https://orcid.org/0000-0003-3429-2737
In this issue of Blood Advances, Nagayama et al1 report that patients aged ≥50 years who receive haploidentical (haplo) stem cell transplantation using posttransplant cyclophosphamide (PTCy-haplo) from donors younger than 40 years have superior outcomes compared with cord blood transplantation (CBT).
Allogeneic hematopoietic stem cell transplantation (HSCT) remains a cornerstone treatment for patients with high-risk hematologic malignancies, particularly with available HLA-matched donors.2,3 However, with fewer siblings, the chances of finding a fully HLA-matched donor within the family decrease and more patients must rely on unrelated donor registries to find a match, a strategy is limited for those with diverse ethnic backgrounds and the centers practicing with limited resources and in developing countries. This has led to the pursuit of alternatives such as haplo donors (haplo-donors) and CBT.2 The PTCy-based haplo approach has become widely used because it does not require graft manipulation, has minimal graft acquisition costs, and overcomes issues of limited cell dose, prolonged periods of neutropenia, and increased risk of infections associated with the use of cord blood grafts.4 However, both alternatives have unique challenges and complications that highlight the importance of meticulous donor selection and other variables such as the donor age.5 The impact of the donor age on the transplantation outcomes is now acknowledged owing to the effect on immune response, stem cell quality, and engraftment success.6,7 Although previous studies reported superior survival outcomes and lower nonrelapse mortality (NRM) with younger haplo-donors,8,9 Nagayama et al were the first to evaluate the haplo-donor age against the CBT outcomes.
Nagayama et al conducted an analysis of 5161 Japanese registry patients, aged 16 to 70 years, undergoing their first HSCT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia. Haplo-donors were categorized into younger (<40 years) and older groups (≥40 years), and patients into younger (<50 years) and older cohorts (≥50 years).1 The study showed higher overall survival (OS) and lower NRM than those undergoing CBT (OS, 55.5% vs 50.8% [P = .006]; NRM, 17.3% vs 28.6% [P < .001]).1 Notably, relapse rates were higher in the older patient group who received younger haplo-donors than CBT (33.0% vs 24.9%; P = .017).1 For older patients who had older haplo-donor transplants, the outcomes were comparable in terms of OS, NRM, and relapse rates.1 In contrast, there were no significant differences in outcomes (OS, NRM, and relapse rates) between CBT and haplo-donors in the younger patient cohort regardless of the donor age.1 The study analysis of causes of NRM revealed significant clinical differences. The study showed higher rates of fatal infections, graft failure, and organ failures after CBT than those with younger haplo-donors, especially in older patients.3 The higher infection-related mortality in CBT patients is likely explained by the delayed engraftment and immune system reconstitution commonly seen with CBT.4,10 Understanding these disparities is crucial for clinicians when assessing the risk-benefit profile of different donor options.
Acute graft-versus-host disease (GVHD) was higher in patients undergoing CBT than younger haplo-donors in both younger and older patients, indicating a potential advantage of pursuing younger haplo-donors.5 In chronic GVHD, the rates were similar across all tested groups, including PTCy-haplo and CBT from both younger and older donors.1 Another finding that reinforced the younger haplo-donors is the GVHD-free relapse-free survival (GRFS). Nagayama et al found that older patient cohort who received younger haplo-donors had higher GRFS than CBT. The inclusion of GRFS, a well-established composite end point, is highly valuable because it provides a comprehensive evaluation of the transplant outcomes by taking into consideration both safety and efficacy.7 The improved GRFS in older patients reinforces the value of using such end point in future transplant research to enhance the focus on patient-centered outcomes.7
In line with previous research comparing haplo and cord blood HSCT, Nagayama et al’s study shows further evidence that using younger haplo-donors for older HSCT can improve survival outcomes and lower the transplant-related mortality.4,10 Nonetheless, this study has several limitations. The retrospective nature of the study raises potential biases in patient selection and in the other different transplant steps.1 Furthermore, the relatively short median follow-up duration limits the study’s ability to evaluate the long-term transplant outcomes.1 Another limitation includes the donor age cutoff used in the study, which, although statistically determined, may not be representative of all patients’ demographics and thus might require further validation. In addition, using different conditioning regimens across the participating centers may have influenced the study results, especially when comparing between groups. To overcome these limitations, future prospective clinical trials and longer-term data are needed to establish and refine the crucial role of the donor age in the setting of haplo transplant and CBT outcomes.9
The choice of alternative donors and consequently the transplant outcomes are largely driven by the regional health care and transplant center practices.10 Nagayama et al’s study is particularly relevant in Japan where CBT is the main alternative donor approach even with the increasing frequency of the haplo transplants.10 Such regional differences in donor selection practices are commonly determined by the center infrastructure availability and clinical practice tradition.2,10 Thus, randomized clinical trials designed to validate the findings of studies, such as Nagayama et al’s study, will need to consider the local practices and diverse health care systems.3
Nagayama et al’s study left multiple vital unanswered questions that require further investigation. First, the durability of the improved outcomes that were achieved by the younger haplo-donors needs confirmation, especially regarding the relapse rates and chronic complications.8 Identifying the biological mechanisms behind the improved outcomes observed with younger donors, particularly those related to the immune response, will eventually help further optimize the donor selection process.6 Furthermore, prospective randomized trials comparing younger and older haplo-donors with CBT in different clinical and conditioning regimens will enhance the current study evidence.9 These are examples for future research that will help advance the transplant protocols, clinical practice, and patients’ outcomes.3
Conflict-of-interest disclosure: The authors declare no competing financial interests.
