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