Oral Arsenic With ATRA for Newly Diagnosed Patients With Acute Promyelocytic Leukemia

Official title

Combination of Oral Arsenic With ATRA and Minimal-Dose Chemotherapy for Newly Diagnosed Patients With Acute Promyelocytic Leukemia: a Study by the International Consortium on APL

Overview

It is a non-randomized, multicenter, prospective study, aiming to treat patients with newly diagnosed acute promyelocytic leukemia with a combination of oral arsenic and atra, with low dose chemotherapy for those with high-risk disease (white blood cell count above 10x10a9/L). The primary objective is to assess the 2-year overall survival (OS) in these patients, comparing with the historical control group of patients treated with ATRA/chemotherapy according to the IC-APL 2006 protocol.

Detailed description

This is a non-randomized, multicenter, prospective study aimed at treating patients with newly diagnosed acute promyelocytic leukemia (APL) using a combination of oral arsenic and ATRA. For patients classified as high-risk (white blood cell count \>10×10⁹/L), low-dose chemotherapy will be added. The primary objective is to evaluate the 2-year overall survival (OS) in these patients, comparing it to a historical control group treated with ATRA and chemotherapy according to the IC-APL 2006 protocol. Secondary objectives include: Comparing complete response rates, disease-free survival, cumulative incidence of relapse, and early mortality with those reported in the IC-APL 2006 study (historical controls), as well as with outcomes reported in developed countries; Comparing the cumulative incidence of myelodysplasia or secondary leukemia; Comparing the toxicity profile with historical data; Assessing the molecular remission rate after consolidation; Evaluating the reduction in PML/RARA transcript levels during treatment; Comparing the duration of patient hospitalization with historical results.

Interventions

• Drug Realgar-Indigo Naturalis Formulation
  Oral Arsenic (Realgar-Indigo Naturalis Formulation) plus ATRA for low-intermediate risk APL pts, combined with daunorubicin for high-risk during induction

Primary outcome measures

• Overall Survival [Time frame: 2 years]

Secondary outcome measures (8)

• Complete hematologic response rate after induction. [Time frame: 30 days]
• Early death rate during induction [Time frame: 30 days]
• Disease-free survival rate [Time frame: 2 years]
• Cumulative incidence of myelodysplasia and secondary leukemia [Time frame: 5 years]
• Cumulative incidence of relapse [Time frame: 2 years]
• Molecular remission rate after consolidation [Time frame: 150 days]
• PML/RARA transcript level during treatment [Time frame: Each 3 months]
• Days of hospitalization during treatment [Time frame: 180 days]

Eligibility criteria

Inclusion criteria

• Informed consent
• New diagnosis of APL by cytomorphology, confirmed for molecular analysis
• Age ≥18 and ≤75 years
• Serum total bilirubin ≤ 3.0 mg/dl (≤ 51 μmol/l)
• Serum creatinine ≤ 3.0 mg/dl (≤ 260 μmol/l)
• Women must meet at least one of the following criteria to be eligible for inclusion in the study: Postmenopausal (12 months of amenorrhea or 6 months of amenorrhea with serum FSH > 40 U/ml); After undergoing hysterectomy or bilateral oophorectomy; Continuous and correct use of a contraceptive method with a Pearl Index <1% (e.g., implants, oral contraceptives, intrauterine devices); Sexual abstinence; Vasectomy of sexual partner.

Exclusion criteria

• High-risk patients who are not eligible for chemotherapy according to the judgment of the treating physician;
• Age <18 or >75 years
• Other active malignancy at the time of study entry
• Lack of diagnostic confirmation at the genetic level
• Significant arrhythmias, ECG abnormalities, or neuropathy: Congenital long QT syndrome; History or presence of significant ventricular or atrial tachyarrhythmia; Clinically significant resting bradycardia (<50 beats per minute); QTc > 500 ms on ECG screening for both sexes; Right bundle branch block with left anterior hemiblock or bifascicular block
• High-risk patients with other cardiac contraindications for intensive chemotherapy (LVEF < 50%)
• Uncontrolled and potentially fatal infections
• Severe uncontrolled pulmonary or cardiac disease
• Severe hepatic or renal dysfunction
• Known HIV and/or hepatitis C infection
• Pregnant or breastfeeding women
• Allergy to the study drug or excipients in the study medication
• Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or the assessment of study outcomes
• Use of other investigational drugs at the time of enrollment or within 30 days before study entry.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 1 center

• Instituto do Cancer do Estado de Sao Paulo — São Paulo

Publications

• Silva WF, Kim HT, Undurraga MS, Navarro-Cabrera JR, Salinas V, Muxi P, Melo RAM, Gloria ABF, Pagnano KBB, Nunes EC, Bittencourt RI, Rojas N, Truyenque SMQ, Ayala-Lugo AI, Oliver AC, Figueiredo-Pontes LL, Traina F, Moreira F, Fagundes EM, Duarte BKL, Mora-Alferez AP, Ortiz P, Untama JL, Tallman MS, Ribeiro RC, Ganser A, Dillon RJ, Valk PJM, Sanz MA, Lowenberg B, Berliner N, Rego EM. Early death and PMID 39479861
• Koury LCA, Kim HT, Undurraga MS, Navarro-Cabrera JR, Salinas V, Muxi P, Melo RAM, Gloria AB, Pagnano K, Nunes EC, Bittencourt RI, Rojas N, Quintana S, Ayala-Lugo A, Oliver AC, Figueiredo-Pontes L, Traina F, Moreira F, Fagundes EM, Duarte BKL, Mora-Alferez AP, Ortiz P, Untama J, Tallman M, Ribeiro R, Ganser A, Dillon R, Valk PJM, Sanz M, Lowenberg B, Berliner N, Rego EM. Clinical networking results PMID 38805638
• Correa de Araujo Koury L, Ganser A, Berliner N, Rego EM. Treating acute promyelocytic leukaemia in Latin America: lessons from the International Consortium on Acute Leukaemia experience. Br J Haematol. 2017 Jun;177(6):979-983. doi: 10.1111/bjh.14589. Epub 2017 May 3. PMID 28466545
• Rego EM, Kim HT, Ruiz-Arguelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, Gutierrez-Aguirre H, Melo RA, Bittencourt R, Pasquini R, Pagnano K, Fagundes EM, Chauffaille Mde L, Chiattone CS, Martinez L, Meillon LA, Gomez-Almaguer D, Kwaan HC, Garces-Eisele J, Gallagher R, Niemeyer CM, Schrier SL, Tallman M, Grimwade D, Ganser A, Berliner N, Ribeiro RC, Lo-Coco F, Lowenberg B, Sanz MA. Improving ac PMID 23319575

Identifiers

NCT: NCT06982274 · 1483/2019

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