Professor Wei Xudong: Advances in the treatment of patients with acute lymphoblastic leukemia with TKIs 2021 China Oncology Congress

Acute lymphoblastic leukemia (ALL) is a more common type of adult leukemia, and Philadelphia chromosome (Ph) positivity is the most common cytogenetic feature of ALL
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With the research progress in recent years, especially the application of tyrosine kinase inhibitors (TKIs), the remission rate and survival rate of Ph+ ALL patients have been greatly improved
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At the 2021 China Conference on Oncology (CCO) held online from April 14 to 17, 2022, Professor Wei Xudong from Henan Cancer Hospital gave the title of "Progress in the treatment of ALL with third-generation TKIs" and started from three parts related introduction
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The benefits and limitations of first- and second-generation TKIs in the treatment of Ph+ ALL Prof.
Wei Xudong first introduced the incidence and survival rates of Ph+ ALL
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ALL accounts for about 20% of adult leukemias, and Ph+ ALL accounts for 25% of ALL patients
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Compared with Ph- ALL, patients with Ph+ ALL have a worse prognosis, with lower 5-year event-free survival (EFS) and overall survival (OS) rates
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Before the 1990s, patients with Ph+ ALL could only rely on chemotherapy alone, and the prognosis was poor, with a 3-year OS rate of less than 30%; after the 1990s, due to the introduction of allogeneic hematopoietic stem cell transplantation (Allo-HSCT), the prognosis of patients improved to some extent.
, the 2-year OS rate reached 40%-50%, and the 3-year OS rate was 36%-44%; in 2006, with the addition of TKIs to the treatment team of Ph+ ALL patients, the prognosis of ALL was significantly improved, and the CR rate reached 95%.
%-100%, and the 5-year OS rate reaches 38%-71%
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The NCCN Guidelines (2021 v4) also affirmed the status of TKIs in the basic treatment of Ph+ ALL, and their specific recommendations are shown in Figure 1
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Figure 1 Prof.
Wei Xudong said that although the first and second generation TKIs have increased the remission rate of Ph+ ALL patients, there are still certain limitations—the recurrence rate of patients is high
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BCR-ABL1 kinase domain gene mutation is the main reason for recurrence after first- and second-generation TKI therapy
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Professor Wei Xudong said that Ph+ ALL patients had a high percentage of gene mutations in the BCR-ABL1 kinase region before TKI treatment
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Professor Wei Xudong finally summarized the content of this part as shown in Figure 2
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Figure 2 The advantages of third-generation TKIs in the treatment of Ph+ ALL Based on the above-mentioned gene mutations that cause treatment limitations, third-generation TKIs were developed, among which the third-generation TKI Ponatinib (Ponatinib) was approved by the FDA, and the approved indications are: Ph+ that is not suitable for first- and second-generation TKIs ALL patients; T351I mutant Ph+ ALL patients
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The NCCN guidelines (2021 v4) also recommend third-generation TKIs as first-line therapy and are the preferred TKIs in combination with hyper-CVAD regimens
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Professor Wei Xudong first introduced the clinical trial progress of third-generation TKI drugs in newly diagnosed Ph+ ALL patients
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In 2018, MD Anderson Cancer Center published a study of three-generation TKI combined with chemotherapy for newly diagnosed Ph+ ALL patients.
The data showed that the CR rate of patients reached 100%, the major molecular response (MMR) rate reached 97%, and the MRD negative rate was 99%.
, the complete molecular remission (CMR) rate reached 83%; the 3-year EFS rate and OS rate were 70% and 76%, respectively
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Similar findings were also published in the PONALFIL study in 2021.
Compared with imatinib combined with chemotherapy, third-generation TKI combined with chemotherapy for newly diagnosed Ph+ ALL patients can significantly improve the survival rate and remission rate
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So what is the efficacy of third-generation TKIs for elderly patients or patients who are not suitable for intensive chemotherapy/transplantation (unfit)? Professor Wei Xudong said that from the research results published in the INCB84344-201 trial in 2021, we can see that after the third-generation TKIs combined with hormones are used in elderly or unfit patients, the 24-week complete hematologic remission (CHR) rate reaches 86.
