In the past two decades, the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) compared with CT alone. This has been achieved by reducing the incidence of relapse and increasing the complete remission (CR) rate, the latter through almost disappearance of cases of resistant leukemia and, in most studies, by reducing the frequency of early deaths.1, 2, 3, 4 In recent APL clinical trials, CR ranging from 90 to 95% have been reported, almost all failures resulting from early death (ED), mainly caused by bleeding, sepsis or differentiation syndrome (DS).5,6 Some recent studies have, however, reported ED rates as high as 15–30% in newly diagnosed APL when patients not included in clinical trials were analyzed together with protocol patients. In addition, when assessed in the United States SEER database,7 ED did not seem to have much improved between 1977 and 2007, in spite of the advent of ATRA treatment.
We retrospectively analyzed the incidence and causes of ED in APL in 17 French centers over a 5-year period (December 2006 to December 2011) included or not in APL 2006 trial, the only active French APL trial during that period. Diagnosis of APL was made on a morphological basis, and had to be confirmed by presence of t(15;17) translocation and/or promyelocytic leukemia gene-retinoic acid recepter alpha gene rearrangement. Every effort was made to collect all APL cases that presented during the 5-year period of analysis but was not included in APL 2006 by checking all APL diagnoses made in the hematology, cytogenetic and molecular laboratories of the institution, and by including patients admitted directly to the hospital intensive care unit (ICU) or to clinical departments of the hospital other than that of hematology to avoid any bias.
In APL 2006 trial, patients aged <70 years received an ATRA plus CT induction course consisting of ATRA 45 mg/m2/d until hematological CR and idarubicin 12 mg/m2/d for 3 days plus aracytin (AraC) 200 mg/m2/d for 7 days. Patients achieving CR were then randomized to consolidation cycles with or without arsenic trioxide (ATO), and to maintenance treatment. Patients aged >70 years received a regimen combining ATRA, ATO and attenuated chemotherapy cycles. Patients not included in APL 2006 generally received ATRA combined with an induction CT regimen similar to that of APL 2006 trial. For each patient, intervals between first blood count, hospital admission and ATRA onset were particularly analyzed. ED was defined as death within 30 days of admission, irrespective of its cause.
As shown in Table 1, 399 cases of newly diagnosed APL were diagnosed between December 2006 and December 2011 in the 17 participating centers. Females accounted for 48% of the patients (193 F/206 M) and median age was 51 years (16–87). Thirty-six (9%) patients were older than 75 years and 105 (26%) older than 65 years. White blood cell (WBC) count <10 000/mm3 (standard-risk APL) was observed in 73% of patients and 27% had WBC >10000/mm3 (high-risk APL). In all, 274 patients (68.7%) were included in APL 2006 trial and 125 (31.3%) were not included. Reasons for non-inclusion in APL 2006 trial were: 29 (7.3%) patients refusing or unable to give consent, 20 (5%) initial admissions in ICU, 20 (5%) older age (median age in those patients was 82.5 years, range 71–87) and/or comorbidities, 9 (2.3%) previous cancers, 11 (2.7%) contraindications to anthracyclines, 5 (1.4%) other exclusion criteria (pregnancy, HIV and poor socioeconomic conditions), 6 (1%) rapid deaths before ATRA onset and 25 (6.3%) unknown reasons. Patients not included in APL 2006 trial were characterized by older age (median 62 vs 47 years, P=0.0001) but a similar proportion of high-risk patients (30% vs 25%, P=0.39), whereas there were no significant differences for other baseline characteristics. Twenty of the 36 (55.5%) patients aged ⩾75 years and 20 of the 32 (62.5%) patients initially admitted in ICU were not included in APL 2006 trial.
Median interval from first abnormal blood count to ATRA onset was 1 day (Q1–Q3: 0–3), and <1 day, 1 day and >1 day in 28%, 26% and 46% of the patients, respectively. Similarly, median interval from hospitalization to ATRA onset was <1 day (Q1–Q3: 0–1) and <1 day, 1 day and >1 day in 51%, 24% and 25% of the patients, respectively. Finally, median interval from bone marrow aspirate to ATRA onset was also <1 day (Q1–Q3: 0–1) and was <1 day, 1 day and >1 day in 68%, 17% and 15% of the patients, respectively.
