EHA Celebrity Interview丨Director Peng Zhiyong: CAR-T bridging transplantation is safe and effective in the treatment of relapsed/refractory AML in children
At present, CAR-T therapy has achieved remarkable results in the treatment of a variety of hematological malignancies, but there are still many challenges in the treatment of acute myeloid leukemia (AML), and it is urgent to explore and optimize the treatment strategy in order to achieve better efficacy. From June 13 to 16, 2024, the 29th Annual Meeting of the European Association of Blood (EHA) was held in Madrid, Spain. At this conference, a study by Peng Zhiyong, director of the Southern Chunfu (Children) Hematology Research Institute of Gaobo Medical (Hematology) Guangdong Research Center, was selected for poster presentation (P1477) to explore the role of CAR-T cell therapy as a bridge for allogeneic hematopoietic stem cell transplantation (HSCT) in children with relapsed/refractory AML, and achieved important results. Director Peng Zhiyong was invited to be interviewed to share and interpret the research in depth.
Director Peng Zhiyong at the EHA meeting
About the study
background
Chimeric antigen receptor T cell (CAR-T) therapy still faces challenges in the treatment of AML. Our previously published studies confirmed the clinical efficacy of CLL1 CAR-T in the treatment of relapsed or refractory AML (R/R AML). Although different targets can be selected, such as CLL1, CD33, and CD123, there are still many problems, such as irreversible aplastic disorders and off-target effects. Overall, the strategy for CAR-T cell therapy for AML should be to serve as a bridge to hematopoietic stem cell transplantation (HSCT).
objective
In this study, we present the safety and efficacy of CAR-T as an HSCT bridge in the treatment of children with R/R AML in our center.
method
From November 2019 to October 2023, a total of 21 R/R AML patients received CAR-T therapy, of which 16 underwent allogeneic HSCT within one month and underwent retrospective analysis. Of these patients, 7 relapsed after chemotherapy, 3 relapsed after the first HSCT, and 6 had primary drug resistance. CAR-T cells include single/dual targets of CLL1, CD123, and CD33. The conditioning regimen for HSCT is based primarily on fludarabine and busulfan or ciotepa. ATG was used in unrelated transplantation and cyclophosphamide was used after transplantation in haploidentical transplantation, except for two patients who underwent haploidentical ɑβ T cell depletion. Tacrolimus plus mycophenolate mofetil is used for graft-versus-host disease (GVHD) prophylaxis in non-ɑβ T cell depletion transplants.
outcome
The median age is 9 years old (3~16 years old). Patients received one or two CAR-T cell treatments after lymphodepletion pretreatment. Of these, 9 patients received CLL1 CAR-T cells (8 autologous and 1 allogeneic), 2 patients received autologous CD123 CAR-T cells, 4 patients received autologous CLL1-CD33 complex CAR-T cells, and 1 patient received allogeneic CLL1-CD123 complex CAR-T cells from donors. The median number of CAR-T cells transfused was 0.9×106/kg (range 0.35~2.58×106/kg). After CAR-T therapy, the patient developed grade 1~2 cytokine release syndrome, but there were no fatal events. Disease status was assessed by bone marrow within 4 weeks after CAR-T therapy: 10 of the 16 patients achieved complete remission with morphological leukemia-free status and flow cytometry minimal residual disease negative, 2 had partial remission, 2 were stable, and the other 2 had progression. All patients had persistent myelosuppression 1 month after CAR-T therapy and subsequently underwent allogeneic HSCT. The donor sources were haploidentical donors in 12 cases, umbilical cord blood in 3 cases, and unrelated donors in 1 case. Only 1 patient who underwent cord blood transplantation experienced primary graft failure and successfully implanted after a second haploidentical transplant. The median time to neutrophil and platelet engraftment was 28 and 32 days after HSCT, respectively. The median follow-up time from HSCT was 24 months (range 3~46 months), and the 3-year overall survival, leukemia-free survival and recurrence rates were 62.2%, 57.7% and 33.7%, respectively. The cumulative incidence of grade 2~4 acute GVHD (aGVHD) is 50%, of which grade 3~4 is 6.2%, cGVHD is 25%, and the extensiveness is 6.2%. Of the five patients who died, four died from relapse and one died from cGVHD. None of the patients developed sinusoidal occlusion.
conclusion
Our clinical results demonstrate that CAR-T therapy achieved very good remission in R/R AML and achieved disease-free survival with subsequent allogeneic HSCT, which is safe and feasible.
Celebrity interviews
Cancer Lookout: CAR-T therapy has been facing many challenges in the treatment of acute myeloid leukemia (AML), such as irreversible aplastic disorders and off-target effects. What strategies has your team adopted to optimize treatment outcomes in response to these challenges?
