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Journal of Clinical Oncology, Vol 22, No 8 (April 15), 2004: pp. 1404-1412 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.008 Outcome of Childhood Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid and ChemotherapyAddress reprint requests to P. Fenaux, MD, PhD, Service d’Hématologie Clinique, Hôpital Avicenne, 125 route de Stalingrad, 93009 Bobigny, France; e-mail: pierre.fenaux{at}avc.ap-hop-paris.fr
PURPOSE: To determine the results of treatment combining all-trans-retinoic acid (ATRA) and chemotherapy (CT) in childhood acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Children (< 18 years) with newly diagnosed APL were included in the APL93 trial, treated by ATRA followed or combined with daunorubicin-cytarabine, and then randomly assigned between no maintenance, intermittent ATRA, continuous CT, or both. RESULTS: Of the 576 patients included in APL93 trial, 31 (5%) were children, including 22 girls (71%) and nine boys (29%). Thirty of the children (97%) obtained complete remission (CR). ATRA syndrome occurred in four children (13%), who all achieved CR, and headaches occurred in 12 children (39%), with signs of pseudotumor cerebri in five children (16%). Seven patients (23%) relapsed. None of the eight patients who received both ATRA and CT for maintenance relapsed. All relapsing patients achieved a second CR. Twenty-two patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients had died. The 5-year event-free survival (EFS), relapse, and overall survival rates were 71%, 27%, and 90%, respectively. No difference between adults and children included in the APL93 trial was seen for CR rate, 5-year relapse rate, EFS, and overall survival, but significantly better survival was seen in children after adjustment on WBC counts (P = .02) and incidence of microgranular M3 variant (P = .04). CONCLUSION: ATRA combined with CT for induction and also probably for maintenance provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.
Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia (AML) characterized by the morphology of blast cells (M3 in the French-American-British classification),1,2 presence of the t(15;17)3 translocation, leading to a fusion between the PML gene, situated in 15q, and the RAR  gene situated in 17q,4,5 and by specific coagulopathy.6,7 Treatment combining all-trans-retinoic acid (ATRA), a differentiating agent, and conventional anthracycline-cytarabine chemotherapy (CT) has improved the prognosis of APL, compared with CT alone, by slightly increasing the complete remission (CR) rate but mainly by reducing the relapse rate.8-14
APL is rare in children (approximately 10% of childhood AML) and is characterized by more frequent incidence of hyperleukocytosis,15 microgranular M3 variant (M3v),15-17 and bcr218 and bcr315,17 isoforms of PML-RAR When CT was the sole treatment option in APL, outcome in children was, at best, equal or less favorable than in adults because of a higher incidence of relapses in some series.19-23 Limited studies24-27 have analyzed the impact of ATRA on outcome of children with APL and its tolerance in that age range. Among the 576 patients included in a European APL trial (APL93 trial) combining ATRA and CT, 31 were younger than 18 years old. Their characteristics and outcome are analyzed here.
We analyzed the characteristics and outcome of children (aged < 18 years) included in a European trial (APL93 trial) combining ATRA and CT in the treatment of newly diagnosed APL. Inclusion criteria of the APL93 trial were diagnosis of APL based on morphology criteria, age 75 years or less, written informed consent of the patient or of parents for children. Diagnosis had to be subsequently confirmed by the presence of t(15;17) or PML-RAR gene rearrangement. In the absence of t(15;17) and if no analysis of the rearrangement could be made, review of initial marrow slides by an independent morphologist was mandatory.
Protocol Design In children, when severe headaches or other signs suggesting benign intracranial hypertension (pseudotumor cerebri, including nausea, vomiting, and visual disturbance) occurred, the ATRA dose was reduced to 25 mg/m2/d. Treatment of coagulopathy during the induction phase was based on platelet support to maintain the platelet count above 50 x 109/L until disappearance of coagulopathy. The use of heparin, tranexamic acid, fresh frozen plasma, and fibrinogen transfusions was optional. CR patients received two CT consolidation courses, including course 2 (identical to course 1) and course 3, consisting of DNR 45 mg/m2/d for 3 days and cytarabine 1 g/m2 every 12 hours for 4 days. Three to 4 weeks after hematologic recovery from this consolidation chemotherapy, patients who were still in CR were randomly assigned both to receive or not to receive intermittent ATRA (45 mg/m2/d, 15 days every 3 months) and to receive or not to receive continuous CT with mercaptopurine (90 mg/m2/d, orally) and methotrexate (15 mg/m2/wk, orally), according to a two-by-two factorial design stratified on the initial induction treatment group. Maintenance treatment was scheduled for 2 years. Randomizations for induction and maintenance were performed through a centralized telephone assignment procedure.
