Clinical impact of clonal hematopoiesis in hematopoietic cell transplantation: a review, meta-analysis, and call to action

Abstract

Hematopoietic cell transplantation (HCT) is the only potentially curative treatment option for many patients with hematologic malignancies. While HCT outcomes have improved drastically over the years, patients and clinicians continue to face numerous survivorship challenges, such as relapse, graft-versus-host disease, and secondary malignancies. Recent literature suggests that clonal hematopoiesis (CH), the presence of a recurrent somatic mutation in hematopoietic cells, in HCT patients or donors may be associated with outcomes in autologous and allogeneic HCT. Herein, we perform a review of the literature and summarize reported associations between CH and clinical outcomes in HCT. For commonly reported outcomes, we used meta-analysis methods to provide estimates of effect sizes when combining results. A total of 32 articles with relevant and independent contributions were included, covering both autologous (N=19) and allogeneic (N=13) HCT. The articles report variable risk for developing outcomes according to CH characteristics, patient disease status, and method of HCT. Using meta-analysis of available results, HCT outcomes with statistically significant effects by CH status include therapy-related myeloid neoplasms (odds ratio =3.65; 95% confidence interval [CI]: 2.18-6.10) and overall survival (hazard ratio [HR]=1.38; 95% CI: 1.20-1.58) in autologous HCT and relapse (HR=0.80; 95% CI: 0.68-0.94) in allogeneic HCT. However, heterogeneity, biases, and limitations in the literature provide challenges for informing the translation of CH to clinical decision- making. We conclude with a call to action and discussion of next steps to build upon the current literature and provide granularity to the true clinical impact of CH in the setting of HCT.

Figure 1.

PRISMA flow diagram for the included studies that investigated hematopoietic cell transplantation outcomes based on clonal hematopoiesis status. HCT: hematopoietic cell transplantation; CH: clonal hematopoiesis.

Figure 2.

Clonal hematopoiesis metrics and results in published studies. (A) Number of genes assessed for clonal hematopoiesis (CH) mutations in autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT). (B) Variant allele frequency (VAF) cutoff used to define CH by HCT type. (C) Prevalence of CH reported in autologous (auto)-HCT studies. Data is presented for all auto-HCT studies and studies that included lymphoma, multiple myeloma (MM), or acute myeloid leukemia (AML) patients only. (D) Prevalence of CH reported in allogeneic (allo)-HCT studies. Data is presented for donors and recipients. Numbers presented are medians; bars are the minimum and maximum values. MRD: matched-related donors; MUD: matched-unrelated donors. *Results for MUD come from a single study that defined CH at a VAF of ≥2% and ≥0.1%.

Figure 3.

Meta-analyses of studies assessing clonal hematopoiesis as a risk factor for clinical outcomes in patients treated with autologous hematopoietic cell transplantation. (A) Forest plot for the outcome of therapy-related myeloid neoplasms. (B) Forest plot for the outcome of overall survival. ^aPoor peripheral blood stem cell mobilizers; ^bnormal peripheral blood stem cell mobilizers. OR: odds ratio; CI: confidence interval; HR: hazard ratio.

Figure 4.

Meta-analyses of studies assessing clonal hematopoiesis as a risk factor for clinical outcomes in patients treated with allogeneic hematopoietic cell transplantation. (A) Forest plot for the outcome of relapse. (B) Forest plot for the outcome of overall survival. (C) Forest plot for the outcome of chronic graft-versus-host disease (GVHD). (D) Forest plot for the outcome of acute GVHD. ^aOther clonal hematopoiesis (CH) (non-DNMT3A, non-TET2); ^bDNMT3A-CH only; ^cTET2-CH only; ^dDNMT3A-CH, no post-transplant cyclophosphamide; ^eDNMT3A-CH, received post-transplant cyclophosphamide. OR: odds ratio; CI: confidence interval; HR: hazard ratio.