A) Paired Exchange. Donors 1 and 2 are incompatible with their intended recipients. However, donor 1 is compatible with recipient 2, and donor 2 is compatible with recipient 1. (B) Extended paired exchange—a “chain.“ Donor 1 is incompatible with her intended recipient (recipient 1, but is compatible with recipient 2, etc).

Potential DDs are also evaluated for adequate organ function and other comorbidities. For DD worldwide, there are detailed, rigid guidelines for the determination of death before organ donation [47]. More recently, criteria have been developed for donation after circulatory death [48].

2.1. LDs Risks, Informed Consent, and Follow‐Up

For both HCT and SOT, ensuring LD safety is an essential goal. Therefore, safe and standardized assessment plus adequate information for informed decision‐making is crucial for donor protection [13, 49, 50, 51, 52, 53, 54]. It must be assured that the potential donor's decision is voluntary, free of coercion, and without a financial incentive, though recognition of donation‐related expenses has been discussed [55, 56, 57]. Informed consent is also required for DD, either through an “organ donor card” signed at a time before death (or in some countries, no clearly stated “objection to donation”), or through family consent [13, 55, 57]. Some countries have presumed consent laws, by which all are potential donors unless the family declines.

A major difference between SOT and HCT is the risk to the donor. The SOT LD undergoes a major operation, and possible risks of both operative and long‐term morbidity and mortality [13, 58, 59]. Historically, death has occurred in about 3/10,000 living kidney donors [58]. In the United States, in the last 10 years, mortality is 1/10,000 [59]. The risk of a major complication is <1%. Risks are higher for liver donors, quoted to be mortality 0.06% and major complications 5.5%., but no donor deaths in the United States for > 5 years [60]. In addition, there are concerns about long‐term LD outcomes after donation, either as a direct consequence of the operation (e.g., biliary complications after liver donation) or long‐term compromised function (kidney donation) [13, 14, 49, 50, 51, 52, 53, 61, 62, 63, 64, 65]. In the general population, reduced glomerular filtration rate is associated with cardiovascular disease (CVD), CVD mortality, overall mortality, chronic kidney disease (CKD) and endstage kidney disease (ESKD) [54, 66].

All potential LDs require a thorough medical and psychosocial evaluation. LDs must be healthy with normal organ function [67]. Notably, up to 50% of potential kidney donor candidates are denied because of medical or psychosocial problems [34, 68].

For HCT, international registries track severe adverse events, including those that affect product quality, and provide long‐term follow‐up [29, 30, 31, 32, 33]. For SOT, there are several registries worldwide, but the data collected is inconsistent [69]. In the United States, short‐term LD outcomes are monitored by the Scientific Registry of Transplant Research (www.srtr.org), Organ Procurement and Transplant Network (https://optn.transplant.hrsa.gov), and the International Liver Transplantation Society (www.ILTS.org). There are numerous single‐center, registry, or national studies on long‐term LD kidney ESKD and/or mortality [49, 50, 51, 58, 59, 60, 61, 62, 63, 64, 65]. However, one challenge is the identification of a healthy matched control group with equivalent long‐term follow‐up [52, 53]. The longest follow‐up, compared to healthy matched controls, has been in studies from Norway (–10 years from donation) with a universal healthcare system and a national database [63, 65]. The Norwegian group reported increased LD CVD, ESKD, and all‐cause mortality [63, 65]. However, these studies have not fully adjusted for family history of kidney disease [50, 53, 54].

2.2. Organ Sharing and Shortage

For HCT, there is generally no shortage of donors due to internationally cooperating URD registries and an established record of safety without long‐term complications [16, 21, 29, 31, 32]. In contrast to HCT, for SOT, there is a worldwide shortage of organs and often long waiting times for DD transplants, with many candidates dying while awaiting transplant [70, 71, 72]. For SOT, DD organ sharing differs by country and can range from local to national (e.g., US) to international (e.g., Eurotransplant, including Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands, and Slovenia).

