Current status of conditioning regimens in haploidentical hematopoietic cell transplantation

ABSTRACT

The development of effective prophylaxis strategies against graft-versus-host disease (GVHD) has contributed to the widespread use of haploidentical related hematopoietic cell transplantation (Haplo-HCT). Currently, GVHD prophylaxis containing posttransplant cyclophosphamide (PTCY) is considered the standard of care in Haplo-HCT, and recent studies have shown comparable results for PTCY-based Haplo-HCT and HCT from other donor sources. The conditioning regimen plays an important role in eradicating tumor cells to prevent disease relapse and suppressing the recipient’s immune system to facilitate engraftment. PTCY-based Haplo-HCT was initially developed using a nonmyeloablative conditioning regimen consisting of fludarabine, cyclophosphamide and low-dose total body irradiation, but high relapse rates reinforced the need to intensify the conditioning regimen. In this respect, various myeloablative and reduced-intensity conditioning regimens have been investigated. However, the optimal conditioning regimens for PTCY-based Haplo-HCT have not yet been established, and this issue needs to be addressed based on data from patients undergoing the procedure. In this article, we review the existing literature on conditioning regimens for PTCY-based Haplo-HCT and discuss future perspectives.

KEYWORDS:

• Allogeneic hematopoietic cell transplantation
• conditioning
• haploidentical
• posttransplant cyclophosphamide

Introduction

Allogeneic hematopoietic cell transplantation (HCT) is a therapy characterized by its maximal antitumor effect against various hematological malignancies [1,2]. The conditioning regimen administered prior to allogeneic HCT eliminates tumor cells and suppresses the recipient’s immune system to facilitate the engraftment of donor hematopoietic cells [3]. However, these beneficial effects are partially compromised by its toxicity, which causes significant treatment-related morbidity and mortality. The use of allogeneic HCT was therefore limited to young, fit patients when only conventional myeloablative conditioning (MAC) was available. Reduced-intensity conditioning (RIC) was subsequently developed to increase the safety [4,5], which expanded the application of allogeneic HCT to patients who would previously not have been candidates for the procedure. The advent of RIC has also expanded our choices for conditioning regimens in each individual patient.

In addition to conditioning, there has been a significant progress in the donor choice in allogeneic HCT. Although human leukocyte antigen (HLA)-matched sibling donors were predominantly used in the early years, the situation today is substantially different due to the introduction of high-resolution HLA typing, innovations in immunosuppressive therapy, improved supportive care measures and the proliferation of donor registries [6]. Even if patients don’t have a matched sibling donor, they can receive allogeneic HCT from unrelated donors, umbilical cord blood grafts or haploidentical related (Haplo) donors [7–9].

Haplo donors have several clinical advantages, including almost universal availability, rapid access to a donor, and the viability of donor-derived cellular therapies after transplantation [6,10]. However, Haplo-HCT has not been performed frequently until recently because of the great concern about graft-versus-host disease (GVHD) [11]. The development of effective prophylaxis strategies for GVHD that incorporate posttransplant cyclophosphamide (PTCY) or anti-thymocyte globulin (ATG) has mitigated the adverse effect of HLA disparity [12,13], which has contributed to the widespread use of Haplo-HCT. Currently, GVHD prophylaxis containing PTCY is the standard of care in Haplo-HCT, and recent studies have shown comparable results for Haplo-HCT using PTCY and HCT from other donor sources [14–19].

The conditioning regimen serves as a key component in allogeneic HCT, for which physicians can choose from multiple available options. As Haplo-HCT is a relatively new treatment modality, the optimal conditioning regimens have yet to be established. This article reviews the existing literature on conditioning regimens with a focus on PTCY-based Haplo-HCT and discusses future perspectives.