Diagnosis and Treatment of ATRA Syndrome
End Points For maintenance treatment, the time to relapse, which was calculated from the date of randomization for maintenance, was the major end point. Overall survival and EFS, which were calculated for the date of this randomization, were secondary end points.
Statistical Methods
Pretreatment Characteristics Between April 1993 and October 1998, 576 patients with newly diagnosed APL from 97 European centers were included in the APL93 European trial. Thirty-one of the patients (5%) were aged less than 18 years. Diagnosis of APL was confirmed by the presence of t(15;17) using conventional cytogenetic methods (n = 25), by the presence of PML-RAR transcript by reverse transcriptase polymerase chain reaction (n = 3), or by review of marrow slides (n = 3). Pretreatment characteristics of the 31 children patients are listed in Table 1. Median age was 15 years (range, 12 months to 17 years), with five children (16%) aged 3 years or less (Fig 1). The 31 patients included 22 girls (71%) and nine boys (29%). Clinical symptoms included fever in 58% of patients, documented infection in 13%, and bleeding in 80% (cutaneous in 75%, mucous in 59%, at the site of venous punctures in 43%, at fundus oculi in 19%, and in CNS in 3%). Organomegaly was present in five (16%) of 31 patients, including splenomegaly (n = 5) and hepatomegaly (n = 2). Extramedullary disease was present in one patient (documented skin involvement).
Median WBC count was 6,500/mm3 (range, 0.8 to 148,000/mm3). Thirteen of the 31 patients (42%) had WBC count greater than 10,000/mm3, and seven (23%) of 31 patients had WBC greater than 25,000/mm3. Morphologically, 21 patients (68%) had classical M3, and 10 patients (32%) had the M3v. Twenty-two patients had t(15;17) translocation as sole rearrangement, and three of the patients (11%) with detectable t(15;17) had additional chromosomal abnormalities. PML-RAR rearrangement was found in the 16 patients tested, with bcr1 isoform in six patients (37.5%), bcr2 isoform in four patients (25%), and bcr3 isoform in six patients (37.5%). Nineteen patients (61%), who had initial WBC more than 5,000/mm3, were included in the high WBC group, eight (26%) and four (13%) in the ATRA  CT and ATRA+CT groups, respectively.
Results of Induction Therapy ATRA syndrome occurred in four patients (13%) after 2, 2, 4, and 21 days of treatment with ATRA, respectively. Three of the four patients had been included in the high WBC group (initial WBC: 8,900, 9,000, and 101,000/mm3, respectively), and the remaining patient had been randomly assigned to the ATRA+CT group. Clinical signs or symptoms of ATRA syndrome included respiratory distress with lung infiltrates in four patients, fever in three patients, hypotension in three patients, pleural effusion in two patients, weight gain in two patients, and renal failure in one patient. Mechanical ventilation was required in two patients. ATRA was stopped in three of the four patients, and all the patients received DXM during 5 to 23 days. All four patients achieved CR. Other side effects of ATRA treatment included headaches in 12 patients (39%), which was isolated in seven patients and associated with other signs of benign intracranial hypertension (pseudotumor cerebri, including, nausea, vomiting, or visual disturbances) in five patients. In the five patients with pseudotumor cerebri, dose reduction of ATRA to 25 mg/m2/d was required in four patients and discontinuation of ATRA with addition of DXM in one patient. The dose of ATRA remained at 45 mg/m2/d in patients with moderate headache. Reversible cardiomyopathy with congestive heart failure attributed to anthracyclines, in the absence of other causes, was seen in one patient during induction treatment. Severe infection was observed during induction treatment in five patients (23%), including septicemia in three patients and pulmonary infection in two patients.
