Treatment of Acute Promyelocytic Leukemia: A Report of 70 Cases

Abstract

Over a period of 14 years, we treated 70 cases of acute promyelocytic leukemia (APL) with 3 different chemotherapy protocols. In protocol 1, patients received high dose daunorubicin (DNR) alone for induction, followed by regular reinduction courses and continuous maintenance therapy with 6 mercaptopurine (6 MP) and methotrexate (MTX) during 3 years. In protocol 2, induction with high dose DNR and Ara C was also followed by regular reinduction courses, but without continuous maintenance therapy. Protocol 3 randomized high dose Amsacrine (AMSA) or Rubidazone in association with Ara C, for induction and consolidation, this was followed by reinduction courses and continuous maintenance therapy with 6 MP and MTX. During the induction all patients received, prophylactic heparinization and platelet transfusions. Fifty six patients (80%) achieved complete remission (CR), 13 patients (18.5%) had early death (ED) or hypoplastic death (HD), and 1 patient had true resistant leukemia. Only two patients died of hemorrhage. Median actuarial disease free survival (DFS) was 16.5 months and a plateau at 29.1% was reached after 29 months. Patients with fever at diagnosis had a significantly lower CR rate while age below 20 years and circulating blasts above 0.5 × 10(9)/1 were associated with shorter DFS. The CR rate did not significantly differ between protocols 1, 2 and 3 (87.5%, 80% and 60% respectively) but 9 of the 30 patients on protocols 2 or 3 had ED or HD, compared to 4 of the 40 treated with protocol 1 (p < 0.05). DFS was significantly shorter in protocol 2, which included no continuous maintenance chemotherapy, than in protocols 1 and 3. Median actuarial survival was significantly shorter in patients treated with protocols 2 or 3, compared to protocol 1. These results suggest that high dose DNR alone, associated with adequate prophylaxis of disseminated intravascular coagulation, gives very high CR rates in APL, with short periods of aplasia and limited toxicity. Combinations of an anthracycline or AMSA at the doses used with regular dose Ara C may be too toxic. Although this was not a randomized trial, our findings also suggest a possible benefit of prolonged continuous maintenance therapy with 6 MP and MTX in APL.

Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia

“…By contrast, the last relapse occurred at 43 months in the chemotherapy group, confirming the rare occurrence of relapses beyond 4 years after chemotherapy alone in APL. [8][9][10][11][12] A large number of studies of APL treated with ATRA and chemotherapy has now been published, but their follow-up is currently not sufficient to confirm whether or not this combination treatment is associated with an increased risk of late relapses. [20][21][22][23][24]29 Data on long-term follow-up of those studies is therefore awaited.…”

“…Censored criteria were analyzed with the Kaplan-Meier estimate, 25 the life-time actuarial estimate, 26 the log-rank test 27 and the Cox's model 26 using 1 January 1999 as the reference date (fifth interim analysis). For each endpoint, treatment comparison was adjusted on a predetermined subset of prognostic factors [8][9][10][11][12][13] using either logistic regression (CR achievement) or Cox's model (other endpoints): age, WBC count, platelet count, absolute number of circulating blasts, M3 subtype ('classical' M3 vs microgranular variant M3), presence of significant coagulopathy, and fibrinogen level. They were introduced as binary covariates after dichotomization according to median values.…”

“…6,7 Until the end of the 1980s, combination chemotherapy with anthracycline-cytosine arabinoside (Ara C) was the only treatment for APL, which gave complete remission (CR) in 65 to 80% of newly diagnosed cases. [8][9][10][11][12] Fifty to 65% of the patients who achieved CR subsequently relapsed. [8][9][10][11][12] All-trans retinoic acid (ATRA) can differentiate abnormal promyelocytes into mature granulocytes in APL in vitro and in vivo [13][14][15][16] and can induce CR in 80% to 90% of newly diagnosed 13,[15][16][17] and first-relapsing APL.…”

“…[8][9][10][11][12] Fifty to 65% of the patients who achieved CR subsequently relapsed. [8][9][10][11][12] All-trans retinoic acid (ATRA) can differentiate abnormal promyelocytes into mature granulocytes in APL in vitro and in vivo [13][14][15][16] and can induce CR in 80% to 90% of newly diagnosed 13,[15][16][17] and first-relapsing APL. 18 Two randomized trials (including our APL91 trial and a US intergroup study) have shown that the combination of ATRA and chemotherapy improved event-free survival and survival in newly diagnosed APL by comparison with chemotherapy alone, mainly by reducing the incidence of relapse.…”

Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience

“…Indeed, in historical series of APL treated with chemotherapy alone, CR rates in elderly patients were in the range of 50%. 10,11 Moreover, in a British MRC study where APL patients received either 5 days of ATRA followed by chemotherapy ('short ATRA') or chemotherapy combined to ATRA until recovery from aplasia ('extended ATRA'), the latter gave higher CR rates in patients o60 years than 'short ATRA' (89 vs 72% CR) but the difference between extended and short ATRA was greater in patients 460 years (73 vs 50%). 12 Relapse and overall survival…”