Conditioning intensity

The intensity of conditioning regimens affects not only the risk of non-relapse mortality (NRM) but also the risk of relapse. Historically, conditioning regimens have been classified as MAC or RIC based on the operational criteria proposed by the European Society for Blood and Marrow Transplantation (EBMT) [20] or the Center for International Blood and Marrow Transplantation Research (CIBMTR) [21]. RIC has the potential advantage of reducing the risk of NRM compared with MAC but at the expense of an increased risk of relapse, which raises discussion about the relative merits of RIC and MAC. Studies comparing the efficacy of RIC and MAC showed mixed results. In particular, four prospective randomized studies that compared RIC and MAC in patients with acute myeloid leukemia (AML) have been published to date [22–25]. One study reported higher relapse incidence (RI), lower NRM, and worse overall survival (OS) with RIC [22], whereas others reported similar RI, NRM, and OS [23–25]. It is also emphasized that transplantation modalities have become highly diversified nowadays [3,6]. Conditioning regimens influence various posttransplant outcomes, such as RI, NRM, engraftment, GVHD, and OS; therefore, the evidence obtained in studies conducted on other types of allogeneic HCT may not fully apply to Haplo-HCT. This situation underscores the importance of evaluating conditioning regimens specific to PTCY-based Haplo-HCT.

Special considerations for haploidentical HCT

Because PTCY-based Haplo-HCT is a unique type of allogeneic HCT, various posttransplant outcomes including engraftment, relapse, toxicity, and immune reconstitution, should be specially considered when selecting conditioning regimens. Haplo-HCT demonstrated high rates of graft rejection before the advent of PTCY owing to significant HLA mismatches between donors and recipients [11]. The initial experience of PTCY-based Haplo-HCT using nonmyeloablative conditioning remained accompanied by graft failure [12], encouraging the use of an intensified conditioning regimen to mitigate the risk. The association of PTCY-based Haplo-HCT with increased posttransplant relapse compared with other types of allogeneic HCT remains unsettled. A phase III study comparing PTCY-based Haplo-bone marrow transplantation (BMT) with double-unit umbilical cord blood transplantation (UCBT) revealed no significant difference in relapse rates [18]. However, the potent effect of GVHD suppression raises a concern about posttransplant relapse as a sequel to the suppressed graft-versus-leukemia effect. Hemorrhagic cystitis (HC) and cardiotoxicity require special attention among the toxicities in patients undergoing PTCY-based Haplo-HCT. Available data indicate that sparing busulfan (BU) from a conditioning regimen may reduce the risk of HC [26,27], and a lower dose of PTCY may decrease both risks [28,29]. PTCY-based Haplo-HCT does not appear to increase infectious complications, except for BK virus reactivation [10], but future studies are warranted to clarify how PTCY modulates immune reconstitution posttransplant.

Researchers at Johns Hopkins Hospital first reported on Haplo-BMT using PTCY in 2002 [30]. Initially, they used a conditioning regimen consisting of fludarabine (FLU) at 150 mg/m² and total body irradiation (TBI) at 2 Gy. After documenting graft failure in two of the first three patients, they added cyclophosphamide (CY) at a dose of 14.5 mg/kg for two days as part of conditioning. This modification resulted in a successful engraftment in eight out of ten patients, and formed the basis of the FLU/CY/TBI regimen, which is now widely used throughout the world. This regimen produced favorable results in terms of engraftment, GVHD, and NRM, but the relapse rate reached 51% at 1 year [12], reinforcing the need to intensify the conditioning regimen to reduce posttransplant relapse.

When using PTCY for GVHD prophylaxis, it is important to bear in mind that PTCY has the potential to increase the toxicity induced by the conditioning regimen. Furthermore, the high dose of CY is known to cause cardiotoxicity itself [31–33]. Although limited data is available regarding whether PTCY by itself increases the risk of cardiotoxicity, a single-center study retrospectively comparing the outcomes of patients who did and did not receive PTCY showed that the use of PTCY increased the risk of early cardiac events [34]. By contrast, another single-center retrospective study found no significant effect of PTCY use on developing acute cardiac toxicity [35]. Notably, both studies reported that the development of cardiac events was associated with worse OS, thereby clarifying the causal relationship in a prospective study or a larger retrospective study is important.

The aim of intensifying the conditioning regimen in PTCY-based Haplo-HCT is not only to reduce relapse, but also to improve engraftment. An early study by the Johns Hopkins group reported that graft rejection developed in 9 out 66 patients (13%) [12], and a recent analysis of the EBMT of 1939 adults with AML reported a 6% incidence of primary graft failure [36]. To facilitate engraftment in PTCY-based Haplo-HCT, several studies suggest the usefulness of adding low-dose TBI. Shah et al. showed that low-dose TBI promotes donor T-cell donor chimerism in patients undergoing PTCY-based Haplo-peripheral blood stem cell transplantation (PBSCT) using RIC [37], and DeZern et al. reported that increasing the TBI dose from 2 Gy to 4 Gy led to better engraftment rates for patients with severe aplastic anemia undergoing PTCY-based Haplo-BMT [38]. In a series of Japanese prospective studies on PTCY-based Haplo-PBSCT with RIC containing TBI of 4 Gy, no graft failure was reported in more than 200 patients who survived the early posttransplant period [39,40].

