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Acute myeloid leukemia (AML) is a malignant clonal disease derived from hematopoietic stem cells, which tends to occur in the elderly, with a median age of onset of 66 years, and the incidence increases with age, and the treatment tolerance of elderly AML patients is poor and the prognosis is poor [1].
Hematopoietic stem cell transplantation is still the only possible cure for AML, and with the emergence and application of a variety of new drugs in recent years, it has not only brought survival benefits to patients who cannot undergo transplantation, but also helped
to improve transplant rates and reduce recurrence rates after transplantation.
Nuclear output protein 1 (XPO1) is an important transporter receptor protein of tumor suppressor proteins from the nucleus to the cytoplasm, and is overexpressed in a range of malignancies, including AML [2].
Seliniso (trade name: Silvio ®) is the world's first novel mechanism of oral selective nuclear output protein inhibitor (SINE), which has been shown to bring effective relief to patients with treatment-new and relapsed refractory (R/R) AML and increase the success rate
of transplantation.
Based on this, Yimaitong specially invited Professor Wang Jianxiang of Hematology Hospital of Chinese Academy of Medical Sciences to share the current status of AML treatment and the progress of
new drugs based on clinical experience.
Professor Wang Jianxiang
Deputy Director of Hematology Hospital, Chinese Academy of Medical Sciences, Director of Leukemia Diagnosis and Treatment Center
Director of the National Clinical Research Center for Hematology
Former Chairman of the Hematology Branch of the Chinese Medical Association
Vice President of the Internal Medicine Branch of the Chinese Medical Doctor Association
Vice President of Hematologist Branch of Chinese Medical Doctor Association
Chairman of Hematology and Oncology Committee, Chinese Anti-Cancer Association (2012-2015)
J Hematol & Oncol Associate Editor, Editorial Board Member of Blood, Editor-in-Chief of Chinese Journal of Hematology (2012-2016)
National-level candidates for "Jieqing" and "Millions of Talents Project in the New Century", experts of the Ministry of Health, and special experts of the State Council
The main developer of CD19 and CD33 CAR-T, the leader of leukemia treatment, prognosis stratification, intensive induction, and whole-process management have significantly improved the efficacy of acute leukemia
Lead the formulation of multiple diagnosis and treatment guidelines for acute myeloid leukemia, acute lymphoblastic leukemia and chronic myeloid leukemia
NIH Postdoctoral Outstanding Research Award, First Prize of the 10th "Wu Jieping Medical Research Award-Paul Janssen Pharmaceutical Research Award", First Prize of Tianjin Science and Technology Progress Award (First Completer)
With the breakthrough of basic research and the clinical application of a variety of new drugs, the treatment of AML has undergone great changes, please briefly introduce the current treatment status of AML in China, what unmet treatment needs still exist in AML patients?
Professor Wang Jianxiang
AML is a group of diseases whose heterogeneity determines the diversity of diseases, which is often associated with
genetic mutations and chromosomal abnormalities in patients.
Therefore, the fine classification of AML can be carried out clinically by morphological detection, gene identification/sequencing and other methods [3], which provides a clinical basis
for subsequent precision treatment.
With the development of science and technology, the classification of AML has become more and more refined, but there are still some patients in the initial diagnosis of the unclear classification, so the clinical classification of AML still has a lot of room for
improvement.
The treatment plan for AML is currently relatively simple, mainly composed of chemotherapy and post-remission treatment, and its treatment goal is to achieve long-term survival and even cure
for patients.
But in fact, for the remission after chemotherapy, 20%-30% of clinical patients cannot achieve complete remission (CR), that is, refractory patients who have failed induction therapy, and how to benefit them is one of
the currently unmet needs.
Patients who achieve remission are usually given novel drugs, hematopoietic stem cell transplantation, and other treatments to continue remission
.
However, 40 to 50 percent of patients still have relapse after transplantation, and the prognosis is usually poor after relapse, which is one of the current treatment challenges [4].
In addition, due to the heterogeneity of AML, the age range of patients is large, and the choice of treatment options and prognosis of patients of different ages are also different
.
Young patients can choose intensive chemotherapy, targeted therapy, transplantation and other treatment options; Elderly patients, on the other hand, are worse than younger patients in overall efficacy because they often have hypertension, coronary heart disease, diabetes, liver/kidney impairment and other diseases, which seriously affect the "feasibility of treatment options" [5].
。 In this regard, some new treatments have been gradually explored at home and abroad, including new targeted drugs, but the number of targeted drugs that have been approved and can be used is limited, including FLT3 inhibitors, BCL2 inhibitors, IDH1 inhibitors, etc.
, and more are targeted drugs that have not yet entered clinical trials or marketing, so the clinical demand for targeted drugs has not yet been met
.
At present, targeted drugs that can be used in elderly patients have significantly improved the efficacy of these patients, but the long-term survival rate of patients is still low
.
