2021 SOHO Big Coffee Commentary | Professor Liu Jiajun's interpretation of the real-world study of the treatment of AML patients with Venecla regimen

Currently, the treatment of acute myeloid leukemia (AML) remains a challenge, especially in elderly patients
.

Venecla is a potent and selective oral BCL-2 inhibitor.
Its single agent is active in both relapsed/refractory (R/R) and newly diagnosed AML patients
.

However, the effectiveness and safety of the Venecla combined regimen in the real world are still unclear
.

At this year's SOHO meeting, Italian researchers reported a single-center experience of Venecla monotherapy or its combination therapy for AML patients who are not suitable for standard induction therapy
.

Yimaitong specially invited Professor Liu Jiajun from the Department of Hematology, the Third Affiliated Hospital of Sun Yat-sen University to comment on this
.

Research methods and research results The study conducted a retrospective analysis of 39 patients with untreated (n=13) or R/R (n=26) AML, and these patients received veneclax monotherapy (n=4).
, Venecla + azacitidine therapy (n=31), Venecla + decitabine therapy (n=3) or Venecla + low-dose cytarabine therapy (n=1), median The age was 71 years (67% of patients were >65 years old)
.

Most patients present a moderate genetic risk
.

Sixteen patients (41%) received treatment with venacola at ≥2 line salvage treatment, and 7 patients (18%) had previously received allogeneic hematopoietic stem cell transplantation
.

The dose of venacola is 400 mg per day (n=22).
In the case of combined use with CYP3A4 inhibitors, the dose is reduced to 200 mg (n=9) or 100 mg (n=8)
.

The most common grade 3 or 4 toxicities are hematological events (49%) or infections (51%)
.

Nineteen patients (49%) achieved complete remission, and the median time to remission was 1 month
.

The 6-month overall survival (OS) rates of patients in the initial treatment group and R/R group were 92% and 45% (p=0.
0186), respectively, and there was no difference between the different genetic risk groups
.

The median disease-free survival is 5 months
.

Regardless of the disease status at the start of treatment, the estimated 6-month OS rate for patients who achieved remission was significantly higher (p<0.
0001)
.

Seven patients underwent allogeneic hematopoietic stem cell transplantation as a consolidation treatment after treatment with the Venecla combined regimen
.

Research conclusions This real-world data confirms that for AML patients who are not suitable for intensive chemotherapy in the first-line and salvage treatment, the Veneclax-containing regimen is a feasible and safe treatment option
.

In addition, the combination of Venecla and demethylating drugs (HMA) has proven to be a viable bridging option for transplantation in elderly patients with AML
.

Experts comment that Venecla is the world's first BCL-2 inhibitor.
It can directly inhibit the BCL-2 anti-apoptotic protein and initiate tumor cell apoptosis without being limited to gene mutations
.

In 2018, the U.
S.
FDA accelerated the approval of the indication for AML with Venecla[2].
In December 2020, the indication for AML with Venecla was approved in China, bringing first-line treatment to AML patients who are not suitable for strong induction chemotherapy in China.
As a new option, Vinekala also has indications for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) worldwide, bringing more options for the treatment of hematological tumor patients[2,3]
.

For patients with Unfit AML, because they cannot receive strong induction chemotherapy, the survival time of these patients is short, the remission rate is low, and the quality of life is poor.
Using previous low-intensity chemotherapy or HMA treatment, the effect is not satisfactory and the prognosis is Poor, the patient's treatment needs have not been met
.

The above-mentioned real-world studies confirmed that the treatment regimen containing venacola is not a feasible and safe treatment option for AML patients with intensive chemotherapy, and the combination of venacola and HMA is also an option for bridging transplantation, which is consistent with the results of previous studies
.

The Viale-A study is a randomized, double-blind, placebo-controlled global phase III clinical study of Venecla, which compares the combination of Venecla with azacitidine and azacitidine alone.
It is not suitable for first-line treatment The effectiveness and safety of intensive chemotherapy for AML patients.
The results of the study showed that compared with the control group, the combination of Venecla and azacitidine increased the median survival of AML patients by 50% (14.
7 months vs.
9.
6 months).
), the combined complete remission rate of Venecla combined with azacitidine reached 66.
4%, which was significantly higher than that of the azacitidine single-agent group by 28.
3%.
The remission rate of minimal residual disease (MRD) increased by nearly three times.
In the azacitidine group, the median time to achieve the first composite complete remission was 1.
3 months, and the duration of remission was 17.
5 months [4], which not only brought longer survival time for patients, but also deeper and faster , More lasting relief
.

