European Journal of Haematology 93 (54–62)
ORIGINAL ARTICLE
Incorporation of arsenic trioxide in induction therapy improves survival of patients with newly diagnosed acute promyelocytic leukaemia € , Lei Gao, Li Chen, Jianmin Yang, Weiping Zhang, Xianmin Song†, Xiaoxia Hu†, Shuqing Lu Jianmin Wang Department of Haematology, Institute of Haematology of PLA, Changhai Hospital, Shanghai, China
Abstract Objectives: For patients with acute promyelocytic leukaemia (APL), negative reading of a promyelocytic leukaemia/retinoic acid receptor-alpha (PML-RARa) transcript after induction therapy correlates with a good prognosis. However, in the majority of patients given all-trans retinoic acid (ATRA)/anthracycline-based induction therapy, PML-RARa transcript remains even when haematologic complete remission is achieved. To facilitate maximal therapeutic efficacy for patients with APL, this study tested whether the addition of arsenic trioxide (ATO) would increase the rate of molecular complete remission after ATRA/anthracyclinebased induction therapy. Methods: Seventy-three patients with APL were induced with a regimen (designated ‘AAA’) consisting of ATO in combination with ATRA and daunorubicin. After this, a consolidation phase of daunorubicin-based chemotherapy and maintenance therapy with ATRA, ATO and methotrexate was administered. The noted outcomes were rates of complete remission, overall survival and disease-free survival. In addition, PML-RARa transcripts were monitored in 48 patients via RT-PCR. Results: Rates of complete remission, overall survival and 5-yr disease-free survival were 95.89%, 94.52% and 96.28%, respectively. At the preconsolidation checkpoint, 68.75% (33/48) of patients had a negative reading for the PML-RARa fusion transcript. These outcomes were not influenced by mutations in FLT3 (fms-related tyrosine kinase 3) or other prognostic factors. Conclusions: The addition of ATO in the induction regimen was associated with an improved overall outcome for patients with de novo APL, with rather low relapse rate and better long-term survival. Key words arsenic trioxide; acute promyelocytic leukaemia; molecular complete remission Correspondence Jianmin Wang, MD, Department of Haematology, Changhai Hospital, 168 Changhai Road, Shanghai 200433, China. Tel/Fax: +86 21 3116 1293; e-mail: [email protected] †These authors contributed equally to this paper. Accepted for publication 26 February 2014
Acute promyelocytic leukaemia (APL) was once known as the most fatal leukaemia subtype, but is now considered potentially curable in adults since the introduction of alltrans retinoic acid (ATRA) therapy in the 1980s (1). The current strategy combines ATRA and anthracycline-based chemotherapy to induce remission, and afterwards consolidation chemotherapy and maintenance therapy. This strategy has yielded complete remission (CR) rates greater than 90% and long-term cure rates of 70–75% (2–4). Nevertheless, 30–40% of patients with APL in high-risk groups fail to
54
doi:10.1111/ejh.12301
maintain remission and require salvage therapy (5, 6). Although risk-adapted strategies have been adopted by some, 10.7–24% of patients are still not cured (3, 4, 7, 8). Exploring a novel approach to reduce the recurrence risk is an important clinical goal in APL, where relapse is a significant cause of mortality. In the 1990s, it was reported that the addition of arsenic trioxide (ATO) improved the outcome of patients with APL (9). ATO has been confirmed to be highly effective in de novo and relapsed APL and is the front-line choice for
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Song et al.
Arsenic trioxide in therapy of APL
relapsed patients (10–12). Combined ATRA and ATO degrade PML-RARa synergistically, resulting in the eradication of APL-initiating cells (13). Several studies have reported the use of ATO as initial induction therapy for APL, either as a single agent (14, 15) or in combination with ATRA (16, 17), with relapse rates that approximate those that result from treatment with ATRA and multiple cycles of chemotherapy. The addition of ATO to a consolidation regimen also improved survival, reported by the North America Intergroup Study C9710 (18). These results suggest that the early use of ATO might be an alternative approach to improve outcomes in APL. Acute promyelocytic leukaemia is associated with gene rearrangements that result in the fusion oncoprotein promyelocytic leukaemia/retinoic acid receptor-alpha (PML-RARa) (19). The PML-RARa gene fusion transcript, determined via reverse transcriptase-polymerase chain reaction (RT-PCR), provides a convenient and practical marker for diagnosing and monitoring APL. It has been shown that rapid reduction in PML-RARa fusion transcripts, or the gradual gain of a negative reading at the early stage, may indicate a good prognosis (16, 20). However, with the conventional ATRA plus chemotherapy regimen, the majority of patients remain positive for the PML-RARa transcript at the end of induction therapy (20–22). It is well recognised that the kinetics of leukaemia clearance with the use of ATO in induction is significantly different from that of ATRA alone or ATRA plus chemotherapy combinations (23). In this study, we explored whether the addition of ATO in induction therapy (designated the ‘AAA’ regimen) would lead to molecular CR (mCR) and provide therapeutic benefit for patients with de novo APL.