PTCY-based Haplo-HCT is increasingly performed on elderly patients, including those over 70 years of age, and emerging data support the viability of the procedure in this elderly population [41,42]. However, special attention needs to be paid to cardiac complications in elderly patients, and a reduction in the dose of PTCY is worth considering. Two consecutive Japanese phase II studies, in which the dose of PTCY was reduced to 80 mg/kg, demonstrated the feasibility of this strategy [40]. Duléry et al. analyzed the results of 38 patients aged >65 years (or >60 years in the presence of a history of cardiac events) who received 80 mg/kg of PTCY, comparing them with those of 55 patients who received 100 mg/kg, and found no significant difference in the incidences of acute and chronic GVHD but better engraftment and less frequent BK virus-associated HC in patients receiving the lower dose [28]. In a retrospective study conducted in Japan, propensity score-matching cases who received 80 mg/kg (n = 425) and 100 mg/kg (n = 425) showed no significant differences in OS, NRM or acute and chronic GVHD [29]. Moreover, Duléry et al. evaluated the outcomes of 33 patients who received 70 mg/kg of PTCY combined with low-dose ATG [43]. They revealed that, compared with PTCY at 100 mg/kg, PTCY at 70 mg/kg was associated with faster engraftment and lower incidences of bacteremia, BK virus-associated HC, and cardiac complications. The absence of an increased risk of GVHD indicates the safety of this approach, warranting its prospective investigation particularly in elderly patients and those with cardiac comorbidities. Taken together, the available data indicate that reducing the dose of PTCY may be a viable option, especially for elderly patients and those with significant comorbidities, and it is hoped that this approach will increase the applicability of PTCY-based Haplo-HCT.