Postremission Outcome
Therefore, 27 patients were eligible for second randomization. Six were not randomized because of ATRA toxicity during induction treatment (n = 2) or medical decision (n = 4), and they received no maintenance (n = 2), maintenance CT alone (n = 3), or ATRA and CT (n = 1). Twenty-one patients were randomly assigned to maintenance and were allocated to no maintenance (n = 2), intermittent ATRA alone (n = 6), CT alone (n = 6), or both (n = 7). One patient refused maintenance treatment after randomization, and one randomized patient relapsed before the onset of maintenance treatment. In patients randomly assigned to maintenance, dose reduction of ATRA was required in two patients because of headaches, and dose reduction of maintenance CT was required in 10 patients because of cytopenias and/or liver enzymes elevation.
Seven patients relapsed after 4 to 36 months, including the patient who received syngeneic BMT, one patient before the onset of maintenance, two patients not randomized to maintenance therapy who received no maintenance treatment (one patient) and CT alone (one patient), one of the two patients allocated to no maintenance therapy, and two of the five patients allocated to ATRA alone (relapses occurred 3 to 8 months after the end of ATRA maintenance therapy) but none of the eight patients who received ATRA+CT for maintenance. Three of the children younger than 3 years relapsed. Six of the seven relapses occurred in the high WBC group, one occurred in the ATRA All relapsing patients achieved a second CR with treatment combining ATRA and CT (five patients), ATRA alone (one patient), and CT alone (one patient). After second CR achievement, three patients received autologous peripheral stem-cell transplantation (all were in molecular remission at the time of stem-cell collection), two patients underwent a matched-sibling allogeneic BMT, the patient who received syngeneic BMT underwent a second syngeneic BMT, and the patient with isolated cutaneous relapse received local irradiation, followed by maintenance therapy combining intermittent ATRA and continuous low-dose CT. One of the allografted patients died in second CR from graft-versus-host disease, and the six other patients remained in second CR after 17+ to 66+ months, all in molecular remission. The second CR duration was greater than the first in five of the six patients still alive. Overall, 22 patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients died. Median follow-up was 67 months. Median follow-up was not reached for EFS and overall survival. The 5-year EFS, relapse, and overall survival rates were 71% (range, 62.5% to 80%), 27% (range, 9% to 45%), and 90% (range, 80% to 100%), respectively. There was no difference in EFS, relapse rate, and overall survival by sex. No long-term cardiac complication was reported.
Comparison Between Children and Adults
The incidence of ATRA syndrome was similar in children (12.9%) and adults (14.6%, P = .99), but there was a trend for a higher incidence of severe headaches in children (20%) compared with adults (9%, P = .083). Hematologic, renal, and liver toxicities were similar in the two age groups. No difference between adults and children was seen for CR rate (97% v 94%, P = .99), incidence of relapse at 5 years (27% v 28%, P = .95), EFS at 5 years (71% v 68%, P = .41; Fig 3), and overall survival at 5 years (90% v 77%, P = .10). However, after adjustment for WBC counts at diagnosis and M3v forms, significantly better survival (P = .02 and P = .04, respectively) was seen in children. There was a trend for better EFS (P = .09) after adjustment for WBC counts but not for M3v (P = .23). No difference for relapse was seen after adjustment for WBC counts and M3v.
Characteristics of childhood APL in this series were generally similar to those previously reported in the literature, where children accounted for 6% to 13% of all APL patients included in large trials (5% in this study).12-14 As in most reports, we found in children a higher incidence of M3v15-17 and bcr218 and bcr3 isoforms15-17 and higher WBC counts than in adults. As in previous series,19,20,27,32 median age of the child population was relatively high (ie, 15 years). However, a previously unreported bimodal age distribution was found in our series, with 16% of the patients being younger than 3 years. The predominance of girls that we observed was found in one study 20 but not in others.24-27 We found a significantly lower incidence of cytogenetic rearrangements in addition to t(15;17) in children (11%) compared with adults (27%).33 A low incidence (13%) of additional chromosomal abnormalities has also been previously reported in one childhood series,19 but no comparison with adults was available. Other reported characteristics of childhood APL, by comparison to adults, include a high incidence of CD2 and CD34 expression, which is generally correlated with bcr3 isoform and M3v.34 Few studies of childhood APL treated with ATRA have been published (Table 3). 24-27 The CR rates for ATRA alone or treatment combining ATRA and anthracycline-based CT ranged from 67% to 95%, with long-term EFS of 67% to 76%. Only one previous report26 observed low CR rates (67%), but, in that study, patients received ATRA during only a mean of 9 days, a regimen that has proved inferior to a longer course of ATRA both for CR achievement and CR duration in adult APL.12 As in adults, CR duration was brief when ATRA was used as the sole agent.35,36 Our study confirms that high CR rates can be achieved with ATRA combined with or followed by CT in childhood APL.
