Adult Acute Lymphoblastic Leukemia Treated With Pediatric Regimen in Brazil (BRALLA)

Adult Acute Lymphoblastic Leukemia Treated With Pediatric Regimen in Brazil - a Prospective Collaborative Study

In this project, the investigators intend to start a prospective registry for patients with newly diagnosed Philadelphia-negative ALL from 16 years old and above in participating centers, provided that all patients will be treated with the same regimen (a pediatric regimen BFM-based incorporating peg-asparaginase). All diagnostic/follow-up (after induction and consolidation blocks) samples will be centrally biobanked at Instituto do Cancer do Estado de Sao Paulo. The main goal of this study is to examine whether the implementation of a pediatric protocol under a prospective registry can increase event-free survival (EFS) and overall survival (OS) of newly diagnosed patients in the participating centers.

Study Overview

• Status: Recruiting
• Conditions: Acute Lymphoid Leukemia; Chemotherapeutic Toxicity; Minimal Residual Disease; Gene Abnormality
• Intervention / Treatment: Drug: Prednisone; Drug: Vincristin; Drug: Daunorubicin; Drug: Peg-asparaginase; Drug: Intrathecal Suspension; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Doxorubicin

Detailed Description

Notably, pediatric regimens for adult acute lymphoblastic leukemia (ALL) have resulted in better long-term outcomes, especially in the Philadelphia-negative counterpart. These regimens are essentially based on higher cumulative doses of asparaginase and the use of less myelotoxic agents, applying allogeneic transplantation only for high-risk ALL subsets. Recent metanalysis encompassing 27 clinical trials demonstrated an improved prognosis when these regimens are adopted. In adults, incorporation of these regimens has been hampered by a perception of higher toxicity and a more complex design, especially with asparaginase. Remarkably, this drug might bring side effects not usually seen with other cancer drugs, such as thrombosis, liver, and pancreatic toxicities. In addition, the incorporation of minimal residual disease (MRD) monitoring throughout the treatment protocol in a scheduled and standardized manner is considered paramount in the contemporary ALL treatment. Treating adult patients with acute leukemia under prospective studies allows accurate data collection and positively impacts the disease prognosis, creating a cooperative scientific environment. In Brazil, few data are available on the clinical- laboratory characteristics of ALL in adults and their outcomes under a standardized treatment protocol. Few single-center reports point to a worse overall survival rate when compared to developed countries. There is great heterogeneity across the centers regarding the treatment regimens and genetic/MRD assessment. In this project, the investigators intend to start a prospective registry for patients with newly diagnosed Philadelphia-negative ALL from 16 years old and above in participating centers, provided that all patients will be treated with the same regimen (a pediatric regimen BFM-based incorporating peg-asparaginase). All diagnostic/follow-up (after induction and consolidation blocks) samples will be centrally biobanked at Instituto do Cancer do Estado de Sao Paulo. At the diagnosis, a genetic characterization encompassing conventional karyotype, fluorescent in-situ hybridization (FISH), and molecular biology in our central laboratory will be performed to classify the cases. Genomic classification will include identifying Philadelphia- like B-cell ALL cases, a recent group of cases with worse prognosis, whose incidence seems higher in Hispanics. In Brazil, there is no study addressing this incidence and, more importantly, evaluating its impact on outcomes under a standardized treatment protocol. MRD analysis will also be centralized to standardize and validate our flow cytometry panel in a homogeneous cohort. Additionally, the investigators plan to assess baseline factors predictive of survival and relapse and those related to major toxicities such as infections, liver toxicity, and thrombosis.

• Study Type: Observational
• Enrollment (Estimated): 180

Contacts and Locations

• Study Contact: Name: Graziela Silva; Phone Number: 551138934677; Email: graziela.sasilva@hc.fm.usp.br
• Study Contact Backup: Name: Bruna Moraes, MSc; Phone Number: 551126628112; Email: pesquisa.hematologia@hc.fm.usp.br

Study Locations

• Brazil
  • SP
    • São Paulo, SP, Brazil, 01246000
      • Recruiting
      • Instituto do Cancer do Estado de Sao Paulo
      • Contact: Wellington F Silva, MD PhD; Phone Number: 551138944677; Email: wellington.fernandes@hc.fm.usp.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All patients from 16 years and above newly diagnosed with Philadelphia-negative ALL and after the signature of informed consent form (ICF). Patients between 16 and 17 years-old will sign a child assent along with a parental consent form. ICF application might be performed even under ALL suspicion only, given the need for sample collection before any therapy, ideally.

