‘All-in-one’ CAR-T, stem cell transplantation induces remission in advanced leukemia
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Key takeaways:
- A sequential CAR-T and HSCT regimen did not need preconditioning or GVHD prophylaxis to confer remission for CD7-positive blood cancers.
- Two patients died during the studies.
A sequential chimeric antigen receptor T-cell therapy and haploidentical hematopoietic stem cell transplantation strategy conferred remissions in certain patients with relapsed or refractory CD7-positive hematologic cancers.
More than half of the patients maintained minimal residual disease-negative remission following the treatment approach, which did not include pre-hematopoietic stem-cell transplantation conditioning or graft-versus-host disease prophylaxis, according to results published in The New England Journal of Medicine.
“Our integrated strategy maximized antileukemic efficacy from both persisting CAR T cells and graft-versus-leukemia potential, providing a feasible approach for patients with relapsed or refractory CD7-positive cancers who are ineligible for conventional allogeneic HSCT,” Yongxian Hu, MD, PhD, of Zhejiang University School of Medicine, and colleagues wrote.
Background and methodology
Individuals with relapsed or refractory hematologic cancers have a 5-year survival rate below 20%, according to background information provided by researchers.
Allogeneic HSCT can be a treatment option for this population, but “its application is impeded by complications including GVHD, conditioning-associated toxic effects, and severe immunosuppression after long-lasting anti-GVHD treatment,” they wrote.
CAR-T continues to produce results in various hematologic cancers, including in CD7-positive types. HSCT has been investigated as a consolidation treatment after CAR-T, but the preconditioning has negated effects of CAR-T and created toxicities.
Researchers attempted to combat these complications using an “all-in-one,” sequential CAR-T plus HSCT treatment without bridging therapy or GVHD prophylaxis.
They enrolled 10 patients with relapsed or refractory CD-7 positive hematologic cancers in one of two trials between November 2021 and September 2023.
Study criteria required participants to have complete remission and incomplete hematologic recovery or pancytopenia following CAR-T and no history of HSCT to be included.
Of the 10 patients in the trial (median age, 56.5 years; 60% women; median number of prior therapies, 9.5), nine received donor-derived CAR T cells and one got universal CAR T cells. Seven of the participants had acute myeloid leukemia.
Study participants received CAR-T at a median of 13.1 months after diagnosis, and had HSCT at a median of 19 days following CAR-T.
Results and next steps
After a median follow-up of 15.1 months after CAR-T, 60% of patients maintained minimal residual disease-negative remission, 78% of evaluable patients had full donor chimerism after a month and another patient reached it at 6 months.
Researchers estimated the 1-year OS rate of 68% (95% CI, 43-100) and 1-year disease-free survival rate of 54% (95% CI, 29-100).
Of the other four participants, two had relapsed CD7-negative leukemia and two died — one of septic shock and encephalitis after 13 days, the other of septic shock after 3.7 months.
Treatment-related adverse events included cytokine release syndrome (in 90% of patients), grade 4 pancytopenia (100%), GVHD (40%; one related to CAR-T, three related to HSCT, infections (50%), and reactivation of Epstein-Barr virus and cytomegalovirus (90%). Study investigators reported no cases of chronic GVHD.
“One patient, with impaired expansion of CAR T cells, had no detectable circulating CAR T cells and an autologous recovery, which emphasizes the importance of circulating CD7-positve CAR T cells in immunosuppression after engraftment,” Didier Blaise, MD, hematologist at Aix Marseille University in France, wrote in an accompanying editorial.
“The absence of severe GVHD, without any prophylaxis, further supports this importance,” Blaise continued. “Furthermore, the persistence of CAR T cells and their possible role in early donor-derived CD7-positive T-cell eradication and long-term CD7-negative/CD3-positive T-cell expansion provide insights into mechanisms potentially preventing GVHD and hypothetically promoting immune reconstitution, respectively. In addition, these latter cells, which are proposed to be associated with a graft-versus-leukemia effect, may contribute to preventing disease recurrence.”
Researchers acknowledged they need to confirm their results in a larger patient cohort.
Blaise wanted further studies to possibly answer a variety of questions.
“Would dual CAR T-cell constructs that target CD7 and another tumor antigen for CD7-negative leukemia be a possibility?” Blaise asked. “Could this strategy be considered as a first-line therapy for newly diagnosed CD7-positive leukemia in patients unable to undergo intensive induction therapy? If so, the described strategy offers hope for advancing treatment paradigms in this difficult realm of [acute myeloid leukemia] with a poor prognosis.”
References:
Blaise D. N Engl J Med. 2024;doi:10.1056/NEJMe2403003.
Hu Y, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2313812.
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