ATRA syndrome is the major complication of ATRA treatment.37,38 Its incidence was similar in our child and adult population and close to that found in previous childhood APL studies treated with ATRA.24-27 As in adults,38,39 we found no recurrence of the syndrome during maintenance therapy with ATRA. Other side effects of ATRA, mainly seen in children, are headaches, which are sometimes associated with signs suggesting cerebral tumor (pseudotumor cerebri).40-42 In our series, headaches were more frequent in children than in adults. Several studies have shown that the increased neurotoxicity of ATRA in children, which is dose dependant and possibly predominates in younger children (< 10 years), is not a result of differing pharmacodynamic properties between adults and children.43,44 Although the maximum-tolerated dose has been reported to be 60 mg/m2/d,43,44 previous reports have shown that signs of pseudotumor cerebri were generally observed with daily ATRA dosing of 45 mg/m2/d (up to 55%).45 One study (although with 9-cis-retinoic acid rather than ATRA) showed that those signs were reduced at lower doses (ie, 35 mg/m2/d).46 In the present report, in which ATRA dosing was 45 mg/m2/d, headaches occurred in 39% of the children but were severe, with signs of pseudotumor cerebri, in only five patients for whom dose reduction to 25 mg/m2/d or even discontinuation of the drug were required. Whether ATRA dosing should be systematically reduced from the onset in children or only in case of relatively important headaches is a matter of discussion. Indeed, it has been shown that the CR rate achieved with ATRA in APL was similar at 25 and 45 mg/m2/d.47 However, it is unknown whether the additive effect of ATRA at 45 mg/m2/d to CT in reducing the relapse rate remains similar at lower ATRA doses, although this could be suggested by the favorable long-term results observed by Mann et al27 with 25 mg/m2/d. In that study, the incidence of headaches was somewhat lower than in our patients (22%), but the incidence of pseudotumor cerebri was similar (5%). Severe headaches were observed during maintenance therapy in two of the 14 children who received ATRA alone or in combination with CT in our experience. Thus, careful neurologic and ophthalmologic examination of children on maintenance therapy with ATRA is warranted. The relapse rate was 27% at 5 years in the present series, similar to that observed in adults,8-14 including after adjustment for WBC counts and M3v forms, two major risk factors for relapse in APL. Our findings are similar to those of Hirota et al24 and Mann et al.27 In APL, irrespective of age, it has been clearly shown that the combination of ATRA and CT reduced the incidence of relapse compared with CT alone.9,10,13 It is also strongly suggested that maintenance with ATRA and/or continuous low-dose CT, can further reduce relapses.9,13 Therefore, it is of note that none of the patients who received maintenance with both ATRA and low-dose CT relapsed, confirming the interest of that approach. Importantly, four of the five children younger than 3 years old had high WBC counts at diagnosis, and three relapsed. It will be important to determine in larger numbers of cases whether a higher incidence of relapses is found in younger children because this might suggest that a more intensive approach is required in that age range. Also of note is that all relapsing patients could be successfully treated with salvage therapy of ATRA, CT, or both and that, with intensification followed by allogeneic or autologous stem-cell transplantation, no subsequent relapse occurred, and the second CR duration was greater than the first in five of the relapses. This better outcome of relapses in children compared with adults (data not shown) was probably a result, at least in part, of the fact that all relapsing children could subsequently receive an intensification with auto- or allograft. It possibly explained in part the better survival of children over adults, which was observed, however, only after adjustment for M3v forms and WBC counts. Interestingly, the favorable outcome of relapses was observed, although none of the relapsing patients received arsenic derivatives. With arsenic trioxide, which is now considered the reference treatment of APL that recurs after ATRA treatment, the United States Intergroup48 obtained a second remission in three of five relapsing children with limited side effects. In conclusion, our results confirm, in a relatively large series, that first-line treatment with ATRA combined with CT for induction and also probably for maintenance therapy provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.