Myeloablative conditioning

CY/TBI and BU/CY are the two most common MAC regimens in HLA-matched HCT [3]. Several TBI- and BU-based MAC regimens have been investigated in PTCY-based Haplo-HCT. Table 1 summarizes the results of selected studies of PTCY-based Haplo-HCT using MAC [26,27,39,44–49]. Solomon et al. from Atlanta conducted a single-center phase II study of PTCY-based Haplo-PBSCT using FLU/BU/CY in 20 patients with high-risk hematologic malignancies [26]. The first five patients received FLU at 180 mg/m², BU at 520 mg/m² and CY at 29 mg/kg, but a high frequency of mucositis led to dose reductions of FLU (125 mg/m²) and BU (440 mg/m²) in the subsequent 15 patients. Donor engraftment was achieved in all patients, and the cumulative incidences of grade 2–4 and grade 3–4 acute GVHD and chronic GVHD were 30%, 10% and 35%, respectively. The 1-year NRM, RI and OS were 10%, 40% and 69%. It is worth noting that HC developed in 75% of patients, with severe manifestations documented in 35%. The same group retrospectively analyzed 82 patients who underwent PTCY-based Haplo-PBSCT using FLU (90 mg/m²)/TBI (12 Gy) [27]. No patient developed graft failure, and the incidences of grade 2–4 and grade 3–4 acute GVHD and chronic GVHD were 52%, 17% and 37%, respectively. The 4-year NRM, RI and OS were 13%, 27% and 67%. Grade 1–2 BK virus-associated HC occurred in 38% of patients, but grade 3 or higher cystitis was documented in only 2%. Chiusolo et al. retrospectively analyzed 150 patients with AML who underwent PTCY-based Haplo-BMT with MAC [44]. Younger patients were eligible for FLU (120 mg/m²)/TBI (9–12 Gy) and older patients received TBF. The TBF regimen consisted of thiotepa (10 mg/kg), BU (9.6 mg/kg), and FLU (150 mg/m²), and the BU dose was reduced to 6.4 mg/kg for patients aged over 60 years of age. The cumulative incidences of engraftment, grade 2–4 acute GVHD and moderate/severe chronic GVHD were 92%, 17% and 15%, respectively. The 4-year NRM and RI were 20%, 24%. The 4-year OS was 72% for patients in complete remission (CR) and 26% for those with advanced disease. Multivariate analysis found no significant impact of FLU/TBI or TBF on OS. Sugita et al. conducted a phase II study of PTCY-based Haplo-PBSCT, wherein 50 patients were enrolled and received either FLU (90 mg/m²)/TBI (12 Gy) or FLU (150 mg/m²)/BU (12.8 mg/kg)/TBI (4 Gy) [39]. Neutrophil engraftment was achieved in 98%, and the incidences of grade 2–4 and grade 3–4 acute GVHD and chronic GVHD were 18% and 8% and 36%, respectively. The 2-year NRM, RI and OS were 10%, 36% and 68%. Symons et al. from Johns Hopkins reported the results of a phase II study of PTCY-based Haplo-BMT with CY (100 mg/kg)/TBI (12 Gy) or BU (12.8 mg/kg)/CY (100 mg/kg) in 96 adult and pediatric patients [45]. Engraftment was achieved in 91%, and the cumulative incidences of grade 2–4 and grade 3–4 acute GVHD and chronic GVHD were 11%, 4% and 15%, respectively. Despite the total CY dose amounting up to 200 mg/kg, a fatal cardiomyopathy was documented in only one patient. The 3-year NRM, RI and OS were 11%, 43% and 54%, respectively. Patients aged >55 years had a higher NRM (19%) than those aged 20–55 years (9%) or those aged <20 years (6%). Several groups have reported promising results with Treosulfan (TREO)-based conditioning in PTCY-based Haplo-HCT. TREO is a hydrophilic analogue of BU with potent myeloablative and immunosuppressive properties and reduced nonhematological toxicities [50]. Cieri et al. reported the outcomes of 40 patients who underwent PTCY-based Haplo-PBSCT with MAC composed of TREO (52 g/m²), FLU (150 mg/m²) and melphalan (MEL) (140 mg/m²) [46]. The donor engraftment was successful in all patients. The cumulative incidences of grade 2–4 and grade 3–4 acute GVHD and chronic GVHD were 15%, 7.5% and 20%, and the 1-year NRM, RI and OS were 17%, 35% and 56%, respectively. Analyzing EBMT registry data, Saraceni et al. compared TREO-based conditioning with TBF in 1123 patients with AML in CR undergoing PTCY-based Haplo-HCT [51]. MAC accounted for 54% of the TREO-based regimens. A matched-pair analysis revealed no significant difference in grade 3–4 acute GVHD, chronic GVHD, NRM, RI or OS between the groups, while there was a trend toward higher grade 2–4 acute GVHD in the TBF group. Dholaria et al. reported the results of two registry-based studies that compared TBI-based MAC and chemotherapy-based MAC; one for patients with AML (n = 1008) [47], and the other for patients with acute lymphoblastic leukemia (ALL) (n = 427) [48]. The type of conditioning regimen did not affect NRM, RI, disease-free survival (DFS) or OS in AML patients, whereas TBI-based MAC was associated with lower NRM and better DFS compared to chemotherapy-based MAC in ALL patients. Swoboda et al. compared two MAC regimens, FLU/TBI (n = 117) and TBF (n = 119), in patients with ALL who underwent PTCY-based Haplo-HCT [49]. When patients transplanted in first or second CR were considered, FLU/TBI presented a lower risk of NRM, but a higher risk of relapse, resulting in no significant difference in OS between FLU/TBI and TBF. In AML patients undergoing ATG-based Haplo-HCT, Ling et al. conducted a randomized study comparing FLU (150 mg/m²)/BU (12.8 mg/kg) versus BU (12.8 mg/kg)/CY (120 mg/kg) [52]. A total of 386 patients were enrolled from 12 hospitals in China. Patients in the FLU/BU arm had lower NRM (7.2% vs. 14.1% at 1 year) compared to those in the BU/CY arm, with similar RI (17.9% vs. 14.2% at 5 years) and OS (72.5% vs. 68.2% at 5 years) between the groups. Grade 3 or higher adverse events were less frequent in the FLU/BU arm.

Table 1. Selected studies of PTCY-based Haplo-HCT using MAC.

