Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7632-7640
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.01.3359
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ortega, J. J.
Right arrow Articles by Sanz, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ortega, J. J.
Right arrow Articles by Sanz, M. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Treatment With All-Trans Retinoic Acid and Anthracycline Monochemotherapy for Children With Acute Promyelocytic Leukemia: A Multicenter Study by the PETHEMA Group

Juan J. Ortega, Luis Madero, Guillermo Martín, Amparo Verdeguer, Purificación García, Ricardo Parody, José Fuster, Antonio Molines, Andrés Novo, Guillermo Debén, Antonia Rodríguez, Eulogio Conde, Javier de la Serna, María J. Allegue, Francisco J. Capote, José D. González, Pascual Bolufer, Marcos González, Miguel A. Sanz

From the Hospital Universitario Materno-Infantil Vall D'Hebron, Barcelona; Hospital Niño Jesús, Madrid; Hospital Universitario La Fe, Valencia; Hospital Universitario La Fe (Infantil), Valencia; Hospital La Paz (Infantil), Madrid; Hospital Universitario Virgen del Rocío, Sevilla; Hospital Universitario Virgen de la Arrixaca (Pediatría), Murcia; Hospital Materno-Infantil de Las Palmas; Hospital Son Dureta, Palma de Mallorca; Hospital Juan Canalejo, La Coruña; Hospital Reina Sofía, Córdoba; Hospital Universitario Marqués de Valdecilla, Santander; Hospital 12 de Octubre, Madrid; Hospital Montecelo, Pontevedra; Hospital Universitario Puerta del Mar, Cádiz; Hospital Insular de Las Palmas; and Hospital Universitario de Salamanca, Spain

Address reprint requests to Miguel A. Sanz, Servicio de Hematología, Hospital Universitario La Fe, Avenida Campanar 21, 46009 Valencia, Spain; e-mail: msanz{at}uv.es


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: To analyze the simultaneous combination of all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for children with acute promyelocytic leukemia (APL).

PATIENTS AND METHODS: Since November 1996, 66 children (younger than 18 years) with genetically proven APL received induction therapy with ATRA and idarubicin. Consolidation therapy consisted of three courses of anthracycline monochemotherapy. After November 1999, patients with intermediate and high risk of relapse received consolidation therapy with ATRA and slightly reinforced doses of idarubicin. Maintenance therapy consisted of ATRA and low-dose mercaptopurine and methotrexate.

RESULTS: Thirty-nine girls (59%) and 27 boys (41%) were included in this study. The WBC count at presentation was more than 10 x 109/L in 26 patients (39%). Sixty-one children (92%) achieved complete remission (CR). Early deaths from hemorrhage and retinoic acid syndrome occurred in three patients and two patients, respectively. Toxicity was manageable during consolidation and maintenance therapy. No deaths in CR, clinical cardiomyotoxicity, or secondary malignancy occurred. Two patients had molecular persistence at the end of consolidation. Three clinical relapses and two molecular relapses were also observed. Apart from one molecular relapse, all these events occurred among children with hyperleukocytosis. The 5-year cumulative incidence of relapse was 17%, whereas disease-free and overall survival rates were 82% and 87%, respectively.

CONCLUSION: A high incidence of hyperleukocytosis in children with APL was confirmed. Besides low toxicity and a high degree of compliance, a risk-adapted therapy combining ATRA and anthracycline monochemotherapy showed an antileukemic efficacy comparable to those previously reported with other chemotherapy combinations in children.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
Acute promyelocytic leukemia (APL) is a rare malignant disorder affecting 4% to 11.5% of children with acute myeloblastic leukemia.1-6 APL in children is characterized by a higher incidence of hyperleukocytosis (defined as WBC count greater than 10 x 109/L) than in adults,7,8 which is usually associated with an increased incidence of microgranular morphologic subtype9-11 and PML/RAR{alpha} isoforms BCR212 and BCR3.7,9-11

Outcomes for children and adults with APL have dramatically changed since the introduction of all-trans retinoic acid (ATRA) therapy. On the basis of several large multicenter trials,13-20 the current recommendations for treatment of patients with APL include ATRA and anthracycline-based chemotherapy for the induction of remission, anthracycline-based chemotherapy for consolidation, and ATRA combined with low-dose chemotherapy for maintenance.21 However, as far as we know, only two relatively small pediatric series from the German-Austrian-Swiss group22 and the European APL group,7 as well as the largest pediatric series from the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA),23 have reported therapeutic results using state-of-the-art approaches.