Increasing demand for organs has resulted in serious problems worldwide, including nonconsensual retrieval and organ trafficking [73]. This concern led the WHO to highlight a need to protect vulnerable people from transplant tourism and the selling of tissues and organs. Furthermore, the WHO and other international organizations emphasize the dangers of international trafficking in organs and human tissues [57, 71, 73]. Educational recruitment efforts and national strategies to encourage safe and ethical organ donation worldwide may enhance access, particularly in LMIC, where both dialysis and SOT may be limited. Global strategies promoting donation have been discussed [74].

2.3. Organ Preservation

HCT—HCT grafts are most often collected and infused fresh, without preservation [75]. In some settings (long travel time from an URD collection site to the HCT center, or uncertainty about the anticipated graft collection (small donor and larger body weight recipient), cryopreservation is performed using a cryoprotectant (e.g., dimethylsulfoxide) and usually controlled rate freezing. An estimated 10%–20% cell loss may follow cryopreservation [76]. Consequently, if freezing is planned, a modestly larger graft is collected. Generally, HCT outcomes are not compromised with graft cryopreservation [75]. As an alternative graft source, UCB for public use is collected and cryopreserved in cord blood banks globally [21].

SOT—Preservation of SOT organs is more complicated, and the goal is to minimize preservation time (cold ischemia time) in order to maximize posttransplant organ function. Ideally, LD kidneys are removed and transplanted in adjoining operating rooms. However, when LD kidneys are shared between centers, they are stored in a specialized ice solution for transport [77]. Prolonged preservation is often associated with delayed graft function and potentially primary nonfunction. The need for short preservation times has been limiting for liver, lung and heart transplantation, requiring the recipient operation to take place shortly after the donor surgery, and minimizing the transport distance before transplantation. A recent innovation, normothermic perfusion (either in situ or post organ removal), has allowed longer preservation times with the possibility of travelling longer distances for organ procurement [78, 79, 80, 81, 82, 83, 84]. In liver and heart transplant homologous red blood cell (RBC) concentrates are used to prime the perfusion devices. Normothermic perfusion in some centers allow liver transplants not to be performed as a nightime emergency, but as a semi‐urgent procedure in the morning.

3. Immunosuppression

Both HCT and SOT require immunosuppression. However, there are differences in the rationale for and goals of immunosuppression, the timing of initiation of therapy, protocols used, and the duration of treatment.

3.1. HCT Initial Immunosuppression

For HCT, conditioning chemo/radiotherapies are initiated pretransplant to eradicate residual malignant cells and to immunosuppress the recipient and limit rejection of donor hematopoietic cells [1]. The conditioning can be myeloablative (MAC), reduced‐intensity (RIC), or non‐myeloablative (NMA), very low intensity tailored to the recipient‘s clinical condition [85, 86, 87]. These differ in resulting in myelosuppression, blood cytopenias, and transfusion requirements. MAC creates weeks of pancytopenia and restoration of recipient hematopoiesis from donor cell engraftment. MAC yields greater malignant disease suppression, yet induces greater toxicity [85, 86]. The RIC and NMA regimens yield lower toxicity and control malignant relapse through the GvL effect. However, their lesser toxicity allows HCT for older patients or those with pre‐existing comorbidities [87]. Selection of conditioning regimen intensity depends on patient age, performance status, HCT comorbidity index, disease type, and remission status [85, 86].

After conditioning, donor grafts are infused intravenously. Infection prophylaxis plus supportive care to manage noninfectious complications is essential. Time to hematopoietic engraftment with neutrophil recovery (usually 12–21 days) and later RBC and platelet transfusion independence is variable and depends on the graft source and cell dose. Following HCT, patients require limited‐duration immunosuppression for the prevention and treatment of GvHD until tolerance is achieved [88]. This often includes a calcineurin inhibitor (CNI) or PTCy along with either methotrexate or mycophenolate (MMF). Other GvHD prophylaxis can include mTOR inhibitors (sirolimus, everolimus) or anti‐T cell serotherapies (ATG [antithymocyte globulin], alemtuzumab) or ex vivo graft T cell depletion before infusion. Rejection after HCT is uncommon unless preformed donor‐specific antibodies (DSA) are present in HLA‐mismatched transplants. Rates of primary HCT graft failure are low due to the eradication of the recipient's immune response [89, 90]. Secondary graft failure, while uncommon, manifests as poor graft function and cytopenias. It is usually due to infection or drug toxicity. Graft failure is slightly more common in nonmalignant disease HCTs [89, 90].

