2022 ASH Review| Professor Liang Yang: CBF-AML with different molecular characteristics has different prognosis, and treatment regimens containing TKI may be effectively reversed

Sorafenib is a first-generation type II multi-target tyrosine kinase inhibitor (TKI) that inhibits various signaling pathways associated with AML development, such as RTK (FLT3, c-KIT).

The objective of this study was to assess the safety and efficacy
of sorafenib in combination with chemotherapy in newly diagnosed adult patients with CBF-AML.

Patients were randomized (1:1) to control (chemotherapy alone) or sorafenib (sorafenib plus chemotherapy).

Patients in the control group received 1 cycle of idabicin (days 1-3, 12 mg/m2) + cytarabine (days 1-7, 100 mg/m2) induction therapy, followed by 1 cycle of idabicin (days 1-3, 8 mg/m2) + cytarabine (days 1-3, q12h, 2g/^m2).
) and 2 cycles of high-dose cytarabine (days 1-3, q12h, 2 g/^m2) consolidation therapy
.
Patients in the sorafenib group received chemotherapy at the same time as sorafenib therapy induction therapy (induction cycle 7-21 days, 400 mg twice daily) and consolidation therapy (400 mg twice daily on days 1-21 of each consolidation therapy cycle) for 12 months
.
After 4 treatment cycles, allogeneic or autologous hematopoietic stem cell transplantation (HSCT) was performed based on measurable residual disease (MRD)
levels and donor availability.
The researchers used real-time quantitative polymerase chain reaction to continuously monitor MRD levels of RUNX1-RUNX1T1 and CBFB-MYH11 transcripts with an expression of (fusion gene/ABL1) × 100 transcript ratio
.
Major molecular responses (MMR) and complete molecular responses (CMR) are defined as transcript ratios < 0.
1% and 0.
001%,<b110> respectively.
The primary endpoint was CMR
of bone marrow (BM) after 4 cycles of treatment.

Between January 2020 and March 2022, a total of 64 patients were enrolled and randomized to control (n=32) or sorafenib (n=32).

There were no significant differences
in age, sex, CBF subtype, percentage of BM blasts, additional chromosomal abnormalities at diagnosis, and gene mutations between the two groups.
The hematologic complete response rates of patients in the sorafenib group and the control group were 96.
9% and 94.
1%, respectively (P=0.
592).

After three treatment cycles, the proportion of patients who achieved MMR in the sorafenib group and the control group were 79.
3% and 46.
9%, respectively (P=0.
009), and the proportion of patients who achieved CMR in the sorafenib group was significantly higher than that in the control group (62.
1% vs 28.
1%, P=0.
009).

After 4 treatment cycles, the MMR increased to 100% in the sorafenib group and 70.
8% in the control group (P=0.
019); Moreover, the proportion of CMR in the sorafenib group was also higher than that in the control group (90.
9% vs 54.
2%, P=0.
006).

There was no significant difference
in the incidence of grade 3 to 4 adverse events between the two groups.
Grade 4 neutropenia (less than 0.
5×10 9/L) and thrombocytopenia (less than 20×10⁹/L)
were observed in all cases.
The median duration of neutropenia was 12 days (range, 6-25 days) in the sorafenib group and 10 days in the control group (range, 5-22 days, P=0.
63); The median duration of thrombocytopenia in the two groups was 12 days (range, 5-33 days) and 9 days (range, 6-19 days, P=0.
52),
respectively.
The most common grade 3 to 4 non-hematologic adverse events in the sorafenib and control groups were pneumonia (31.
3% vs 57.
4%, P=0.
019), mucositis (21.
9 vs 24.
1%, P=0.
816), and bloodstream infection (37.
5% vs 31.
5%, P=0.
568).

After 4 cycles of sorafenib plus chemotherapy, the proportion of patients achieving CMR increased significantly, and the incidence of hematologic and non-hematologic adverse events did not increase
significantly.
The effect of sorafenib in combination with chemotherapy on relapse and survival in patients with CBF-AML needs further follow-up
.

In the newly published 5th edition of WHO classification of myeloid tumors and ICC international consensus published in 2022, CBF-AML is listed as a separate leukemia subtype
。 In the European Leukemia Collaborative Group ELN2017 classification, CBF-AML was considered to be the type with a better prognosis, but validation in different ethnic populations was not fully reported, and limited studies in Asian populations showed that t(8; 21)(q22; q22)-AML has the characteristics of easy remission but more likely to recur, but it is the same as CBF-AML t(16; 16)(p13.
1; q22)-Whether the clinical outcomes of AML are the same deserves further study
.
The above two reports in this ASH meeting have clarified that under standard chemotherapy, t(16; 16)(p13.
1; q22)-AML had better clinical outcomes than t(8; 21)(q22; Q22)-AML trend, clinical prognosis determination, high leukocytes at diagnosis, KIT mutation as a poor prognostic parameter
of CBF-AML.
Therapeutically, because CBF-AML may have the characteristics of overactivation of the tyrosine kinase pathway, prospective use of sorafenib brings deeper remission within a limited follow-up time, although the long-term efficacy needs to be further observed and confirmed, this important finding provides a very clinical reference for
the diagnosis and treatment of CBF-AML.
It is recommended that the sample be expanded and a phase III randomized controlled study confirmed by the above results
.

Professor Liang Yang

• Director of the Department of Hematology and Oncology, Sun Yat-sen University Cancer Hospital, researcher and doctoral supervisor
• Leader of the research group of the State Key Laboratory of Oncology in South China
• Member of the Plasma Cell Disease Group of the Hematology Branch of the Chinese Medical Association
• Member of the Chinese and Western Integrative Medicine Group of the Hematology Branch of the Chinese Medical Association
• Member of the MDS Academic Working Committee of the First Committee of the Hematology Branch of the Chinese Geriatrics Society
• Member of the Standing Committee of Hematologist Branch of Guangdong Medical Association
• Deputy leader of Guangdong Slow Leaching Working Group
• Guangdong Province high-level introduction of talents, Pearl River Talent Program, Sun Yat-sen University "Hundred Talents Program" scholars
• Ph.
  D.
  of Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University, postdoctoral fellow in the Department of Hematology, Yale Cancer Center, specializing in the pathogenesis and targeted therapy of hematological tumors
• He has presided over and participated in a number of National Natural Science Foundation of China and provincial and ministerial projects, published a number of clinical and scientific research articles in high-level peer-reviewed professional journals such as Nature Reviews Disease Primers, Cancer Cell, etc.
  , with a cumulative citation of more than 2300 times, and is a reviewer for high-level international journals such as Leukemia, Journa of ImmunoTherapy of Cancer, eLife, etc

1.
Jonathan Hyak, Deedra Nicolet, Jessica Kohlschmidt, et al.
Characterization of Survival Outcomes and Clinical and Molecular Modulators in Adult Patients with Core-Binding Factor Acute Myeloid Leukemia (CBF-AML) Treated with Hidac Consolidation: An Alliance Legacy Study.
2022 ASH.
Abstract#536.

2.
Pengcheng Shi, Xi Jia, Naying Liao, et al.
Prospective Evaluation of Sorafenib Combined with Chemotherapy in Newly Diagnosed Adult Core-Binding Factor Acute Myeloid Leukemia: An Open-Label, Randomized Controlled, Multicenter Phase II Trial.
2022 ASH.
Abstract#830.