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Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

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ClinicalTrials.gov Identifier: NCT00504764
Recruitment Status : Completed
First Posted : July 20, 2007
Last Update Posted : October 28, 2014
Information provided by (Responsible Party):

Study Description
Brief Summary:

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

Condition or disease Intervention/treatment Phase
Acute Promyelocytic Leukemia Drug: Arsenic Trioxide Procedure: Autologous Transplantation Procedure: Allogenic Transplantation Drug: ATRA Phase 4

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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 Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: APL-R2007: Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
Study Start Date : July 2007
Primary Completion Date : October 2014
Study Completion Date : October 2014

Arms and Interventions

Intervention Details:
    Drug: Arsenic Trioxide

    Induction ATO 0.15 mg/kg/day IV until CR or a maximum of 60 days In isolated molecular relapse ATO will be administered at same dose, 5 days a week, during 6 weeks.

    Consolidation ATO 0.15 mg/kg/day IV 5 days week, during 5 weeks

    Procedure: Autologous Transplantation
    Autologous Transplantation
    Procedure: Allogenic Transplantation
    Allogenic Transplantation
    Drug: ATRA
    Consolidation: ATRA 45 mg/m²/day oral during 5 weeks

Outcome Measures

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

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

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 )
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00504764

  Show 85 Study Locations
Sponsors and Collaborators
PETHEMA Foundation
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 de Valencia
More Information

Additional Information:
Responsible Party: PETHEMA Foundation
ClinicalTrials.gov Identifier: NCT00504764     History of Changes
Other Study ID Numbers: LAP-R2007
First Posted: July 20, 2007    Key Record Dates
Last Update Posted: October 28, 2014
Last Verified: October 2014

Keywords provided by PETHEMA Foundation:
Relapsed Acute Promyelocytic Leukemia
Arsenic Trioxide

Additional relevant MeSH terms:
Leukemia, Promyelocytic, Acute
Neoplasms by Histologic Type
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Arsenic trioxide
Antineoplastic Agents