Acute GvHD is an early posttransplant risk and occurs in 25%–65% of patients, varying with donor/recipient HLA matching and GvHD prophylaxis [91]. Its pathophysiology involves antigen presentation by hematopoietic and nonhematopoietic cells, inflammation driven by damage‐associated molecular patterns (DAMPs), chemokines expressed in inflamed tissues, and recruitment of effector cells (T cells, neutrophils, and monocytes) to target tissues [92]. Conditioning intensity is associated with acute GvHD risks, perhaps by release of sterile triggers of inflammation from stressed or dying cells, activating the immune system, and enhancing acute GvHD. GvHD is prevented by peri‐HCT immunosuppression, extensive graft T cell depletion, or PTCy, which deletes proliferating alloreactive donor T cells. GvHD associates with more potent donor‐derived antineoplastic GvL effect and reduced relapse risks [4, 92]. Acute GvHD can affect the skin, liver, and gastrointestinal tract and various organs in its chronic form, resembling autoimmune disease [88, 91]. Infection is a risk during early neutropenia, later due to incomplete immune regeneration, from immunosuppressive medications, and immunocompromise by GvHD and its treatment [93, 94].

3.2. HCT Long‐Term Immunosuppression

Transplantation of the donor graft yields complete replacement of the recipient's hematopoietic and immune system with cells of donor origin, termed full donor chimerism. This includes donor‐derived immune reconstitution with restoration of protective, anti‐infective host immunity, reestablishment of expanded T cell and B cell repertoires yielding functional donor/host tolerance and accompanying GvT effects [88]. Modest intensity immunoprophylaxis with combination immunosuppressive drugs is administered for 2–4 months. The goal is to taper and discontinue immunosuppression after engraftment, tolerance induction, and resolution of GvHD. Even in those with chronic GvHD, approximately 75% of patients can discontinue immunosuppression by 2 years post‐HCT [88, 91, 95].

3.3. SOT Initial Immunosuppression

Immunosuppression for SOT begins either shortly before or more commonly at the time of transplant. The goal is to minimize the immune response to the transplanted organ while preserving the patient's systemic defenses. Immunosuppressive protocols differ by organ type, but generally include a short‐term “induction phase” (brief high‐intensity immunosuppression), followed by a long‐term “maintenance phase” [96, 97]. The induction phase may include antibody (polyclonal antibody or interleukin‐2 receptor antagonist) targeting lymphocytes, and/or higher doses of the drugs later used for maintenance therapy [98]. Current protocols usually include a CNI plus either MMF or an mTOR inhibitor (e.g., sirolimus), with or without prednisone [99, 100, 101, 102, 103, 104]. The doses/blood levels for these drugs vary by transplant type. Generally, there is a reduction in doses and levels over time. Some centers may attempt to wean to a single drug (more often for liver transplant) [105]. Early posttransplant infection prophylaxis (e.g., for CMV, other viruses) is provided [104, 105, 106, 107, 108].

After SOT, rejection can be mediated by preformed DSA associated with antibody‐mediated rejection [109]. Cellular rejection involving T cells and macrophages in donor renal grafts is generally under 10% versus liver, lung, or heart transplants. It is limited by peri‐transplant induction immunosuppression plus long‐term, usually lifetime anti‐rejection immunosuppression. CNI and MMF, sirolimus, and various anti‐lymphocyte antisera (ATG, ALG; rabbit or horse) or anti‐T cell or anti‐costimulatory biologics are used most often [110]. Anti‐rejection maintenance medications are intensified for heart and lung transplants, but may be less intense for liver transplants or for renal grafts, where dialysis can rescue organ failure. In case of antibody‐mediated rejection, apheresis and IVIG‐based therapy are used [111]. ABO compatible transplants are performed only in rare, specific settings requiring intensive protocols of desensitization, plasmapheresis, B‐cell depletion (using rituximab or other agents), or immunosuppressive induction therapy [112].

