2022CSH Prof. Kailin Xu: The powerful combination of CAR-T and allo-HSCT benefits patients with B-ALL even more

The 17th National Hematology Academic Conference of the Chinese Medical Association was grandly opened in Shanghai on September 23-25, 2022, with the theme of "respect, inheritance, collaboration and innovation", and invited well-known experts at home and abroad to talk about the latest progress
in the field of blood diseases 。 At this conference, Professor Xu Kailin of the Affiliated Hospital of Xuzhou Medical University introduced the application status
of CAR-T cell therapy in relapse/refractory B-ALL (R/R B-ALL) from the basic situation, efficacy and joint application of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from the three aspects of "CAR-T and hematopoietic stem cell transplantation B-ALL".

At present, the hottest CAR-T cell therapeutic targets in R/R B-ALL include CD19, CD20, CD22, etc.
, of which CD19 research is the most mature
.
At present, there are commercialized CD19 CAR-T cell therapy applications in R/R B cell lymphoma in China, but there is no commercial CD19 CAR-T cell therapy for R/R B-ALL
.
Professor Xu Kailin mentioned that it is believed that in the near future, there will be CAR-T cell therapy for B-ALL and multiple myeloma (MM) on the market
in China.

The First Affiliated Hospital of Zhejiang University, the Affiliated Hospital of Xuzhou Medical University, the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, the Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Shanghai Tongji Hospital of Tongji University School of Medicine, and Hebei Yanda Ludaopei Hospital are the earliest hospitals
in China to carry out R/R B-ALL related CAR-T clinical trials.

CD19 CAR-T was not initially effective in B-ALL, but improved with the optimization of the "CAR" structure
.
Emily, the first R/R B-ALL patient to be cured by CAR-T, has survived for 10 years
without disease.
Based on the ELIANA trial, the most well-known CAR-T clinical trial in the B-ALL field, the world's first CD19 CAR-T cell therapy, tisagenlecleucel, was approved by the FDA in 2017 for R/R B-ALL children and younger patients (≤ 25 years old
).
The trial was conducted by 25 centers around the world, and the results of the latest 5-year follow-up data showed that the overall response rate (ORR) of R/R B-ALL patients receiving CAR-T cell therapy could reach 82%.

China has also followed up with many clinical trials on the treatment of R/R B-ALL on CD19 CAR-T cells, and has achieved good results (complete response [CR] rate of 80%-96%)
.
However, there is still a gap between
China and the international leading level in the design of the "CAR" structure.

In addition to CD19 targets, CD22 targets have also been
studied in B-ALL.
CD22 CAR-T cell therapy has a CR rate of about 70% in R/R B-ALL, and the efficacy is slightly lower than CD19 CAR-T, but it has a good effect in CD19 dim and CD19-negative B-ALL patients, and is a good complementary treatment method
for CD19 CAR-T.

CAR-T cell therapy has good near-term efficacy in R/R B-ALL, but the long-term efficacy is unsatisfactory
.
The follow-up results of the ELIANA trial showed that the 6-month event-free survival (EFS) rate was 73% for patients and 50% for 12-month EFS; The 6-month overall survival (OS) rate was 90% and the 12-month OS rate was 76%.

The follow-up results of another trial related to CD19 CAR-T cell therapy showed that the median follow-up was 29 months, and the median EFS was 6.
1 months and the median OS was 12.
9 months for patients receiving CD19 CAR-T cell therapy
.

In addition, the results of a multicenter trial in China showed that CD19 CAR-T cells treated patients with B-ALL of the central nervous system had a bone marrow ORR of 87.
5% and a central nervous system ORR of 85.
4%.

Professor Xu Kailin mentioned that with the optimization of the "CAR" structure, the safety of CAR-T cell therapy has gradually improved, and how to reduce patient recurrence and improve the long-term efficacy of CAR-T cell therapy has become a research hotspot
in the field of B-ALL therapy in the future.

• CAR-T sequentially allo-HSCT

In order to improve the long-term efficacy of CAR-T cell therapy, Chinese researchers have explored
the role of bridging allo-HSCT in B-ALL after CAR-T cell therapy 。 Beijing Lu Daopei Hospital conducted a clinical trial of 135 patients who obtained CR after CAR-T cell therapy, and bridging allo-HSCT after reaching CR, and the results showed that the 2-year OS rate of MRD-negative CR patients could reach 83.
6%, the 2-year survival rate without leukemia (LFS) could reach 80%, the 2-year OS rate of MRD-positive CR patients could also reach 61.
5%, and the 2-year LFS rate could reach more than
50%.