We report here the disease characteristics and therapy outcomes from 66 consecutive children (younger than 18 years) with newly diagnosed PML/RAR{alpha}-positive APL, who were enrolled in two sequential studies of the PETHEMA Group (Programa de Estudio y Tratamiento de las Hemopatías Malignas).18,20 They were treated with the same strategy and chemotherapy as adult patients, except for a reduction in the ATRA dose from 45 to 25 mg/m2/d in all therapeutic phases.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
Eligibility
Patients aged less than 18 years with de novo APL with demonstration of the t(15;17) or PML/RAR{alpha} rearrangements were included. Other eligibility criteria were (1) normal hepatic and renal functions, (2) no cardiac contraindications for anthracycline chemotherapy, and (3) Eastern Cooperative Oncology Group performance status less than 4.

Informed consent from parents or legal guardians was obtained for all children. Institutional review board approval was required.

Induction Therapy
The induction regimen consisted of oral ATRA (25 mg/m2/d), divided into two daily doses, which was maintained until complete remission (CR), or for a maximum of 90 days, and idarubicin (12 mg/m2/d) given as an intravenous bolus dose on days 2, 4, 6, and 8.

Treatment was started as soon as a diagnosis of APL had been made by cytologic criteria.24,25 For patients in whom the diagnosis was not confirmed by genetic studies, ATRA treatment was withdrawn and alternative chemotherapy was given at the physician's discretion.

Consolidation Therapy
Between November 1996 and October 1999 (LPA96 study), all patients in CR received three monthly consolidation courses. The first course consisted of idarubicin (5 mg/m2/d on days 1 to 4), the second of mitoxantrone (10 mg/m2/d on days 1 to 5), and the third of idarubicin (12 mg/m2 on day 1).

From November 1999 (LPA99 study), intermediate- and high-risk patients (see Definitions and Study End Points) received ATRA (25 mg/m2/d for 15 days) combined with reinforced single-agent chemotherapy courses.20 To reinforce chemotherapy of consolidation, the idarubicin dose in the first course was increased to 7 mg/m2/d, and idarubicin was administered for two consecutive days instead of one day in the third course.

Maintenance Therapy
After completion of consolidation, patients who tested negative for PML/RAR{alpha} (see Laboratory Studies) were started on oral mercaptopurine (50 mg/m2/d), intramuscular methotrexate (15 mg/m2 per week) and oral ATRA (25 mg/m2/d) for 15 days every 3 months. Doses of mercaptopurine and methotrexate were decreased by 50% if the WBC count was less than 3.5 x 109/L and discontinued if it was less than 2.5 x 109/L. Maintenance therapy was continued for 2 years. Maintenance therapy was also temporarily reduced or discontinued at the physician's discretion in case of abnormal liver function tests (≥ 3x the upper limit of normal values).

CNS prophylaxis was not given in these studies.

Supportive Therapy
Coagulopathy, loosely defined by hypofibrinogenemia, increased fibrinogen-fibrin degradation products, elevated levels of D-dimer, and prolonged prothrombin and thrombin times, was treated with fresh frozen plasma or fibrinogen. Platelet transfusions were given to maintain a platelet count above 30 x 109/L until resolution of any significant sign of coagulopathy. Once the coagulopathy was under control, platelet transfusions were given when the platelet count dropped below 20 x 109/L or more liberally for patients with infectious or hemorrhagic manifestations. In the LPA99 study, tranexamic acid (100 mg/kg/d) was administered by continuous intravenous infusion until the platelet count was higher than 50 x 109/L. As prophylaxis for retinoic acid syndrome (RAS), patients in the LPA99 study received prednisone (0.5 mg/kg/d) on days 1 through 15. At the first signs of suspected RAS, ATRA was temporarily discontinued and patients were given 10 mg of dexamethasone every 12 hours.

