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Originally published as JCO Early Release 10.1200/JCO.2006.08.1596 on November 20 2006 © 2006 American Society of Clinical Oncology. Is Cytarabine Useful in the Treatment of Acute Promyelocytic Leukemia? Results of a Randomized Trial From the European Acute Promyelocytic Leukemia Group
From the Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Service d'Hématologie Clinique, Paris 13 University, Bobigny; Hospital Saint Louis; Hotel Dieu, Paris; Centre Hospitalier Universitaire (CHU), Lille; CHU Nancy; CHU Bordeaux; Institut Paoli-Calmettes, Marseille; CHU Rennes; CHU Toulouse; CHU Strasbourg; CHU Besancon; CHU Lyon; CHU Montpellier, France; Universitatsspital Basel, Basel, Switzerland; and the Université Catholique de Louvain, Brussels, Belgium Address reprint requests to Pierre Fenaux, MD, PhD, Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Service d'Hématologie Clinique, Paris 13 University, 125 rue de Stalingrad, 93009 Bobigny, France; e-mail: pierre.fenaux{at}avc.aphp.fr
PURPOSE: Several phase II studies have suggested that cytarabine (AraC) was not required in the treatment of newly diagnosed acute promyelocytic leukemia (APL) patients receiving all-trans-retinoic acid (ATRA), an anthracycline, and maintenance therapy, and we aimed at confirming this finding in a randomized trial. PATIENTS AND METHODS: Newly diagnosed APL patients younger than age 60 years with a WBC count of less than 10,000/µL were randomly assigned to receive either ATRA combined with and followed by three daunorubicin (DNR) plus AraC courses and a 2-year maintenance regimen (AraC group) or the same treatment but without AraC (no AraC group). Patients older than age 60 years and patients with initial WBC count of more than 10,000/µL were not randomly assigned but received risk-adapted treatment, with higher dose of AraC and CNS prophylaxis in patients with WBC counts more than 10,000/µL. RESULTS: Overall, 328 (96.5%) of 340 patients achieved complete remission (CR). In the AraC and the no AraC groups, the CR rates were 99% and 94% (P = .12), the 2-year cumulative incidence of relapse (CIR) rates were 4.7% and 15.9% (P = .011), the event-free survival (EFS) rates were 93.3% and 77.2% (P = .0021), and survival rates were 97.9% and 89.6% (P = .0066), respectively. In patients younger than age 60 years with WBC counts more than 10,000/µL, the CR, 2-year CIR, EFS, and survival rates were 97.3%, 2.9%, 89%, and 91.9%, respectively. CONCLUSION: These results support a role for AraC in addition to ATRA and anthracyclines in the treatment of newly diagnosed APL, at least using DNR at the cumulative dose we used and with the consolidation and maintenance regimens we used.
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by morphology,1 a life-threatening coagulopathy,2 and t(15;17)3 leading to the PML-RAR  4,5 chimeric protein that blocks myeloid differentiation.6 Until the late 1980s, anthracycline plus cytarabine (AraC) chemotherapy was the only treatment approach for APL.7-11 All-trans-retinoic acid (ATRA) can differentiate in vivo leukemic blasts into mature granulocytes in APL.12-15 Many studies, including our randomized APL 1991 trial, have shown that ATRA followed by anthracycline-AraC chemotherapy significantly decreased relapses and improved survival in newly diagnosed APL patients compared with chemotherapy alone.16,17 In a subsequent randomized trial (APL 1993), we found that early addition of anthracycline-AraC chemotherapy to ATRA and maintenance treatment with continuous low-dose chemotherapy (mercaptopurine plus methotrexate [MTX]) and intermittent ATRA further reduced the incidence of relapse to approximately 15%.18 However, this approach led to a mortality rate of 5% as a result of myelosuppression during consolidation and maintenance treatment, reaching 10% in elderly patients.19 Several groups, especially the Spanish Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) group (in their successive LPA96 and 99 trials), obtained high complete remission (CR) rates and low relapse rates in newly diagnosed APL patients by combining ATRA and anthracyclines without AraC, suggesting that avoiding AraC in the chemotherapy of APL reduced treatment toxicity without increasing relapses.20-23 However, none of those studies were randomized. We tried to confirm those findings in a phase III randomized trial challenging the role of AraC in addition to ATRA and anthracycline in newly diagnosed APL patients.
