Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation

Abstract

Purpose: Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.

Patients and methods: We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant.

Results: CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed long-term engraftment in recipients after transplantation, including clones with a variant allele fraction < 0.01. DNMT3A-CH with a variant allele fraction ≥ 0.01, but not smaller clones, was associated with improved recipient overall (hazard ratio [HR], 0.79; P = .042) and progression-free survival (HR, 0.72; P = .003) after adjustment for significant clinical variables. In patients who received calcineurin-based graft-versus-host disease prophylaxis, donor DNMT3A-CH was associated with reduced relapse (subdistribution HR, 0.59; P = .014), increased chronic graft-versus-host disease (subdistribution HR, 1.36; P = .042), and higher interleukin-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In seven of eight cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations.

Conclusion: Donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome-associated mutations or germline predisposition in donors.

FIG 1.

Characteristics of CH in transplant donors age 40 years and older. (A) The proportion of donors with and without CH in each cohort, subdivided by donor age decade. CH with VAF 0.005-0.0099 is in blue, and CH with VAF ≥ 0.01 is in red. (B) The number of mutations in each gene mutated in two or more donors, with variants at VAF 0.005-0.0099 again in blue and variants at VAF ≥ 0.01 in red. (C) The patterns of comutation among donors with CH. Each column represents a donor, with rows for donor age and the most commonly mutated genes or gene groups. Donors were hierarchically grouped on the basis of the presence of mutations in genes other than DNMT3A or TET2, DNMT3A, and then TET2. Genes mutated more than once in the same donor are in red. (D) The distribution of donor age on the basis of CH status and mutations in individual genes or groups of genes. Medians and IQRs are reported below each column. CH, clonal hematopoiesis; IQR, interquartile range; VAF, variant allele fraction.

FIG 2.

Association of donor CH with recipient clinical outcomes. (A) The association between donor CH at either VAF 0.005-0.0099 or VAF ≥ 0.01 and recipient PFS in multivariable Cox proportional hazards models. (B) The association between donor CH at VAF ≥ 0.01 and recipient OS, PFS, relapse, and NRM in multivariable models divided by gene group. The groups consist of CH with any mutation other than DNMT3A or TET2 (Other CH), remaining DNMT3A mutations, and then remaining TET2 mutations. (C) The 5-year cumulative incidence of chronic GVHD split by DNMT3A-CH status (VAF ≥ 0.01) and receipt of PTCy for GVHD prophylaxis. (D) The 5-year cumulative incidence of relapse split by DNMT3A-CH status (VAF ≥ 0.01) and receipt of PTCy. (E) The 5-year PFS split by DNMT3A-CH status (VAF ≥ 0.01) and receipt of PTCy. (F) The associations between DNMT3A-CH and outcomes among recipients who did or did not receive PTCy in multivariable Fine-Gray competing risk regressions (chronic GVHD, relapse) and Cox proportional hazards models (PFS and OS). CH, clonal hematopoiesis; GVHD, graft-versus-host disease; HR, hazard ratio; NRM, nonrelapse mortality; OS, overall survival; PFS, progression-free survival; PTCy, post-transplant cyclophosphamide; sHR, subdistribution hazard ratio; VAF, variant allele fraction.

FIG 3.

Engraftment of donor CH in recipients after transplantation. (A) The VAFs of 102 donor mutations assessed in 69 recipients after transplantation. Each row is an individual mutation, with columns representing the VAFs in the donors at the time of transplant and in the recipients at 3 and 12 months after transplant. VAFs are color-coded from white (lower VAF) to red (higher VAF), with blue indicating that the mutation was not detected. Mutations that were detectable in recipients at 12 months (engrafted) are on top and those that were not engrafted are on bottom. (B) The donor VAFs of DNMT3A, TET2, ASXL1, and other mutations that did or did not engraft in recipients. (C) The proportion of R882 and non-R882 DNMT3A mutations assessed post-transplant (n = 10 and 54, respectively) that did or did not engraft in recipients at 12 months. (D) The VAFs for expansion of non-R882 (left) and R882 DNMT3A mutations (right) in donors and corresponding 12-month samples from recipients. (E) The plasma levels of IL-12p70 at 12 months after transplant in recipients of DNMT3A-CH (n = 21, red) compared with other recipients (n = 241, teal). (F) Correlations between 10 plasma cytokines measured at 12 months after transplant in the same recipients with and without DNMT3A-CH. Correlations are color-coded from blue (negative correlation) to red (positive correlation). CH, clonal hematopoiesis; IFN-γ, interferon gamma; IL, interleukin; n.d., not detected; TNF-α, tumor necrosis factor alpha; VAF, variant allele fraction.

FIG 4.

Clinical and genomic features of DCLs. (A) The clinical and genomic features of eight DCLs that developed in the cohort during the study period. Recipient diseases: AML, NHL, MDS, ALL. DCL type: AML, MDS, or MDS/MPN overlap syndrome. Somatic mutations reported include both those meeting criteria for CH and lower abundance mutations identified by sequencing the donor cell leukemia sample. For donor samples with multiple somatic mutations, the maximum VAF is reported. Mutations present in the donor cell leukemia are reported for the six of eight DCLs with available samples. (B) The distribution of donor age for recipients who did or did not develop DCL. (C) The total number of DCLs in each genetic subgroup of CH on the left and the corresponding proportion of recipients in each group who developed DCL on the right. Note that CH is defined here as VAF ≥ 0.005, meaning that two of the donors with low-abundance splicing factor mutations reported in (A) are classified as no CH. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CH, clonal hematopoiesis; DCL, donor cell leukemia; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; NHL, non-Hodgkin lymphoma; VAF, variant allele fraction.