Laboratory Studies
Bone marrow samples were obtained at diagnosis, after induction, after the last cycle of consolidation, and periodically during maintenance and beyond, as reported elsewhere.18 In addition to morphologic evaluation, samples were processed for RNA extraction and reverse transcriptase–polymerase chain reaction (RT–PCR) for detecting PML/RAR{alpha}. RT–PCR tests were carried out by 14 different laboratories involved in an external quality control program, which included inter-laboratory exchange of samples, as reported.26,27 If a PCR-positive or doubtful result was reported after consolidation or beyond, a new bone marrow sample was obtained 2 to 4 weeks later and sent to one of two of the reference laboratories.

Definitions and Study End Points
Response criteria were defined according to the recently revised criteria by Cheson et al.28 According to Frankel et al,29 RAS was defined as definitely present, indeterminate, or definitely absent.

Risk of relapse was established at diagnosis according to a predictive model on the basis of patient leukocyte and platelet counts at diagnosis, as reported.30 Low-risk patients had a WBC count equal to or less than 10 x 109/L and a platelet count more than 40 x 109/L; intermediate-risk patients had a WBC ≤ 10 x 109/L and a platelet count ≤ 40 x 109/L; and high-risk patients had a WBC count greater than 10 x 109/L.

Statistical Analyses
Rates of CR were evaluated using contingency tables. Un-adjusted time-to-event analyses were performed using the Kaplan-Meier method31 and, for comparisons, the log-rank tests.32 The probability of relapse was also estimated by the cumulative incidence method (marginal probability).33,34 For all estimates in which the event relapse was considered as an end point, hematologic and molecular relapses, as well as molecular persistence, were each considered as uncensored events. The follow-up of the patients was updated on June 30, 2004. All P values reported are two-sided. Multivariate analysis was performed using the Cox proportional hazards model.35 Except for the cumulative incidence method, computations were performed using the 4F, 1L, and 2L programs from the BMDP statistical library (BMDP Statistical Software, Los Angeles, CA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
Accrual and Patient Characteristics
Between November 1996 and June 2004, 639 consecutive patients with newly diagnosed APL from Spain, the Netherlands, Belgium, Argentina, and the Czech Republic, were included in the PETHEMA LPA96 and LPA99 studies. Sixty-seven of the patients (10.5%) from 35 institutions (see Appendix) were aged less than 18 years. One patient was ineligible for the study because of secondary APL. The main clinical and biologic characteristics of the remaining 66 patients assessable for induction in this series are shown in Table 1 .


View this table:
[in this window]
[in a new window]
  		Table 1. Characteristics of Children With APL and Results of Induction

 
Induction Therapy
Of these 66 patients, 61 achieved hematologic CR (92%; 95% CI, 85% to 98%). The remaining five children died early because of hemorrhage (two pulmonary, one cerebral) and RAS (two children). The low number and variety of causes of failures prevented us from analyzing the prognostic impact of the characteristics at presentation and of prophylactic measures (prednisone and tranexamic acid) in the response rate. Age distribution, response to induction therapy, and causes of failure are shown in Figure 1.



View larger version (4K):
[in this window]
[in a new window]
  		Fig 1. Age distribution of the 66 children with acute promyelocytic leukemia, response to induction therapy, and causes of failure. CR, complete remission; RA, retinoic acid.

 
RAS was definitely present in three patients (4.5%), two of whom died from it (aged 3 and 6 years). An indeterminate RAS was reported in 10 children (15%). Despite prednisone prophylaxis, the incidence of indeterminate and definitely present retinoic acid syndrome in the LPA99 study was not statistically different to that observed in the LPA96 trial (17% v 28%; P = .3). The ATRA therapy was temporarily discontinued in nine children (14%) because of presumed RAS. Therapy recommenced within a median time of 3 days (range, 3 to 12 days). In one additional boy, ATRA was definitively discontinued after 3 days of treatment. The median time of ATRA administration was 35 days (range, 20 to 51 days).

Headaches and pseudotumor cerebri were observed in 20 children (30%) and four children (6%), respectively. All these side effects were transient, reversible, and never a cause of death. The ATRA therapy was permanently discontinued on days +21 and +23 in two of the four patients with pseudotumor cerebri. In the remaining two children, ATRA therapy was temporarily discontinued and resumed without dose reduction after 3 days and 7 days.

The median time to attain 1 x 109 neutrophils/L and the incidence of other significant nonhematologic toxicities are listed in Table 2. The most prevalent microorganism isolated among microbiologically documented infections was coagulase-negative Staphylococcus. No fungal infections were documented.


