Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia

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Brief Title

Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia

Official Title

Molecular Remission With Arsenic Trioxide in Acute Promyelocytic Leukemia: Indian APL Study Group - IAPLSG

Brief Summary

      There is very limited data on the use of arsenic trioxide in newly diagnosed patients with
      acute promyelocytic leukemia. The use of arsenic trioxide was limited to relapsed patients
      mainly because of the superior efficacy of ATRA as primary therapy for newly diagnosed APML.
      Though the early study by Niu et al showed 72% remission rates in 11 newly diagnosed
      patients, the role of arsenic trioxide as primary therapy was limited by the hepatic toxicity
      seen in this study. Studies from our centre have shown remission rates of 70-75% in newly
      diagnosed patients with acute promyelocytic leukemia. There was no major toxicity seen
      related to the administration of arsenic trioxide. Follow up data on these patients continue
      to show long term remission rates above 70%. These remission rates are similar to the data
      available in patients with acute promyelocytic leukemia treated with ATRA. Lu et al studied
      19 patients treated with oral arsenic (Tetra-arsenic tetra-sulfide) wherein 84% achieved
      hematological remission with disease free survival of 76% at 3 years. Studies from other
      groups using arsenic trioxide alone or in combination with ATRA have shown similar remission
      rates. Arsenic trioxide as primary therapy for patients with newly diagnosed acute
      promyelocytic leukemia is a very attractive treatment option for developing countries mainly
      because of the low cost involved along with the favorable toxicity profile. However long term
      remission data is still not available and the ideal course and duration of treatment still
      needs to be defined. This multi-center study aims to further clarify the efficacy of this
      agent in the treatment of newly diagnosed cases of acute promyelocytic leukemia and to study
      the optimal maintenance regimen.
    

Detailed Description

      This multicenter trial will study the clinical and molecular response among patients with
      newly diagnosed acute promyelocytic leukemia (APL) who fulfill the inclusion and exclusion
      criteria.

      Patients included in this trial should have been diagnosed to have Acute Promyelocytic
      Leukemia morphologically on FAB criteria. This is sufficient to initiate therapy with arsenic
      trioxide (ATO) but this diagnosis has to be confirmed using either Fluorescent in situ
      hybridization (FISH) for t(15;17) or reverse transcriptase polymerase chain reaction assay
      (RT-PCR) for PML-RARalpha transcripts within 7 days of inclusion into the study.

      All these patients would have in the absence of this study received only palliative therapy
      due to the lack of resources to support standard chemotherapy.

      Women who are pregnant will not be considered for this study.

      Treatment Protocol: All patients who are included in this study will be initiated on
      treatment with ATO. Arsenic tri-oxide (10 mg/10ml) will be diluted in 500 ml of Dextrose
      Saline (only glass bottles to be used) and infused intravenously over 3 - 4 hours once a day.

      No premedication is required prior to administration of the drug. The dosage schedule for
      administration will be as follows:

      Adults: 10 mg once a day Children or adults <45kg: 0.15 mg/kg/day (maximum dose = 10mg) once
      a day

      The total courses of therapy will be as follows:

      Induction therapy: Induction therapy will be continued till ANC> 1.5 x 10e9/L and Platelet
      count > 100 x 10e9/L along with the absence of abnormal promyelocytes in peripheral smear on
      2 consecutive occasions. Once this is achieved, bone marrow studies will be done to assess
      remission. If the bone marrow shows < 5% of myeloblasts and promyelocytes along with a
      normocellular to mildly hypocellular marrow, arsenic can be stopped. If not in CR, arsenic is
      continued for an additional 2 weeks and a repeat bone marrow is done to confirm CR. Arsenic
      tri-oxide will be given for a maximum of 60 days following which the patient would be
      considered a non-responder/partial responder and excluded from further treatment. If bone
      marrow shows <5% blasts and promyelocytes at 60 days but peripheral blood count criteria for
      CR are not fulfilled, patient can be still be continued on the study regimen.

      Consolidation therapy: All patients who achieve CR will receive consolidation therapy for a
      period of 28 days after an interval of 4 weeks from achieving hematological CR. The dosage
      and mode of administration will be similar to the schedule followed in induction.

      Maintenance therapy: All patients who are in molecular CR at the end of consolidation therapy
      will be randomized into 2 groups:

      Group A: This group will receive 12 months of maintenance therapy. ATO will be administered
      for 10 days every month for a period of 12 months.

      Group B: This group will receive 6 months of maintenance therapy. ATO will be administered
      for 10 days every month for a period of 6 months.

      All patients who continue to be RT-PCR positive at the end of consolidation will not be
      randomized and will continue to receive all the courses of maintenance treatment. Subsequent
      therapy will be individualized based on the molecular monitoring results.

      A total of 400 patients will be recruited at the time of initiation into this study. We
      expect a loss to follow up/treatment failure/death of approximately 10% of the study
      population and hence 360 patients will be randomized into the final 2 arms of the study ie
      maintenance therapy for 12 months versus 6 months after completing the consolidation therapy.

      Patients with CNS disease will be treated with therapeutic Radiotherapy and intrathecal
      chemotherapy using Cytosine, Hydrocortisone and Methotrexate.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Measure complete hematological remission rate

Secondary Outcome

 Document early and late toxicities

Condition

Acute Promyelocytic Leukemia

Intervention

Single agent arsenic trioxide

Study Arms / Comparison Groups

 A
Description:  Duration of maintenance therapy with single agent ATO of 12 months

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

400

Start Date

June 2004

Completion Date

July 2009


Eligibility Criteria

        Inclusion Criteria:

          -  Patients included in this trial should have been diagnosed to have Acute Promyelocytic
             Leukemia morphologically on FAB criteria. This is sufficient to initiate therapy with
             arsenic tri-oxide but this diagnosis has to be confirmed using either Fluorescent in
             situ hybridization (FISH) for t(15;17) or reverse transcriptase polymerase chain
             reaction assay (RT-PCR) for PML-RARalpha transcripts within 7 days of inclusion into
             the study.

          -  All these patients would have in the absence of this study received only palliative
             therapy due to the lack of resources to support standard chemotherapy.

        Exclusion Criteria:

          -  Women who are pregnant

          -  Patients with acute promyelocytic leukemia who are found on standard karyotyping/
             FISH/RTPCR to have t(11;17) or t(5;17).
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Mammen Chandy, MD, 91-416-2282891, [email protected]

Location Countries

India

Location Countries

India

Administrative Informations


NCT ID

NCT00517712

Organization ID

IAPLSG2004

Secondary IDs

BT/PR4460/Med/14/531/2003


Study Sponsor

Christian Medical College, Vellore, India

Collaborators

 Ministry of Science and Technology, India

Study Sponsor

Mammen Chandy, MD, Principal Investigator, Christian Medical College, Vellore, India


Verification Date

August 2007