In patients not included in APL trial, 90 (72%) received ATRA plus anthracycline-based CT; 26 (24.2%) received ATRA plus non-anthracycline-based CT: 4 (3.2%) received ATRA plus ATO, 3 (2.6%) received ATRA plus AraC and ATO, and 15 (12%) received ATRA alone. The remaining nine non-included patients (7%) died without having received any treatment. Median age of those nine patients was 72 years and five had baseline WBC >10 000/mm3. In two of them, aged 71 and 84 years, attending physicians decided not to start treatment owing to major comorbidities, whereas one, aged 87, refused treatment. Of the remaining six patients, three were initially admitted in ICU, and all six died within 24 h of their admission, mainly due to central nervous system (CNS) bleeding.
CR was achieved in 362/399 (90.4%) of the patients, 9 patients died before treatment onset, 1 patient had resistant leukemia and 27 patients (6.9%) had ED after treatment onset. Causes of ED included DS (n=4), CNS bleeding (n=11, including 5 patients who died before treatment), sepsis (n=7), myocardial infarction (n=2), multiple organ failure (n=5) and uncertain (n=7). After exclusion of patients who died before receiving ATRA, ED was seen in 2.5% of patients included in APL 2006 trial and 17% of non-protocol patients (P<0.0001). Other prognostic factors of ED were older age (P=0.005) and initial admission in ICU (P<10−4), whereas high WBC (P=0.155) count had no significant impact.
None of the three intervals analyzed here (from first abnormal blood count, from hospitalization and from bone marrow aspirate to ATRA onset) had any influence on the ED rate. Moreover, 20 (64.5%) of the 31 patients admitted directly in ICU, 30 (83%) of the 36 patients aged 75 or greater, and 93 (86%) of the 108 high-risk patients achieved CR. Twenty-nine patients had prolonged intervals (⩾5 days) from hospitalization to ATRA onset, including three high-risk patients. Three of them, all with standard-risk APL at baseline, had ED.
Thus, in our series, the ED rate was 9.6%, and appeared lower than the 17–29% ED rates reported in several recent studies where protocol and non-protocol APL patients were included7, 8, 9, 10, 11, 12 (Table 2). Our results were closer to the 11% ED rate reported in another similar study.10 Reasons to explain those differences are uncertain. One would tend to attribute our relatively low ED rate to the fact that a large majority of patients were very rapidly admitted, and that ATRA was rapidly started, as soon as APL was suspected by bone marrow morphology: 51% of our patients received ATRA on the day of admission, 68% received ATRA on the day bone marrow aspirate was done and only 25% received ATRA >1 day after admission. Altman et al.10 reported that the percentage of ED secondary to bleeding increased significantly when the onset of ATRA was delayed beyond the day APL was suspected. In our study, we found no significant difference between patients who experienced ED and those who achieved CR when analyzing intervals from hospital admission to ATRA onset, but the number of patients with delay in treatment onset was quite small. Also of note was the fact that, in our report, all patients were diagnosed and treated after 2006, whereas the five previous reports analyzing EDs in APL included patients often diagnosed in the 1990s, when the importance of rapid onset of ATRA treatment was possibly less appreciated. Moreover, in a recent Canadian study, ED rate improved over time, suggesting that the importance of rapid treatment was less appreciated in the 1990s.12
In the present report, 31.3% of the patients were not included in the current French national trial, mainly owing to older age, comorbidities, direct admission in ICU and rapid death. Although the proportion of patients included in clinical trials was probably lower in the other reports, this number was available only in the Stanford University experience (10 of the 70 patients included in a clinical trial).9 Not unexpectedly, the outcome of non-protocol patients was significantly poorer than that of patients included in the trial (82% vs 97.5% CR). This was largely attributable to the higher incidence of ED seen in patients older than 75 and patients with direct admission to ICU. Older age was found to be a prognostic factor of ED in all previously published APL series.7, 8, 9, 10 Nevertheless, the CR rate of 83% in elderly patients remains quite high. As APL is not associated with a higher relapse risk in elderly patients, avoiding ED is a priority in that age group. Likewise, the CR rate of 64.5% observed in APL patients initially admitted to the ICU is rather high.
