Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

October 27, 2014 updated by: PETHEMA Foundation

APL-R2007: Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

Summary Acute promyelocytic leukemia is defined by a characteristic morphology (AML FAB M3/M3v), by the specific translocation t(15;17) and its molecular correlates (PML/RARa and RARa/PML). Thereby it can be separated from all other forms of acute leukemia.

By all-trans retinoic acid in combination with chemotherapy cure rates of 70 to 80% can be reached. On average, about 10% of patients still die in the early phase of the treatment and about 20 to 30% relapse. Molecular monitoring of the minimal residual disease (MRD) by qualitative nested RT-PCR and quantitative REAL-time PCR of PML/RARa allows to follow the individual kinetics of MRD and to identify patients with an imminent hematological relapse.

A standardized treatment for patients with relapsed APL has not yet been established. With arsenic trioxide (ATO) monotherapy remission rates over 80% were achieved and long-lasting molecular remissions are described. The drug was mostly well tolerated. ATO exerts a dose dependent dual effect on APL blasts, apoptosis in higher and partial differentiation in lower concentrations. ATO was also successfully administered before allogeneic and autologous transplantation. ATO is approved for the treatment of relapsed and refractory APL in Europe and in the USA.

After remission induction, there are several options for postremission therapy Previous studies shows that risk of relapse is higher in patients treated with ATO postremission in monotherapy , than in other that receive ATO plus chemotherapy or transplantation (TPH). Also, compared with chemotherapy, ATO induction and consolidation has a favorable impact in posterior response to transplantation. It is due to a low toxicity or a best quality of remission to TPH. It seems better, for these reasons, the intensification with TPH (autologous or allogenic) in patients with relapsed APL treated with ATO. For another hand, patients no candidates to TPH can be treated with ATO combined with other active agents in APL, as ATRA, anthracyclines o Mylotarg

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Induction ATO 0.15 mg/kg/día IV in continuous perfusion 1-2 hours/day until complete response (CR) or maximum of 60 days.

Oral hydroxyurea treatment (initial dose 2 g/day)is recommended in patients with leucocyte counts at relapse >10x109/L or in the two first weeks of induction.

Isolated molecular relapsed patients will be treated with ATO (same dose) 5 days at week, during 6 weeks.

Consolidation ATO 0.15 mg/kg/día IV 5 days at week, during 5 weeks, combined with oral ATRA 45 mg/m²/day during the same 5 weeks.

Post-consolidation therapy TPH (autologous or allogenic) in candidate patients. In case of molecular remission, is recommended autologous-TPH.

Patients no candidates to auto-TPH or alo-TPH, should will follow treatment with ATO cycles + ATRA +/- Mylotarg.

  1. Option Alo-TPH If PCR post-consolidation is negative is recommended auto-TPH. However, if alo-TPH is decided, it will be done immediately without preceding chemotherapy.

    If PCR post-consolidation is positive, should done alo-TPH.

  2. Option Auto-TPH If PCR post-consolidation is negative it will be administered one cycle of MTZ + Ara-C follow by auto-TPH.

    In cas of failure: a) if patient has autologous stem cells preserved (PCR negative) are suitable for auto-TPH; b) patients with HLA-compatible donor who are suitable for allogenic stem cell transplantation should be transplanted; c) Patients who are not eligible for allogenic or autologous transplantation, receive various cycles with ATO + ATRA combined or not with Mylotarg.

    If PCR post-consolidation is positive and patient is eligible for allogenic TPH, should be done a allogenic TPH.

    If patient is no eligible for allogenic TPH or dont has compatible donor, will be administrate one cycle of MTZ + Ara-C and collect stem cells. Autologous transplantation will be done if after this cycle, a molecular remission is obtained. No molecular remission or no enough stem cells collection, patient follows treatment with subsequent cycles of ATO + ATRA combined or no with Mylotarg.

  3. ATO + ATRA combined or no with Mylotarg Patients no eligible to autologous TPH or allogenic TPH follows treatment with subsequent cycles of ATO + ATRA combined or no with Mylotarg.

If Mylotarg is no possible, treatment will be with subsequent cycles of ATO + ATRA.

ATO + ATRA + Mylotarg: Mylotarg 6 mg/m2 day 1, ATO 0.15 mg/kg days 1 to 5 and 8 to 12, and ATRA 45 mg/m2/d days 1 to 15. Doses of mylotarg should be reduced to 3 mg/m2 in patients aged over 60 years. Administration of 3 cycles with a month interval, follow of 3 to 6 cycles of ATO + ATRA without Mylotarg. After, ATRA 45 mg/m2/d 15 days every 3 months until complete two years of maintenance.

