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• W2046409247 abstract "Currently, between 20% and 30% of newly diagnosed acute promyelocytic leukaemia (APL) patients treated with current standard of care will develop disease recurrence or drug resistance (Wang & Chen, 2008). To further improve the clinical outcome of APL, almost all large randomized clinical trials have adopted strategies of intensified induction and consolidation treatment, such as the addition of standard or high-dose cytarabine to anthracyclines (Lengfelder et al, 2009), high-dose anthracyclines as single agents (Avvisati et al, 2002), etc. However, these strategies have at least three main problems: Firstly, APL differentiation syndrome (DS) is a relatively frequent and serious complication in newly diagnosed APL patients who undergo induction with standard dose (45 mg/m2 per d) all trans retinoic acid (ATRA) (Montesinos et al, 2009). Secondly, more intensified induction chemotherapy inevitably leads to prolonged neutropenia, severe infections and increased mortality (Lengfelder et al, 2009). Thirdly, although the molecular remission rate is roughly 95% in patients receiving two further cycles of anthracycline-based chemotherapy after induction, the vast majority of relapses take place during the maintenance phase (Sanz et al, 2005), and few clinical trials focus on maintenance therapy. In order to solve the problems mentioned above, two hypotheses were tested. The first hypothesis was that low-dose ATRA in induction would reduce the toxicities of standard dose ATRA, especially APL DS. The second hypothesis was that intensified maintenance treatment incorporating cytotoxic drugs and differentiating agents would decrease the disease relapse including extramedullary relapse, and further increase the cure rate. We present a retrospective clinical study that used low-dose ATRA (20 mg/m2 per d; most patients received 30 mg/d) to treat 69 newly diagnosed APL patients, between April 2000 and December 2007. This trial was approved by ethical committees in Anhui Provincial Hospital, and all patients gave signed informed consent. Patients were classified according to the risk of relapse on the basis of white blood cell (WBC) and platelet counts (PLT) at diagnosis (Sanz et al, 2000): low risk, WBC < 10 × 109/l and PLT ≥ 40 × 109/l; intermediate risk, WBC < 10 × 109/l and PLT < 40 × 109/l; high risk, WBC ≥ 10 × 109/l. The induction regimen consisted of oral ATRA (20 mg/m2 per d), divided into two daily doses, which was maintained until complete haematological remission, and daunorubicin 45 mg/m2 per d for at least 3 d was initiated if WBC count was >10 × 109/l during treatment with ATRA. After achieving complete remission (CR), consolidation treatment consisted of three intensive chemotherapy courses with anthracycline regimens (daunorubicin 45 mg/m2 per d or idarubicin 8 mg/m2 per d, or mitoxantrone 10 mg/m2 per d, on days 1–3), and ATRA (30 mg/m2 per d) was given on days 1–15 in combination with the above three courses. All patients received an intrathecal administration of cytarabine (Ara-C) (50 mg) and dexamethasone (5 mg) at the end of every consolidation course. The systematic use of post-consolidation therapy is still a controversial matter in patients achieving molecular remission at the end of consolidation. Two randomized studies showed an advantage of ATRA-based maintenance therapy (Tallman et al, 1997; Fenaux et al, 1999), but two randomized studies more recently reported no benefit from maintenance regimens (Avvisati et al, 2003; Asou et al, 2007). Despite the uncertainty of the benefit provided by maintenance therapy, it is a fact that some patients who are polymerase chain reaction (PCR)-negative at the end of consolidation will ultimately relapse, especially among those presenting with WBC counts >10 × 109/l. We believe that, during the maintenance period, treatment schedule cycles composed of intensive chemotherapy with cytotoxic drugs [MM (6-mercaptopurine and methotrexate), DA (daunorubicin and Ara-C), and HA (homoharringtonine and Ara-C)] and strengthening differentiation treatment with differentiating agents [ATRA and Arsenic trioxide (ATO)] may improve