2022 SHS Professor Tang Xiaowen: AML transplantation needs to pay attention to the whole process management, and myeloid CAR-T treatment has broad prospects

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults, with an increasing incidence with age and a poor
overall prognosis.
With the deepening of research, the treatment of AML has developed rapidly, but it also faces certain challenges, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT) as an important treatment option for AML, but also has the problem of high recurrence rate after transplantation, which still needs to be deeply explored
by hematologists.
In addition, although CAR-T therapy provides new treatment options for AML patients, CAR-T therapy is still in its infancy in the field of AML treatment, and there is still a broader space for development worth exploring
in the future.
On October 7-9, 2022, the "2022 Suzhou Hematology Summit and National Continuing Medical Education Study Class" was grandly opened
in Suzhou.
On this occasion, Professor Tang Xiaowen of the First Affiliated Hospital of Soochow University was invited to express his views
on the possible mechanism and prevention of recurrence after transplantation in AML patients, as well as the research status and prospect of CAR-T treatment of AML.

Allo-HSCT is an important means of AML treatment, but the recurrence rate after transplantation is high, which seriously affects the long-term survival of AML patients, and exploring the mechanism of transplant recurrence may provide new prevention and treatment ideas
for post-transplant recurrence.
What do you think are the possible mechanisms of post-transplant recurrence?

Immune evasion and clonal evolution are the main causes of
post-transplant recurrence.
First, the mechanisms of immune escape include mismatched loss of human leukocyte antigen (HLA) alleles, imbalance in the production of anti-inflammatory and pro-inflammatory factors, expression of immune checkpoint ligands, and acquisition of new mutations
.
Among them, HLA allele loss is an important mechanism for immune evasion in haplo-HSCT, accounting for about 33%.

T cells are usually activated after recognizing incompatible HLAs, and the loss of HLA alleles leads to suppression
of the T cell-mediated immune response.
In patients who relapse after HLA allele loss, stop-off immunosuppressants and donor lymphocyte transfusions (DLIs) are usually ineffective
.
In addition, when patients with recurrent HLA allele loss type undergo secondary transplantation, it is not appropriate to choose the original donor, and another suitable donor should be selected, especially HLA allele loss type donors
.
Overall, it is necessary to detect HLA allele loss in patients with AML who relapse after transplantation; The imbalance in the production of anti-inflammatory and pro-inflammatory factors is another mechanism
that causes immune escape in leukemia cells.
For example, a decrease in the secretion of the pro-inflammatory factor IL-15 inhibits the activation of T cells and NK cells, thereby weakening the graft-resistant leukemia effect (GVL); Suppressive immune checkpoints are also a major contributor
to immune escape.

In addition, clonal evolution is also one of the important causes of
recurrence after transplantation.
Under the dual pressure of pretreatment and GVL, some clones are removed and restored to the pre-malignant or progenitor state; Most treatment-sensitive clones disappear after treatment; Some dominant clones are transformed into weak clones; However, a small number of clones with new mutations showed vigorous proliferation and immune resistance, gradually becoming dominant clones, and eventually causing post-transplant relapse
.
There are two clonal evolution patterns for post-transplant recurrence in AML patients: (1) leukemia cells at the time of relapse after transplantation have some of the same genetic background as leukemia cells at first diagnosis, and the relapsed clones may originate from the subclones at the time of initial diagnosis and gradually develop into dominant clones in the process of post-transplant relapse, which may also be accompanied by the acquisition
of new gene mutations.
(2) Leukemia cells at the time of relapse after transplantation have a completely different genetic background from leukemia cells at the time of initial diagnosis, and the recurrent clones may originate from new leukemia clones produced after acquiring new gene mutations, and these clones evolve into dominant clones and induce disease recurrence
.

Yimaitong: What are the main prevention and treatment points of recurrence after allo-HSCT in AML patients?