From June 2000 to February 2004, 356 patients with newly diagnosed APL from 63 centers in France, Switzerland, Germany, and Belgium were included in the APL 2000 trial. This trial was approved by ethical committees in all participating countries. Inclusion criteria were diagnosis of APL based on the French-American-British morphologic criteria, no contraindication to intensive chemotherapy, and written informed consent. Diagnosis had to be subsequently confirmed by presence of t(15;17) or PML-RAR gene rearrangement.
Study Design
Patients  60 years old with WBC count of less than 10,000/µL were randomly assigned to receive either the reference ATRA plus chemotherapy treatment of our previous trial, which included ATRA 45 mg/m2/d until hematologic CR and chemotherapy with daunorubicin (DNR) 60 mg/m2/d for 3 days and AraC 200 mg/m2/d for 7 days starting on day 3 of ATRA treatment (AraC group), or the same treatment but without AraC (no AraC group). Consolidation courses consisted of two DNR-AraC courses in the AraC group and two DNR courses in the no AraC group (Fig 1). Random assignment for induction was performed through a centralized telephone assignment procedure.
Patients Treatment of coagulopathy during the induction phase was based on platelet support to maintain platelets more than 50,000/µL until the disappearance of coagulopathy. The use of heparin, tranexamic acid, fresh frozen plasma, and fibrinogen transfusions was optional, according to each center's policy. Prophylaxis and treatment of ATRA syndrome was performed using high-dose dexamethasone if WBC count was more than 10,000/µL (before or during treatment with ATRA) or at the earliest sign of ATRA syndrome.24,25 In the absence of rapid (< 24 hours) improvement of symptoms, ATRA was transiently stopped until clinical control was obtained. In all patients, maintenance treatment combined continuous low-dose chemotherapy (mercaptopurine 90 mg/m2/d orally plus MTX 15 mg/m2/wk orally) and intermittent ATRA (ATRA 45 mg/m2/d for 15 days every 3 months) for 2 years. During this potentially myelosuppressive maintenance treatment, all patients had blood counts every second week. Follow-up blood counts were continued every 3 weeks after discontinuation of maintenance therapy. Hematologic CR was defined by normal bone marrow cellularity without abnormal promyelocytes, neutrophils more than 1,500/µL, platelets more than 100,000/µL, and no transfusion requirement. Molecular CR was defined as previously described.26-30 Treatment failures were classified as early death (death occurring during ATRA or chemotherapy or during the phase of aplasia, before CR has been reached, without evidence of leukemic resistance) and leukemic resistance. Hematologic relapse was defined by usual blood and marrow criteria, extrahematologic relapse was defined by the presence of blasts in other tissues, and molecular relapse was defined by the switch to positive reverse transcriptase polymerase chain reaction (RT-PCR) in patients who had previously become RT-PCR negative. Minimal residual disease was assessed by qualitative RT-PCR analysis for PML-RAR rearrangement performed on bone marrow cells at diagnosis, after consolidation chemotherapy, and during subsequent follow-up (every 3 months during the 2 first years and then every 4 months during the third year). RT-PCR tests were carried out by laboratories involved in a quality control program (sixth programme cadre de recherche et developpement [PCRD]). Techniques used were characterized by their rather high sensitivity (10–5 to 10–6) compared with lower sensitivity techniques used by several other groups.28 Overall, 300 (88%) of 340 patients had successful RT-PCR analysis at diagnosis and at least one point during follow-up, and 235 patients were successfully tested immediately after consolidation treatment. A median of three follow-up RT-PCR analyses were performed in these patients. The remaining 40 patients (12%) had no assessable RT-PCR follow-up because of a too small number of cells or RNA degradation in diagnosis and/or follow-up samples.