Study	N	Study type	Median age (range), years	Disease	Conditioning regimen	NRM	Relapse	OS
Solomon et al. [26]	20	Prospective	44 (25–56)	Various	FLU/BU/CY	10% at 1 year	40% at 1 year	69% at 1 year
Solomon et al. [27]	82	Retrospective	42 (19–61)	Various	FLU/TBI	13% at 4 years	27% at 4 years	67% at 4 years
Chiusolo et al. [44]	150	Retrospective	51 (17–74)	AML	FLU/TBI or TBF	20% at 4 years	24% at 4 years	57% at 4 years
Sugita et al. [39]	50	Prospective	36 (17–60)	Various	FLU/TBI or FLU/BU/TBI	10% at 2 years	36% at 2 years	68% at 2 years
Symons et al. [45]	96	Prospective	42 (1–65)	Various	CY/TBI or BU/CY	11% at 3 years	43% at 3 years	54% at 3 years
Cieri et al. [46]	40	Retrospective	55 (21–78)	Various	FLU/MEL/TREO	17% at 1 year	35% at 1 year	56% at 1 year
Dholaria et al. [47]	919	Retrospective	47 (18–78)	AML	Chemotherapy-based	24% at 2 years	28% at 2 years	55% at 2 years
Dholaria et al. [47]	89	Retrospective	38 (19–65)	AML	TBI-based	21% at 2 years	34% at 2 years	50% at 2 years
Dholaria et al. [48]	239	Retrospective	32 (18–65)	ALL	Chemotherapy-based	31% at 2 years	32% at 2 years	47% at 2 years
Dholaria et al. [48]	188	Retrospective	32 (18–68)	ALL	TBI-based	21% at 2 years	34% at 2 years	51% at 2 years
Swoboda et al. [49]	117	Retrospective	31 (18–60)	ALL	FLU/TBI	20% at 2 years	35% at 2 years	54% at 2 years
Swoboda et al. [49]	119	Retrospective	36 (19–62)	ALL	TBF	31% at 2 years	27% at 2 years	53% at 2 years

ALL: acute lymphoblastic leukemia; AML; acute myeloid leukemia; BU: busulfan; CY: cyclophosphamide; FLU: fludarabine; Haplo-HCT: haploidentical related hematopoietic cell transplantation; MAC; myeloablative conditioning; MEL: melphalan; NRM: non-relapse mortality; OS: overall survival; PTCY: posttransplant cyclophosphamide; TBF: thiotepa/busulfan/fludarabine; TBI: total body irradiation; TREO: treosulfan

Accumulating data from phase II and retrospective studies confirm the efficacy and safety of FLU/TBI- and FLU/BU-based MAC regimens for selected patients undergoing PTCY-based Haplo-HCT. Determining the conditioning regimen of choice based on the currently available evidence is premature, but the optimal regimen likely depends on disease and disease status.

