Editor’s note: In recent years, haploidentical donor hematopoietic stem cell transplantation has gradually been developed in malignant hematologic tumors, greatly solving the problem of previous donor shortages. From April 14th to 17th, 2024, the 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) was held in Glasgow, the third-largest city in the UK. At this EBMT Annual Meeting, Professor Yue Lu from Lu Daopei Hospital reported on a latest clinical research result. The study confirmed that in haploidentical hematopoietic stem cell transplantation, using non-direct related donors can be comparable to direct related donors in terms of efficacy and safety. This also provides further evidence to expand the range of selectable donors in clinical practice. Our journal invited Professor Yue Lu to share the important results and clinical significance of this study with colleagues.

Oncology Frontier – Hematology Frontier: Could you please introduce the background of this study and the clinical pain points we hope to address through it?

Professor Yue Lu: With the optimization and improvement of conditioning regimens, the proportion of haploidentical hematopoietic stem cell transplantation in allogeneic hematopoietic stem cells has been steadily increasing in recent years. In our hospital, haploidentical donors account for 70% of the transplantation types, and the Chinese Hematopoietic Stem Cell Transplantation Registry Group has also reached over 60% in recent years. Although there are multiple options for haploidentical donors, some patients still cannot access direct related donors for various reasons. In such cases, non-direct related donors are considered as an alternative option. However, the safety and effectiveness (including engraftment rate of stem cells, incidence of GVHD, NRM, and final OS, LFS, GRFS, etc.) and whether patients can ultimately benefit from non-direct related donors still need further exploration.

Currently, there are relatively few studies on non-direct related haploidentical transplantation, with only three published case-control studies. Such studies can reduce bias in comparison by controlling differences in observed covariates, leading to more reliable conclusions. The earliest study was published in the BMT Journal in 2014 by Peking University People’s Hospital, comparing non-direct related donors (NFD, n=30) and direct related donors (FD, n=120) in haploidentical transplantation under the Beijing protocol system. The results suggested that the NFD group had prolonged platelet engraftment (18 days vs. 15 days, P=0.027), increased II–IV grade aGVHD (27.6% vs. 39.4%, P=0.058) and 2-year extensive cGVHD (36.7% vs. 20.2%, P=0.03), with no statistically significant differences in 2-year relapse rate (26.7% vs. 14.8%, P=0.17), 3-year OS rate (56.7% vs. 70.4%, P=0.224), and 3-year LFS rate (50.0% vs. 65.4%, P=0.103). The results of this study indicated that NFD haploidentical transplantation can be a safe and effective treatment for malignant hematologic system diseases and can serve as an alternative treatment when FD is not available.

Subsequently, in 2018, a multicenter retrospective study led by the First Affiliated Hospital of Zhejiang University compared the results of NFD (33 cases) and FD (66 cases) haploidentical transplantation under low-dose ATG/G-CSF+PBSC system. The study showed that all patients achieved successful engraftment of granulocytes and platelets, with no statistically significant differences between the two groups in terms of 100-day cumulative incidence of aGVHD, 2-year cumulative relapse rate/cGVHD/NRM, 2-year OS rate, and GRFS rate. Multivariate analysis suggested that donor type (NFD vs. FD) had no impact on OS, PFS, GRFS, CIR, II–IV grade aGVHD, or moderate to severe cGVHD; donor age (per 10-year increase) was correlated with increased II–IV grade aGVHD (HR=1.64, P=0.03), moderate to severe cGVHD (HR=1.92, P=0.01), and lower GRFS (HR=1.40, P=0.02); low-level donor-recipient HLA match was closely related to increased moderate to severe cGVHD (HR=4.07, P=0.02), and patients in CR had better OS (HR=0.21, P=0.01) and PFS (HR=0.3, P=0.03). In summary, this study indicated that when FD donors are unavailable for haploidentical hematopoietic stem cell transplantation, NFD donors are a feasible alternative.

The last study came from the largest case-control study reported at the 2023 EBMT Congress. The study included patients aged 18 and above with acute leukemia in CR status undergoing first-time haploidentical transplantation (NFD group 154 cases; FD group 2549 cases), using exact matching and propensity score matching statistical methods for 1:3 matching, with 123 cases of NFD and 324 cases of FD ultimately included in the study. The median ages of patients in the NFD and FD groups were 35.6 years and 37.2 years, respectively, with both groups achieving over 95% engraftment rates. The comparison results between the two groups showed similar outcomes in terms of 2-year relapse rate and NRM, 2-year OS rate, LFS rate, and GRFS rate, 180-day II–IV, III–IV acute GVHD, as well as chronic limited and extensive cGVHD. This conclusion further confirms that for patients with acute leukemia undergoing haploidentical transplantation, when FD donors are unavailable, NFD-related donors can be equally substituted.

Oncology Frontier – Hematology Frontier: Could you please introduce the main design and results of the study you presented at this year’s EBMT conference?

Professor Yue Lu: Similarly, it’s a case-control study where we included 4583 patients with malignant hematologic diseases, among which were NFD (n=90) and FD (n=4493) cases. The primary diseases included AML (n=2249), ALL (n=1983), MDS (n=241), and MPAL (n=154). We conducted a 1:2 matching between the two groups, ensuring no differences in common known prognostic factors before transplantation (such as donor/patient age, gender, primary disease, disease risk stratification, pre-transplant disease remission status, and transplantation timing), thus minimizing bias in comparing the two groups. Ultimately, we conducted comparative analyses in 86 matched NFD and 172 matched FD cases. Additionally, differences between the two groups were compared under our center’s ATG/G-CSF mobilization followed by BM+PBSC+third-party UCB haploidentical transplantation system.