Outcomes
Statistical Analysis CR rates were compared using the Fisher's exact test. Censored end points were estimated by the nonparametric Kaplan-Meier method31 and then compared between randomized groups by the log-rank test,32 after checking for proportional hazards. Cox models were used to estimate hazard ratio (HR) of events with 95% CIs.33 Crude estimates, adjusted for imbalanced and prognostic covariates when appropriate, were computed. In estimating relapses, we took into account, for competing risks, deaths in first CR using the cumulative incidence curves and then compared results using the Gray test,34 whereas the Fine and Gray model35 was used to estimate subdistribution HR. Type I error was fixed at the 5% level. All tests were two tailed. Statistical analysis was performed on SAS 9.1 (SAS Inc, Cary, NC) and R software packages. The protocol scheduled three interim analyses, each performed at the nominal value of 0.01 to address an overall type I error rate of 0.05. The first interim analysis was performed in June 2004, at the reference date of October 1, 2003, in the 300 patients included before that date, dealing with the main end point and overall survival. This analysis led to early termination of the trial in June 2004 and trial amendment in patients still receiving consolidation courses. We present here the results of the second interim analysis performed at the reference date of May 1, 2005, based on all patients included in the trial before February 1, 2004 (ie, all patients who had received the original treatment schedule).
Early Termination of the Trial In the first interim analysis, which was made in the 300 initial patients included (172 of whom were assigned to the two random assignment arms), P value for testing equality of CIRs in randomly assigned groups was below this threshold, showing statistical significance and thus leading to discontinuation of random assignment. Indeed, a significantly higher incidence of relapse and lower EFS were seen in the no AraC group, leading to discontinuation of accrual in this group and in the elderly low-WBC group, who were also receiving treatment without AraC. Results of the second interim analysis are presented here.
Initial Characteristics of the Patients Clinical and hematologic characteristics of the patients are listed in Tables 1 and 2. Overall, median age was 47 years, including 8.0% children younger than 18 years and 70 patients (20.7%) older than 60 years. Ninety-two patients had WBC counts of more than 10,000/µL at diagnosis; 74 of these patients who were age 60 or younger were included in the young high-WBC group, and 18 patients older than 60 years were included in the elderly high-WBC group. Fifty-two patients older than 60 years with WBC count of less than 10,000/µL were included in the elderly low-WBC group. The remaining 196 patients were randomly assigned between the AraC (95 patients) and no AraC (101 patients) arms. Pretreatment characteristics were well-balanced between these two randomly assigned groups (Table 1).
Overall Results Median follow-up time was 35 months. Overall, 328 patients (96.4%) achieved hematologic CR, two had resistant leukemia, and 10 experienced early death as a result of bleeding (n = 5) or sepsis (n = 5). ATRA syndrome was observed in 37 patients (10.8%). Forty-four patients experienced relapse (36 hematologic relapses and eight molecular relapses), 13 died in first CR, and 271 were still alive in first CR. Deaths in CR occurred during consolidation treatment (n = 9) or maintenance treatment (n = 4) 36 to 325 days (median, 115 days) after CR achievement. Causes of death in CR included bleeding (n = 4), sepsis (n = 4), heart failure (n = 2), pulmonary embolism (n = 2), and relapse of a previous cancer (n = 1). The estimated 2-year CIR, EFS, and overall survival rates were 8.4% (95% CI, 5.3% to 11.5%), 84.5% (95% CI, 80.5% to 88.5%), and 91.9% (95% CI, 88.9% to 94.9%), respectively. No extrahematologic relapse (especially CNS relapse) was seen.
