Meta-Analysis Reveals Potential Role of Clonal Hematopoiesis on Allogeneic and Autologous HSCT Outcomes

Shyam A. Patel, MD,PhD

A meta-analysis evaluating the effect of donor-engrafted clonal hematopoiesis on patients receiving hematopoietic stem cell transplant (HSCT) revealed differences in outcomes for those undergoing autologous or allogeneic transplants, according to Shyam A. Patel, MD, PhD.

Findings from the meta-analysis, which included 9 autologous and 5 allogeneic studies, published in Bone Marrow Transplantation showed that donor-engrafted clonal hematopoiesis after allogeneic-HSCT was associated with a lower risk of disease relapse (HR, 0.79, 95% CI, 0.67-0.93); however, outcomes were similar for overall survival (OS; HR, 0.91; 95% CI, 0.75-1.11), progression-free survival (PFS; HR, 0.94; 95% CI, 0.63-1.41), and non-relapse mortality (HR, 1.06; 95% CI, 0.81-1.39).¹

Conversely, patients undergoing autologous HSCT who had pre-transplant clonal hematopoiesis experienced worse OS (HR, 1.30; 95% CI, 1.16-1.46) and PFS (HR, 1.35; 95% CI, 1.18-1.54), and had a higher risk for therapy-related myeloid neoplasm (HR, 4.85; 95% CI, 2.39-9.82).

“[There] is an ongoing debate about prospective clonal hematopoiesis of indeterminate potential [CHIP] screening in stem cell donors,” Patel said. “However, our meta-analysis supports the idea that for autologous HSCT, it's worth performing CHIP screening in that autologous donor because the presence of pre-transplant clonal hematopoiesis can increase the likelihood of an inferior outcome. However, in allogeneic HSCT, we do not necessarily see that same effect, so it might not be worth performing CHIP screening for allogeneic HSCT donors.”

In an interview with OncLive^®, Patel highlighted the rationale behind conducting this meta-analysis, expanded on the key findings from the study, and discussed the potential implications of these data.

Patel is an assistant professor at the University of Massachusetts Chan Medical School in Worcester.

OncLive: What was the rationale for investigating the effect of clonal hematopoiesis in relation to disease relapse and outcomes with both allogeneic and autologous HSCT?

Patel: The role of clonal hematopoiesis in the context of stem cell donor candidacy remains to be explored. Currently, there are a lot of single-institution studies that have reported various outcomes on clonal hematopoiesis in the donor, but the results have not been uniform.

In this study, we sought to perform a meta-analysis to examine all the primary literature on donor-engrafted clonal hematopoiesis and to determine its effect on the outcomes for allogeneic and autologous HSCT. This would help the field establish a more uniform recommendation on whether it's appropriate to screen donors for clonal hematopoiesis prior to stem cell transplantation.

How did you select studies to use in this meta-analysis?

We separated this study into autologous HSCT and allogeneic HSCT. We had 9 primary studies that looked at autologous HSCT and 5 primary studies that looked at allogeneic HSCT.

[In the latter group], these were all primary, mostly retrospective cohort studies that examined the impact of donor-derived clonal hematopoiesis in the allogeneic HSCT setting. They used a variety of different stem cell donor types, including matched-related donors, matched-unrelated donors, mismatched-unrelated donors, and haploidentical donors. The graft source was sometimes bone marrow and sometimes peripheral blood. Within those primary articles, they also had a wide array of clonal hematopoietic mutations; mostly, they were comprised of DNMT3A and TET2 mutations within the donors, and the variant allele frequency ranged from very low in the 0.01% range to up to approximately 2%.

What was the methodology of the meta-analysis and how was the random-effects model used to analyze the impact of clonal hematopoiesis?

We performed standard meta-analysis procedures using a random-effects model to analyze 5 allogenic HSCT studies and 9 autologous HSCT studies. The random-effects model included 3192 donor-recipient pairs, as well as 2854 autologous HSCT recipients. From there, we proceeded with the meta-analysis. This was mostly conducted by Yiyu Xie, MD, [of UMass Memorial Medical Center and UMass Chan Medical School], who has expertise in meta-analysis statistics. This random-effects model was mostly based on the primary literature. Originally, that publication was by George A. Kelley, DA, FACSM, and colleagues in the World Journal of Methodology in 2012.² That was a statistical model for meta-analysis that Dr Xie performed.

How did donor-engrafted clonal hematopoiesis affect the risk of disease relapse and survival outcomes in patients who received allogeneic HSCT and those who underwent autologous HSCT?

