Pediatric-inspired Regimen Combined With Venetoclax for Adolescent and Adult Patients With de Novo Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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The pediatric-inspired regimen has greatly improved the prognosis of adult patients with with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL), but relapse remains a great challenge. Venetoclax (Ven) is an oral, selective inhibitor of B-cell lymphoma 2 (Bcl-2). Although this drug is currently used primarily for acute myeloid leukemia, in vitro as well as small cohort studies suggest a effect in acute lymphoblastic leukemia. This study proposes to combine pediatric-inspired regimen with venetoclax for the treatment of adult patients with Ph- ALL, aiming to improve the MRD-negative complete remission rate measured by flow cytometry after induction and to reduce relapse, thus further improving patients overall survival.

Official Title
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Pediatric-inspired Regimen Combined With Venetoclax for Adolescent and Adult Patients With de Novo Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Conditions
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Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention / Treatment
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* Drug: Vincristine
* Drug: Daunorubicin
* Drug: Cyclophosphamide
* Drug: Pegaspargase
* Drug: Prednisone
* Drug: Cytarabine
* Drug: 6-mercaptopurine
* Drug: Dexamethasone
* Drug: Methotrexate
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: De novo and primary Ph/BCR-ABL1 negative acute lymphoblastic leukemia diagnosed by the bone marrow cytomorphology, immunophenotyping, cytogenetics and molecular biology according to WHO classification Age: 14 -60 years Male or female ECOG Performance Status 0-2 Adequate end organ function as defined by: Total bilirubin ≤ 1.5 x upper limit of normal（ULN）; serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) ≤ 2.5 x ULN or ≤5 x ULN if leukemic involvement of the liver is present; Creatinine ≤ 1.5 x ULN; Serum amylase and lipase ≤ 1.5 x ULN; Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related; normal electrolytes: Potassium ≥ LLN; Magnesium ≥ LLN; Phosphorus ≥ LLN; Cardiac color Doppler ultrasound ejection fraction ≥ 45%; Subject has provided written informed consent prior to any screening procedure Exclusion Criteria: Burkitt lymphoma/leukemia Acute Leukemia of Ambiguous Lineage Female patients who are pregnant or breast feeding Uncontrolled active serious infections that could, in the investigator's opinion, potentially interfere with the completion of treatment History of pancreatitis Poorly controlled diabetes, defined as glycosylated hemoglobin (HbA1c) values of >7.5%. Patients with preexisting, well-controlled diabetes are not excluded History of active gastrointestinal bleeding within the last 6 months History of arterial/venous thrombosis within the last 6 months Known HIV seropositivity Any serious psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pediatric-inspired Regimen Combined With Venetoclax<br>Induction therapy is administered as follows：Vincristine (VCR) 1.4 mg/m2 (maximum dose 2 mg) IV on D1,8,1,5,22; Daunorubicin (DNR) 30 mg/m2/day IV on D1-3; Cyclophosphamide (CTX) 1200 mg/m2 IV on D1,15; Pegaspargase 2500u/m2 IM on D5; Prednisone 1 mg/kg/d PO on D1-14, 0.5 mg/kg/d PO on D15-28; Venetoclax 100 mg PO on D6，200 mg on D7, 400mg on D8-14, All patients underwent bone marrow aspiration on day 14 during induction. Patients with bone marrow blasts ≥10% on day 14 of induction received 7 additional days of Venetoclax on day 15-22. Consolidation therapy is a combination of multi-drug pediatric-inspired regimen chemotherapy and Venetoclax. Maintenance therapy consisted of a monthly VMMP regimen (vincristine, mercaptopurine, methotrexate, prednisone) continuing until 3 years for male and 2.5 years for female patients. | Drug: Vincristine<br>* Anti-tumor alkaloids<br>Drug: Daunorubicin<br>* Anthracycline<br>Drug: Cyclophosphamide<br>* Alkylating agent<br>Drug: Pegaspargase<br>* Polyethylene glycol (PEG) conjugated to L-asparaginase<br>Drug: Prednisone<br>* Glucocorticoids<br>Drug: Cytarabine<br>* Pyrimidine antimetabolites<br>Drug: 6-mercaptopurine<br>* Cell cycle-specific antitumor drug<br>Drug: Dexamethasone<br>* Glucocorticoids<br>Drug: Methotrexate<br>* Antifolate antineoplastic drug<br>Drug: Venetoclax<br>* Selective inhibitor of B-cell lymphoma 2 (Bcl-2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD-negative complete remission rate measured by flow cytometry |  | After induction (4 week) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission (CR) rate |  | After 2 cycles of chemotherapy, an expected average of 3 months | 
| Overall survival (OS) | From the date of registration to the date of death resulting from any cause | Up to 5 years post-registration | 
| Relapse free survival (RFS) | From the date of complete remission(CR) until the date of documented relapse or death due to any cause or the last follow-up day | Up to 5 years post-registration | 
| Disease-free Survival (DFS) | From CR1 to relapse, death from any cause or last follow-up | Up to 5 years post-registration | 
| The rate of adverse events |  | An expected average of 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Philadelphia Chromosome-Negative, Acute Lymphoblastic Leukemia, Adolescent and Adult, Pediatric-inspired Regimen, Venetoclax