Description

Inclusion Criteria: Patients between 16 and 50 years-old with newly diagnosed ALL, negative for Philadelphia chromosome not previously treated (except for hydroxyurea, corticosteroids, or intrathecal chemotherapy) with 20% or more lymphoblasts in bone marrow or peripheral blood.

Exclusion Criteria:

• Burkitt leukemia
• Prior myeloproliferative disease
• Philadelphia chromosome positivity through whichever methodology (RT-PCR, FISH, or conventional karyotype)
• ECOG>2 (appendix 3)
• Total bilirubin>2x upper limit of normal (ULN)
• Transaminases>5x ULN
• Creatinine>2,5 mg/dl
• Positive serology for HIV or HTLV
• Heart failure NYHA Class III or IV (appendix 4)
• Severe psychiatric disorder which prevents adequate compliance
• Prior treatment with intravenous chemotherapy
• Refusal to participate in the study
• Down syndrome

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Eligible patients; All patients deemed eligible to intensive protocol of treatment are going to be included as sole group. There is no intervention or control group in this trial.

Drug: Prednisone; 60 mg/m2 D1 to D21; Drug: Vincristin; 1.5 mg/m2 D1, D8, D15 and D22; Drug: Daunorubicin; 40 mg/m2 D1, D8, D15 and D22; Drug: Peg-asparaginase; 2000 UI/m2 D12 and D26; Drug: Intrathecal Suspension; MTX 12 mg, Dexamethasone 2 mg, Cytarabine 60 mg D1, D8, D15, D22, D29; Drug: Cyclophosphamide; 1000 mg/m2 D36 and D64; Drug: Cytarabine; 75 mg/m2 D36 to D39, D43 to D46, D50 to D53 and D57 to D60; Drug: Mercaptopurine; 30 mg/m2 D36 to D63 and D1 to D56 of consolidation; Drug: Methotrexate; 3.000 mg/m2 D8, D22, D36 and D50; Drug: Doxorubicin; 30 mg/m2 D1 and D22

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	cumulative proportion of patients alive (considering the time between the date of diagnosis and death or last follow-up)	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	time between enrollment in the study and the occurrence of any event: refractoriness after the first two cycles of induction, death or relapse.	4 years
Early death rate	proportion of patients who died before the first bone marrow evaluation of response (after induction I)	60 days
Complete response rate	proportion of patients with bone marrow aspirate with less than 5% blasts and evidence of normal hematopoiesis; CSF without blasts and recovery of peripheral blood (neutrophils≥ 1,000/μL and platelets≥100,000/μL), without the need for transfusion	60 days
Cumulative incidence of relapse	rate of disease relapse after CR calculated considering death as a competing event.	4 years
HSCT rate	proportion of patients eligible for the protocol who were able to perform the procedure in their first CR	2 years

Collaborators and Investigators

• Sponsor: Instituto do Cancer do Estado de São Paulo
• Collaborators: Servier
• Investigators: Principal Investigator: Wellington F Silva, MD PhD, Instituto do Cancer do Estado de Sao Paulo; Study Chair: Eduardo M Rego, MD PhD, Instituto do Cancer do Estado de Sao Paulo

Publications and helpful links

General Publications

• Silva WF, Amano MT, Perruso LL, Cordeiro MG, Kishimoto RK, de Medeiros Leal A, Nardinelli L, Bendit I, Velloso ED, Rego EM, Rocha V. Adult acute lymphoblastic leukemia in a resource-constrained setting: outcomes after expansion of genetic evaluation. Hematology. 2022 Dec;27(1):396-403. doi: 10.1080/16078454.2022.2052602.

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2023
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: July 17, 2023
• First Submitted That Met QC Criteria: July 17, 2023
• First Posted (Actual): July 25, 2023

Study Record Updates

• Last Update Posted (Actual): May 7, 2025
• Last Update Submitted That Met QC Criteria: May 3, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Neoplastic Processes; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia; Neoplasm, Residual; Leukemia, Lymphoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Antiviral Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Methotrexate; Prednisone; Cyclophosphamide; Cytarabine; Doxorubicin; Daunorubicin; Asparaginase; Pegaspargase; Mercaptopurine
• Other Study ID Numbers: 3011/22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No