ATO + ATRA: ATO 0.15 mg/kg days 1 to 5 and 8 to 12, and ATRA 45 mg/m2/d days 1 to 15, every 29 days. Administration of 9 cycles, and followed by ATRA 45 mg/m2/d during 15 days every 3 months until complete two years of maintenance.

Study Type

Interventional

Enrollment (Anticipated)

60

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Albacete, Spain
        • Complejo Hospitalario Universitario de Albacete
      • Alcorcón, Spain
        • Fundación Hospital Alcorcón
      • Alicante, Spain
        • Hospital General de Alicante
      • Alzira, Spain
        • Hospital de La Ribera
      • Avila, Spain
        • Hospital Ntra. Sra. Sonsoles
      • Barcelona, Spain
        • Hospital del Mar
      • Barcelona, Spain
        • Hospital de la Santa Creu i Sant Pau
      • Barcelona, Spain
        • Hospital Clínic
      • Barcelona, Spain
        • Hospital Valle Hebrón
      • Basurto, Spain
        • Basurtuko Ospitalea
      • Bilbao, Spain
        • Hospital de Cruces
      • Cáceres, Spain
        • Complejo Hospitalario de Caceres
      • Cádiz, Spain
        • Hospital Puerta del Mar
      • Córdoba, Spain
        • Complejo Hospitalario Reina Sofía
      • Donostia, Spain
        • Hospital Donostia
      • Elda, Spain
        • Hospital General de Elda
      • Fuenlabrada, Spain
        • Hospital De Fuenlabrada
      • Granada, Spain
        • Hospital Virgen de las Nieves
      • Guadalajara, Spain
        • Hospital General de Guadalajara
      • Huelva, Spain
        • Area Hospitalaria Juan Ramón Jimenez
      • Huesca, Spain
        • Hospital de San Jorge
      • Jaen, Spain
        • Hospital Médico Quirúrgico Ciudad de Jaén
      • Jerez de la Frontera, Spain
        • Hospital de Jerez de la Frontera
      • La Coruña, Spain
        • Hospital Juan Canalejo
      • Lanzarote, Spain
        • Hospital General de Lanzarote
      • Leon, Spain
        • Complejo Hospitalario León
      • Lleida, Spain
        • Hospital Arnau de Vilanova
      • Lugo, Spain
        • Complexo Hospitalario Xeral-Calde
      • Madrid, Spain
        • Hospital Clínico San Carlos de Madrid
      • Madrid, Spain
        • Hospital 12 de Octubre
      • Madrid, Spain
        • Fundacion Jimenez Diaz
      • Madrid, Spain
        • Hospital Doce de Octubre
      • Madrid, Spain
        • Hospital La Paz
      • Madrid, Spain
        • Hospital de La Princesa
      • Madrid, Spain
        • Clínica Puerta de Hierro
      • Madrid, Spain
        • HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARANON, MADRID
      • Madrid, Spain
        • Clínica Moncloa
      • Madrid, Spain
        • Clinica Ruber
      • Madrid, Spain
        • Hospital Central de la Defensa
      • Madrid, Spain
        • Clínica La Concepción
      • Manresa, Spain
        • Althaia, Xarxa Asistencial de Manresa
      • Martorell, Spain
        • Fundación Hospital Sant Joan de Déu de Martorell
      • Murcia, Spain
        • Hospital General Morales Meseguer
      • Málaga, Spain
        • . Hospital Clínico Universitario Virgen de la Victoria
      • Mérida, Spain
        • Hospital de Mérida
      • Móstoles, Spain
        • Hospital De Mostoles
      • Palencia, Spain
        • Hospital del Río Carrión
      • Palma de Gran Canaria, Spain
        • Hospital de Gran Canaria Doctor Negrin
      • Palma de Mallorca, Spain
        • Hospital Son Llatzer
      • Palma de Mallorca, Spain
        • Hospital Son Dureta
      • Palma de Mallorca, Spain
        • Hospital Verge del Toro
      • Pontevedra, Spain
        • Complejo Hospitalario de Pontevedra_Hospital Montecelo
      • Pontevedra, Spain
        • Complejo Hospitalario de Pontevedra_Hospital Provincial
      • Sabadell, Spain
        • Corporació Sanitària Parc Taulí
      • Sagunto, Spain
        • Hospital de Sagunto
      • Salamanca, Spain
        • Hospital Clinico De Salamanca
      • Sant Pere de Ribes, Spain
        • Clínica Sant Camil
      • Santander, Spain
        • Hospital Universitario Marqués de Valdecilla
      • Segovia, Spain
        • Hospital General de Segovia
      • Sevilla, Spain
        • H.U. Virgen del Rocio
      • Tarragona, Spain
        • Hospital Joan XXIII
      • Tenerife, Spain
        • Hospital Universitario de Canarias
      • Toledo, Spain
        • Hospital Nuestra Señora del Prado
      • Valencia, Spain
        • Fundacion Instituto Valenciano de Oncologia
      • Valencia, Spain
        • Hospital La Fe
      • Valencia, Spain
        • Hospital General Universitario
      • Valencia, Spain
        • Hospital Clínic
      • Valencia, Spain
        • Hospital Dr. Peset
      • Valencia, Spain
        • Hospital Francesc de Borja
      • Valladolid, Spain
        • Hospital Clínico de Valladolid
      • Valls, Spain
        • Hospital Comarcal Pius de Valls
      • Vigo, Spain
        • Complejo Hospitalario Xeral-Cies
      • Vinaros, Spain
        • Comarcal de Vinaros
      • Vitoria, Spain
        • Hospital Txagorritxu
      • Vizcaya, Spain
        • Hospital de Galdakao
      • Zaragoza, Spain
        • Hospital Miguel Servet
      • Zaragoza, Spain
        • Hospital Clinico Lozano Blesa
    • Asturias
      • Oviedo, Asturias, Spain
        • Hospital Central de Asturias
    • Barcelona
      • Badalona, Barcelona, Spain
        • Hospital Germans Trias i Pujol
      • Mataró, Barcelona, Spain
        • Hospital de Mataro
    • Castellón
      • Castello, Castellón, Spain
        • Hospital General de Castellon
    • La Coruña
      • Santiago de Compostela, La Coruña, Spain
        • Complejo Hospitalario Universitario de Santiago
    • Madrid
      • Alcorcón, Madrid, Spain
        • Hospital de Alcorcón
    • Navarra
      • Pamplona, Navarra, Spain
        • Clínica Universitaria de Navarra
    • Tarragona
      • Tortosa, Tarragona, Spain
        • Hospital Verge de la Cinta

