Treatment of acute promyelocytic leukemia with arsenic trioxide: clinical results and open questions

Abstract

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia. The specific translocation t(15;17), which results in the fusion gene PML–RARA is the diagnostic and pathomechanistic hallmark of APL. By combination, treatment consisting of the differentiating agent all-trans retinoic acid (ATRA), which targets this molecular lesion, and cytotoxic chemotherapy, cure can be achieved in over 70% of patients. Recently, arsenic trioxide (ATO) has emerged to be the most active single agent in the treatment of APL. Previous studies employing ATO in relapse settings reported average complete remission rates of 85% and a mean overall survival of over 60%. In recent approaches installing ATO in first-line treatment, ATO-induced response rates comparable to previous combination regimen. The results of these newer studies indicate that the backbone of chemotherapy can be dramatically reduced or completely replaced by ATO and ATRA with similar or even better outcome.

Keywords::

• arsenic trioxide
• early death
• frontline therapy
• hematopoietic stem cell transplantation
• prognostic factors
• relapse

Financial & competing interests disclosure

Eva Lengfelder was consultant for Cepalon/Teva and has received research funding, Daniel Nowak received honoraria from Teva as speaker, Wolf-Karsten Hofmann has nothing to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • The morphologic diagnosis of APL is confirmed by the detection of the specific translocation t(15;17) corresponding to the fusion genes PML–RARA and RARA–PML. About 70–80% of APL patients included in clinical studies are cured with ATRA in combination with chemotherapy, up to 20% relapse and approximately 10% die from ED.

• • ATO is the most effective single agent in the treatment of APL and has moderate toxicity. It has a curative potential in patients with relapse after combination therapy with ATRA and chemotherapy as well as in first-line therapy of APL.

• • In vitro experiments and in vivo data showed a remarkable intensification of the antileukemic effects by the combination of ATO and ATRA.

• • The role of ATO in salvage therapy after frontline therapy with ATRA and chemotherapy is well established. Long-term stabilization and probable cure seems possible in over 60% of patients. The best postconsolidation therapy remains controversial.

• • Lacking data, no established recommendation exists for treatment of relapse after frontline therapy with ATO.

• • In newly diagnosed APL, induction therapy with ATO induces response rates, which are similar to combination therapy with ATRA and chemotherapy. Regimens including ATO for consolidation instead of chemotherapy showed promising results. In a recent randomized comparison including low/intermediate-risk patients with newly diagnosed APL, treatment with ATO and ATRA was at least as effective and less toxic compared with ATRA and idarubicin.