Reduced-intensity conditioning

Table 2 summarizes the results of selected studies of PTCY-based Haplo-HCT using RIC [12,39,53–60]. FLU/BU and FLU/MEL are among the most frequently used RIC regimens in HLA-matched HCT [3]. Several BU- and MEL-based RIC regimens have been studied in the expectation of better disease control than the original FLU/CY/TBI regimen. Devillier et al compared the reduced-intensity TBF regimen with FLU (150 mg/m²)/CY (29 mg/kg)/ TBI (2 Gy) in 490 patients with AML in CR [59]. The TBF group had lower RI, comparable NRM, better DFS and better OS in patients aged <60 years. Conversely, there were no significant differences in RI, DFS, and OS in patients aged >60 years, and TBF was associated with a significantly higher risk of NRM than FLU/CY/TBI. Sugita et al. reported the results of 77 patients who underwent a RIC regimen consisting of FLU (150 mg/m²), BU (6.4 mg/kg) and TBI (4 Gy) in a Japanese phase II study [39]. Neutrophil engraftment was achieved in 94%, and the incidences of grade 2–4 and 3–4 acute GVHD were 14% and 5%, respectively. The incidences of overall and moderate/severe chronic GVHD at 2 years were 27% and 20%, respectively. The 2-year NRM, RI and OS were 20%, 45% and 44%. Patients aged 50–60 years with no history of previous allogeneic HCT had a 6% NRM at 2 years. As for FLU/MEL-based conditioning regimens, Ciurea et al. reported on 43 AML patients who received FLU (160 mg/m²)/MEL (100–140 mg/m²) in combination with thiotepa (5 mg/kg) or TBI (2 Gy) [56]. Except for one patient who succumbed to early death, 42 (98%) achieved engraftment. The cumulative incidences of grade 2–4 and 3–4 acute GVHD were 35% and 5%, respectively, and that of chronic GVHD was 9% at 2 years. The incidence of NRM was 21% at day 100, 30% at 1 year and 34% at 2 years. The 2-year RI and OS were 24% and 42%. Tanaka et al. published the results of a phase I/II study of PTCY-based Haplo-PBSCT in 18 patients with adult T-cell leukemia/lymphoma [58]. The conditioning regimen consisted of FLU (180 mg/m²), MEL (80 mg/m²) and TBI (2 Gy). Neutrophil engraftment was achieved in all patients at a median of 16 days. The cumulative incidences of grade 2–4 and grade 3­–4 acute GVHD and moderate/severe chronic GVHD were 39%, 11% and 17%, respectively. The 2-year OS was 73%, and the cumulative incidences of NRM and disease progression were 11% and 28% at 1 year. TREO is increasingly administered as part of ‘reduced-toxicity conditioning regimens’ that are characterized by potent cytoreductive properties with low toxicity [61]. Several phase II studies showed promising results with a conditioning regimen consisting of FLU and TREO in patients undergoing allogeneic HCT mostly from HLA-matched related or unrelated donors [62–66]. To prove the non-inferiority of FLU/TREO to FLU/BU, Beelen et al. conducted a phase III study in patients with AML or myelodysplastic syndrome (MDS) who were considered ineligible for MAC regimens because of advanced age and/or significant comorbidities in a matched allogeneic HCT setting [67]. The primary endpoint of the study was 2-year event-free survival (EFS), defined as the time from transplantation to relapse or disease progression, graft failure, or death. The interim analysis of 476 patients demonstrated a clinically meaningful EFS advantage of FLU/TREO over FLU/BU (64.0% vs. 50.4% at 2 years; P < 0.0001 for non-inferiority; P = 0.0051 for superiority), which led to reguratory approval of TREO in combination with FLU by the European Medicines Agency in 2019. The final study results of 570 patients securing a median follow-up duration of 29 months showed that FLU/TREO was associated with higher EFS (59.5% vs. 49.7% at 3 years), higher OS (66.8% vs. 56.3% at 3 years), similar RI (25.9% vs. 26.0% at 3 years), and lower NRM (21.0% vs. 14.2% at 3 years) compared with FLU/BU [68]. The improved outcomes in patients undergoing FLU/TREO support its potential to become a standard conditioning regimen, especially in patients not eligible for MAC. Recently, the use of FLU/TREO is being investigated in PTCY-based Haplo-HCT [51,69]. Although these studies were not confined to patients who underwent PTCY-based Haplo-HCT using RIC, FLU/TREO has been shown to provide at least comparable outcomes to conventional conditioning regimens [51,69]. In addition, conditioning regimens containing total marrow and lymphoid irradiation (TMLI) have been explored. TMLI can deliver high doses of radiation to the bone marrow and other target organs without increasing off-target radiation exposure in healthy tissues [70]. In a phase I study conducted at the City of Hope National Medical Center, 31 patients with refractory leukemia or MDS underwent PTCY-based Haplo-PBSCT with FLU (125 mg/m²)/CY (29 mg/kg) in conjunction with TMLI [60]. The cumulative incidences of grade 2–4 and 3–4 acute GVHD were 52% and 6%, respectively, and the 2-year cumulative incidence of chronic GVHD was 35%. The 2-year NRM was 13%. For those treated with 20 Gy TMLI, the 1-year NRM, RI and OS were 9%, 17% and 83%.

Table 2. Selected studies of PTCY-based Haplo-HCT using RIC.