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • ECOG ≤ 3.
  • Patients in first or subsequent hematological or molecular relapse of APL
  • Persistence of a positive PCR (positive PCR after 3 consolidation cycles of first line therapy).
  • Diagnostic measures Confirmation of relapse by RT-PCR of PML/RARa, cytogenetics, FISH or positive PGM3.
  • Age over 18 years (No upper age limit)
  • Informed consent of the patient

Exclusion Criteria:

  • ECOG 4.
  • Heart failure NYHA grade III and IV.
  • Renal or hepatic failure WHO grade ³III
  • Positive HIV.
  • Psychological dysfunction
  • Associated active neoplasia
  • Pregnancy.
  • Arsenic Hypersensibility.
  • QTc-interval prolonged over 460 msec before therapy (normal electrolytes, no other drugs prolonging the QT-interval )

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Evaluate the hematological and molecular remission rate after induction and consolidation with ATO
Time Frame: 1 year
1 year
Evaluate the induction mortality with ATO in monotherapy
Time Frame: 1 year
1 year
Evaluate the hematological and molecular relapse rate in patients treated with autologous transplantation, allogenic transplantation or ATO + ATRA +/- Mylotarg
Time Frame: 1 year
1 year

Secondary Outcome Measures

Outcome Measure
Time Frame
Overall survival
Time Frame: 2 years
2 years
Evaluate kinetics of the MDR of PML/RARa during and after ATO
Time Frame: 2 years
2 years
Evaluate the mortality related with postremission treatment
Time Frame: 1 year
1 year
Side effects of ATO and the different treatments post-consolidation
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

PETHEMA Foundation

Investigators

  • Study Chair: Sanz Miguel Angel, Dr, Hospital La Fe
  • Study Chair: Esteve Jordi, Dr, Hospital Clinic of Barcelona
  • Study Chair: Montesinos Pau, Dr, Hospital General Universitario de Valencia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2007

Primary Completion (ACTUAL)

October 1, 2014

Study Completion (ACTUAL)

October 1, 2014

Study Registration Dates

First Submitted

July 19, 2007

First Submitted That Met QC Criteria

July 19, 2007

First Posted (ESTIMATE)

July 20, 2007

Study Record Updates

Last Update Posted (ESTIMATE)

October 28, 2014

Last Update Submitted That Met QC Criteria

October 27, 2014

Last Verified

October 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LAP-R2007

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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