Prof. Peng Zhiyong: At present, CAR-T has been widely used in the treatment of leukemia, but there are still challenges in the treatment of myeloid leukemia. Our center is actively responding to the problem of T cell collection and quality through innovative strategies such as the use of transplant donor/allogeneic T cells to prepare CAR-T, or universal CAR-T. Development of dual-target CAR-T to improve therapeutic specificity; Bridging transplantation as soon as possible after CAR-T to alleviate the long-term and even irreversible bone marrow toxic side effects caused by myeloid CAR-T; and take several measures to prevent cytokine release syndrome (CRS). By continuously optimizing treatment strategies, we can bring better outcomes to patients.
Tumor Monitor-Blood Times: At this conference, you brought the study "CAR-T therapy bridging allogeneic hematopoietic stem cell transplantation (HSCT) in children with relapsed/refractory AML", can you please outline the design highlights and main results of the study?
Prof. Zhiyong Peng: At the EHA Congress, we reported the results of a clinical study of myeloid CAR-T bridging transplantation in children with relapsed/refractory AML. Our study successfully overcomes the limitations of myeloid CAR-T, such as bone marrow suppression and insufficient cell expansion. After 2~4 weeks of CAR-T in vivo expansion and killing to remove the tumor, the allogeneic hematopoietic stem cell transplantation was bridged as soon as possible, and the study emphasized the importance of myeloid CAR-T bridging transplantation and the optimal time for entry. In addition, based on the antigen expression characteristics of tumor cells in children, we have implemented precise and diversified selection of CAR-T targets and T cell sources, covering single targets such as CLL1, CD123, CD33, and dual-target CLL1-CD33, including both autologous and allogeneic sources. These innovative strategies have opened up new avenues for AML treatment in children.
Tumor Lookout-Blood News: CAR-T therapy bridging HSCT enables disease-free survival in children with relapsed/refractory AML. How do you see the future of this therapeutic strategy in AML?
Prof. Peng Zhiyong: At present, the treatment of relapsed/refractory AML is still extremely limited, and the efficacy is also unsatisfactory. The general principle of treatment is to recommend hematopoietic stem cell transplantation, and how to achieve deep remission of tumor cells before transplantation is the most important factor in determining the final outcome of transplantation. In order to break through the response rate of R/R AML from chemotherapy, it is already a major bottleneck in treatment, and precision targeted therapy and biological immunotherapy are the main treatment strategies in the future. Targeted therapy is limited by the availability of tumor genes and drugs, and the most popular research in immunotherapy is CAR-T therapy based on T cell immunity, and the specific selection of target antigens for CAR-T therapy is essentially the perfect combination of precision therapy and immunotherapy. CAR-T has great potential in the treatment of relapsed/refractory AML, but it also faces challenges. The combination of CAR-T and hematopoietic stem cell transplantation is expected to achieve complementary advantages. With the advancement of technology, it is believed that more and better results will be demonstrated in the future, bringing hope to R/R AML patients.
Tumor Monitor: Looking ahead, what other potential research directions or technological innovations do you think may further promote the clinical application and efficacy of CAR-T therapy in AML?
Prof. Peng Zhiyong: With the continuous development of CAR-T-related technologies, the field of CAR-T therapy for myeloid leukemia will definitely be further improved in the future. The development of next-generation CAR-T technologies, including universal CAR-T, FAST CAR-T, multi-target or sequential target CAR-T, as well as universal CAR-T prepared from umbilical cord blood-derived T cells, donor CAR-T and regulation of insertion of different signaling molecules, etc., it is believed that CAR-T therapy will show greater potential for efficacy in clinical applications.
Peng Zhiyong
Gaobo Medical (Hematology) Guangdong Research Center, Southern Chunfu (Children) Hematology Research Institute
Deputy Chief Physician of Southern Chunfu (Children) Institute of Hematology, Guangdong Research Center of Gaobo Medical (Hematology).
Winner of the 2017 Soong Ching Ling Pediatric Medicine Award
Director and member of the Treatment Professional Committee of Guangdong Thalassemia Prevention and Control Association
Member of the Standing Committee of the Youth Committee of the Pediatric Oncology Professional Committee of the Guangdong Anti-Cancer Association
Member of the Neuro-Oncology Professional Committee of the Guangdong Anti-Cancer Association and a member of the Youth Committee
Member of the Immunology Group of the First Committee of the Rare Disease Branch of Guangdong Medical Association
He has been engaged in clinical work for nearly 20 years, and his main research direction is pediatric hematology and hematopoietic stem cell transplantation, especially in the diagnosis and treatment of JMML, with a success rate of more than 90%, and the results have been reported as posters at the annual meeting of the United States Society of Hematology (ASH) for 3 times;
In 2017, the first clinical study of gene therapy for Eastern Mediterranean in China was completed, and CAR-T cell therapy for ALL/AML was carried out early;
He has presided over and participated in the publication of more than 20 papers, and the results of CLL1-CAR-T cell therapy for AML were published in the journal Leukemia in September 2022.