It can be seen that there are many problems to be solved in terms of the disease itself, the difference in patients' physical ability and the availability of drugs, and more efforts are needed to overcome
.
Therefore, both international and domestic guidelines suggest that on the basis of the existing treatment options for AML, the introduction of other new therapeutic drugs can be considered to explore new therapies through clinical research, so as to prolong the survival of AML patients and improve the prognosis [5].
Yimaitong: The rapid development of targeted drugs has brought progress to AML treatment, and studies have shown that the combination regimen of XPO1 inhibitor Selinisosol can be used to treat AML patients.
Professor Wang Jianxiang
Although the traditional treatment method has brought benefits to some patients, a considerable number of patients still develop drug resistance and relapse
.
In recent years, with the rapid progress in molecular biology fields such as sequencing technology, many new therapeutic targets and new targeted drugs have been explored to try to improve the effect of
previous treatments.
The Guidelines for the Diagnosis and Treatment of Relapsed and Refractory Acute Myeloid Leukemia in China (2021 Edition) have moved "new targeted therapy drugs" to the first place in the treatment principle, highlighting its important position [7].
XPO1 is a new type of clinically proven therapeutic target, the expression of XPO1 in tumor patients increases, so that many tumor suppressor proteins of the original nucleus are transferred to the cytoplasm, and the change of functional site will cause changes in cell function, resulting in cell carcinogenesis [8].
The novel targeted drug Selinisol specifically inhibits XPO1, promotes the intranuclear retention of a variety of tumor suppressor proteins, reduces the level of intracytoplasmic oncogenic proteins, and plays a good anti-tumor role
mediated by multiple pathways.
To explore the use of celinisol in AML, a Phase 1 study of Selinisol combined with high-dose cytarabine and mitoxantrone (HiDAC/Mito) for treatment-païve and R/R AML showed a total response rate (ORR) of 70%, of which 50% of patients achieved CR, CR/CR with incomplete recovery (CRi) rate of 65%, and 8 (57%) of 14 patients in response successfully underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT).
。 All patients were followed up at a median follow-up of 6 months, and the 1-year overall survival (OS) rate was expected to be 69% and the 1-year progression-free survival (PFS) rate was 68%.
Common adverse reactions are febrile neutropenia, followed by gastrointestinal toxicity including diarrhea, anorexia, etc.
, mostly grade 1 or 2
.
It can be seen from this study that celinisol, as a new targeted therapy drug, combined with the traditional treatment regimen of AML, has good efficacy and safety [9].
At present, the new drugs being explored are mainly used in the back-line treatment of AML patients, and more are used to treat patients with R/R AML, and the efficacy and safety of some drugs have been preliminarily confirmed
.
It is expected that these new drugs can be tried in combination in frontline therapy to further reduce the recurrence/refractory occurrence of patients and prolong the survival and remission period
of patients.
The research of new drugs is in full swing, and it is hoped that more new drugs can enter clinical trials and contribute to the improvement of efficacy
.
Transplantation is the only cure for AML patients, but there are still some patients who have a recurrence
of the disease after transplantation.
If effective drugs are used before transplantation, the success rate of transplantation can be improved, the recurrence rate after transplantation can be significantly reduced, and patients can achieve more durable remission
.
Could you please explain to us the relevant research on the use of cerinixole-related treatment options before transplantation?
Professor Wang Jianxiang
Based on the current treatment strategy, the clinical trial is mainly based on the risk stratification of AML patients to choose whether to undergo hematopoietic stem cell transplantation
after remission.
Transplantation is clinically recommended for low- and intermediate-risk patients at high risk of achieving negative remission of minimal residual disease (MRD
).
For low- and intermediate-risk patients who require transplantation but have not yet achieved MRD negativity, remission
should be achieved before transplantation if possible.
Improving the effectiveness of transplantation is closely related to pre-transplant remission, and achieving MRD-negative remission can help improve the success rate
of subsequent transplantation.
Therefore, how to improve the remission rate and improve the quality of remission in patients before transplantation needs to be explored
.
One serinisol in combination with "7+3" (cytarabine 100 mg/m2iv.
d1-7 + daunorubicin 60mg/m2iv.
D1-3) The results of phase II study of standard regimen induction, consolidation, and maintenance therapy in treatment-new-treated elderly AML patients showed that the ORR in the celinixole combination group was significantly increased compared with the standard group.
Compared with the standard group, CR/CRi in the Seliniso combination group was 86% vs 43%, of which the CR rate in the Seliniso combination group was 76% and the MRD negative rate in CR patients was 81%; The median OS (839 versus 265 days) and median PFS (558 versus 108 days) were prolonged in the combined Seliniso group, with transplant rates of 33 versus 14 percent and recurrence rates of 22 versus 33 percent
.