View this table:
[in this window]
[in a new window]
  		Table 2. Toxic Effects During Induction and Consolidation Therapy

 
As to cardiac toxicity, three children developed tachycardia, hypotension, and hemodynamic instability, requiring inotropic drugs, two in a context of sepsis and one during severe RAS. Both patients with sepsis had favorable response to treatment and complete resolution of acute cardiotoxicity, while the other child died of RAS with normal echocardiographic evaluation. The fourth child, who had a transient severe bradycardia caused by marked hypokalemia, died of cerebral hemorrhage on day +3. There were no cases of idarubicin induced cardiomyopathy recognized.

Consolidation Therapy
All patients who achieved CR proceeded to consolidation therapy and all of them, except for one 14-year-old girl who became pregnant after the second consolidation course, received the three consolidation courses as scheduled. Hematologic toxicity was higher during the second course of consolidation. Febrile neutropenia occurred in 17 children and 15 children during the first and the third course of chemotherapy, respectively; whereas, 39 episodes of febrile neutropenia were observed during the second course. No deaths occurred during consolidation therapy. The median time to attain 1 x 109 neutrophils/L and the incidence of other significant nonhematologic toxicities observed in each consolidation course are listed in Table 2.

Tests for PML/RAR{alpha} using RT–PCR were carried out on 46 children (75%) at the end of consolidation therapy. The two patients with molecular persistence at this point were among the 20 high-risk patients.

Maintenance Therapy
All patients proceeded to maintenance therapy. Cytopenias, especially neutropenia, and slight abnormalities in liver function tests were commonly observed in this phase, often requiring dose reduction of 6-mercaptopurine (25 children) or temporary discontinuation (4 children) of chemotherapy. No refusals to injections of methotrexate were reported during maintenance therapy. No deaths in remission occurred during maintenance therapy.

Outcomes
In addition to two children with molecular persistence at the end of consolidation, three children had clinical relapses at 5 months, 32 months, and 48 months, and two had molecular relapses at 12 months and 16 months from the achievement of CR. The remaining patients are in continuous CR from 4 months to 89 months (median, 38 months). All clinical relapses occurred in high-risk patients and two relapses were in the CNS. Because of the small number of children with low risk of relapse (n = 7), they were analyzed together with the intermediate risk group (ie, patients with WBC counts less than 10 x 109/L were compared with those with more than 10 x 109/L). The characteristics and outcomes of patients who had molecular persistence and molecular or clinical relapses are shown in Table 3.


View this table:
[in this window]
[in a new window]
  		Table 3. Characteristics and Follow-Up of Children With Molecular Persistence, Molecular Relapse, or Clinical Relapse

 
Among the 15 patients who were not tested by RT-PCR at the end of consolidation therapy, one high-risk patient from the LPA96 trial relapsed at 4 months.

Cumulative Incidence of Relapse
With a median follow-up of 39 months (range, 6 months to 90 months) for all surviving patients, the 5-year cumulative incidence of relapse (CIR) was 17% (Fig 2A), being 25% and 11% for patients in the LPA96 and LPA99 studies, respectively (P = .3). The CIR rate for low- and intermediate-risk groups when analyzed together was 3.5%, whereas for the high-risk group it was 31% (P = .01; Fig 2B).



View larger version (5K):
[in this window]
[in a new window]
  		Fig 2. Cumulative incidence of relapse from the time of complete remission among all 61 children (A) and according to presenting WBC counts (B).

 
Disease-Free and Overall Survival
The 5-year estimate of disease-free survival (DFS) was 82% ± 14% (Fig 3). For children in the LPA96 study, the DFS was 75% ± 25%, whereas in the LPA99 study, it was 89% ± 12% (P = .3). The DFS rates for low- and intermediate-risk groups together and for the high-risk group were 96% ± 7% and 68% ± 24%, respectively (P = .01).



View larger version (3K):
[in this window]
[in a new window]
  		Fig 3. Kaplan-Meier product-limit estimate of disease-free survival.

 
The probability of remaining alive after 5 years was 87% ± 9% (Fig 4). For children in the LPA96 study, the overall survival was 71% ± 24%, whereas in the LPA99 study, it was 91% ± 8% (P = .06). The overall survival rates for low- and intermediate-risk groups together and for the high-risk group were 88% ± 12% and 83% ± 12%, respectively (P = .6).



