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The patients in this arm will receive SCCLG-M5 2022 regimen for newly dignosed acute monocytic leukemia (M5) ,including two courses of CLAG(cladribine, darubicin and cytarabine) in the induction period and followed by three courses(HA1M, HA2E, HA3) in consolidation therapy prescribed as the NOPHO-AML 2004 protocol.

The targeted drugs sorafenib 200mg/m2/day orally is used for FLT3 positive acute monocytic leukemia until molecular biology remission for 2 years.

5mg/㎡/day d1-5 in 2 hours, before the use of Cytarabine

5ug/kg/day d0-5,if Peripheral blood leukocytes\<20,000/ul

G-CSF

2g/㎡/day d1-5 in 4 hours, after the use of Cladribine

Idarubicin 10mg/m2/day or mitoxantrone 10mg/m2/day on day 1-3 in the induction therapy II

200mg/m2/day was taken orally until molecular biology remission for 2 years

dunhua zhou, M.D

riling chen, M.D

lina wang, M.D

yawei zhou, M.D

huiqin chen, M.D

lihua yang, M.D

beiyan wu, M.D

wuqing wan

changda liang, M.D

qiwen chen, M.D

dunha zhou, M.D

This is a multicenter, single arm, prospective, intervention trial. Since cladribine can enhance the biological activity and self-protection of cytarabine, giving cladribine and cytarabine together may kill more cancer cells. 10 centers from South China Childhood Leukaemia Collaborative Group carry out the SCCLG-M5-2022 regimen including two courses of CLAG(cladribine, darubicin and cytarabine) in the induction period for the treatment of newly dignosed acute monocytic leukemia (M5). The targeted drugs sorafenib is used for FLT3 positive acute monocytic leukemia to inhibit the serine / threonine kinase activity of FLT3.

PRIMARY OBJECTIVES

1.To study the 3 year-overall survival of newly diagnosed monocytic leukemia treated with Cladribine and cytarabine in children.

SECONDARY OBJECTIVES

1. To describe the complete response rate following CLAG (cladribine, cytarabine and granulocyte stimulating factor) in newly diagnosed monocytic leukemia in children for intensive induction therapy.
2. To evaluate the 3-year progression-free survival in response to CLAG in children.
3. To assess the toxicity of CLAG including cumulative infection incidence, cumulative adverse effects and chemotherapy-related mortality (TRD).
4. To study the progression-free survival and overall survival (1 year, 2 year and 3 year) of newly diagnosed monocytic leukemia with positive FLT3 treated with CLAG in children and the side effects of sorafenib.

OUTLINE:

1. The induction phase includes two parts including induction therapy I(CLAG) and induction therpay II(CLAG+I/M).
2. The diagnosis and classified criteria is according to the 2016 WHO classification criteria for hematopoietic and lymphoid tissue tumors, and the consolidation therapy consists the therapeutic phases as the NOPHO-AML 2004 protocol prescribed.

   INDUCTION THERAPY I: Patients receive cladribine intravenously (IV) at a dose of 5mg/m2/day combined with cytarabine 2g/m2/day on day 1-5 and granulocyte stimulating factor 5ug/kg/day on day 0-6. When blood count recover(WBC\>2.0×109/L， ANC1.0×109/L、PLT≥50×109/L) , Patients achieving a morphological leukemia free state (\< 5% blasts) or MRD\< 1% receive a second course treatment as above.

   INDUCTION THERPAY II: Patients receive cladribine intravenously (IV) at a dose of 5mg/m2/day combined with cytarabine 2g/m2/day on day 1-5, mitoxantrone/idarubicin 10mg/m2/day on day 1-3 and granulocyte stimulating factor 5ug/kg/day on day 0-6. Patients achieving blast count≥5% or MRD ≥1% proceed to induction II therpy.
3. For FLT3 positive acute monocytic leukemia children, sorafenib 200mg/m2/day was taken orally until molecular biology remission for 2 years.
4. After two courses of indution phase, patients with incomplete response（MRD≥0.1%）are recommended into hematopoietic stem cell transplantation.
5. After two courses of indution phase, patients with persisting positive adverse prognosis cytogenetic abnormalities are recommended into hematopoietic stem cell transplantation.

Patients must meet one of the following risk criteria:

Standard-risk (SR) group meeting all of the following criteria:

Initial WBC \< 10,000/μL

M1 (\<5%) blasts or MRD\<1% in bone marrow after the first course of induction therapy

M1 (\<5%) blasts or MRD\<0.1% in bone marrow after two courses of induction therapy

Cytogenetic abnormalities with good prognosis

Intermediate-risk (IR) group meeting the following criteria:

Lack of low-risk and high-risk conditions

High-risk (HR) group meeting ≥ 1 of the following criteria:

M2/M3(≥5%) blasts or MRD\>5% in bone marrow after the first course of induction therapy

MRD≥0.1% in bone marrow after two course of induction therapy

Cytogenetic abnormalities with poor prognosis

Treateament of Newly Diagnosed Acute Monocytic Leukemia in Children

Treateament of Newly Diagnosed Acute Monocytic Leukemia in Children： A Prospective Multicenter Study in South China

TOS was defined as time from diagnostic date through the date of death due to any reasons. For all other participants, the last follow-up available was taken as the last control. If the participant had not completed the study, the date of the last visit available was considered.

According to the time point specified in the treatment plan (22 days after the end of induction I, 29-43 days after the end of induction II and before each consolidation scheme) bone marrow puncture and lumbar puncture were performed. The follow-up contents included the detection of the count of primitive / immature lymphocytes and flow MRD. If there was a positive gene at the onset, the quantitative monitoring of the gene should be performed as MRD data at the same time. If the gene cannot be analyzed quantitatively, PCR qualitative analysis should still be performed as the monitoring basis

During treatment, closely monitor relevant laboratory tests, register adverse reaction records, and report the records according to the requirements of CRF form.