Results in Randomly Assigned Groups (AraC and No AraC Groups) Molecular CR at the end of consolidation treatment was achieved in 90% (65 of 72 patients) and 82% (57 of 69 patients) of the patients who were molecularly assessable at that point in the AraC and no AraC groups, respectively (P = .18; Table 1). The remaining patients had no assessable RT-PCR follow-up at that time point as a result of a too small number of cells or RNA degradation in bone marrow samples. During follow-up, similar blood monitoring and a similar number of bone marrow follow-up samples for RT PCR analysis (mean, three samples) were available in both treatment groups. Eight patients experienced relapse (including two molecular relapses) in the AraC group compared with 22 patients (including three molecular relapses) in the no AraC group. The 2-year CIR rate was 15.9% in the no AraC group compared with 4.7% in the AraC group (P = .011), and the 2-year EFS rate was 77.2% in the no AraC group compared with 93.3% in the AraC group (P = .0021; Fig 2). This difference in CIR remained statistically significant when only hematologic relapses were taken into account (CIR of 14.8% v 4.7% in no AraC and AraC groups, respectively; P = .015). The 2-year overall survival rate was significantly better in the AraC group than in the no AraC group (97.9% v 89.6%, respectively; P = .0066; Fig 2).
Because there were slightly more early deaths in the no AraC group than in the AraC group (four v one deaths, respectively), we also analyzed the overall survival of patients who had reached CR, which remained significantly different between the two groups (P = .026). Greater myelosuppression was observed in the AraC group, with significantly longer median days in hospital and on antibiotics and greater number of platelet and RBC transfusions during consolidation courses and, to a lesser extent, during the induction course (data not shown).
Results in Groups Not Randomly Assigned
In the elderly low-WBC group, the hematologic CR rate was 98.1% (51 of 52 patients), and the molecular CR rate after consolidation treatment was 88% (30 of 34 molecularly assessable patients). Seven patients experienced relapse, and five patients died in first CR, whereas 39 remained alive in first CR. The 2-year CIR, EFS, and overall survival rates were 9.4%, 79.1%, and 88.3%, respectively (Table 2). In the elderly high-WBC group, the hematologic CR rate was 88.9% (16 of 18 patients), and the molecular CR rate after consolidation treatment was 67% (six of nine molecularly assessable patients). Two patients experienced relapse, and one patient died in first CR, whereas 13 patients remained alive in first CR. The 2-year CIR, EFS, and overall survival rates were 6.3%, 77.8%, and 83.3%, respectively (Table 2).
Our results show that, in APL patients with WBC counts less than 10,000/µL (ie, standard-risk APL, considered at low risk of relapse with current regimens combining ATRA and chemotherapy for induction, consolidation chemotherapy, and maintenance with ATRA and mercaptopurine plus MTX),22 using DNR alone for chemotherapy instead of the classic DNR-AraC combination may lead to an increased risk of relapse. This higher risk of relapse also translated into significantly lower EFS and poorer survival. These results, obtained in a randomized trial, do not support recently published results, especially by the M.D. Anderson and Spanish PETHEMA groups20-21,23,36 (summarized in Table 3), that showed that ATRA and chemotherapy with an anthracycline alone for induction and consolidation followed by maintenance treatment resulted in very low relapse rates and could become a gold standard for the treatment of APL patients with a low WBC count. Although PETHEMA results were obtained in nonrandomized phase II studies, they were based on large numbers of patients with adequate follow-up.21-23
Several explanations for the different results between our study and the M.D. Anderson and PETHEMA group studies are possible. One possibility may be a better antileukemic activity of idarubicin and mitoxantrone (used in the PETHEMA trials) compared with DNR, which has already been suggested in several randomized AML trials, although not specifically in APL.37-39 Cumulative doses of anthracyclines used in the different trials may be another explanation. The PETHEMA group used cumulative doses of idarubicin and mitoxantrone of 80 mg/m2 (100 mg/m2 in LPA 99 trial for intermediate-risk patients) and 50 mg/m2, respectively, which may correspond to 130% to 150% of the cumulative anthracycline dose we used (495 mg/m2 of DNR).40 It has been suggested that higher