View larger version (2K):
[in this window]
[in a new window]
  		Fig 4. Kaplan-Meier product-limit estimate of overall survival.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix
 Authors' Disclosures of...
 REFERENCES
 
This study confirms a high incidence of hyperleukocytosis at presentation in children with APL. A risk-adapted strategy based on the combination of a reduced dose of ATRA (25 mg/m2/d) with anthracycline monochemotherapy for induction and consolidation, followed by ATRA and low-dose methotrexate and mercaptopurine for maintenance therapy, produced high antileukemic efficacy, moderate toxicity, and a high degree of compliance.

Information about therapeutic results with state-of-the-art treatments in children with APL (ie, with combinations of ATRA and anthracycline-based chemotherapy) is still scarce. To our knowledge, only three series, of 22, 31, and 110 children from the German-Austrian-Swiss,22 European APL,7 and GIMEMA groups, respectively, have reported therapeutic results using such approaches. The main characteristics and therapeutic results of those studies and of the present one are summarized in Table 4. It should be noted that the three largest studies show a relatively high proportion of children with hyperleukocytosis at presentation, ranging from 35% to 48%. This is clearly higher than in adults, in whom it is usually around 20% to 25%. However, other characteristics that have been reported with increased incidence in children, such as the microgranular M3 variant9–11 and the PML/RAR{alpha} isoforms BCR3,7,9–11 were found not to be consistently increased in the GIMEMA and PETHEMA studies, when compared with adults. In fact, the incidences of 18% and 43% of microgranular M3 variant and of the BCR3 isoform, respectively, in the present pediatric series do not differ from the 19% and 44% previously reported for the whole series of patients included in both LPA96 and LPA99 studies of the PETHEMA group.20 The predominance of girls in the series of children reported by de Bottom et al.7 was also seen in our study, but not in the largest one reported by the GIMEMA group. In our opinion, this finding should be interpreted cautiously because we have found an erratic distribution of male and female patients in the two studies carried out by the PETHEMA group, with a significantly higher proportion of women in the LPA99 study than in the LPA96.20 It should be noted that the median age ranged widely, from a low of 7.2 years in the German-Austrian-Swiss study22 to a high of 15 years in the European APL study.7 Regarding the low incidence of additional chromosomal abnormalities reported in other small pediatric series,2,7 this finding was not confirmed here, in which the proportion of children with additional chromosomal abnormalities did not differ from that reported in the PETHEMA studies for adult patients.36 All patients in our study, as in the GIMEMA study, were genetically proven APL, unlike the German-Austrian-Swiss and the European APL studies, in which genetic diagnosis was not confirmed in 14% of patients and 10% of patients, respectively.


View this table:
[in this window]
[in a new window]
  		Table 4. Four Series of Children With Newly Diagnosed APL Treated With Combinations of ATRA and Anthracycline-Based Chemotherapy

 
Most pediatric series treated with the simultaneous combination of ATRA and anthracycline-containing chemotherapy have consistently reported remission rates above 90% (ranging from 92% to 97%), and all of them confirm the virtual absence of leukemia resistance using state-of-the-art treatments. Sample sizes, eligibility criteria, and some aforementioned differences in characteristics with potential impact on responses to therapy can—at least partially—explain these apparently different results, which in fact are not statistically significant. The apparently lower incidence of pseudotumor cerebri and headache, together with the excellent therapy results obtained with ATRA at 25 mg/m2/d, when compared with the administration of ATRA at 45 mg/m2/d, suggest that 25 mg/m2 could be the recommended dose, at least for children. Nevertheless, this issue should be definitively settled in a randomized study.

The variability in the reported incidence of ATRA syndrome, ranging from 7.5% in the GIMEMA study to 20% in our study, is probably because of the definition criteria used. In fact, if only definitely present RAS is considered, GIMEMA and PETHEMA studies, both using the same AIDA regimen for induction therapy, reported a similar low rate of RAS. It is noteworthy that this severe complication and pulmonary or CNS hemorrhages were the only causes of death during induction therapy in the present series.