The efficacy of transplantation in AML patients is affected by many links, which are closely related to the patient's pre-transplant preparation, transplant plan optimization, post-transplant minimal residual disease (MRD) whole process monitoring and maintenance of consolidation therapy, so the prevention and treatment of post-transplant recurrence in AML patients lies in the overall management of the whole process of transplantation, mainly in four aspects:

(1) Pre-transplant preparation, including patient evaluation and donor selection
.
When assessing patients, risk stratification is carried out from diagnosis, an overall treatment plan is designed for the patient, and the patient is planned to receive hematopoietic stem cell transplantation (HSCT) at the most appropriate time
.
Before initiating transplantation, it is necessary to comprehensively evaluate the recipient's transplant indications and transplant timing, as well as the patient's disease status, physical status, nutritional status, underlying comorbidities, etc.
, to assess the risk
of transplantation.
At the same time, it is also necessary to pay attention to the patient's economic situation, the psychological state and cultural level of the patient and his family, and evaluate other factors affecting the prognosis of transplantation, such as transplant-related social factors
and patient compliance.
In addition, in terms of donor selection, "who is the best donor" is a question
that needs to be carefully considered before transplantation is currently performed.
In order to reduce post-transplant recurrence, acute and chronic graft-versus-host disease (GVHD), in addition to donor-recipient HLA compatibility, other factors such as stem cell source, HLA antibodies, donor age and sex, donor and recipient serum cytomegalovirus (CMV) infection status, ABO blood group compatibility and other factors need to be considered to select the best donor
.
In practice, donor selection should be based on the patient's circumstances (whether the disease is at high risk of recurrence; Age; Physical condition), the specific situation of the alternative donor, and the experience of the transplant are considered
comprehensively.

(2) Transplantation protocol optimization, including pretreatment plan optimization and GVHD prevention program optimization
.
In terms of pretreatment protocol optimization, with the increase of pretreatment intensity, the killing effect on tumor cells is enhanced, but at the same time, the toxicity related to treatment will also increase, so effective and safe pretreatment regimens are needed to improve patient prognosis
.
Our center uses a low-dose decitabine (DAC) combined with a modified busulfan+cyclophosphamide (BuCy) pretreatment regimen to reduce the recurrence rate of patients after transplantation, without increasing transplant-related mortality, especially improving the prognosis
of patients who did not remission before transplantation.
In addition, other studies have found that the addition of drugs such as G-CSF, BCL-2 inhibitors, or CD45 monoclonal antibodies to the conditioning regimen may also improve transplant outcomes
in AML patients.
In the optimization of GVHD prevention regimens, immunosuppressants can significantly improve the survival rate of grafts, but most drugs have problems such as
narrow treatment windows and large individual differences.
Pharmacokinetic-pharmacodynamic research is helpful to find the law of individualized drug use, and in recent years, the research on pharmacogenomics has added a new basis
for the precision treatment of immunosuppressants.
In the future, by optimizing the administration strategy of immunosuppressants, the benefits and disadvantages of drugs can be better balanced, and the survival rate of transplant patients can be improved and the quality of life
of patients can be improved.

(3) Full monitoring and maintenance of consolidation therapy
for MRD after transplantation.
Among them, MRD monitoring should be carried out throughout the transplantation process, and MRD should be monitored as soon as possible after transplantation to predict patient prognosis
.
The combination of multiple MRD monitoring methods can improve the sensitivity
of predicting recurrence after transplantation.
Maintenance consolidation therapy needs to minimize toxic side effects while maximizing the effects of GVL and removing residual leukemic stem cells
.
Our central retrospective study found that regular DAC consolidation therapy after transplantation in patients with AML significantly improved prognosis
.
A number of studies have reported that preventive DLI can enhance the anti-leukemia effect of T cells, reverse T cell depletion, reduce the expression of inhibitory receptors on the surface of T cells, and effectively prevent the recurrence
of leukemia after transplantation.
In addition, maintenance therapy with FLT3 inhibitors or TKIs after transplantation improves outcomes
in patients with FLT3-ITD mutations or positive BCR/ABL1 fusion genes.

(4) Preemptive treatment and salvage therapy for recurrence after transplantation, mainly including chemotherapy, new drug therapy, targeted therapy, immunotherapy and secondary transplantation
.
Among them, chemotherapy, as a traditional treatment method for leukemia, is one of
the important treatment options for recurrence after transplantation.
The chemotherapy regimen should be based
on a comprehensive assessment of the type of disease, the condition at the time of recurrence, and the efficacy of previous chemotherapy regimens.
Patients with early post-transplant relapse are thought to be insensitive to chemotherapy and have high chemotherapy-related mortality, while patients with late post-transplant relapse may tolerate re-induction chemotherapy
.
New drugs such as BCL-2 inhibitors can induce endogenous apoptotic pathways leading to rapid apoptosis of leukemia cells, eradicate quiescent leukemia stem cells, and directly activate T cells in vivo and in vitro to increase their cytotoxicity
to leukemia.
MDM2/MDMX inhibitors can activate p53 and restore its tumor suppressive activity
.
In addition, new drugs such as Eprenetapopt (APR-246) and MENIN inhibitors have also achieved initial results
in clinical application.
In terms of targeted therapy, including FLT3 inhibitors, IDH inhibitors, etc
.
Now that we have entered a new era of immunotherapy, antibody drugs, cell immunotherapy CAR-T, etc.
have come out, providing new hope and dawn for patients with relapse after transplantation
.
In addition, secondary transplantation is an effective way to treat relapse after transplantation, and it is also an important means for relapsed patients to obtain long-term survival, but the high recurrence rate and non-relapse mortality faced by it are still urgent clinical problems
.

