Arsenic Trioxide (Trisenox®) Therapy for Acute Promyelocytic Leukemia in the Setting of Hematopoietic Stem Cell Transplantation

Abstract

The relapse-free survival of patients with acute promyelocytic leukemia (APL) has significantly increased during the last decade. The introduction of all-trans retinoic acid (ATRA) doubled the survival of patients with this disease. However, despite ATRA and anthracycline-based chemotherapy, 12%-30% of patients will still relapse. Arsenic trioxide (ATO) has demonstrated efficacy and safety in patients with first and subsequent relapsed or refractory APL, regardless of the disease-free interval. Treatment of relapsed and refractory patients with this novel therapy produces complete remission in 87% of patients and molecular remission in 83%. Studies have documented the efficacy of autologous and allogeneic transplantation as salvage therapy in relapsed and refractory APL. The introduction of ATO into the treatment regimen for APL has stimulated discussion on its role in the transplantation setting. Investigators recently met to discuss the issue and make recommendations regarding ATO therapy in patients who are in their second or subsequent complete remission and are candidates for transplantation. This article describes the pivotal studies of this novel agent, discusses risk factor stratification for relapse in patients with APL, and proposes protocols for treatment incorporating ATO therapy. In addition, it describes scientific issues in ongoing and proposed clinical trials of ATO therapy for this disease. The Oncologist 2003;8:132-140 The Oncologist 2003;8:132-140 www.TheOncologist.com Correspondence: Dan Douer, M.D., Bone Marrow Transplantation Program, USC/Norris Cancer Center, 1441 Eastlake Avenue, Room 3460, Los Angeles, California 90033, USA. Telephone: 323-865-3145; Fax: 323-865-0060; e-mail: douer_d@mikey.hsc.usc.edu Received November 1, 2002; accepted for publication February 24, 2003. ©AlphaMed Press 1083-7159/2003 The Oncologist ® LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Explain how to treat patients with relapsed acute promyelocytic leukemia.2. Describe how to use arsenic trioxide in acute promyelocytic leukemia and be familiar with drug's side effects.3. Identify the role of bone marrow transplantation in acute promyelocytic leukemia.Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com CME CME This material is protected by U.S.

Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR

“…The optimal consolidation strategy following salvage therapy with ATO-containing regimens remains to be defined. 118 In a small retrospective study in patients with relapsed APL treated with ATO-containing induction and consolidation therapy, outcome of further consolidation with autologous HSCT was compared with maintenance (without autologous HSCT) with ATO with or without ATRA. 113 In this analysis, all patients had achieved second molecular remission following induction and consolidation therapy with ATO-containing regimens; subsequently, 14 patients underwent autologous HSCT and 19 patients opted for ATOcontaining maintenance regimen.…”

A Canadian Consensus on the Management of Newly Diagnosed and Relapsed Acute Promyelocytic Leukemia in Adults

“…Background: Although some evidence suggests that treatment intensification with hsct can improve patient outcomes after ato-induced second remission 42 , the best consolidation treatment in that setting remains unknown 8 . The selection of the best treatment option (hsct or chemotherapy) in second cr after ato-and also the choice between allogeneic and autologous hsct-depends on several factors, including molecular status at second complete response, duration of first remission, age, and donor availability 8 .…”

Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RAR -positive leukemic stem cells

“…The data we present here support recent clinical studies showing that when As2O3 is used as a single agent for induction, consolidation, and maintenance in the treatment of newly diagnosed cases of APL, it is associated with durable remissions, which are comparable to those achieved with conventional ATRA plus chemotherapy regimens. 8,[29][30][31] However, longer follow-up is required to exclude the possibility of late relapses. 29,30 Regarding the mechanisms of action of ATRA, the effects on the PML/RARα-positive HSC can be considered an amplification of the physiological effects of ATRA on normal HSC.…”

“…7 In contrast to ATRA, As2O3 as a single agent is able to induce both CR and CMR followed by long-term relapse-free survival in about 50% of APL patients, even following relapse after treatment with chemotherapy regimens containing ATRA . 8 Both As2O3 and ATRA have tumor cell-specific activity in APL, with almost no toxic effect on normal hematopoiesis. In fact, treatment of APL patients with either As2O3 or ATRA is not accompanied by the bone marrow aplasia normally seen with conventional chemotherapy.…”

“…8 Treatment with ATRA as a single agent results in CR but not complete molecular remission (CMR), because the t(15;17)-associated PML/RARα fusion transcript remains detectable. In about 29% of patients CMR can be induced by ATRA if double the dosage is administered as a liposomal formulation.…”