treatment efficacy. In our centre, low-risk patients were maintained with a 3-month cycles of sequential therapy consisting of ATRA (30 mg/m2 per d for the first month), MM regimen (6-mercaptopurine 50 mg/m2 per d and methotrexate 10 mg/m2 per week for the second month) and As4S4 (Tetra-arsenic tetrasulfide, 8·1 g/d, the third month). For intermediate- and high-risk patients, each treatment cycle consisted of seven chemotherapy courses with ATO, MM, ATRA, DA, MM, ATRA and HA regimens. Maintenance therapy was continued for 3–3·5 years (12 cycles for low-risk patients, and six cycles for intermediate- and high-risk patients) (Fig 1). Treatment schedule on the APL patients. 1ATRA, all-trans retinoic acid; 2DNR, daunorubicin; 3IDA, idarubicin; 4MIT, mitoxantrone; 5As4S4, tetra-arsenic tetrasulfide; 6MM, mercaptopurine and methotrexate; 7ATO, arsenic trioxide; 8DA, daunorubicin and cytarabine; 9HA, homoharringtonine and cytarabine. () Total of 12 cycles in low-risk group. Each cycle consisted of ATRA (30 mg/m2 per d for the first month), MM (6-mercaptopurine 50 mg/m2 per d and methotrexate 10 mg/m2 per week for the second month) and As4S4 (tetra-arsenic tetrasulfide, 8·1 g/d for the third month). () Total of six cycles in intermediate- and high-risk groups, and each cycle consisted of seven chemotherapy courses with ATO (arsenic trioxide 10 mg/d, total of 14 d for the first month), MM (6-mercaptopurine 50 mg/m2 per d and methotrexate 10 mg/m2 per week for the second month), ATRA (30 mg/m2 per d for the third month), DA (daunomycin 45 mg/m2 d1-3, and cytarabine 150 mg/m2 d1-7 for the fourth month), MM (6-mercaptopurine 50 mg/m2 per d and methotrexate 10 mg/m2 per week for the fifth month), ATRA (30 mg/m2 per d for the sixth month) and HA (homoharringtonine 2 mg/m2 d1-7, and cytarabine 150 mg/m2 d1-7 for the seventh month) regimens. Overall, CR was obtained in 65 (94·2%) of 69 patients at a median of 40 d (range, 30–52), while 4 (5·8%) patients had early death following fatal bleeding. No patient had resistant leukaemia. In the low-risk group, mild and transient leucocytosis (median WBC count, 12 × 109/l) occurred in 15 patients during remission induction, and no patients had DS. Hyperleucocytosis (WBC ≥ 10 × 109/l) was observed in 43 patients in the intermediate- and high-risk groups, who achieved a maximal WBC count (25–203 × 109/l, median 54 × 109/l) between days 4 and 15, and only two patients in the high-risk group had moderate DS, which was reversed by dexamethasone and daunorubicin. All the increased WBC counts were controlled by daunorubicin. Non-haematological side effects of ATRA, such as headache and dryness of mucosa were considered tolerable and negligible. Reverse transcription PCR for PML/RARA was carried out in 42 cases at the end of consolidation therapy, and 39 patients (93%) were shown to obtain complete molecular remission. At a median follow-up of 52 months (range, 29–68 months), 9 (13·8%) of the 65 patients had relapsed, which occurred in the central nervous system in four patients. The 5-year disease-free survival and overall survival estimates were 88·2% vs. 82·6% and 93·6% vs. 86·7% in low-risk and intermediate or high-risk patients, respectively (Table I). From the above data, we conclude that ATRA at a dose of 20 mg/m2 per d was quite effective in inducing CR in APL patients, and may provide advantages through decreased DS and other side-effects. Based on the current consolidation approach of anthracycline combined with ATRA chemotherapy, our risk-adapted sequential maintenance treatment cycle also presented good results with limited toxicities, lower incidence of relapse, and better survival. However, this was a non-comparative and non-prospective study, and the number of patients was small; further studies are needed to determine the optimum ATRA regimen and to evaluate the efficacy of sequential intensified maintenance cycle described here." @default.
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• W2046409247 title "Strategy to further increase of cure rate in acute promyelocytic leukaemia: low-dose all-trans retinoic acid and sequential maintenance cycle" @default.
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