Feasibility of Using Haploidentical Donors for alloHCT Shown in Patients With Ph+ CML

Haploidentical donor (HD)-derived allogeneic hematopoietic cell transplant (allo-HCT) is a feasible option for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and it appears to have similar results compared with other donor types, according to a presentation given during the 48th EBMT Annual Meeting.

The overall survival (OS) observed with HD-derived allo-HCT was similar to allo-HCT from match-related donors (MRD) with a hazard ratio (HR) of 0.94 (95% CI, 0.66-1.34). In comparison with matched-unrelated donors (MUD) the HR was 0.90 (95% CI, 0.63-1.29), and compared with mismatched-unrelated donors, the HR was 0.98 (95% CI, 0.65-1.47). Similar comparability between HD-derived allo-HCT and the other donor was shown with relapse-free survival (RFS) and composite graft-versus-host relapse-free survival (GRFS).

Current treatment of PH+ CML commonly includes allo-HCT, but for most patients with PH+ CML in chronic phase (CP), there is a low probability of them getting to transplant within 5 years, according to Francesco Onida, MD, professor in the Hematology-Bone Marrow Transplantation Center at the University of Milan in Italy.

“There's been a recent population-based analysis showing that 62.5% of these patients undergo transplant. Patients diagnosed with CML in younger age, let's say younger than 65 have accumulated a probe cumulative probability of undergoing ultrasound within 5 years of about 10%, and allo transplant is indicated for with advanced phase if they are eligible,” said Onida, during his EBMT presentation.

Although patients with PH+ CML in CP have good survival outcomes using MRD or MUD, there are currently no published data on HD-derived allo-HCT. Considering that 70% of patients who require allo-HCT do not have an HLA fully matched family donor and the chances of finding matched unrelated donors ranges from 30% to 60%, HP derived donors may be another option.

“Haploidentical transplant may be particularly beneficial in these patients given the well-known sensitivity of the disease to the graft-versus-leukemia effect,” said Onida. “And transplantation from a haploidentical donor is not inferior to that from identical sibling for patients with the Philadelphia chromosome-positive CML in blast crisis or in chronic phase from blast crisis according to another recent paper.”

The primary goals of the retrospective study were to compare the OS, RFS, and GRFS in patients with PH+ CML according to donor type from the time of transplantation. Additionally, the study compared the cumulative incidence of non-relapse mortality (NRM), and the cumulative incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD). Other variables included outcomes based on Karnofsky performance score, disease stage at treatment, age, and more were also evaluated.

Data for the retrospective analysis were from the EBMT database. The information included was from patients with adult Ph+ CML who had their first allo-HCT between January 2012 and December 2019. The source was either peripheral blood or bone marrow for all patients included, and all patients had either MRD, HP-derived donors, MUD, or MMUD. The study excluded patients transplanted with MRD, MUD, or MMUD who had post-transplant cyclophosphamide as their GVHD prophylaxis platform.

A total of 1686 patient profiles were included in the analysis, and 62% of them were male. The median age of the patient population was 46 years. The Karnofsky performance score at the time of treatment was ≥ 90 in 78.4% of patients and < 90 in 21.6%. Disease status at the time of treatment was CP1 for 43.4%. CP ≥ 2 for 26.9%, accelerated phase (AP) for 11.7%, and blast phase (BC) for 17.9% of patients. Eighty-four percent of patients had a peripheral blood stem cell source and 15.9% has a bone marrow source. Lastly, only 33.2% of patients has reduced intensity conditioning.

Results for engraftment showed a 6.3% rate of primary graft failure and 8.7% rate of secondary graft failure in patients who had HD-derived allo-HCT. In comparison, the rate of primary graft failure in patients with MRD, MUD, and MMUD was 0.8%, 0.7%, and 2.9%, respectively (P < .0001). The secondary graft failure rate in the MRD-, MUD-, and MMUD-derived allo-HCT groups was 4.1%, 3.1%, and 3.3%, respectively, in comparison with the HD-derived allo-HCT group (P < .0001).

The cumulative incidence of relapse after more than 60 was 37% in the HD group, which was similar in comparison with patients MRD-, MUD-, and MMUD -derived allo-HCT (P = .06). Moreover, the cumulative incidence of NRM was 21%, also comparing similarly to 3 other donor groups (P =n ot significant [NS]).

In terms of GVHD, the rate of grade 2-4 aGVHD at day +100 was 25% (range, 18%-33%) with HD donor-derived allo-HCT compared with 27% (range 24%-31%) with MRD, 31% (range, 27%-34%) with MUD, and 39% (range 32%-46%) with MMUD (P =.008). The rate of cGVHD at +60 months was 36% (range 26%-47%) in the HD group compared with 49% (range, 44%-53%) in the MRD group, 40% (range, 35%-44%) in the MUD group, and 48% (range, 39%-56%) in the MMUD group (P = .006).

By analyzing GVHD, investigators saw a lower cumulative incidence of both aGVHD and cGVHD with HD-derived allo-HCT compared with MRD or MUD, and MMUD.

The final key outcome of GRFS was also similar in the patient who underwent HD-derived allo-HCT at 23% compared with 22% with MRD-derived transplantation, 32% with MUD, and 26% with MMUD (P < .001). However, Onida noted that a significantly better RFS and GRFS in patients transplanted from MUD versus MRD, HD, and MMUD.

The additional study outcomes signaled that HD-derived allo-HCT was not completely similar to the other donor-derived allo-HCT options. Specifically, disease stage and performance status at the time of transplant appear to be prognostic factors for all the key efficacy outcomes.

Onida stated in conclusion; “there results should be interpreted with caution given the limited number of patients who had haploidentical donors in comparison to others.”

_REFERENCE:

_{Onida F, Ge J, Koster L, et al. Allogeneic transplantation FOR Ph+ chronic myeloid leukemia: A retrospective analysis from the ebmt chronic malignancies working party (EBMT-CMWP) comparing outcomes according to donor type. Presented at: 48th EBMT Annual Meeting; March 19-23, 2022. Abstract OS03-07. Virtual.}