All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia: a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies

Abstract

Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two entire cohorts. Complete remission (CR) rate was significantly higher in the PETHEMA/HOVON (94 %) than in the IC-APL cohort (85 %) (P = 0.002). The distribution of causes of induction failure and the time to achieve CR were similar in both cohorts. Patients who achieved CR had comparable cumulative incidence of relapse and disease-free survival rates, but lower overall and event-free survivals were observed in the IC-APL cohort, which was mainly due to a higher death rate during induction therapy. A higher death rate during consolidation therapy was also observed in the IC-APL. These results show that daunorubicin and idarubicin have similar antileukaemic efficacy in terms of primary resistance, molecular persistence, as well as molecular and haematological relapse rates when combined with ATRA in treatment of APL. However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov].

Current standard treatment of adult acute promyelocytic leukaemia

“…No studies have directly compared the type of anthracycline used for induction and consolidation, although a recent matched‐pair analysis comparing idarubicin and daurorubicin showed no significant difference in antileukaemic effect (Sanz et al , ).…”

Treating acute promyelocytic leukaemia in Latin America: lessons from the International Consortium on Acute Leukaemia experience

“…Although no significant differences in the proportion of deaths due to haemorrhage, infection and DS was observed, DS‐associated mortality among those patients developing moderate or severe DS was significantly higher in the IC‐APL study compared with PETHEMA/HOVON study (12% vs. 3%, respectively; P = 0·01) (Sanz et al , ). Another difference between the studies was seen in non‐relapse mortality during consolidation, which was higher in IC‐APL (4·8% vs. 1·2%; P = 0·04) (Sanz et al , ). The most likely explanation for these discrepancies is differences in supportive care, management of DS and suboptimal prevention and treatment of infections during consolidation therapy in the IC‐APL cohort.…”

“…The IC‐APL trial had an identical treatment to that the LPA2005 trial, except for the replacement of idarubicin by daunorubicin, and this similar design offered a unique opportunity to compare the outcomes of a study conducted in developing countries (IC‐APL) to those in developed countries (PETHEMA/HOVON). A matched‐pair analysis was performed to minimize the effects of non‐treatment‐related variables on outcomes (Sanz et al , ), which showed that daunorubicin and idarubicin have similar anti‐leukaemic efficacy in terms of primary resistance and molecular persistence, as well as molecular and haematological relapse rates. A cost/effectiveness analysis was not performed, but we consider that the proposed policy was highly effective and applicable to other developing countries, based on the fact that the standard treatment still is considered to be ATRA and anthracycline and that daunorubicin has the lowest cost among the anthracyclines with similar anti‐leukaemic activity.…”

“…As treatment, the consortium adopted the combination of ATRA and anthracycline, using the same design of the Programa Español de Tratamiento en Hematologia/Dutch‐Belgian Haemato‐Oncology Cooperative Group (PETHEMA/HOVON) LPA2005 protocol (Sanz et al , , ), except that idarubicin was replaced by daunorubicin at a ratio of 1:5 (Fig ). This change aimed to reduce cost and to ensure the availability of the required drugs in all centres.…”

Molecular and hematologic relapses in adult patients with acute promyelocytic leukemia: a cohort study

“…Moreover, Karim et al 20 in a study with 26 patients, found a 11.5% relapse rate of both molecular and of the central nervous system (CNS). In the matched-pair analyses of the PETHEMA LPA-2005 and IC-APL-2006 studies, 21 relapse rates were 7.4% and 5%, respectively. No CNS relapse was detected in this series.…”