Trial Information

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

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.