4%, and the median EFS is At 14.
3 months, the inhibition rate was 11.
4%; the median CMR was 11.
6 months, and the 24-week CMR rate was 40.
9%
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Professor Wei Xudong then introduced the clinical research progress of third-generation TKIs in patients with relapsed/refractory Ph+ ALL
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In 2013, the PACE study published its findings.
After the second-generation TKI-resistant or intolerant Ph+ ALL patients were treated with third-generation TKIs, the 6-month major hematologic response (MHR) rate was 41%, and the major cytogenetic response (McyR) rate was 41%.
The rate of complete cytogenetic remission (CcyR) was 47%, the rate of complete cytogenetic remission (CcyR) was 38%, the 12-month OS rate was 40%, and the median OS was 8 months
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A retrospective study published in the journal BLOOD in 2022 showed that after using third-generation TKIs in patients with T315I mutation or relapsed/refractory Ph+ ALL, the CR/CRi rate reached 89.
5%, the MRD-negative rate was 73.
7%, the MMR rate was 57.
9%, and the CMR rate was 89.
5%.
The rate was 42.
1%; there were no special treatment-related adverse events
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In 2021, the American Society of Clinical Oncology (ASCO) announced the preliminary results of a third-generation TKI combined with belintuzumab in the treatment of newly diagnosed or relapsed/refractory Ph+ ALL patients.
The final follow-up was 14 months, and the CMR rate was as high as 86%.
The 1-year OS rate was 94%
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Professor Wei Xudong said that the results of this study bring very promising treatment options for elderly or unfit Ph+ ALL patients
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Professor Wei Xudong finally summarized the content of this part as shown in Figure 3
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Figure 3 The third-generation TKI approved in China - Orebatinib Orebatinib is the first third-generation TKI approved in China.
It effectively inhibits wild-type and multiple mutant types of BCR-ABL proteins including the T315I resistance mutation
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The IC50 concentration of orebatinib was lower, and its inhibitory intensity against the T315I mutation was higher
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Professor Wei Xudong said that at the 63rd American Society of Hematology, the poster presented the ongoing Phase 1b bridging study of orabatinib in refractory chronic myeloid leukemia and Ph+ ALL, which is expected to end in 2024 On January 31, 2010; Professor Wei Xudong expressed his expectation for the research results of the experiment
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Summary Professor Wei Xudong finally concluded that with the application of first- and second-generation TKIs to Ph+ ALL patients, Ph+ ALL treatment has entered the era of TKI, but there are certain limitations in first- and second-generation TKIs
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Compared with first- and second-generation TKIs, third-generation TKIs can significantly improve the remission rate and survival rate, whether in newly diagnosed or relapsed/refractory Ph+ ALL patients, and bring more promising treatment options to patients
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Prof.
Wei Xudong Director of Hematology Department, Henan Cancer Hospital (Affiliated Cancer Hospital of Zhengzhou University), second-level professor and doctoral supervisor Member of the Hematologist Branch of the Chinese Medical Doctor Association Member of the Standing Committee of the Hematology and Oncology Professional Committee of the China Anti-Cancer Association Vice Chairman of the Leukemia Branch of the Chinese Medical Education Association Member of the Standing Committee of the Leukemia Alliance of the Chinese Clinical Oncology Association, Member of the Standing Committee of the Hematology and Immunology Professional Committee of the Chinese Association of Immunology, Member of the Leukemia and Lymphoma Group of the Hematology Branch of the Chinese Medical Association / Corresponding author published 100 papers in the "Traditional" Chinese brand magazine, hosted two general projects of the National Natural Science Foundation of China, established the "Dan Baisha" program for the treatment of acute myeloid leukemia Review: Quinta Typesetting: Quinta Execution: Quinta pokes "read the original text" , we progress together