Medical: Patients with relapsed/refractory (R/R) AML have a poor prognosis and a high rate of recurrence after transplantation, requiring new drugs and regimens to improve long-term survival
in these patients.
The rapid development of CAR-T therapy has provided new treatment options for AML patients, but compared with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), the progress of CAR-T therapy for AML is relatively slow and still in its infancy.

At present, CAR-T cell therapy has not made breakthroughs in the field of AML therapy, and the core problem is that no myeloid target with both efficacy and safety like CD19 has
been found.
Since 2010, the exploration of myeloid CAR-T targets has never stopped, including Leiws Y, CD33, CD123, CD44v6, NKG2D and FRβ, but in the end, due to low efficiency and serious off-target effect, large-scale clinical studies
have not been carried out.
It can be seen that the two bottlenecks of efficacy and safety seriously restrict the popularization and application
of myeloid CAR-T in clinical practice.
To this end, our center has carried out many explorations, using CD38, CD19, CD7, PD-1 knockdown CLL-1 CAR-T and CD33 CAR-NK for the treatment of R/R AML, all of which have achieved good clinical results and are original clinical research results
.
In addition, in recent years, three domestic centers have successively reported that CLL1 CAR-T and CLL1/CD33 CAR-T have achieved a complete response (CR) rate
of more than 70% in the treatment of AML.

In the future, the field of myeloid CAR-T therapy is still a broad world, and it is hoped that with the assistance of multi-omics, artificial intelligence and big data, safer and more effective myeloid targets can be
explored.
At the same time, through the selection of better targets, the optimization of pretreatment schemes, the prediction and early intervention of CAR-T-related complications, and the maintenance therapy after CAR-T, each patient can receive personalized CAR-T treatment, thereby minimizing CAR-T-related toxicity, improving the efficacy and durability of CAR-T, and making CAR-T therapy a powerful weapon
for the treatment of patients with R/R AML.

Professor Tang Xiaowen

• Deputy Director of Hematology, Chief Physician, Professor, Doctoral Supervisor, Department of Hematology, The First Affiliated Hospital of Soochow University

• Vice Chairman of the Hematology Professional Committee of the Cross-Strait Medical and Health Exchange Association

• Vice Chairman of the Transplant Infection Academic Working Committee of the First Committee of the Hematology Branch of the Chinese Geriatrics Society

• Standing Committee Member of Hematology Branch of Chinese Geriatrics Society

• Member of Hematology Branch of Chinese Medical Doctor Association

• Deputy leader of the Hematopoietic Stem Cell Transplantation Group of the Hematology Branch of the Chinese Medical Association

• Chairman of Hematopoietic Stem Cell Transplantation and Immunotherapy Branch of Jiangsu Research Hospital Association

• Vice Chairman of the CAR-T Cell and Immunotherapy Professional Committee of Jiangsu Research Hospital Association

• Member of Hematology Branch of Jiangsu Medical Association

• Head of Hematopoietic Stem Cell Transplantation and Cell Therapy Group of Hematology Branch of Jiangsu Medical Association

• Jiangsu Province is a key medical talent of "rejuvenating health through science and education" and "strengthening health through science and education"

• Editorial Board Member of Chinese Journal of Blood

• Member of the Editorial Board of the 7th Editorial Board of the International Journal of Blood Transfusion and Hematology

• As the first person in charge of the project, he undertook 26 projects of the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu Province, the Key Project of Clinical Frontier Technology of Social Development in Jiangsu Province and other provincial, departmental and municipal projects, as the main investigator, he has successively won 1 second prize of National Science and Technology Progress Award, 20 provincial and ministerial level science and technology progress awards and new technology introduction awards, innovatively carried out 8 new technologies and new therapies, obtained 1 national invention patent authorization as the first inventor, participated in the editing of 5 monographs, published more than 132 monographs, and worked in JCO.
  Leukemia, Clin Infect Dis and other journals have published several SCI papers and are contributing reviewers
  for journals such as Annals of Hematology.