The comparison of postremission outcomes shows no clear differences between the four series. It is important to highlight that no deaths in remission, severe clinical cardiomyopathy, or secondary malignancies were reported in these series, except for two children who developed therapy-related myelodysplasia in the GIMEMA-AIEOP study.23 As in the Italian study, the functional evaluation of late asymptomatic cardiomyopathy is ongoing. On the other hand, a possible association has been suggested between the use of ATRA and an increased incidence of CNS involvement. However, the low CNS relapse rate observed in the present series does not support this hypothesis. This is in line with a large study of the GIMEMA comparing the incidence of CNS relapse in patients treated with or without ATRA that failed to demonstrate this correlation.37

The 3.5% CIR at 5 years among patients with WBC counts of less than 10 x 109/L (ie, children in the low- and intermediate-risk groups, together accounting for two-thirds of all patients) suggest that there is probably room for reducing chemotherapy in the future for this setting. Risk-adapted strategies focusing on children with WBC counts greater than 10 x 109/L at presentation are warranted, and this high-risk group of children with APL should, therefore, be the major subject of future clinical trials.


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
Authors' Disclosures of...
 REFERENCES
 
The following institutions and investigators participated in the study: Argentina (Grupo Argentino de Tratamiento de la Leucemia Aguda) —Hospital Clemente Álvarez, Rosario, S. Ciarlo, Hospital Rossi, La Plata, C. Canepa; Spain (Programa de Estudio y Tratamiento de las Hemopatías Malignas) —Complejo Hospitalario, León, F. Ramos, Hospital 12 de Octubre, Madrid, J. de la Serna and J. Martínez, Hospital Carlos Haya, Málaga, S. Negri, Hospital Central de Asturias, Oviedo, C. Rayón, Hospital Clínico San Carlos, Madrid, J. Díaz Mediavilla, Hospital Clínico San Carlos (H. Infantil), Madrid, C. Gil, Hospital Clínico Universitario, Valencia, M. Tormo and I. Marugán, Hospital de Navarra, Pamplona, K. Pérez-Equiza, Hospital General de Alicante, C. Rivas, Hospital General de Alicante (Oncología Pediátrica), C. Esquembre, Hospital General de Castellón, G. Cañigral, Hospital General de Especialidades Ciudad de Jaén, A. Alcalá, Hospital Insular de Las Palmas, J.D. González San Miguel, Hospital Juan Canalejo, A Coruña, G. Debén, Hospital La Paz (Infantil), Madrid, P. García, Hospital Materno-Infantil de Las Palmas, A. Molines, Hospital do Meixoeiro, Vigo, C. Loureiro, Hospital Montecelo, Pontevedra, M.J. Allegue, Hospital Niño Jesús, Madrid, L. Madero, Hospital Ramón y Cajal, Madrid, J. García-Laraña, Hospital Reina Sofía, Córdoba, J. Román and A. Rodríguez, Hospital San Rafael, Madrid, B. López-Ibor, Hospital San Pedro de Alcántara, Cáceres, J.M. Bergua, Hospital Son Dureta, Palma de Mallorca, A. Novo, Hospital Universitario de Salamanca, M. González and M.C. Chillón, Hospital Universitario La Fe, Valencia, M.A. Sanz, G. Martín, P. Bolufer, and E. Barragán, Hospital Universitario La Fe (Hospital Infantil), Valencia, A. Verdeguer, Hospital Universitario Marqués de Valdecilla, Santander, E. Conde García, Hospital Universitario Puerta del Mar, Cádiz, F.J. Capote, Hospital Universitario Materno-Infantil Vall D'Hebron, Barcelona, J.J. Ortega, Hospital Universitario Virgen de la Arrixaca (Pediatría), Murcia, J.L. Fuster, Hospital Universitario Virgen del Rocío, Sevilla, R. Parody, and Hospital Universitario Virgen de la Victoria, Málaga, I. Pérez.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   Acknowledgment
 
We thank Luis Benlloch for data collection and management.