3.4. SOT Long‐Term Immunosuppression

With the development of more powerful immunosuppressive protocols, there have been marked improvements in patient and graft survival. However, unlike HCT, recipients of SOTs (other than identical twins) require lifetime immunosuppression. There have been only a few small clinical trials with highly selected donors (e.g., HLA‐identical) and specialized treatment (e.g., total body irradiation, experimental targeted antibody), allowing successful withdrawal of maintenance immunosuppression. There are anecdotal reports of recipients discontinuing their immunosuppressive drugs and maintaining long‐term graft function in kidney transplantation [111]. In liver transplantation, a sizable, but still small (≈ 10%) fraction of long‐term survivors develop spontaneous tolerance [113]. The mechanism by which they avoid graft rejection has not been defined. The need for daily maintenance therapy and drug side effects leads to nonadherence as a major clinical problem, leading to late rejection episodes and even graft failure. Minimizing the need for and risks of maintenance therapy is a major goal of SOT research. Numerous trials aim to minimize complications without provoking an organ‐related immune response, while reducing toxicity with minimal maintenance drugs. Another promising approach is to induce tolerance by combining organ and cell transplantation [106, 107].

4. Complications and Long‐Term Outcomes

HCT. Outcomes of HCT vary according to the diagnosis and risk status, the patient's overall health and comorbidities, donor/recipient HLA‐mismatch, and the graft source [2]. In recent years, HCT outcomes have markedly improved due to advances in HLA typing and refined donor selection [108]. Reduced conditioning toxicity, better GvHD prevention and treatment, and supportive care advances have lessened early mortality (first 6 months) [2, 108]. Malignant disease relapse is the major failing of HCT, though uncommon beyond 2 years post‐HCT [114, 115]. In nonmalignant diseases, the primary goal is minimizing chronic GvHD while retaining donor graft function for normal hematopoiesis: that is, normal hemoglobin in sickle cell anemia, safe blood counts in marrow failure syndromes, and infection defenses in immunodeficiency syndromes. Long‐term HCT complications include chronic GvHD, late infections, and second malignancies [115]. These require monitoring by an experienced interdisciplinary team using published guidelines [116].

SOT. Long‐term outcomes of SOT vary by organ type and by donor and recipient characteristics [14]. In the last 2 decades, short‐term outcomes for all organs have improved, though with variable improvements long‐term [117, 118].

In contrast to HCT, SOT has associated surgical complications [119, 120, 121]. As with any operation, there is a risk of death and risks of perioperative complications, including thrombosis or bleeding at vascular anastomoses. There are also potential organ‐specific peri‐operative complications (e.g., ureteral injury for the kidney; biliary injury for the liver) [14, 119, 120, 121]. A small percentage of organs never function because of either immune or nonimmune issues. Other potential early problems are delayed organ function, requiring support during that interval (e.g., dialysis in kidney transplantation). Despite modern immunosuppressive regimens, acute rejection is the major early problem, occurring in more than 10% of SOTs (highest for lung) [14, 117]. Acute rejection episodes are initially treated with steroids and, if resistant, with T‐cell‐depleting antibody.