The appendix is included in the full-text version of this article, available on-line at http://www.jco.org. It is not included in the PDF (via Adobe® Acrobat Reader®) version. Dr P. Fenaux and Dr L. Degos served as cochairmen, and Dr C. Chastang and S. Chevret-Chastang (Department of Biostatistics, Hopital St Louis, Paris, France) served as biostaticians. The following clinical departments participated in APL93 trial: French APL group: S. Castaigne, H. Dombret (Paris), R. Zittoun (Paris), E. Archimbaud (Lyon), P. Travade (Clermont Ferrand), C. Gardin (Clichy), A. Guerci (Nancy), S. de Botton (Lille), A.M. Stoppa (Marseille), F. Dreyfus (Paris), F. Stamatoulas (Rouen), F. Rigal-Huguet (Toulouse), H. Guy (Dijon), J.J. Sotto (Grenoble), F. Maloisel (Strasbourg), J. Reiffers (Pessac), A. Gardembas (Angers), D. Bordessoule (Limoges), N. Fegueux (Montpellier), A. Veil (Paris), T. Lamy (Rennes), M. Hayat (Villejuif), E. Deconinck (Besancon), E. Guyotat (St Etienne), M. Martin (Annecy), E. Cony-Makhoul (Bordeaux), J.P. Abgrall (Brest), O. Reman (Caen), B. Desablens (Amiens), J.L. Harousseau (Nantes), Y. Bastion (Lyon), J.P. Pollet (Valenciennes), J. Pulik (Argenteuil), M. Lepeu (Avignon), M. Renoux (Bayonne), P. Morel (Lens), P. Henon (Mulhouse), N. Gratecos (Nice), P. Colombat (Tours), D. Machover (Villejuif), A. Dor (Antibes), P. Casassus (Bobigny), J. Donadio (Castelnou), B. Salles (Chalon), B. Legros (Clermont Ferrand), P. Audhuy (Colmar), A. Dutel (Compiègne), N. Philippe (Lyon), B. Benothman (Meaux), C. Christian (Metz), C. Margueritte (Montpellier), F. Witz (Nancy), A. Pesce (Nice), A. Baruchel (Paris), L. Sutton (Paris), C. Quetin (Pointe à Pitre), B. Pignon (Reims), E. Vilmer (Paris), E. Bourquard (St Brieuc), J.P. Marolleau (Paris), P. Robert (Toulouse), B. Despax (Toulouse), G. Nedellec, P. Auzanneau (Paris), and M. Janvier (St Cloud). Spanish AML group: O. Rayon (Oviedo), M. Sanz (Valencia), J. San Miguel (Salamanca), J. Montagud (Valencia), E. Condé (Santander), P. Javier de la Serna (Madrid), G. Martin (Valencia), M. Perez Encinas (Santiago), J.P. Torres Carrete (Juan Canalejo), J. Zuazu (Barcelone), J. Odriozola (Madrid), E. Gomez-Sanz (Madrid), L. Palomera (Zaragoza), L. Villegas (Almeria), A. Deben (Juan Canalejo), and P. Besalduch (Palma de Mallorca). Cooperative AML study group, Germany: H. Link (Hannover), A. Ganser (Frankfurt), E. Wandt (Nurnberg), A. Breitenbach (Stuttgart), B. Brennscheidt (Freiburg), D. Herrmann (Ulm), H. Soucek (Dresden), and H. Strobel (Erlangen). SAKK Swiss AML group: K. Geiser (Berne), M. Fey (Berne), T. Egger (Berne), and E. Jacky (Berne). Belgian groups: J.L. Michaux (Bruxelles), A. Bosly (Yvoir), E. Meeus (Anvers), and A. Boulet (Mons). Dutch groups: P. Daenen (Groningen) and P. Muus (Nijmegen).
The authors indicated no potential conflict of interest.
A complete listing of participants may be found in the online-only Appendix. From the European APL Group. Supported by the Programme Hospitalier de Recherche Clinique (Centre Hospitalier Universitaire Lille), the Association de Recherche contre le Cancer, and the Ligue Nationale contre le Cancer (Comité du Nord). S.d.B. and V.C. contributed equally to this work. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
.05 denoting statistical significance. 