Common nonhematologic toxicities include diarrhea, hyponatremia, nausea, and the most common grade 3/4 treatment-related adverse events are febrile neutropenia, diarrhea, and no ceriniso-related deaths [10].
This study suggests that the combination of chemotherapy with cellinixole significantly improved chemotherapy outcomes, providing it with a statistically significant survival benefit (839 versus 265 days, P=0.
0472), providing transplant opportunities for more patients, and further improving transplant outcomes
.
It can be seen that the introduction of cellinisol during AML treatment helps to improve the efficacy
of AML.
AML is a clonal disease with a high degree of heterogeneity, the emergence of new drugs has brought new hope to patients, what are your expectations or prospects for the treatment prospects of AML in China?
Professor Wang Jianxiang
The entire clinical diagnosis and treatment of AML, from refined diagnosis, to induction therapy, post-remission treatment and maintenance therapy, involves the whole process of patient monitoring and management
.
Improving the response rate of induction therapy, monitoring disease progression more timely and accurately, detecting MRD more sensitively, improving the negative rate of MRD, and clearing MRD more effectively after the emergence of MRD are all development goals
for long-term survival and better prognosis.
In addition, paying attention to adjuvant therapies such as blood transfusion and anti-infection is also crucial to
ensure that AML patients achieve good outcomes.
Therefore, we not only look forward to organically linking the various treatment stages in the future to make the overall treatment process efficient and smooth, but also look forward to innovative changes
in disease management, system and mechanism.
The treatment of AML, in addition to paying attention to the management of the disease itself, also needs to pay attention to multidisciplinary cooperation to escort the entire disease treatment and management process, so as to further improve
the efficacy.
It is expected that more new drugs will emerge in the treatment of AML to continuously improve the efficacy
.
In addition to chemotherapy and targeted therapy, it is also hoped that the emergence of new technologies will enrich treatment strategies, such as clearing leukemia cells by improving patients' own immunity, while maintaining normal hematopoietic cell function and ensuring their treatment safety
.
In summary, it is expected that new drugs and new technologies will emerge to eventually enable AML patients to achieve cure
.
Note: Civio ® is the trade name
of Seliniso.
In December 2021, China's National Medical Products Administration (NMPA) approved Antengene's new drug application for Selinisol to treat previously treated relapsed or refractory multiple myeloma (R/R MM)
with at least one proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody in combination with dexamethasone.
In June 2020, the U.
S.
Food and Drug Administration (FDA) approved Selinisole for the treatment of patients with third-line or above diffuse large B-cell lymphoma (DLBCL); In addition, Seliniso is also approved in multiple countries for the treatment of patients with
relapsed and refractory DLBCL.
The content of the article is only for academic communication of medical and health professionals, if you are a non-medical and health professional, please take the initiative to exit browsing and reading, otherwise the related risks and consequences arising therefrom shall be borne
by yourself.
References:
[1] CHEN Xu.
Treatment status and progress of adult relapsed/refractory acute myeloid leukemia [D]; Chongqing Medical University.
[2] SWEET K, BHATNAGAR B, DÖHNER H, et al.
A 2:1 randomized, open-label, phase II study of selinexor vs.
physician's choice in older patients with relapsed or refractory acute myeloid leukemia [J].
Leuk Lymphoma, 2021, 62(13): 3192-203.
[3] SWERDLOW S H, CAMPO E, PILERI S A, et al.
The 2016 revision of the World Health Organization classification of lymphoid neoplasms [J].
Blood, 2016, 127(20): 2375-90.
[4] DÖHNER H, ESTEY E, GRIMWADE D, et al.
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel [J].
Blood, 2017, 129(4): 424-47.
[5] Leukemia Lymphoma Group, Chinese Society of Hematology.
Guidelines for diagnosis and treatment of acute myeloid leukemia (non-acute promyelocytic leukemia) in adults in China (2021 edition)[J].
Chinese Journal of Hematology, 2021, 42(8): 617-23.
[6] QIU Lin, MA Jun.
Research progress of targeted therapy for acute myeloid leukemia[J].
Leukemia Lymphoma, 2022, 31(4): 7.
[7] Leukemia Lymphoma Group, Chinese Society of Hematology.
Guidelines for the diagnosis and treatment of relapsed and refractory acute myeloid leukemia in China (2021 edition)[J].
Chinese Journal of Hematology, 2021, 42(8): 7.
[8] NIE D, XIAO X, CHEN J, et al.
Prognostic and therapeutic significance of XPO1 in T-cell lymphoma [J].
Exp Cell Res, 2022, 416(2): 113180.
[9] WANG A Y, WEINER H, GREEN M, et al.
A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia [J].
J Hematol Oncol, 2018, 11(1): 4.
[10] Richard S, et al.
Blood (2019) 134 (Supplement_1): 1388.
； 2020ASH.
Blood (2020) 136 (Supplement 1): 24–25.
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