Although we probably captured all APL cases admitted in the 17 centers analyzed in this report, which were the largest centers treating APL patients in France, we cannot be certain that the proportion of patients included in APL 2006 trial was similar in other smaller French centers. In those centers, a potential higher proportion of non-protocol patients could potentially contribute to a higher ED rate. One could also argue that we overlooked some possible APL deaths occurring before reaching a hematology department. However, evaluating the number of those potential cases will always remain difficult, as those patients precisely do not reach specialized centers able to make a definite diagnosis of APL.
Thus, we found that, in large French centers, APL patients are generally rapidly admitted to the hospital where ATRA is rapidly started on the basis of morphological diagnosis. This may have contributed to the relatively low rate of ED (9.6%) observed. Avoiding ED in APL is particularly crucial given the low relapse rate now observed, even in high-risk patients.11 Whether substitution of ATRA–ATO regimens for ATRA–chemotherapy regimens, at least in standard-risk APL, will further reduce the ED rate, will have to be confirmed.
Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997; 337: 1021–1028.
Ades L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol 2006; 24: 5703–5710.
Sanz MA, Montesinos P, Rayon C, Holowiecka A, de la Serna J, Milone G et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010; 115: 5137–5146.
Lo Coco F, Avvisati G, Vignetti M, Fioritoni G, Liso V, Ferrara F et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation: results of the AIDA-2000 Trial of the Italian GIMEMA Group. blood 2004; 104: 392.
Montesinos P, Bergua JM, Vellenga E, Rayon C, Parody R, de la Serna J et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-transretinoic acid and anthracycline chemotherapy: characteristics, outcome and prognostic factors. Blood 2008; 113: 775–783.
De Botton S, Dombret H, Sanz M, Miguel JS, Caillot D, Zittoun R et al. Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1998; 92: 2712–2718.
Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2011; 118: 1248–1254.
Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Mollgard L et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 2011; 25: 1128–1134.
McClellan JS, Kohrt HE, Coutre S, Gotlib JR, Majeti R, Alizadeh AA et al. Treatment advances have not improved the early death rate in acute promyelocytic leukemia. Haematologica 2012; 97: 133–136.
Altman JK, Rademaker A, Cull E, Weitner BB, Ofran Y, Rosenblat TL et al. Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res 2013; 37: 1004–1009.
Kelaidi C, Chevret S, De Botton S, Raffoux E, Guerci A, Thomas X et al. Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience. J Clin Oncol 2009; 27: 2668–2676.
Paulson K, Serebrin A, Lambert P, Bergeron J, Seftel M et al. Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: a pan-Canadian epidemiological study. Br J Haematol 2014; 166: 660–666.
XT, CR, NV, JD, ED, PH, DB, J-BM, AS, CM, CP, PB, J-PM, MH-B, NF, ER and HD provided the data. RR collected the data. LD, PF and LA designed the research. RR, PF and LA wrote the paper. LA analyzed the data.
The authors declare no conflict of interest.
About this article
Cite this article
Rahmé, R., Thomas, X., Recher, C. et al. Early death in acute promyelocytic leukemia (APL) in French centers: a multicenter study in 399 patients. Leukemia 28, 2422–2424 (2014). https://doi.org/10.1038/leu.2014.240
All-trans retinoic acid 45 mg/m2 is superior to 25 mg/m2 as the first induction regimen for the treatment of acute promyelocytic leukaemia: a retrospective analysis in a real-world clinical setting
Blood Cancer Journal (2021)
Early Mortality in Children and Adolescents with Acute Promyelocytic Leukemia: Experience of the Boldrini Children’s Center
Journal of Pediatric Hematology/Oncology (2020)
No prognostic significance of normalized copy number of PML-RARA transcript at diagnosis in patients with acute promyelocytic leukemia
Hematology/Oncology and Stem Cell Therapy (2020)
RNA-sequencing of acute promyelocytic leukemia primary blasts reveals novel molecular biomarkers of early death events
Leukemia & Lymphoma (2020)
Safety and efficacy of arsenic trioxide and all-trans retinoic acid therapy in acute promyelocytic leukemia patients with a high risk for early death
Annals of Hematology (2020)