What is the best donor or graft source for patients lacking HLA-matched donors?

Rohtesh S. Mehta et al. previously reported that bone marrow (BM) grafts from matched sibling donors achieve better results in terms of graft-versus-host disease (GvHD)-free relapse-free survival (GRFS) when compared to peripheral blood (PB) grafts from any donor or to umbilical cord blood (UCB).¹ However, this study did not include patients with a haploidentical donor who received GvHD prophylaxis with post-transplantation cyclophosphamide (PTCy) or other alternative donor choices currently used.

To date, there is no clear conclusion about the superiority of an alternative donor choice, although several studies have compared one donor with another. In this new analysis, Mehta and colleagues add new data to this critical medical gap providing a direct comparison of multiple alternative donors and graft sources. Their results have been published in the Journal of Clinical Oncology, and this article summarizes the principal conclusions.²

Methods and patient characteristics²

The investigators obtained all data from patients registered at the Center for International Blood and Marrow Transplant Research (CIBMTR) receiving an alternative donor transplantation following diagnosis with acute myeloid leukemia, acute lymphoblastic leukemia (in remission), chronic myeloid leukemia or myelodysplastic syndrome. Data were analyzed in terms of

• GRFS: defined as the absence of Grade 3–4 acute GvHD (aGvHD), chronic GvHD (cGvHD) requiring systemic therapy, relapse, or death
• cGvHD-free relapse-free survival (CRFS): defined as the absence of cGvHD requiring systemic therapy, relapse or death
• Both, GRFS and CRFS, were co-primary endpoints of the study; secondary endpoints included disease-free survival (DFS), overall survival (OS), incidence of Grade 3–4 aGvHD, incidence of cGvHD, and risk of relapse

Overall, eight groups of patients were compared according to

• Donor or graft source (UCB, haploidentical, single HLA-locus mismatched [7/8]- BM, or 7/8- PB)
• Conditioning intensity (myeloablative conditioning [MAC] or reduced-intensity conditioning [RIC])
• Use or lack of serotherapy with either alemtuzumab or antithymocyte globulin

After selecting adult patients who underwent a first alternative donor hematopoietic stem cell transplantation (HSCT; except for HLA-matched sibling or URD), and excluding patients with previous autologous/allogeneic HSCT or UCB transplantation with any unit having less than a 4/6 HLA match; a total of 2,198 patients were included in the analysis. Relevant patient characteristics can be found in Tables 1 and 2. Of note, 78% of patients in the haploidentical group received RIC and 71% BM grafts, and none received serotherapy. Therefore, they were analyzed as a single cohort.

Table 1. Characteristics of patients treated with MAC²

 Table 2. Characteristics of patients treated with RIC. The 7/8 BM-RIC groups were excluded because of a small sample size ²

Results²

Due to the shorter follow-up in the haploidentical group, all patients were censored at 3 years after HSCT.

GRFS

Multivariate analysis showed that

• Patients with haploidentical grafts experienced significantly longer GRFS than all other groups: 2-year GFRS of 26% (95% CI, 19–33) (Table 3)
• All haploidentical HSCTs included PTCy for GvHD prophylaxis, which was not used in any other groups; and the most commonly used regimen for RIC was fludarabine, cytarabine, and total body irradiation (TBI) (77%)
• Significantly lower GRFS rates were associated with high or very high disease risk index (DRI) and Karnofsky performance score (KPS) < 90
• Among the MAC groups, patients in 7/8-PB without serotherapy subgroup had significantly inferior GRFS (2-year GFRS 3% [95% CI, 2–5]), compared to those with serotherapy (Hazard ratio [HR] ,1.65; 95% CI, 1.35–2.00; p < 0.0001) or those receiving 7/8-BM graft (HR, 1.50; [95% CI, 1.22–1.84; p = 0.0001)
• Results of patients with UCB grafts and different degree of HLA matching did not differ in terms of GRFS

CRFS

Multivariate analysis showed that

• Patients in the haploidentical group presented with a significantly better CRFS rate than the other groups: 2-year CRFS of 27% (95% CI, 20–34) (Table 3)
• Patients with significantly inferior CFRS were those with high or very high DRI and those with KPS < 90
• Between MAC groups, there were no differences in terms of CFRS, except for the 7/8-PB without serotherapy subgroup, that experienced a shorter CFRS (3%; 95% CI, 2–6) compared to the 7/8-PB with serotherapy subgroup (HR, 1.41; 95% CI, 1.17–1.69; p = 0.0002)

aGvHD and cGvHD

 Multivariate analysis revealed the following

• Incidence of Grade 3–4 acute GvHD (aGvHD) and risk of cGvHD was significantly higher in all MAC subgroups and the 7/8-PB (RIC without serotherapy) (Table 3)
• Risk of cGvHD was high in both 7/8-PB RIC subgroups, but patients without serotherapy were at higher risk than the rest of RIC groups (2-year cGvHD, 52%;95% CI, 46–59; p < 0.0001)
• No differences were found between haploidentical and UCB (RIC) groups: 100-day aGvHD Grade 3–4 was 8% vs 15%; 2-year cGvHD was 32% vs 27%, respectively

DFS, risk of relapse and OS

Multivariate analysis revealed

• Significantly inferior DFS was observed in the UCB (RIC) subgroup (2-year rate, 27%;95% CI, 23–32), and no significant differences could be determined between the rest of the groups (Table 3)
• Patients who received MAC with UCB or 7/8-BM grafts had a significantly lower risk of relapse than those who received haploidentical grafts
• In terms of OS, better outcomes were seen in patients who received haploidentical grafts (2-year OS, 53%;95% CI, 45–61) compared with all other groups
• Shorter DFS and OS, and a higher risk of relapse was associated with high or very high DRI and KPS < 90

Table 3. Univariate estimates of major study outcomes

Conclusions

Patients with a haploidentical donor (using BM graft and RIC) presented the best GRFS, CRFS, and OS compared with those with a one-antigen mismatched unrelated donor using either a BM or PB graft, or those receiving a UCB graft after RIC. If a haploidentical donor is not available, these data support the preferable use of either 7/8-PB (RIC with or without serotherapy) or UCB.

Despite some conflicting results in previous reports, this study showed that patients receiving MAC were at lower risk of relapse with either 7/8-BM or UCB grafts than haploidentical grafts (mostly RIC). Moreover, 7/8-PB with serotherapy showed a significantly superior GRFS and CRFS compared to the 7/8-PB group without serotherapy.

When comparing RIC vs MAC groups (except haploidentical), some subgroups presented a higher risk of relapse with RIC, but no significant difference was demonstrated in any other survival outcome.

Some of the limitations faced by this retrospective study include the limited sample for some subgroups and the potential existence of center selection bias in choosing donors. Such caveats can be avoided with trials like the ongoing study by the University of Wisconsin (trial 1101, NCT01597778) that is prospectively comparing haploidentical vs UCB HSCT using RIC conditioning.