4.1. Other Complications

Other SOT complications include infections, malignancy, GvHD, and cardiometabolic problems. CMV risk is greatest with a CMV seropositive donor and a CMV seronegative recipient, occurring mostly within 6 months post‐transplant. Many centers use anti‐viral prophylaxis for high‐risk donor‐recipient pairings [122, 123]. Immunosuppressed SOT recipients (particularly renal) may reactivate BK‐Polyoma virus (BKV), latent in tubulo‐uroepithelial cells, with seropositivity in 80%–90% of adults [123, 124]. This can yield asymptomatic viremia, graft dysfunction (BK nephropathy tubulointerstitial nephritis), cystitis or ureteritis ± stenosis. Treatment for either CMV or BKV is the reduction of immunosuppression, plus anti‐viral for CMV viremia/disease. GvHD can occur after SOT, almost exclusively in liver transplant recipients, and clinically resembles transfusion‐associated GvHD. GvHD after SOT, though rare, may be mediated by passenger donor lymphocytes, particularly in lymphocyte‐rich liver or lung grafts. These donor lymphocytes can rarely induce marrow aplasia in an HLA‐mismatched recipient. GvHD in SOT recipients has a very high mortality. Post‐SOT GvHD generally presents with fever, skin rash, diarrhea, and marked leukopenia and is generally therapy resistant. The preferred management of GvHD after SOT is uncertain.

Long‐term complications after SOT include slow deterioration of graft function due to immune and nonimmune processes, including both DSA and medication nonadherence [124, 125, 126, 127, 128, 129, 130, 131, 132]. In kidney transplants, this results in continuing inflammation, tubular atrophy, and interstitial fibrosis; in the lung, to chronic lung allograft dysfunction; and in the heart, to graft vasculopathy. Antibody‐mediated rejection in liver transplant recipients is poorly defined. Additionally, premature death with a well‐functioning graft can result from comorbidities or complications of long‐term immunosuppression; chiefly CVD, infection, and malignancy [126, 128, 133, 134].

5. Regulation and Oversight of Transplantation

Most, but not all, countries have national cell/tissue and organ regulatory frameworks to ensure MPHOs are used ethically and in accordance with safe medical practice [135, 136, 137]. These address the prevention of transmissible infectious agents and encourage robust systems for MPHO's traceability. Many national regulations require mandatory reporting of severe (and fatal) adverse events.

For SOT and HCT, the American Society of Histocompatibility and Immunogenetics and the European Federation of Immunogenetics have developed standards and certification programs for immunogenetics, tissue typing, and transplantation [138, 139].

HCT benchmarking has been integrated into the Foundation for the Accreditation of Cellular Therapy‐Joint Accreditation Committee of the International Society for Cellular Therapy (FACT‐JACIE) quality management standards, along with the European Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research [135, 136]. The NMDP (BeTheMatch), Anthony Nolan, WMDA, WBMT, and other international bodies promote the facilitation of HCTs [140, 141, 142]. For countries with limited resources, FACT‐JACIE and other international organizations, including the WBMT, have developed a stepwise process based on minimum standards to certify quality‐assured HCT services and promote standardized implementation in new centers [141, 142]. The first steps for an HCT program emphasize patient and donor safety plus quality measures. Subsequent steps advance toward an active quality management system [142].

For SOT, regulation and oversight stringency varies by country and geographical region. In the US, there are requirements for LD or DD evaluation and determination of death; and recipient evaluation before being listed for a DD transplant [56, 57, 69, 70]. Transplant center outcomes (1‐ and 3‐ year survival) are publicly reported. There are also regulations for Organ Procurement Organizations, and a national system with organ‐specific algorithms for DD allocation [48, 56]. Other countries have developed registries with ongoing attempts to create a global registry [56].

6. Additional Challenges for Both HCT and SOT

6.1. Multidisciplinary Team

Both HCT and SOT require trained multidisciplinary teams for donor and recipient evaluation; pre‐transplant, in‐hospital, and post‐transplant care; plus long‐term follow‐up to prevent and treat complications, record and evaluate results, and share data with regional and international registries. The SOT and HCT primary teams include physicians specializing in transplantation and transplant infectious disease; HLA‐laboratory, coordinators, nurses, social workers, pharmacists, and dieticians. However, both successful HCT and SOT require tremendous additional support, both from specialists within the institution (e.g., interventional radiology, blood bank, anesthesiology, pathology) and the community (referring physicians). Due to scientific advances and more complex treatments, continuous structured training for all staff members is important to ensure competency. To develop the health workforce required, fellowship programs, possibly requiring rotation to high‐volume transplant centers, international collaboration, and twinning with other institutions, are valuable. These can transfer skills, mentor local teams, and provide clinical guidance, including telemedicine consultations, to promote quality measures and worldwide exchange of expertise [140, 141, 142].

