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[Effect of all-trans retinoic acid on the newly diagnosed acute promyelocytic leukaemia: our experience].

UNLABELLED
Acute promyelocytic leukaemia (APL) is characterised by the morphology of bias cells (M3), t(15;17) translocation, and coagulopathy combining disseminated intravascular coagulation (DIC) and fibrinolysis. Anthracy cline-cytosine arabinoside (Ara C) intensive chemotherapy yields a complete remission in 50 percent (%) to 80% of newly diagnosed APL patients. Failure to achieve complete remission results in fatal bleeding due to coagulopathy or fatal sepsis during the phase of aplasia. It has been recently shown that all trans retinoic acid (ATRA) selectively differentiates abnormal promyelocytes into mature granulocytes in APL, both in vitro and in vivo, and induced complete remission in 80% to 90% of the newly diagnosed patients. It has also been observed that therapy with ATRA rapidly improved coagulopathy, and induced no aplasia. However, in 30% of patients the treatment with ATRA as a single drug was associated with rapid increase in leukocytes and signs of "ATRA syndrome", which could have fatal outcome. Therefore the European study group initiated in 1991 a multicentre randomised trial comparing chemotherapy with daunorubicin Ara C (chemotherapy group) and ATRA combined to the same chemotherapy (ATRA group) in newly diagnosed APL patients, aged 65 years or less. Results of this study strongly suggest that ATRA should be incorporated in the front line therapy of newly diagnosed APL. The aim of our study was to confirm their results in our newly diagnosed patients.


PATIENTS AND METHODS
In our study we had 15 subsequently hospitalised patients with APL in whom diagnosis was made according to MIC classification, and who were treated with ATRA (Vesanoid-Hoffman La Roche) combined with chemotherapy according to the recommendation of the European study groups. The comparison of the effect of ATRA we has evaluated by the outcome of APL in 12 patients who received only combined chemotherapy in induction phase according to the Yu-AML-89 protocol 12 or 01-AM-86 protocol. Both protocols include daunorubicin and Ara C. In all patients MIC classification was performed. Characteristics of the patients included in the study with special emphasis to symptoms at presentation, are given in Table 1.


TREATMENT
Patients treated with ATRA plus chemotherapy received daily oral dose of ATRA 45 mg/m2 until the complete remission, or for a maximum of 90 days. After complete remission they received three courses of daunorubicin 60 mg/m2 for 3 days, and Ara C 200 mg/m2 for 7 days. However, course one was added to ATRA on day one of treatment of initial leukocyte counts were greater than 5 x 10(9)/L or rapidly started to increase to above 6 x 10(9)/L or more. Patients treated with chemotherapy received only in induction phase daunorubicin 45 mg/m2 for 4 days and Ara C 200 mg/m for 7 days as well as the intensive platelet support, heparin, fresh frozen plasma in those with bleeding. During the study haemostasis monitoring was performed in all patients. Complete remission was defined according to the criteria of the European study group. Early death was defined as a death during the therapy with ATRA or chemotherapy due to "ATRA syndrome", bleeding, aplasia, or resistant leukaemia. Statistical analysis was performed according to the Kruskal-Wallis test.


RESULTS
Relevant haematological and pathobiological characteristics at presentation are shown in Table 2. It can be seen that there were no significant characteristic differences at presentation between ATRA group and chemotherapy group. The effects of the treatment are shown in Table 3. It can be seen that complete remission was achieved in 87% of patients receiving ATRA combined with chemotherapy and only in 42% of patients who received combined chemotherapy. This difference is significant (p < 0.01). Duration of complete remission lasted for 14 months (median) in the patients receiving ATRA while only 5 months (median) in the patients who received combined chemotherapy. Fatal outcome in ATRA group occurred in 13% due to the "ATRA syndrome" and in 58% of the patients treated with combined chemotherapy due to bleeding. Table 4 shows four selected patients from ATRA group in whom complete remission was followed with disappearance of t (15;17), thus providint the evidence of the eradication of clonal abnormalities. It should be emphasised that 2 of 15 patients developed ATRA syndrome during the early phases of the treatment with a feature of cardiorespiratory distress. The therapy with steroid was unsuccessful. Nine of 13 patients in ATRA group had moderate side effects with no necessity to discontinue the therapy.


DISCUSSION
Our clinical trial shows for the first time in our county a beneficial effect of ATRA in addition to chemotherapy compared with chemotherapy alone in newly diagnosed APL, thus comfirming the results of the European study group. The only flaw of in our study may come from the fact that the patients included in the study were not randomised and that for the comparison of the ATRA group were used previously treated patients with chemotherapy alone. However, we believe that this flaw has been overcome since uniform diagnostic procedure and particularly MIC classification were performed in all patients. In addition to that, all patients included in the trial were subjected to the analysis of haemostatic status as well as to precise biochemical studies, ECG and abdominal echography. It is interesting to note that in our study, similarity to the European study group, 13% of patients developed "ATRA syndrome". Therefore, it is recommended that further effort should be made in order to prevent this fatal and not yet resolved syndrome.