Non-HLA characteristics, donor age and kinship, affect haplo-SCT outcomes

Haploidentical stem cell transplantation (haplo-SCT) followed by a high-dose of post-transplant cyclophosphamide (PTCy) has increasingly gained clinical interest in cases where a matched related or unrelated donor is unavailable, or the need for transplantation is very urgent.^1,2 Due to the potential wide range of available family donors for haplo-SCT, careful donor selection is key for maximising post-transplantation outcomes. Unlike the unrelated donor transplantation setting, human leukocyte antigen (HLA) mismatches between donor and recipient do not seem to greatly impact event-free survival or the incidence of graft-versus-host disease (GvHD) following haplo-SCT/PTCy.^1,2 Therefore, the effect of non-HLA donor characteristics on haplo-SCT outcomes has been widely studied. Based on this research, a recent consensus for optimal donor selection for haplo-SCT was published by the European Society for Blood and Marrow Transplantation (EBMT)¹. Selection criteria in the EBMT consensus include the presence of donor-specific antibodies, ABO compatibility, age, sex, and cytomegalovirus (CMV) serology. Nevertheless, donor age and kinship are two non-HLA characteristics with conflicting data regarding their impact on haplo-SCT outcomes.² Therefore, Jacopo Mariotti et al.² published in Blood Advances a large retrospective study investigating the effect of donor age and kinship on haplo-SCT/PTCy outcomes. We hereby summarize the key results of this study.

 Study design

 The retrospective, observational, cohort study included N = 990 patients who were treated with haplo-SCT/PTCy for hematological malignancies in eight centers in Italy and France. Graft source was either bone marrow (62%) or peripheral blood stem cells (PBSC; 38%).

• Inclusion criteria:
  • Patients of ≥ 18 years of age who had received high-dose PTCy and had no previous allogeneic SCT
  • Donors were first- or second-degree relatives, identical at one HLA locus and mismatched at ≥ 2 loci
• Conditioning regimens:
  • Myeloablative (MAC): Conditioning with either total body irradiation with a total dose of > 8 Gy or intravenous busulfan of a total dose of > 6.4 mg/kg
  • Reduced intensity conditioning (RIC): All other conditioning regimens other than MAC where considered as RIC
• GvHD prophylaxis was achieved with either of the following two regimens:
  • Standard PTCy: PTCy at 50 mg/kg on Day 3 and 4 plus tacrolimus (total dose 1 mg) or cyclosporine A (3 mg/kg) plus mycophenolate mofetil (25 mg/kg) from Day 5 onwards
  • Modified PTCy: PTCy at 50 mg/kg on Day 3 and 5 plus tacrolimus or cyclosporine A from Day 0 plus mycophenolate mofetil from Day 1 onwards

Patient baseline characteristics are shown below in Table 1.

Table 1. Patient baseline characteristics²

 Results

The median donor age was 37 years and the most common donor kinship was that of an offspring (47%), followed by sibling (35%), and parent (15%; Table 1).

Graft failure occurred in 4.5% of patients while median times to neutrophil and platelet recovery were 19 days (25% to 75% CI, 16–23) and 27 days (25% to 75% CI, 21–35), respectively. Hematopoietic recovery was not associated with either donor age or kinship.

 Acute GvHD incidence

•  The 100-day cumulative incidence of Grade 2–4 acute GvHD (aGvHD) for all patients was 22%
• Multivariate analysis revealed that donor age analyzed by 5-year increments, PBSC graft source, and lymphoid disease were associated with a significantly higher risk for Grade 2–4 aGvHD (Table 2)
• With increasing donor age, a concomitant increase in the cumulative incidence of Grade 2–4 aGvHD was observed. Results by age group are shown below in Table 3
• A higher risk of aGvHD was observed as the donor age increased only when the donor was a sibling, an offspring, or a collateral but not when the donor was the mother. In contrast, in the case of father donors, increasing age seemed to be somewhat protective against aGvHD
• The 100-day cumulative incidence of Grade 3–4 aGvHD for all patients was 6%
• Multivariate analysis showed that the cumulative incidence of grade 3–4 aGvHD was significantly increased only with HCT-CI ≥ 3, PBSC graft source, and MAC conditioning (Table 2)