Patients and methods Patients
This is a retrospective study of patients with newly diagnosed APL treated at the Department of Haematology, Changhai Hospital, between March 2004 and July 2012 (Table 1). All patients were followed up until 31 October 2013. The Ethics Committee of Second Military Medical University approved the study protocol, and all patients or legal guardians gave written informed consent for treatment and prospective data collection in accordance with the Declaration of Helsinki. APL was diagnosed and characterised in accordance with the WHO and FAB classification schemes (24). APL was confirmed by evidence of the PML-RARa fusion gene gained through cytogenetic analysis for t(15, 17), RT-PCR, fluorescence in situ hybridisation or a combination of these. Cases with variant non-PML gene rearrangements, specifically t(11, 17) and t(5, 17), were excluded. Induction protocol
Induction therapy consisted of oral ATRA (25 mg/m2/d) divided into two daily doses maintained until haematologic complete remission (hCR); daunorubicin (DNR, 45 mg/m2/ d) given intravenously on days 3, 4 and 5; and continuous ATO (0.16 mg/kg/d, maximum 10 mg/d) infused intravenously from day 2 until hCR (Fig. 1). For patients with white blood cell (WBC) count >10 9 109/L, DNR was started on day 1. When patients achieved hCR, 25 mg/m2/d ATRA was administrated until the commencement of consolidation therapy.
Table 1 Pretreatment demographics, clinical features and outcomes after induction therapy Patients, n (%) Age, yr
ORIGINAL ARTICLE
Incorporation of arsenic trioxide in induction therapy improves survival of patients with newly diagnosed acute promyelocytic leukaemia € , Lei Gao, Li Chen, Jianmin Yang, Weiping Zhang, Xianmin Song†, Xiaoxia Hu†, Shuqing Lu Jianmin Wang Department of Haematology, Institute of Haematology of PLA, Changhai Hospital, Shanghai, China
Abstract Objectives: For patients with acute promyelocytic leukaemia (APL), negative reading of a promyelocytic leukaemia/retinoic acid receptor-alpha (PML-RARa) transcript after induction therapy correlates with a good prognosis. However, in the majority of patients given all-trans retinoic acid (ATRA)/anthracycline-based induction therapy, PML-RARa transcript remains even when haematologic complete remission is achieved. To facilitate maximal therapeutic efficacy for patients with APL, this study tested whether the addition of arsenic trioxide (ATO) would increase the rate of molecular complete remission after ATRA/anthracyclinebased induction therapy. Methods: Seventy-three patients with APL were induced with a regimen (designated ‘AAA’) consisting of ATO in combination with ATRA and daunorubicin. After this, a consolidation phase of daunorubicin-based chemotherapy and maintenance therapy with ATRA, ATO and methotrexate was administered. The noted outcomes were rates of complete remission, overall survival and disease-free survival. In addition, PML-RARa transcripts were monitored in 48 patients via RT-PCR. Results: Rates of complete remission, overall survival and 5-yr disease-free survival were 95.89%, 94.52% and 96.28%, respectively. At the preconsolidation checkpoint, 68.75% (33/48) of patients had a negative reading for the PML-RARa fusion transcript. These outcomes were not influenced by mutations in FLT3 (fms-related tyrosine kinase 3) or other prognostic factors. Conclusions: The addition of ATO in the induction regimen was associated with an improved overall outcome for patients with de novo APL, with rather low relapse rate and better long-term survival. Key words arsenic trioxide; acute promyelocytic leukaemia; molecular complete remission Correspondence Jianmin Wang, MD, Department of Haematology, Changhai Hospital, 168 Changhai Road, Shanghai 200433, China. Tel/Fax: +86 21 3116 1293; e-mail: [email protected] †These authors contributed equally to this paper. Accepted for publication 26 February 2014
Acute promyelocytic leukaemia (APL) was once known as the most fatal leukaemia subtype, but is now considered potentially curable in adults since the introduction of alltrans retinoic acid (ATRA) therapy in the 1980s (1). The current strategy combines ATRA and anthracycline-based chemotherapy to induce remission, and afterwards consolidation chemotherapy and maintenance therapy. This strategy has yielded complete remission (CR) rates greater than 90% and long-term cure rates of 70–75% (2–4). Nevertheless, 30–40% of patients with APL in high-risk groups fail to
54
doi:10.1111/ejh.12301
maintain remission and require salvage therapy (5, 6). Although risk-adapted strategies have been adopted by some, 10.7–24% of patients are still not cured (3, 4, 7, 8). Exploring a novel approach to reduce the recurrence risk is an important clinical goal in APL, where relapse is a significant cause of mortality. In the 1990s, it was reported that the addition of arsenic trioxide (ATO) improved the outcome of patients with APL (9). ATO has been confirmed to be highly effective in de novo and relapsed APL and is the front-line choice for
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Song et al.