The results showed that in both NFD and FD groups, all patients achieved granulocyte engraftment, with platelet engraftment rates within 100 days being 95.3% (95%CI: 91.1%-99.9%) and 98.2% (95%CI: 96.2%-100%), respectively, with no statistically significant difference (P=0.200). The median follow-up time was 36 (11-102) months for the NFD group and 36 (11-128) months for the FD group. Cumulative incidence rates of relapse (CIR) and non-relapse mortality (NRM) were similar, with 3-year CIR being 15.8% (95%CI: 10.2%-20.4%) and 10.9% (95%CI: 8.2%-13.6%), respectively (P=0.659); NRM being 28.1% (95%CI: 23.1%-33.1%) and 19.6% (95%CI: 16.2%-23.0%), respectively (P=0.072). Overall survival (OS), leukemia-free survival (LFS), and GVHD-free/relapse-free survival (GRFS) rates also showed no significant differences, with 3-year OS rates being 63.3% (95%CI: 58.0%-68.6%) and 71.5% (95%CI: 67.8%-75.2%), respectively (P=0.112); LFS being 63.3% (95%CI: 58.0%-68.6%) and 71.5% (95%CI: 67.8%-75.2%), respectively (P=0.112); GRFS being 56.9% (95%CI: 50.9%-62.9%) and 57.2% (95%CI: 52.5%-61.9%), respectively (P=0.386).

In terms of acute GVHD occurrence rates, II-IV acute GVHD rates were 35.2% (95%CI: 29.9%-40.3%) and 28.5% (95%CI: 25.1%-31.9%) in the NFD and FD groups, respectively (P=0.433), and III-IV acute GVHD rates were 16.3% (95%CI: 12%-20.6%) and 12.8% (95%CI: 10.1%-15.5%), respectively (P=0.672), with no difference in 100-day CIR. Regarding cGVHD occurrence rates, they were 39.3% (95%CI: 32.6%-34.0%) and 29.1% (95%CI: 25.2%-34.0%) in the NFD and FD groups, respectively (P=0.290); moderate to severe cGVHD rates were 36.0% (95%CI: 29.3%-42.7%) and 23.5% (95%CI: 19.0%-27.2%), respectively (P=0.147), with no difference in 3-year CIR between the two groups.

Multivariate analysis showed that donor type (NFD vs. FD) had no effect on OS, LFS, GRFS, CIR, NRM, II-IV acute GVHD, or moderate to severe cGVHD.

Oncology Frontier – Hematology Frontier: Could you discuss the clinical implications of these research findings?

Professor Yue Lu: Our study first expands the range of selectable donors for haploidentical transplantation and confirms that using non-direct related donors for haploidentical transplantation in patients where direct related donors are not available is safe, feasible, and effective. Typically, direct related haploidentical donors include parents, children, and half-matched siblings, while non-direct related donors include aunts, uncles, cousins, and third-generation grandchildren. Generally, the preferred order for selecting direct related donors is based on factors such as DSA negativity, followed by young age, male gender, and non-inherited maternal antigen mismatch. Additionally, the age and gender of the donor are also important prognostic factors. We are also considering whether, for some patients lacking optimal direct related donors, peripheral relatives can be considered, such as whether younger peripheral relatives are preferred over older parents as donors.

Secondly, there is an increasing demand for transplantation among elderly patients. Previously, patients aged over 55 were not often considered, but now many centers accept patients over 70. For these elderly patients, their siblings as potential donors are often elderly or deceased, and their children are around 50 years old. In such cases, whether younger third-generation grandchildren are preferable to older second-generation children is also a question worth exploring.

Finally, in the current system, how to further optimize GVHD prevention strategies to minimize the incidence of aGVHD and cGVHD and thus improve LFS and GRFS is an area for further research in the future.

Oncology Frontier – Hematology Frontier: Could you share your thoughts and takeaways from attending the 2024 EBMT Annual Meeting, as well as your research plans for the future?

Professor Yue Lu: Our study confirms that in situations where direct related donors are unavailable, non-direct related donors can be equally effective and safe substitutes. Next, we want to ascertain the optimal and precise donor selection among the numerous available direct and non-direct related donors, considering factors such as donor age and gender. For example, as mentioned earlier, whether younger peripheral relatives are preferable to older parents or paternal donors, and the preferred order of selection for peripheral half-matched donors, including factors such as generation, gender, age, blood type, and HLA matching degree.

In summary, there are currently not many studies on non-direct related haploidentical transplantation, and they are still in the retrospective research stage, with no prospective studies yet. We hope that in the future, prospective and better-designed studies can further explore the optimal selection of haploidentical donors (including non-direct related donors).

Expert Biography

Professor Yue Lu

Director and Chief Physician of the Transplantation Department, Hebei Yanda Lu Daopei Hospital (Vice Director Level)

Council Member of the Beijing Hematology Society

Member of the Hematopoietic Stem Cell Transplantation Application Group, Chinese Medical Association Hematology Society

Member of the Hematology Professional Committee, Cross-Strait Medical Exchange Association

In October 2016, he went to the Fred Hutchinson Bone Marrow Transplantation Center in Seattle, USA for clinical training

As of the end of 2023, he has completed more than 1500 cases of allogeneic hematopoietic stem cell transplantation

Published over 10 SCI papers in journals such as Frontiers in Immunology, British Journal of Haematology, Bone Marrow Transplantation, and Biology of Blood Marrow Transplantation.