Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

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.

• 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.

• 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.

• 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.

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 )