Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation

Abstract

The purpose of this study was to assess the safety and efficacy of stem cell transplantation (SCT) mainly autologous SCT as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2). Fifty adult patients with a first relapsed APL, of whom 39 had been previously treated with ATRA, entered a multicenter trial of oral ATRA until complete remission (CR) achievement followed by timed sequential chemotherapy (EMA combining etoposide 200 mg/m 2 /day for 3 days, mitoxantrone 12 mg/m 2 /day for 3 days, and cytarabine 500 mg/m 2 /day for two sequences of 3 days). EMA was started either after CR achievement, or on day 1 of ATRA because of initial white blood cell (WBC) counts Ͼ5 × 10 9 /l, or rapidly added to ATRA in order to prevent ATRA syndrome because WBC count increased under ATRA. Forty-five patients (90%, 95% CI 78%-97%) were in CR after induction therapy. Five patients died from infection during aplasia following EMA chemotherapy. Eleven patients who achieved CR had a familial HLA-identical donor and were allografted. The median disease-free survival (DFS) of allografted patients was 8.2 months. The 34 other CR patients were scheduled for autologous peripheral blood (PB) SCT (intent-to-treat group). Actually, autologous transplantation was only carried out in 22 patients (65%) (17 PBSCT and five autologous bone marrow transplantation (BMT)). Reasons for not autografting were early relapse (three patients), severe toxicity of EMA chemotherapy (six patients), and refusal or failure of stem cell harvest (three patients). The 3-year DFS rate of patients actually autografted was 77%. Among the 17 autografted patients still in CR2, nine patients have already reached a longer CR2 than first CR (CR1). Results of detection of PML/RAR␣ by RT-PCR after autologous transplantation show negative findings in eight of the nine patients tested. We conclude that (1) ATRA combined to EMA chemotherapy is effective in the treatment of relapsed APL; (2) allogeneic BMT may be too toxic after salvage treatment including EMA intensive chemotherapy; (3) clinical outcome of autografted patients and preliminary molecular results regarding detection of PML/RAR␣ after autologous PBSCT are encouraging. Leukemia (2000) 14, 1006-1013.

The role of bone marrow transplantation in acute promyelocytic leukemia

“…The patient with secondary leukemia, however, received a different preparative regimen. It can be concluded from this study that patients with negative PCR after their CR2 will fare favorably with AUTO-HSCT, and patients with posi- Table 2 Results of allogeneic hematopoietic stem cell transplantation in APL 37 chemotherapy patients died either from infections or GVHD a The 2nd relapse patient died at 3 months. CR = complete remission; ATRA = all-trans retinoic acid; N/A = not available; LFS = leukemia-free survival; OS = overall survival; TRM = transplantrelated mortality; GVHD = graft-versus-host disease.…”

“…35,36 Importantly, ATRA induced CR in relapsed patients who were previously treated with ATRA or with chemotherapy. 37 The best choice of therapy in relapsed patients is still under investigation. It is acceptable to treat relapsed patients with ATRA if they were not treated with this agent previously, or if the ATRA-free period is 6-12 months.…”

Clinical Experience of Arsenic Trioxide in Relapsed Acute Promyelocytic Leukemia

“…For the approximately 20%-30% of patients who relapse, treatment with ATRA and/or chemotherapy can usually produce a second CR, but stem cell transplantation may provide greater benefit. This approach was tested in a population of patients who relapsed and achieved a second CR with ATRA followed by timed etoposide/mitoxantrone/cytosine arabinoside therapy [28]. After CR, patients underwent myeloablation followed by either autologous or allogeneic (HLA-compatible donor and < 55 years of age) transplant.…”

Role of hematopoietic stem cell transplantation for relapsed acute promyelocytic leukemia: A retrospective analysis of JALSG‐APL97

“…Further prospective studies with larger patient numbers are required to confirm the impact of HSCT alone and in combination with arsenic trioxide on outcomes for patients with APL in CR2. (Cancer Sci 2013; 104: 1339-1345 T he introduction of all-trans retinoic acid (ATRA) has brought about marked progress in the treatment of acute promyelocytic leukemia (APL), but relapse still occurs in approximately 15-25% of patients.(1-3) Most of the relapsed patients were able to achieve second complete remission (CR2) using ATRA-based salvage regimens (4)(5)(6) or recent arsenic trioxide (ATO)-based salvage regimens. (7,8) After achieving CR2, most patients need to receive post-remission treatments to reduce minimal residual disease (MRD).…”

“…(1-3) Most of the relapsed patients were able to achieve second complete remission (CR2) using ATRA-based salvage regimens (4)(5)(6) or recent arsenic trioxide (ATO)-based salvage regimens. (7,8) After achieving CR2, most patients need to receive post-remission treatments to reduce minimal residual disease (MRD).…”