Study	N	Study type	Median age (range), years	Disease	Conditioning regimen	NRM	Relapse	OS
Luznik et al. [12]	68	Prospective	46 (1–71)	Various	FLU/CY/TBI	15% at 1 year	51% at 2 years	36% at 2 years
Burroughs et al. [53]	28	Retrospective	32 (14–62)	HL	FLU/CY/TBI	9% at 2 years	40% at 2 years	58% at 2 years
Kasamon et al. [54]	271	Retrospective	61 (50–75)	Various	FLU/CY/TBI	12% at 1 year	46% at 3 years	46% at 3 years
Brammer et al. [55]	22	Retrospective	46 (20–62)	Lymphoma	FLU/MEL + TT or TBI	19% at 1 year	27% at 2 years	54% at 2 years
Ciurea et al. [56]	43	Retrospective	61 (55–69)	AML, MDS	FLU/MEL + TT or TBI	34% at 2 years	24% at 2 years	42% at 2 years
Sugita et al. [39]	77	Prospective	58 (22–65)	Various	FLU/BU/TBI	20% at 2 years	45% at 2 years	44% at 2 years
Castagna et al. [57]	47	Prospective	43 (20–68)	Lymphoma	FLU/CY/TT + TBI or TMLI	15% at 4 year	28% at 4 years	64% at 4 years
Tanaka et al. [58]	18	Prospective	59 (27–64)	ATLL	FLU/MEL/TBI	11% at 1 year	28% at 1 year	73% at 2 years
Devillier et al. [59]	97	Retrospective	52 (43–57)*	AML	FLU/CY/TBI	16% at 2 years	43% at 2 years	51% at 2 years
Devillier et al. [59]	106	Retrospective	53 (44–57)*	AML	TBF	22% at 2 years	15% at 2 years	63% at 2 years
Devillier et al. [59]	117	Retrospective	68 (66–70)*	AML	FLU/CY/TBI	23% at 2 years	28% at 2 years	55% at 2 years
Devillier et al. [59]	170	Retrospective	65 (63–68)*	AML	TBF	30% at 2 years	22% at 2 years	54% at 2 years
Al Malki et al. [60]	31	Prospective	37 (21–58)	Various	FLU/CY/TMLI	9% at 1 year	17% at 1 year	83% at 1 year

*Interquartile range.

AML; acute myeloid leukemia; ATLL: adult T-cell leukemia/lymphoma; BU: busulfan; CY: cyclophosphamide; FLU: fludarabine; Haplo-HCT: haploidentical related hematopoietic cell transplantation; HL: Hodgkin lymphoma; MDS: myelodysplastic syndrome; MEL: melphalan; NRM: non-relapse mortality; OS: overall survival; PTCY: posttransplant cyclophosphamide; RIC: reduced-intensity conditioning; TBF: thiotepa/busulfan/fludarabine; TBI: total body irradiation; TMLI: total marrow and lymphoid irradiation; TT: thiotepa

In addition to the original FLU/CY/TBI regimen, FLU/BU- and FLU/MEL-based regimens, mostly combined with low-dose TBI, have been investigated, with promising results. Novel regimens, such as FLU/TREO, are increasingly being used in clinical practice with the hope of reducing toxicity without impairing efficacy.

Myeloablative conditioning versus reduced-intensity conditioning

In the PTCY-based Haplo-HCT setting, no randomized studies comparing MAC and RIC have been published to date, but there have been several retrospective comparative studies. Two single-center studies compared MAC and RIC in PTCY-based Haplo-PBSCT, adjusting for a propensity score calculated as the probability of receiving MAC versus RIC. Huselton et al. from Washington University Medical Center showed lower RI and higher NRM for patients receiving MAC versus RIC, resulting in no difference in OS [71], whereas Modi et al. from Karmanos Cancer Institute reported no significant difference in NRM, RI or OS between MAC and RIC [72]. Using the CIBMTR database, Solomon et al. compared outcomes of patients with AML, ALL or MDS who received MAC (n = 526) or RIC (n = 799) [73]. In younger patients (18–54 years), RIC was associated with a higher RI, similar NRM and worse DFS and OS compared to MAC. On the other hand, neither RI, DFS nor OS differed between MAC and RIC in older patients (55–70 years); however, RIC was associated with a lower NRM than MAC. Santoro et al. analyzed data from the EBMT registry on 912 AML patients aged ≥45 years, 78% of whom received PTCY [74]. There was no difference in NRM, RI, DFS or OS between patients conditioned with MAC or RIC. The results of these comparative studies are summarized in Table 3 [71–74]. Acuri et al. carried out a meta-analysis of 17 Haplo-HCT studies that used PTCY in more than 70% of patients to compare MAC and RIC [75]. The use of MAC was associated with higher NRM and lower RI, but there was no difference in OS between MAC and RIC.

Table 3. Selected studies of PTCY-based Haplo-HCT comparing MAC and RIC.