The Affiliated Hospital of Xuzhou Medical University has also conducted relevant studies, and the results show that regardless of the number of CAR-T cell treatments, the long-term efficacy of bridging allo-HSCT after CAR-T cell therapy is better than that of patients who
only undergo CAR-T cell therapy.
In addition, there are also a number of medical centers in the world to carry out CAR-T cell therapy bridging allo-HSCT related research, the vast majority of research results show that CAR-T cell therapy bridging allo-HSCT can improve the long-term efficacy
of B-ALL patients.
A few studies have shown that bridging allo-HSCT after CAR-T cell therapy did not improve long-term efficacy in patients compared with CAR-T cell therapy alone, which may be related
to the relatively high proportion of pediatric patients in the included studies.
This suggests that not all patients need to bridge allo-HSCT after CAR-T
.

Based on the available data, Professor Kailin Xu evaluated
whether allo-HSCT was bridged after CAR-T cell therapy from three aspects: disease factors, CAR-T cell therapy-related factors and patient factors.
Professor Xu Kailin mentioned that when patients have the following related factors (Figure 1), they should be prepared to
bridge allo-HSCT at the time of CAR-T cell therapy or when CR is reached.

Figure 1

The pre-allo-HSCT disease state is closely related to the success of allo-HSCT, and choosing the right time to bridge allo-HSCT is critical
to improving the long-term efficacy of CAR-T cell therapy.
Professor Xu Kailin mentioned that most patients with effective CAR-T cell therapy reached CR within 1 month of CAR-T cell infusion and obtained MRD negative, and most cytokine release syndrome (CRS) and immune effector cell-related neurotoxicity syndrome (ICANS) were resolved
within 3-4 weeks after CAR-T cell infusion.
Recurrence of B-ALL occurs within
6 months after CAR-T cell infusion.
Therefore, the timing of bridging allo-HSCT should be within
3-6 months after CAR-T cell infusion.

• CAR-T is used for recurrence of B-ALL after allo-HSCT

At present, the treatment needs of patients with recurrent B-ALL after allo-HSCT have not been met
.
The results of a retrospective analysis of 1706 patients showed that the CR rate of salvage therapy in patients with recurring B-ALL after allo-HSCT was less than 40%, the 1-year OS rate was 26%, and the 3-year OS rate was 11%.

Donor lymphocyte infusion (DLI) is one of the main means of treating recurrence after transplantation, but its efficacy still needs to be improved
.
The results of the study at the First Affiliated Hospital of Soochow University showed that CAR-T was more effective than DLI in patients with recurrent B-ALL after allo-HSCT (CR rate: 61.
5% vs 13.
3%)
.
Peking University People's Hospital also conducted a similar study, the results of which showed that patients with B-ALL who relapsed after allo-HSCT had a CR rate of 85.
7% after receiving CAR-T cell therapy, and the incidence of ≥grade 3 CRS was only 11.
8%.

The results of a clinical trial involving multiple centers in China showed that after receiving donor-derived CAR-T cell therapy, the CR rate of patients with recurrence of B-ALL after allo-HSCT could reach 79%, and the incidence of ≥-level 3 CRS was only 16.
3%.

Based on the above results, CAR-T cell therapy in patients with B-ALL recurrence after allo-HSCT, some researchers have proposed whether CAR-T cell therapy can be used to prevent recurrence
after allo-HSCT in B-ALL patients.
In this regard, Professor Xu Kailin said that for patients with persistent positive MRD, especially patients with high risk factors for recurrence, it will be possible to use CAR-T cell therapy to prevent post-transplantation recurrence
in the future.

CAR-T cell therapy is a powerful treatment for R/R B-ALL, but the long-term efficacy needs to be improved
.
Bridging allo-HSCT after CAR-T cell therapy can improve the long-term efficacy of CAR-T
.
In addition, for patients who relapse after allo-HSCT, CAR-T cell therapy allows patients to remission again, buying time
for a second transplant or other salvage treatment.
Whether CAR-T cell therapy is needed to prevent B-ALL recurrence after allo-HSCT still needs to be slowly explored
in the future.

Professor Xu Kailin

• Director of the Institute of Hematology, Xuzhou Medical University

• Director of Hematopoietic Stem Cell Transplantation Center of Xuzhou Medical University Affiliated Hospital

• Director of Jiangsu Provincial Key Laboratory of Bone Marrow Stem Cells

• He is a member of the Hematology Branch of the Chinese Medical Association and the deputy leader of the experimental diagnostics group

• Member of the Standing Committee of the Hematology Branch of the Chinese Medical Doctor Association

• Chairman of Jiangsu Hematology Branch

• Expert of the preliminary and final examination of the National Natural Science Foundation of China

• Young and middle-aged experts with outstanding contributions from the Ministry of Health and Jiangsu Province

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