EFS was estimated from date of diagnosis until date of one of the following events: relapse, refractory disease, second malignancy or death from any reason.

Third Affiliated Hospital, Sun Yat-Sen University

Maternal and Child Health Hospital of Foshan

The First Affiliated Hospital of Guangzhou Medical University

Second Xiangya Hospital of Central South University

Jiangxi Province Children's Hospital

Southern Medical University, China

The First Affiliated Hospital of Nanchang University

Guangzhou First People's Hospital

First Affiliated Hospital of Shantou University Medical College

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Venetoclax

Azacitidine

Chidamide 10mg orally daily for 7 days (d1-d7), AZA 75mg/m2 daily for 7 days (d1-d7) and VEN orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28); If the bone marrow assessment is CR/CRi/MLFS/PR/NR on the 21th-28th day in the first cycle, the second cycle of treatment will be started; If the bone marrow assessment is PR/NR, the patient needs to withdraw from the trial, If the bone marrow assessment is CR/CRi/MLFS, the patient will start post-remission therapy. For post-remission therapy, if the patients ineligible for intensive chemotherapy, continue with the same regimen until progression or recurrence of the disease, and the patients need to withdraw from the trial. If the patients were fit for intensive chemotherapy, patients will receive consolidation chemotherapy with other regimens or transplantation, and the patients needs to withdraw from the trial if progression or recurrence of the disease.

AZA 75mg/m2 daily for 7 days (d1-d7) and VEN orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28); If the bone marrow assessment is CR/CRi/MLFS/PR/NR on the 21th-28th day in the first cycle, the second cycle of treatment will be started; If the bone marrow assessment is still PR/NR, the patient needs to enter VEN+AZA+Chidamide group. If the bone marrow assessment is CR/CRi/MLFS, the patient will start post-remission therapy. For post-remission therapy, if the patients ineligible for intensive chemotherapy, continue with the same regimen until progression or recurrence of the disease, and the patient needs to withdraw from the trial. If the patients fit for intensive chemotherapy, patients will receive consolidation chemotherapy with other regimens or transplantation, and the patient needs to withdraw from the trial if progression or recurrence of the disease.

Chidamide 10mg orally daily for 7 days (d1-d7)

Chidamide

azacytidine 75mg/m2 daily for 7 days (d1-d7)

Venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28)

Sheng-Li Xue, M. D.

Sheng-Li Xue, M.D.

This study is to investigate the therapeutic efficacy and side effect of venetoclax, azacytidine combined with chidamide for newly diagnosed acute monocytic leukemia patients that are ineligible for intensive chemotherapy

Acute myeloid leukemia (AML) is one of the most aggressive blood cancers, with a very low survival rate and few options for patients who are unable to undergo intensive chemotherapy. Venetoclax in combination with hypomethylation agents or cytarabine has been approved by the Food and Drug Administration (FDA) for the treatment of patients with newly diagnosed AML unfit for intensive chemotherapy. However, resistance to venetoclax can be acquired through the upregulation of anti-apoptotic proteins in the BCL2 family, such as myeloid cell leukaemia 1 (MCL1). MCL1 plays a critical role in cell apoptosis regulation and high expression of MCL1 is observed in acute monocytic leukemia (AML-M5) . Chidamide, a newly designed selective histone deacetylase inhibitor, resulted in a decrease in the protein level of MCL1. This study is to investigate the therapeutic efficacy and side effect of venetoclax, azacytidine combined with chidamide for newly diagnosed AML-M5 patients that are ineligible for intensive chemotherapy.

Venetoclax and Azacitidine Combined With Chidamide (VAC) for the Treatment of Newly Diagnosed Acute Monocytic Leukemia

A Multicenter, Randomized, Controlled Clinical Trial of Venetoclax, Azacytidine Combined With Chidamide for the Treatment of Newly Diagnosed Acute Monocytic Leukemia Patients That Are Ineligible for Intensive Chemotherapy

The composite complete remission rate(complete remission plus complete remission with incomplete blood cell count recovery)

The overall response (completed remission without minimal residual disease, completed remission with incomplete blood count recovery, morphologic leukemia-free state and partial remission)

It is measured the time from initial response to subsequent disease progression or relapse

It is measured from the time of entry into this trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive

It is measured from the time from randomization to progression or death

Record of adverse events in hematological system during and after VEN+AZA+Chidamide regimen induction (agranulocytosis days, PLT/RBC transfusion units)

Record of adverse events in other organs or systmes during and after VEN+AZA+Chidamide regimen induction (infection and organ injury)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Treateament of Newly Diagnosed Acute Monocytic Leukemia in Children	NCT05313958	Leukemia, Monoc... Pediatric AML	Cladribine G-CSF Cytarabine Idarubicin Mitoxantrone Sorafenib	1 Month - 14 Years	Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Venetoclax and Azacitidine Combined With Chidamide (VAC) for the Treatment of Newly Diagnosed Acute Monocytic Leukemia	NCT05566054	Acute Monocytic... Newly Diagnosed	Chidamide Azacitidine Venetoclax	18 Years -	The First Affiliated Hospital of Soochow University
Treateament of Newly Diagnosed Acute Monocytic Leukemia in Children	NCT05313958	Leukemia, Monoc... Pediatric AML	Cladribine G-CSF Cytarabine Idarubicin Mitoxantrone Sorafenib	1 Month - 14 Years	Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Spots Global Cancer Trial Database for acute monocytic leukemia