More about post-transplant cyclophosphamide in haploidentical grafts: full or reduced doses?

ABSTRACT

Haploidentical hematopoietic can be conducted on an outpatient basis but the two main reasons to accept into the hospital a patient in this setting are complications of the hematological toxicity and/or the cytokine-release syndrome. With the aim of reducing the post-transplant cyclophosphamide-dependent toxicity without compromising its effectivity, attempts to reduce the dose of post-transplant cyclophosphamide have been made: Decreases from the conventional total dose of post-transplant cyclophosphamide (100 mg/Kg) have been explored worldwide, showing that decreasing the total dose to even 50 mg/Kg significantly decreases the toxicity of the procedure without compromising its efficacy, safety and results. We present here the salient data of the attempts to diminish the doses of post-transplant cyclophosphamide which have been done and published worldwide, information that suggests that the conventional doses of post-transplant cyclophosphamide can be significantly reduced thus decreasing the toxicity, without compromising the effectiveness of the procedure, mainly the development of graft versus host disease.

KEYWORDS:

• Allogeneic hematopoietic stem cell transplantation
• post-transplantation cyclophosphamide
• graft-versus-host disease
• outpatient
• cytokine release syndrome
• allograft
• haploidentical hematopoietic stem cell transplantation
• acute leukemia

Introduction

Allogeneic hematopoietic cell transplantation (HSCT) is the most important curative modality for several hematologic malignancies, but an HLA-matched sibling or unrelated donor is not always available, particularly for ethnic minorities and multiethnic families [1]. This problem has led to the expansion of the donor pool to include alternative donor sources such as HLA-haploidentical (Haplo) relatives, HLA-mismatched unrelated donors, and HLA-matched or mismatched cord blood. Post-transplantation cyclophosphamide (PT-Cy)-containing graft-versus-host disease (GVHD) prophylaxis, pioneered at Johns Hopkins [2] has significantly revolutionized Haplo-HSCT with acceptable rates of engraftment, GVHD, relapse, and survival [3]. The use of PT-Cy has contributed considerably to the increase in the number of haplo-HSCT performed, particularly in low and middle-income countries (LMIC) [4]. PT-Cy has emerged as a powerful platform to overcome the human leucocyte antigen (HLA) barrier and reduce the incidence of both acute and chronic graft-versus-host disease (GVHD) [5]. PT-Cy is now a successful and widely used GVHD prophylaxis, considered the standard of care for haplo-HSCT and is actively being investigated for HSCT with other donor sources [5,6]. However, in the context of haplo-HSCT, PT-Cy is associated with toxicities and organ damage, such as delayed engraftment and immune recovery [7], cardiac events [8], and hemorrhagic cystitis (HC) [9], especially in elderly patients. While toxicities can be correlated with the total cyclophosphamide dose [10], few studies have compared the safety and efficacy of different PT-Cy doses. We [11] and others [12] have shown that Haplo-HSCT can be conducted safely on an outpatient basis, using peripheral blood stem cells, thus leading to substantial decreases in costs. Outpatient-based Haplo-HSCT has turned into the solution of the HSCT in LMIC [13]. The employed doses of PT-Cy are usually 50 mg/Kg. on days +3 and +4 of the HSCT [14] and there is preliminary information about diminished doses of PTCy, being equally effective in the prevention of GVHD and substantially less toxic [15].

The Mexican experience

In a pilot study [15], we studied 29 patients given an haplo-HSCT employing the ‘Mexican Method’ to conduct Haplo-HSCT [16], (see Figure 1): 21 patients received the conventional dose of PTCy (50 mg/Kg on days 3 and 4), whereas 8 were given reduced doses of the drug (25 mg/Kg on days 3 and 4). There were no significant differences in terms of age, sex, hematological recovery, and type of conditioning regimen between these two groups. Cytokine release syndrome (CRS) and toxicity were less frequent in the group of persons given a diminished dose of PT-Cy, whereas the prevalence of both acute and chronic graft versus host disease was similar in the two groups; the overall survival (OS) was not statistically different in these groups, whereas the relapse-free survival (RFS) was better in the patients grafted with the PT-Cy 25 mg/kg (5.1 vs. 2.1 mo) [15]. We have recently expanded our experience studying a group of 35 patients given either full (50 mg/Kg, days +3 and +4, n = 21) or reduced (25–30 mg/Kg, n = 14) doses of PT-Cy and confirmed our initial observation of both CRS being less frequent in persons given reduced doses of PT-Cy, whereas the GVHD prevalence, PFS and OS were similar in the two groups. Interestingly, there were no significant differences between the results obtained with either 25 or 30 mg/Kg PT-Cy. Figure 2 depicts the OS of these two groups of patients.

