Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
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
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.
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 )