In this study, we saw a bimodal effect of donor-derived clonal hematopoiesis in stem cell transplant. In autologous HSCT, we noticed that there were inferior outcomes in terms of various clinical parameters [in patients with pre-transplant clonal hematopoiesis], including OS, PFS, and risk for therapy-related myeloid neoplasm. However, in allogeneic HSCT, there was no effect [of donor-engrafted clonal hematopoiesis] on OS, PFS, or non-relapse mortality. There was a decreased risk for disease relapse for donor-engrafted clonal hematopoiesis in the setting of allogeneic HSCT; we thought it could be the case that donor-engrafted clonal hematopoiesis is a surrogate for the graft-vs-leukemia effect. We thought this might explain the improved outcomes for patients who underwent allogeneic HSCT and received cells from donors who have clonal apoptosis.

That's in sharp contrast to autologous HSCT, in which almost all clinical parameters showed an inferior outcome [when clonal hematopoiesis was present]. In preclinical and basic science studies, various labs have shown there's a functional dominance of mutant hematopoietic stem cells over wild type hematopoietic stem cells with regard to bone marrow engrafting. It's more likely that a functionally mutated hematopoietic stem cell will engraft within the bone marrow microenvironment compared with wild type hematopoietic stem cells for a variety of reasons. The engraftment potential of cancerous donor cells is likely higher than that of normal donor cells.

What are some potential areas for future research based on the findings of the meta-analysis, particularly regarding genotype-specific risk stratification or the potential relevance of high-risk mutations, such as TP53?

In our systematic review and meta-analysis, we did not look at each individual mutation or varying allele frequency because the primary literature didn't contain that granular level of information. However, in the future, it's likely that this study would merit additional studies looking at details of the genomics of donor-engrafted clonal hematopoiesis with regard to particular gene mutations, as well as varying allele frequencies. We don't know the exact risk that donor-engrafted clonal hematopoiesis poses on a patient-by-patient basis; however, on a large scale with this analysis, we did find some information about the potential adverse effect of donor-engrafted clonal hematopoiesis in autologous HSCT.

What might be important for the future is that additional studies could look at individual gene mutations within donors and varying allele frequencies for those genes to determine the ultimate effect on the recipient. In the case of TP53 [mutations], for example, it's known that TP53 confers the highest hazard of all known recurrent myeloid mutations, and we would generally presume that a donor hematopoietic stem cell with a TP53 mutation would lead to worse outcomes. However, we don't know that for sure. Other gene mutations that are high risk in acute myeloid leukemia might also predict inferior outcomes in allogeneic or autologous HSCT recipients.

In general, there is a call to action to bring multiple institutions together to work on this in a collaborative approach so that the sample size can be higher and more meaningful conclusions can be made. Ultimately, it would be worthwhile to put together a consortium such that we can put forth guidelines or recommendations on the value of screening for donor clonal hematopoiesis prior to transplantation.

What are the pros and cons associated with screening donors for clonal hematopoiesis?

In general, there are various pros and cons for screening of donor clonal hematopoiesis prior to HSCT. There are factors in favor of CHIP screening in donors prior to HSCT; there's an increased knowledge, [meaning] you would have information about genetic risk, and you would also be able to potentially determine family risk for certain hereditary or germline mutations. You might be able to ensure a higher integrity product of donor stem cells if you can perform screening first and ensure that there are no high-risk mutations. There could be improved transplant outcomes, which we showed here in the setting of autologous HSCT. The other factor that's in favor of donor CHIP screening would be general health maintenance to ensure that somebody has knowledge about their risk for eventual development of a myeloid neoplasm.

On the other hand, there are some cons or disadvantages for screening for donor clonal hematopoiesis prior to HSCT. The most obvious disadvantage is the cost, which is an important factor because [current] next-generation sequencing [NGS] does cost a fair amount of money, and it would be difficult to get funding or authorization for performing NGS on donors prior to transplant. Another disadvantage to screening prior to HSCT is that it could potentially limit the unrelated donor pool. [For example], if recipients for [allogeneic] HSCT have high-risk hematologic diseases such as high-risk leukemia, we might not afford to be able to wait an extra few weeks prior to transplant, and they might not be able to wait the extra weeks for the NGS results to return from the donor, so the donor pool could potentially be limited.

There's also an ethical aspect where we would be performing NGS on donors who might not know this information, and if we find a high-risk mutation, is it important to relay this information? [Donors] might have to adjust their lives. Another con for screening is that there are no consensus guidelines in place that provide a body of evidence in favor of screening. Finally, the psychological impact of finding a high-risk mutation in a donor and somebody who is seemingly healthy is another con for screening.

References

1. Xie Y, Kazakova V, Weeks LD, et al. Effects of donor-engrafted clonal hematopoiesis in allogeneic and autologous stem cell transplantation: a systematic review and meta-analysis. Bone Marrow Transplant. Published online August 25, 2024. doi:10.1038/s41409-024-02403-2
2. Kelley GA, Kelley KS. Statistical models for meta-analysis: a brief tutorial. World J Methodol. 2012;2(4):27-32. Published 2012 Aug 26. doi:10.5662/wjm.v2.i4.27