   NOTES
 
Presented in part at the 45th Annual Meeting of the American Society of Hematology, San Diego, California, December 3-7, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
1. Creutzig U, Zimmermann M, Ritter J, et al: Definition of a standard-risk group in children with AML. Br J Haematol 104:630-639, 1999[CrossRef][Medline]

2. Raimondi S, Chang MN, Ravindranath Y, et al: Chromosomal abnormalities in 478 children with acute myeloid leukemia: Clinical characteristics and treatment outcome in a Cooperative Pediatric Oncology Group Study-POG8821. Blood 94:3707-3716, 1999[Abstract/Free Full Text]

3. O'Brien TA, Rissell SJ, Vowels MR, et al: Results of consecutive trials for children with acute myeloid leukemia from the Australian and New Zealand Children's Cancer Study Group. Blood 100:2708-2716, 2002[Abstract/Free Full Text]

4. Perel Y, Auvrignon A, Leblanc T, et al: Impact of addition of maintenance therapy to intensive induction acute myeloblastic chemotherapy for childhood acute myeloblastic leukemia: Results of a prospective randomized trial, LAME 89/91. J Clin Oncol 20:2774-2782, 2002[Abstract/Free Full Text]

5. Stevens RF, Hann JM, Wheatly K, et al: Marked improvements in outcome with chemotherapy alone in pediatric acute myeloid leukemia: Results of the United Kingdom Medical Research Council's 10th AML trial. Br J Haematol 101:130-140, 1998[CrossRef][Medline]

6. Woods WG, Kobrinsky N, Buckley JD, et al: Timed-sequential induction therapy improves post-remission outcome in acute myeloid leukemia: A report from the Children's Cancer Group. Blood 87:4979-4989, 1996[Abstract/Free Full Text]

7. de Botton S, Coiteux V, Chevret S, et al: Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. J Clin Oncol 22:1404-1412, 2004[Abstract/Free Full Text]

8. Sanz MA, Vellenga E, Rayón C: All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood 104:3490-3493, 2004[Abstract/Free Full Text]

9. Guglielmi C, Martelli MP, Diviero D, et al: Immunophenotype of adult and childhood acute promyelocytic leukemia: Correlation with morphology, type of PML gene breakpoint and clinical outcome—A cooperative Italian study on 196 cases. Br J Haematol 102:1035-1041, 1998[CrossRef][Medline]

10. Rovelli A, Biondi A, Cantu-Rajnoldi A, et al: Microgranular variant of acute promyelocytic leukemia in children. J Clin Oncol 10:1413-1418, 1992[Abstract/Free Full Text]

11. Biondi A, Rovelli A, Cantu-Rajnoldi A, et al: Acute promyelocytic leukemia in children: Experience of the Italian Pediatric Hematology and Oncology Group (AIEOP). Leukemia 8:1264-1268, 1994[Medline]

12. Kane JR, Head DR, Balazs L, et al: Molecular analysis of the PML/RAR alpha chimeric gene in pediatric acute promyelocytic leukemia. Leukemia 10:1296-1302, 1996[Medline]

13. Mandelli F, Diverio D, Avvisati G, et al: Molecular remission in PML/RAR{alpha}-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood 90:1014-1021, 1997[Abstract/Free Full Text]

14. Tallman MS, Andersen JW, Schiffer CA, et al: All-trans retinoic acid in acute promyelocytic leukemia. N Engl J Med 337:1021-1028, 1997[Abstract/Free Full Text]

15. Asou N, Adachi K, Tamura J, et al: Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. J Clin Oncol 16:78-85, 1998[Abstract/Free Full Text]

16. Burnett AK, Grimwade D, Solomon E, et al: On behalf of the MRC Adult Leukemia Working Party: Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: Result of the randomized MRC trial. Blood 93:4131-4143, 1999[Abstract/Free Full Text]

17. Fenaux P, Chastang C, Sanz MA, et al: A randomized comparison of ATRA followed by chemotherapy and ATRA plus chemotherapy, and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. Blood 94:1192-1200, 1999[Abstract/Free Full Text]

18. Sanz MA, Martín G, Rayón C, et al: A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RAR{alpha}-positive acute promyelocytic leukemia. PETHEMA Group. Blood 94:3015-3021, 1999[Abstract/Free Full Text]

19. Lengfelder E, Reichert A, Schoch C, et al: Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: Effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group. Leukemia 14:1362-1370, 2000[CrossRef][Medline]

20. Sanz MA, Martín G, González M, et al: Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: A multicenter study by the PETHEMA Group. Blood 103:1237-1243, 2004[Abstract/Free Full Text]

21. Tallman MS, Nabhan CH, Feusner JH, et al: Acute promyelocytic leukemia: Evolving therapeutic strategies. Blood 99:759-767, 2002[Abstract/Free Full Text]