6.2. Infrastructure

HCT and SOT require institutions and governmental authorities committed to their success [137, 138, 139]. Hospitals must offer commitment and program resources, including funding for pre‐ and post‐transplant coordinators for early and long‐term patient follow‐up, plus trained operating room staff. Internationally, a barrier for both HCT and SOT is access to a well‐resourced center. Both require infrastructure for donor identification, acquisition and preservation of cells or organs, transport of the cells or organs to the center, and careful recipient selection. Since HCT remains a highly specialized, resource‐intensive, and costly medical procedure, the capacity for HCT is limited in many countries [128, 129]. HCT programs differ in their transplant population, indications, case complexity, and preferred graft sources. Multiple components are needed for successful and safe HCT, both for patients and donors. The WBMT works to expand HCT access globally and has defined pertinent elements for establishing a new HCT program [140, 141, 142]. Other essential requirements include access to critical care, emergency, and multispecialty consultation. Proper leadership, a dedicated, multidisciplinary team, and institutional support are essential for a successful HCT or SOT program.

7. Future Directions for Clinical Advances and Cost Saving Challenges

7.1. Combined HCT and SOT

Early experimental studies in mice showed that injection of hematopoietic cells into a recipient's immature immune system tolerizes the recipient to the introduced donor antigens [143]. Subsequent research extended into the adult, mature immune system [144]. Long‐term outcomes after SOT remain limited by chronic immune‐mediated graft injury and by morbidity from immunosuppression [110, 126], making immunosuppression‐free tolerance an important research goal. Co‐transplantation of donor hematopoietic cells has been investigated in organ transplantation to establish anti‐donor tolerance [145]. A few dozen reported cases identified patients treated with HCT for a conventional indication who later developed chronic renal failure and received a kidney from the original HCT donor. The kidneys were accepted without immunosuppression, providing real‐life proof that HCT‐induced SOT tolerance occurs in humans. Importantly, a retrospective analysis showed this group of HCT‐SOT recipients had significantly superior graft survival compared to a matched patient group maintained on conventional immunosuppression [146].

Alternatively, co‐transplantation of donor hematopoietic cells has been evaluated for the sole purpose of tolerance induction (without a conventional indication for HCT). Three protocols of simultaneous HCT and kidney transplantation have been tested in prospective pilot trials, demonstrating that tolerance can be actively induced in –50% of recipients of combined HCT‐SOT [147, 148, 149]. GvHD occurred in a few in only one of these trials [149]. Most clinicians argue that GvHD is not an acceptable risk for the indication of LD kidney transplantation. Therefore, efforts are ongoing to develop HCT protocols specifically for tolerance induction in SOT with an acceptable risk‐benefit profile [150]. Combined HCT plus SOT offers the unique opportunity to study both the distinct and common aspects of both types of transplant in one patient group.

7.2. Sustained Availability of Drugs, Generic Drugs, and Biosimilars

High healthcare expenditures hinder access to care, more so in LMICs. Transplant medications are expensive, constituting 8%–39% of the total transplant costs [151, 152, 153]. Antimicrobials, growth factors, and immunosuppressives are major cost drivers. Reliable supplies of essential HCT drugs for prolonged treatment are important to minimize complications (surveyed by WBMT [151]). Drugs used for infection prophylaxis and treatment [152, 153], GvHD or rejection prophylaxis with CNIs, mTOR inhibitors, MMF, and other immunosuppressants are required, along with pharmacologic dose monitoring.

Use of biosimilars/generic drugs may decrease healthcare costs and expand access in developing countries [154, 155]. Besides periodic global or regional drug shortages, some drugs are unavailable in certain countries, and restrictions limit their import. Licensing, regulatory approval, supplier/manufacturer interest, limited usage, and cost are all barriers to expanding worldwide access to safe, contemporary HCT and SOT care with all the most valuable drugs.