Figure 1. Scheme of the ‘Mexican Method’ to conduct haploidentical hematopoietic stem cell transplants on an outpatient basis. Cy = cyclophosphamide; pre-transplant Cy: 500 mg/m²; post-transplant Cy: 25 mg/Kg. Flu = fludarabine, 25 mg/m². Tac = tacrolimus.

Figure 2. Overall survival in patients treated with conventional and reduced doses of cyclophosphamide in México.

Worldwide experience

The allograft tolerance induced by Cy has been the subject of intensive research since the 1960s [17]. In 2008, Luznik et al established PT-Cy in two doses at 50 mg/kg as a safe and efficient platform for GVHD prophylaxis after Haplo-HSCT [3]. Since then, most studies have employed this dose. The addition of antithymocyte globulin (ATG) [18,19] was employed to reduce the optimal dose of PT-Cy with the aim of reducing the incidence of GVHD while lessening the risk of Cy-induced toxicities [20,21]. Recent studies conducted in Japan have shown that PT-Cy total dose can be safely reduced to 80 mg/kg (divided into two doses of 40 mg/kg) without increasing the incidence of GVHD in a haploidentical HCT setting with peripheral blood stem cells (PBSC) [22,23]. Compared to a PT-Cy total dose of 100 mg/kg, platelet and neutrophil recovery were improved with 80 mg/kg. However, the dose reduction did not allow a significant reduction of nonhematologic toxic events and was not associated with improved survival. Recently, Dulery et al, in France [24] published a study with a more substantial dose reduction to 70 mg/kg, adding ATG in 32 patients and found no major differences between patients treated with either 70 or 100 mg/Kg of PT-CY in terms of toxicity or GVHD, see Table 1.

Table 1. Salient features of the papers published exploring the possibility of reducing the doses of post-transplant cyclophosphamide (PTCy).

PTCy, mg/Kg days 3 + 4	80	80	80	70	50–60
Number	57	80	38	33	14
Female	18	28	19	15	8
Male	39	52	19	18	6
Median age	61 (18–70)	61 (18–70)	69 (63–77)	69 (21–74)	19 (2–68)
Acute leukemia	12%	15%	11%	61%	70%
Cardiac toxicity			11%	12%	0%
CRS	91%	88%	16%	48%	20%
Days to > 0.5 × 10e + 9/L neutrophils	15	16	18	16	14
Days to > 20 × 10e + 9/L platelets	28	25	29	30	11
Acute GVHD, II-IV	26%	24%	32%	18%	28.5%
Chronic GVHD	35%	28%	41%	27%	7.14%
2 years OS	51%	58%	70%	68%	38%
2 years DFS	42%	48%	65%	65%	41%
Median follow up (months)	25	25	22	24	2
References	Sugita et al. 2021 [22]	Sugita et al. 2021 [22]	Duléry et al. 2023 [23]	Duléry et al. 2023 [24]	These data

CRS = Cytokine release syndrome. GVHD = Graft versus host disease. OS = Overall survival. DFS = Disease-free survival.

Reduced doses of PT-Cy and outpatient conduction of Haplo-HSCT

We have previously shown that conducting allografts on an outpatient basis is associated with less toxicity, less GVHD both acute and chronic, less infections and improved long-term survival [11]. We have also shown that Haplo-HSCT can be conducted on an outpatient basis [14,16] and that the two main reasons to accept into the hospital a patient given an Haplo-HSCT on an outpatient basis are complications of the hematological toxicity and/or cytokine-release syndrome (CRS) [12]. If the Cy-dependent toxicity can be reduced without compromising its effectivity, the possibility of completing a Haplo-HSCT fully on an outpatient basis should result in a reduction of costs and in turn, in more allografts being conducted. By now, there are several papers dealing with the employment of reduced doses of PT-Cy in the setting of Haplo-HSCT; decreases from the conventional total dose of PT-Cy (100 mg/Kg) to 50–80 mg. have been explored, showing that decreasing the total dose to even 50 mg/Kg significantly decreases the toxicity of the procedure without compromising its efficacy, safety and results. These observations should be considered as an idea to conduct prospective randomized studies to explore the possibility of significantly reducing the doses of PT-Cy in the setting of Haplo-HSCT and may contribute to shed light on crucial outcomes such as immune reconstitution and the overall quality of life experienced by transplanted patients, thus leading into increased possibilities of outpatient conduction of the Haplo-HSCT, which in turns leads into diminished costs, a critical point for patients living in LMIC, where over 80% of the inhabitants of the world currently live.

One of the main safety concerns when reducing PT-Cy dose is its impact on GVHD [3]. In all the studies conducted up to now, that reduction was not associated with a higher incidence of acute or chronic GVHD of any grade [15, 22–24]. Interestingly, most studies have shown an increased OS employing diminished doses of PT-Cy [15, 22–24].

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors reported there is no funding associated with the work featured in this article.