Brief Title
Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
Official Title
APL-R2007: Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
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
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 Phase
Phase 4
Study Type
Interventional
Primary Outcome
Evaluate the hematological and molecular remission rate after induction and consolidation with ATO
Secondary Outcome
Evaluate kinetics of the MDR of PML/RARa during and after ATO
Condition
Acute Promyelocytic Leukemia
Intervention
Arsenic Trioxide
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
60
Start Date
July 2007
Completion Date
October 2014
Primary Completion Date
October 2014
Eligibility Criteria
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 )
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Sanz Miguel Angel, Dr, ,
Location Countries
Spain
Location Countries
Spain
Administrative Informations
NCT ID
NCT00504764
Organization ID
LAP-R2007
Responsible Party
Sponsor
Study Sponsor
PETHEMA Foundation
Study Sponsor
Sanz Miguel Angel, Dr, Study Chair, Hospital La Fe
Verification Date
October 2014