 Chronic GvHD incidence

•  The 2-year cumulative incidence of moderate-to-severe chronic GvHD (cGvHD) was 11% for all patients
• Multivariate analysis showed that sex donor/recipient mismatch from female to male, CMV seropositivity, and MAC conditioning were all associated with a higher risk of moderate-to-severe cGvHD (Table 2)

Table 2. Multivariate outcomes for GvHD incidence²

Table 3. Incidence of aGvHD by donor age²

 OS, PFS and GRFS

•  3-year overall survival (OS) was 55%, 3-year progression-free survival (PFS) was 48%, and 3-year GvHD/relapse-free survival (GRFS) was 41%
• Multivariate analysis showed that active disease prior to transplant (HR = 2.57; p < 0.001), increasing recipient age (HR = 1.03; p = 0.001), HCT-CI ≥ 3 (HR = 1.34; p = 0.002), and CMV recipient seropositivity (HR = 1.46; p < 0.001) were all independently associated with worse OS
• Donor age was protective for PFS (HR = 0.97; p = 0.036) but did not affect OS or GRFS
• Multivariate analysis showed that active disease prior to transplant, HCT-CI ≥ 3, and CMV recipient seropositivity were all independently associated with worse PFS and GRFS

 NRM and relapse

•  Non-relapse mortality (NRM) occurred in 23% of patients with the two main causes of death being infections and GvHD. Other causes of death included veno-occlusive disease/transplant-related microangiopathy, central nervous system toxicity, graft failure/poor graft function, and cardiac toxicity
• Multivariate analysis revealed that increasing recipient age (HR = 1.010; p = 0.004), active disease prior to transplant (HR = 1.61; p < 0.001), and recipient CMV seropositivity (HR = 1.74; p = 0.042) were independent predictors of increased NRM
• Donor age was not significantly associated with NRM incidence, however, when examined in conjunction with kinship, increasing donor age was associated with increased NRM in the cases of sibling or offspring donors, but it was protective in the case of father donors
• Multivariate analysis showed that increasing donor age (HR = 0.92; p = 0.001) and complete remission prior transplant as compared with progressive disease (HR = 2.50; p < 0.001) were significantly associated with reduced risk of relapse

 Donor/recipient relationship and transplant outcome

 The above results indicate that donor kinship directly influences the donor-aging effect on haplo-SCT outcomes and is different in the case of sibling/offspring donors vs parent donors. To address this further, the authors split their cohort into recipients ≤ 40 years old (donor mainly parent or sibling) and > 40 years old (donor mainly sibling or offspring). No difference in haplo-SCT outcomes were detected following grafts from siblings or offsprings in the > 40 years old subgroup. On the contrary, in the ≤ 40 years old recipients, parent grafts (mother or father) were associated with a higher risk for relapse (p < 0.001), as well as worse PFS (p < 0.001) and GRFS (p < 0.001). Poor PFS was most likely due to the higher incidence of cGvHD associated with father grafts (p = 0.017) and a higher risk of relapse associated with mother grafts (p = 0.001). Mother grafts were linked to worse OS, PFS, and GRFS when compared with father grafts.

 Conclusion

 The results of this large retrospective study indicate that increasing donor age is associated with a higher risk of Grade 2–4 aGvHD. However, increasing donor age was protective in terms of PFS and risk of disease relapse following haplo-HCT/PTCy, independently of disease subtype (myeloid vs lymphoid) and pre-transplant disease status. Further studies will be needed to clarify the impact of this effect on different subsets of malignancies and to uncover the underlying biological mechanisms. Interestingly, the effect of donor age on haplo-SCT outcomes was independent of recipient age but it was influenced by donor kinship, with parent donors and especially mother grafts being associated with worse PFS, GRFS, and a higher relapse risk, when compared with sibling or offspring donors. Thus, parent donors are not recommended in ≤ 40 years old recipients.