7.3. Healthcare System

To ensure equitable access, national insurance systems should include support for both SOT and HCT. Access to and success of transplant depend on government investment in general health and tertiary care. HCT is costly and competes for resources with primary or other specialty care. Curative HCT for some patients may be life‐sustaining and thus cost‐effective with longer survival, while continuing care for patients with some diseases (hemoglobinopathies: ongoing hemodialysis for ESRD) remains costly [156, 157]. A recent report suggested that allogeneic HCT limits healthcare utilization and costs compared to standard‐of‐care therapy in high‐risk adult sickle cell patients [159]. Since allogeneic HCT is a highly specialized, technologically sophisticated procedure requiring elaborate infrastructure, governmental investment into expanding HCT facilities can benefit multiple areas across the healthcare system, including blood component supply, laboratory and radiology facilities, as well as pharmacy and supportive care.

Digital health technology, including mobile applications and virtual reality‐delivered interventions, may simplify supportive care for transplant patients. Telehealth can decrease costs through gains in productivity, patient adherence, and improved care access through remote monitoring, away from the HCT center [158, 159, 160]. Telemedicine‐based patient navigation to improve education about HCT has been reported [161].

7.4. Referral for Treatment, Access, and Financial Coverage

Referral to transplant requires an interplay of patients, referring physicians, payors, and transplant centers [162, 163, 164, 165]. Scarcity of medical specialists (hematologists or nephrologists) in certain regions constrains knowledge on the benefits of transplantation and limits referrals to transplant centers. Disparities in access are also limited by fewer HCT or SOT referrals for women and racial/ethnic minorities, and those in socioeconomically deprived areas. For patients with malignant diseases that may be amenable to HCT, timely referral from local/regional care is essential, as late referrals for advanced disease may compromise opportunities for potentially curative HCT. Timely referrals may be constrained by education gaps, biases, and financial challenges, including travel and housing costs at a center remote from the patient's home. These all may yield underutilization of transplantation versus locally delivered therapies [163, 164, 165, 166, 167].

Challenging logistics and expenses are also barriers for many patients. Comprehensive insurance is needed for both SOT and HCT referral and treatment [162]. Several reports note that third‐party financial coverage (private, public, or government‐supported insurance, managed vs. non‐managed care) and availability of any insurance influence transplantation access and utilization. These economic factors directly influence management, including decisions for transplantation referral [162, 163, 164, 165, 166]. A recent systematic review found that older age, lower socioeconomic status (SES), and non‐White race are associated with reduced HCT access [167, 168]. Adverse social determinants of health (SDOH) have been increasingly recognized as factors linked to non‐relapse mortality and overall survival in patients with AML [169]. These socioeconomic challenges compromise post‐HCT outcomes, as does poor community health and neighborhood impact on outcomes [169, 170].

Access limits expanded use of SOT for any organs. It is constrained by transplant center capacity, government or other funding, and limited organ availability to meet patient needs. The shortages in SOT accentuate disparities in access [171]. In SOT and HCT, women and racial minorities have less access to lifesaving transplants. They are referred to less often by healthcare professionals, along with existing financial, distance, and opportunity barriers [108, 164, 165, 166, 167, 171, 172, 173].

8. Conclusions

Comprehensive recognition of these barriers constrains the expansion of transplantation across world regions. For transplantation to be sustainable, investment in infrastructure, professional training, and public awareness campaigns to promote organ and cell donation is required.

Collaborative study may directly advance care and advise governmental policy to improve the utilization and success of both SOT and HCT—saving many lives and healthcare expenditures. Safe and efficient transplantation programs with protection for both donors and recipients are essential. For these reasons, we encourage public standards and accreditation of transplant facilities and the standardized reporting of outcome data.

Author Contributions

All authors contributed to the design, analysis, writing, and approval of the final manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Greinix H. T., Matas A., Koh M. B. C., et al. “Similarities and Differences Between Allogeneic Hematopoietic Cell and Organ Transplantation and What We Can Learn From Each Other to Guide Global Health Strategy.” Clinical Transplantation 39, no. 10 (2025): e70346. 10.1111/ctr.70346

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.