Researchers report good results for pediatric patients with acute leukemia who were treated with TCRαβ/CD19 cell-depleted human leukocyte antigen (HLA)-haploidentical transplantation.
A recent study, reported in Blood Advances, builds on researchers’ previous phase I/II clinical trial that assessed the technique in 80 children with acute leukemia and found that it made using haploidentical donors safer, reduced the risk of graft-versus-host disease (GVHD), and had a low incidence of both acute and chronic GVHD and non-relapse mortality (NRM). These results underpinned survival outcomes comparable to those of patients receiving an unmanipulated graft from an HLA-compatible donor.
The current study reports on the original 80 patients, plus 133 more children and young adults with either acute lymphoblastic leukemia or acute myeloid leukemia who received TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation between September 2011 and January 2022. All patients received an antiviral prophylaxis with antiviral acyclovir, antifungal prophylaxis with agents active on both yeast and molds such as liposomal amphotericin B twice a week, and cotrimoxazole against Pneumocystis jirovecii pneumonia. The current study involved longer follow-up, a median of 47.6 months for surviving patients, than those in the first study, said first author Pietro Merli, MD, of the Ospedale Pediatrico Bambino Gesù in Rome.
“This study was in a setting of transplantation for patients who lacked HLA-matched donors or needed an urgent transplant,” Dr. Merli said. “Finding an unrelated matched donor often requires time. Especially during pandemics, it is not always easy to do.”
Researchers reported a five-year cumulative incidence of NRM of 5.2% (95% CI 2.8-8.8) and a cumulative incidence of relapse of 22.7% (95% CI 16.9-29.2). Projected 10-year overall survival and disease-free survival were 75.4% (95% CI 68.6-80.9) and 71.6% (95% CI 64.4-77.6), respectively. Cumulative incidence of both grade II-IV acute and chronic GVHD were low, at 14.7% and 8.1%, respectively.
In a multivariable analysis for disease-free survival, the researchers identified factors that were independently associated with outcomes. Those factors included disease type, use of total body irradiation in the conditioning regimen (hazard ratio [HR] = 0.5; 95% CI 0.26-0.98; p=0.04), disease status at hematopoietic cell transplantation (HCT; complete response (CR)>3 vs. CR1/2; HR=2.23; 95% CI 1.20-4.16; p=0.01), and high levels of pre-HCT measurable residual disease (MRD; HR=2.09; 95% CI 1.01-4.33; p=0.04).
The researchers recorded viral infections in a significant proportion of patients as a result of the lack of donor pathogen-specific T lymphocytes transferred with the graft. Overall, 129 patients developed a viral infection from cytomegalovirus, adenovirus, or human herpes virus type 6. Twenty-two patients had two or more infections at a median time of 24 days after HCT. The one-year cumulative infection incidence was 61.9% (95% CI 55.1-68.7). Strict monitoring and timely intervention are key for managing infection risk, the researchers emphasized.
Disease recurrence was the main cause of treatment failure, particularly in patients in CR3 or more advanced CR, and those with high levels of pre-HCT MRD. For these patients, the researchers recommend personalized approaches aimed at reducing the risk of relapse.
Noting current debate about options for children with acute leukemia, “this transplant approach results in outcomes that are superimposable to those of transplant from HLA-matched donors,” Dr. Merli said.
“If you don’t have a matched donor, with this approach you have an alternative that is at least as good,” Dr. Merli added. “This is the ideal platform for post-transplant adoptive cell therapies because patients do not receive pharmacologic immunosuppression such as cyclosporine.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Merli P, Algeri M, Galaverna F, et al. TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis [published online ahead of print, 2023 Sep 22]. Blood Adv. doi: 10.1182/blood.2023021336.