Study	N	Study type	Median age (range), years	Disease	Conditioning regimen	NRM	Relapse	OS
Huselton et al. [71]	61	Retrospective	48 (19–70)	Various	MAC	39% at 1 year	21% at 1 year	51% at 1 years
Huselton et al. [71]	87	Retrospective	55 (19–73)	Various	RIC	27% at 1 year	37% at 1 year	43% at 1 years
Modi et al. [72]	24	Retrospective	47 (21–78)	Various	MAC	22% at 1 years	22% at 1 year	69% at 1 year
Modi et al. [72]	65	Retrospective	62 (22–78)	Various	RIC	22% at 1 years	18% at 1 year	67% at 1 year
Solomon et al. [73]	381	Retrospective	NA (18–54)	AML, ALL, MDS	MAC	18% at 3 years	38% at 3 years	54% at 3 years
Solomon et al. [73]	308	Retrospective	NA (18–54)	AML, ALL, MDS	RIC	17% at 3 years	51% at 3 years	49% at 3 years
Solomon et al. [73]	145	Retrospective	NA (55–70)	AML, ALL, MDS	MAC	30% at 3 years	34% at 3 years	42% at 3 years
Solomon et al. [73]	491	Retrospective	NA (55–70)	AML, ALL, MDS	RIC	24% at 3 years	46% at 3 years	38% at 3 years
Santoro et al. [74]	373	Retrospective	55 (45–79)	AML	MAC	31% at 2 years	25% at 2 years	48% at 2 years
Santoro et al. [74]	539	Retrospective	61 (45–76)	AML	RIC	30% at 2 years	29% at 2 years	44% at 2 years

ALL: acute lymphoblastic leukemia; AML; acute myeloid leukemia; Haplo-HCT: haploidentical related hematopoietic cell transplantation; MAC; myeloablative conditioning; MDS: myelodysplastic syndrome; NA: not available; NRM: non-relapse mortality; OS: overall survival; PTCY: posttransplant cyclophosphamide; RIC: reduced-intensity conditioning.

At the moment, there is no clear consensus on the preference between MAC or RIC in PTCY-based Haplo-HCT. MAC may reduce the risk of relapse, but if so, this beneficial effect does not seem to translate into better OS due to an increased risk of NRM. Prospective randomized studies are needed focusing on PTCY-based Haplo-HCT to draw meaningful conclusions.

Discussion

The diversification of transplant modalities makes it advisable to determine the optimal conditioning regimen for each modality. PTCY-based Haplo-HCT is a unique form of allogeneic HCT that uses differentiated GVHD prophylaxis to overcome the HLA barrier, and this feature is thought to have a significant influence on posttransplant outcomes. Therefore, the optimal conditioning regimen for PTCY-based Haplo-HCT needs to be addressed based on data from patients undergoing PTCY-based Haplo-HCT. All existing studies comparing different conditioning regimens in PTCY-based Haplo-HCT are retrospective. It is well known that retrospective studies are subject to inherent biases, such as patient selection, treatment heterogeneity, and the confounding effects of unmeasured factors, and these biases can only be resolved by a prospective randomized study. Despite the significant growth of PTCY-based Haplo-HCT in recent years, it represents <20% of all allogeneic HCTs [8,9], which makes it very challenging to conduct prospective randomized studies focusing on PTCY-based Haplo-HCT. In this context, well-designed large-scale retrospective studies can be useful, with the potential to provide the best available evidence.

Posttransplant relapse is the greatest obstacle to the success of allogeneic HCT [76,77]. Therefore, developing more effective conditioning regimens is a matter of clinical concern. An alternative strategy is a sequential approach to administering chemotherapy before conditioning. Several prospective studies are being conducted to evaluate the efficacy and safety of novel conditioning regimens, including clofarabine (NCT00824135 and NCT00857389), cladribine (NCT03384225), bendamustine (NCT04942730), mitoxantrone liposomes (NCT05739630), and TMLI (NCT04187105 and NCT04262843), in a PTCY-based Haplo-HCT setting, and other studies are investigating a standard RIC regimen following sequential chemotherapy (NCT03035422 and NCT04002115).

Although PTCY-based Haplo-HCT was initially developed using a nonmyeloablative conditioning regimen, RIC and MAC have proven to be viable options. The important issue for future clinical research is to identify which regimen is most suitable for which patients. The accumulated evidence based on retrospective studies and anticipated prospective studies is expected to establish optimal conditioning regimens specialized for PTCY-based Haplo-HCT.

Author contributions

All authors drafted, edited, and approved the manuscript.

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Funding

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