cumulative doses of anthracyclines give better results in APL, including in a randomized trial performed before the ATRA era.9,11 Furthermore, in AML in general, the Cancer and Leukemia Group B also demonstrated the feasibility of administering substantially higher doses of DNR (90 mg/m2 x 3) in combination with AraC and etoposide during induction treatment.41 However, our cumulative dose of DNR was already relatively high (495 mg/m2). A higher cumulative dose may lead to cardiac toxicity. A third explanation may be the addition of ATRA during consolidation courses in the last PETHEMA LPA 99 trial, which could have contributed to better outcome in intermediate-risk patients, although such benefit would, of course, have to be confirmed in a randomized trial. Younger patients with WBC counts of more than 10,000/µL (ie, high-risk APL)22 treated with our standard APL regimen but with higher doses of AraC during the last consolidation course (2 g/m2/12 hours during 5 days) obtained a very high CR rate (97.3%) and had very few relapses (2.9%), supporting a role for treatment reinforcement to reduce relapses in APL patients with high WBC counts, either by high-dose AraC, as already suggested by the German study group,42 or by new approaches like arsenic derivatives.43-48 Finally, high-dose AraC and/or intrathecal chemotherapy probably contributed to the absence of CNS relapse observed in this group of patients at risk for this type of relapse.49 Results in elderly patients without a high WBC count, who were treated without AraC, showed high CR rates with very few early deaths, further supporting a role for reduction of the intensity of the first chemotherapy course in these patients. However, not unexpectedly, the relapse rate was similar to that seen in younger patients without a high WBC count treated in the no AraC group, suggesting that nonmyelotoxic agents active in APL (especially arsenic derivatives) may be required in addition to ATRA and anthracyclines in this population.43-48 The main conclusion of the randomized part of this trial, however, is that, at least with daunorubicin as the anthracycline and at the schedule and cumulative dose used and with the rest of the treatment program used (ATRA for induction and maintenance and low-dose maintenance chemotherapy), avoiding AraC leads to an increased risk of relapse in standard-risk newly diagnosed APL patients. This conclusion may not apply to other treatment schedules, with other anthracyclines, and so on. Whether other drugs, in particular arsenic derivatives, can replace AraC in this situation is also under investigation.
The following are members of the French APL Group: H. Dombret (Paris, Hopital Saint Louis), S. Castaigne (Versailles), R. Zittoun (Paris, Hotel Dieu), X. Thomas (Lyon), P. Travade (Clermont Ferrand), C. Gardin (Clichy), A. Guerci (Nancy), P. Fenaux (Bobigny, Paris 13), S. de Botton (Lille), A.M. Stoppa (Marseille), F. Dreyfus (Paris, Hopital Cochin), F. Stamatoulas (Rouen), F. Rigal-Huguet (Toulouse), H. Guy (Dijon), J.J. Sotto (Grenoble), F. Maloisel (Strasbourg), A. Pigneux, N. Milpied (Pessac), A. Gardembas (Angers), D. Bordessoule (Limoges), N. Fegueux (Montpellier), F. Lefrere (Paris, Hopital Necker), T. Lamy (Rennes), J.H. Bourhis (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), L. Sutton (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), 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, Hopital Saint Louis), V. Leblond (Paris, Hopital Pitié Salpétrière), C. Quetin (Pointe à Pitre), B. Pignon (Reims), E. Vilmer (Paris, Hopital Robert Debré), E. Bourquard (St Brieuc), J.P. Marolleau (Amiens), P. Robert (Toulouse), B. Despax (Toulouse), T. de Revel (Paris), and M. Janvier (St Cloud). The following are members of the 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). The following are members of the SAKK Swiss AML Group: M. Wernli (Aarau), A. Gratwohl (Basel), Th. Papst (Bern), M. Gregor (Luzern), F. Hitz (St Gallen), C. Sessa (Ticino), and E. Jacky (Zürich). The following are members of the Belgian groups: J.L. Michaux (Bruxelles), A. Bosly (Yvoir), E. Meeus (Anvers), and A. Boulet (Mons).
The authors indicated no potential conflicts of interest.
published online ahead of print at www.jco.org on November 20, 2006. Supported by the Programme Hospitalier de Recherche Clinique and the Centre Hospitalier Universitaire of Lille-France, the Association pour la Recherche sur le Cancer, and the Ligue Contre le Cancer (Comité du Nord). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10,000/µL (young high-WBC group) received the same treatment as patients age 