Arsenic trioxide in therapy of APL
relapsed patients (10–12). Combined ATRA and ATO degrade PML-RARa synergistically, resulting in the eradication of APL-initiating cells (13). Several studies have reported the use of ATO as initial induction therapy for APL, either as a single agent (14, 15) or in combination with ATRA (16, 17), with relapse rates that approximate those that result from treatment with ATRA and multiple cycles of chemotherapy. The addition of ATO to a consolidation regimen also improved survival, reported by the North America Intergroup Study C9710 (18). These results suggest that the early use of ATO might be an alternative approach to improve outcomes in APL. Acute promyelocytic leukaemia is associated with gene rearrangements that result in the fusion oncoprotein promyelocytic leukaemia/retinoic acid receptor-alpha (PML-RARa) (19). The PML-RARa gene fusion transcript, determined via reverse transcriptase-polymerase chain reaction (RT-PCR), provides a convenient and practical marker for diagnosing and monitoring APL. It has been shown that rapid reduction in PML-RARa fusion transcripts, or the gradual gain of a negative reading at the early stage, may indicate a good prognosis (16, 20). However, with the conventional ATRA plus chemotherapy regimen, the majority of patients remain positive for the PML-RARa transcript at the end of induction therapy (20–22). It is well recognised that the kinetics of leukaemia clearance with the use of ATO in induction is significantly different from that of ATRA alone or ATRA plus chemotherapy combinations (23). In this study, we explored whether the addition of ATO in induction therapy (designated the ‘AAA’ regimen) would lead to molecular CR (mCR) and provide therapeutic benefit for patients with de novo APL.
Patients and methods Patients
This is a retrospective study of patients with newly diagnosed APL treated at the Department of Haematology, Changhai Hospital, between March 2004 and July 2012 (Table 1). All patients were followed up until 31 October 2013. The Ethics Committee of Second Military Medical University approved the study protocol, and all patients or legal guardians gave written informed consent for treatment and prospective data collection in accordance with the Declaration of Helsinki. APL was diagnosed and characterised in accordance with the WHO and FAB classification schemes (24). APL was confirmed by evidence of the PML-RARa fusion gene gained through cytogenetic analysis for t(15, 17), RT-PCR, fluorescence in situ hybridisation or a combination of these. Cases with variant non-PML gene rearrangements, specifically t(11, 17) and t(5, 17), were excluded. Induction protocol
Induction therapy consisted of oral ATRA (25 mg/m2/d) divided into two daily doses maintained until haematologic complete remission (hCR); daunorubicin (DNR, 45 mg/m2/ d) given intravenously on days 3, 4 and 5; and continuous ATO (0.16 mg/kg/d, maximum 10 mg/d) infused intravenously from day 2 until hCR (Fig. 1). For patients with white blood cell (WBC) count >10 9 109/L, DNR was started on day 1. When patients achieved hCR, 25 mg/m2/d ATRA was administrated until the commencement of consolidation therapy.
Table 1 Pretreatment demographics, clinical features and outcomes after induction therapy Patients, n (%) Age, yr