22. Mann G, Reinhardt D, Ritter J, et al: Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children. Ann Hematol 80:417-422, 2001[CrossRef][Medline]

23. Testi AM, Biondi A, Lo-Coco F, et al: GIMEMA-AIEOP AIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 106:447-453, 2005[Abstract/Free Full Text]

24. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the acute leukemias. Br J Haematol 33:451-461, 1976[Medline]

25. Bennett JM, Catovsky D, Daniel MT, et al: A variant form of hypergranular promyelocytic leukemia (M3). Ann Intern Med 92:280-288, 1980[Abstract/Free Full Text]

26. Bolufer P, Barragán E, Sanz MA, et al: Preliminary experience in external quality control of RT-PCR PML/RAR{alpha} detection in promyelocytic leukemia. Leukemia 12:2024-2028, 1998[CrossRef][Medline]

27. Bolufer P, Lo Coco F, Grimwade D, et al: Variability in the levels of PML-RAR{alpha} fusion transcripts detected by laboratories participating in an external quality control program using several reverse transcription polymerase chain reaction protocols. Haematologica 86:570-576, 2001[Abstract/Free Full Text]

28. Cheson BD, Bennett JM, Kopecky K, et al: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642-4649, 2003[Abstract/Free Full Text]

29. Frankel SR, Eardley A, Heller G, et al: All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study. Ann Intern Med 120:278-286, 1994[Abstract/Free Full Text]

30. Sanz MA, Lo Coco F, Martín G, et al: Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: A joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96:1247-1253, 2000[Abstract/Free Full Text]

31. Kaplan EL, Meier P: Nonparametric estimations from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

32. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline]

33. Gray RJ: A class of K-sample test for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988[CrossRef]

34. Pepe MS, Mori M: Kaplan-Meier, marginal or conditional probability curves in summarizing competing risks failure time data? Stat Med 12:737-751, 1993[Medline]

35. Cox DR: Regression models and life tables (with discussion). J R Stat Soc B 34:187-220, 1972

36. Cervera J, Martin G, Hernandez JM, et al: Additional chromosome abnormalities have no prognostic value in acute promyelocytic leukemia patients treated with simultaneous ATRA and anthracycline-based chemotherapy: An update of the APL96 and APL99 PETHEMA. Blood 104(suppl 1):557 (abstr 2019)

37. Specchia G, Lo Coco F, Vignetti M, et al: Extramedullary involvement at relapse in acute promyelocytic leukemia patients treated or not with ATRA. A report by the GIMEMA Group. J Clin Oncol 19:4023-4028, 2001[Abstract/Free Full Text]

Submitted January 24, 2005; accepted June 30, 2005.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 BloodHome page
M. A. Sanz, D. Grimwade, M. S. Tallman, B. Lowenberg, P. Fenaux, E. H. Estey, T. Naoe, E. Lengfelder, T. Buchner, H. Dohner, et al.
Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet
Blood, February 26, 2009; 113(9): 1875 - 1891.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
C. J. Cifelli and A. C. Ross
Chronic Vitamin A Status and Acute Repletion with Retinyl Palmitate Are Determinants of the Distribution and Catabolism of all-trans-Retinoic Acid in Rats
J. Nutr., January 1, 2007; 137(1): 63 - 70.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
C. J. Cifelli and A. C. Ross
All-trans-retinoic acid distribution and metabolism in vitamin A-marginal rats.
Am J Physiol Gastrointest Liver Physiol, August 1, 2006; 291(2): G195 - G202.
[Abstract] [Full Text] [PDF]

Home page
 ASH Education BookHome page
M. A. Sanz
Treatment of Acute Promyelocytic Leukemia
Hematology, January 1, 2006; 2006(1): 147 - 155.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
M. A. Sanz, M. S. Tallman, and F. Lo-Coco
Practice Points, Consensus, and Controversial Issues in the Management of Patients with Newly Diagnosed Acute Promyelocytic Leukemia
Oncologist, November 1, 2005; 10(10): 806 - 814.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ortega, J. J.
Right arrow Articles by Sanz, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ortega, J. J.
Right arrow Articles by Sanz, M. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

About
JCO		 Editorial
Roster		 Advertising
Information		 Librarians &
Institutions		 Rights &
Permissions		 PDA Services

Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online