For patients with relapsed and refractory Unfit AML, the abstract S139 published on the 2021 EHA reported a new combination regimen (FLAVIDA: venacral, fludarabine, cytarabine, idarubicin) in R/ Efficacy and safety in R AML patients, the study included a total of 30 R/R AML patients who received at least one course of FLAVIDA regimen.
The median age was 54 years (range: 19-70).
FLAVIDA combined regimen was used to treat R/R AML.
The ORR of R AML was 73% (22/30), and 18 patients (60%) achieved CR/CRi
.

4 patients who achieved bone marrow-free leukemia status underwent alloHCT before blood count recovery, and subsequently reached CR
.

Among the 17 patients whose MRD status can be assessed, 8 patients reached MRD negative
.

The patient's median OS was 12 months, and the median EFS was 9 months
.

The median RFS of patients who achieved CR/CRi did not reach [5]
.

Regarding AML transplantation bridging, EBMT announced a study in 2021 to explore the efficacy and safety of Veneclax combined with HMA in the treatment of newly-treated AML and R/R AML, and to evaluate the role of this program in bridging transplantation
.

The study included 24 patients, with a median age of 69 years (range: 27-80 years), 14 patients (60%) had newly-treated AML or had poor/complex cytogenetic characteristics, and 10 patients (40%) Suffer from R/R AML
.

The study included patients who received 400 mg of Veneclair per day, of which 15 patients (63%) received Decitabine 20 mg/m2 on days 1-5 of each treatment cycle (28-day cycle), and 9 patients (37%) Patients receive azacitidine 75mg/m2 on days 1-7 of each treatment cycle
.

A median of the patients in the study received 3 cycles (range: 1-19) of Venecla combined with HMA
.

The results of the study showed that after a median of 3 cycles of Venecla and HMA treatment, 9 patients (6 R/R AML, 3 naïve AML) received allogeneic hematopoietic stem cell transplantation (6 haplotypes) , 1 case of matched related donors, 2 cases of MUD)
.

[6] After treatment with the combination regimen of Veneclair and HMA, nearly half of the patients have received transplantation, which is an ideal regimen for AML bridging transplantation
.

In the clinical application of Venecla, the combination of Venecla and azacitidine has good safety.
Common adverse reactions mainly include hematological toxicity and gastrointestinal reactions, except that the incidence of neutropenic fever is slightly higher.
Except for azacitidine alone, there is no statistical difference[7].
For patients with a markedly decreased blood picture, it can be managed by shortening the treatment days of a single course of treatment (from 28 days to 21 days), if the blood picture is still not recovering well , The treatment cycle can also be appropriately delayed [8], and the gastrointestinal reaction can be treated symptomatically
.

Professor Liu Jiajun, Chief Physician, Doctoral Supervisor, Director of the Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University, Member of the Anti-Cancer Branch of the European Tumor Association Member of the Chinese Immunization Association Member of the Standing Committee of the Guangdong Medical Industry Association Member of the Guangdong Society of Hematology, etc.
Main research direction: Leukemia cell apoptosis Research on the mechanism of signal transduction, hematopoietic stem cell transplantation, molecular targeted therapy of hematological tumors, gene therapy and new anti-tumor drugs
.

Medical expertise: More than 20 years of clinical medical work in internal medicine and hematology
.

For many years, he has been engaged in the research of leukemia cell apoptosis signal transduction mechanism and molecular targeted therapy of hematological tumors
.

Proficient in diagnosis and treatment of various anemias, bleeding diseases and hematological tumors
.

Diagnosis and treatment of diseases including hematopoietic stem cell transplantation for blood diseases, chemotherapy for leukemia, malignant lymphoma and multiple myeloma and other individualized treatment options for malignant hematological diseases, various unexplained anemia, unexplained long-term fever, and differential diagnosis of lymphadenopathy and treatment
.

References: [1]Giusy Ceparano, et al.
2021 SOHO.
AML-272.
[2]https:// :// CD, et al.
N Engl J Med.
2020 Aug 13;383(7):617-629[5]Rabia Shahswar, et al.
2021 EHA.
S139.
[6]V.
Federico, M.
Dargenio, R.
Matera, et al.
Venetoclaxcombined with hypomethylating agent(HMA) is safe and effective may be a goodbridge to transplant in high-risk acute myeloid leukemia.
The 47th Annual Meetingof the EBMT.
Abstract OS17-5.
[7]DiNardo CD, et al.
N Engl J Med.
2020 Aug 13;383(7):617-629.
[8]Venecla Film Chinese Manual.
Stamp" to read Original ", we make progress together