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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Hospital Universitario La Fe, Valencia, Spain;
University "La Sapienza," Rome, Italy; Hospital Central de
Asturias, Oviedo, Spain; Ospedali Riuniti di Bergamo, Bergamo, Italy;
Hospital Clínico San Carlos, Madrid, Spain; Ospedale "Civile
Spirito Santo"; Pescara, Italy; Hospital Insular de Las Palmas, Las
Palmas, Spain; University of Bari, Bari, Italy; Hospital Clinic,
Barcelona, Spain; Ospedale Cardarelli, Napoli, Italy; Policlinico S. Matteo, Pavia, Italy; Hospital Universitario, Salamanca, Spain; S. Bartolo Hospital, Vicenza, Italy; Hospital U. Germans Trias i Pujol,
Badalona, Spain.
Preliminary independent reports of the Italian GIMEMA and the
Spanish PETHEMA trials for newly diagnosed acute promyelocytic leukemia
(APL) indicated a similarly high antileukemic efficacy in terms of
complete remission and disease-free survival rates. To better
investigate these studies and the prognostic factors influencing
relapse risk, this study analyzed the updated results of 217 patients
with PML/RAR During the past decade, clinical and laboratory
research has contributed important advances in the management of acute
promyelocytic leukemia (APL). The 2 main determinants of such progress
have been the inclusion of all-trans retinoic acid (ATRA) in
front-line therapy and the cloning of the disease-specific t(15;17)
karyotypic aberration. Data from recently reported large multicenter
trials1-7 indicate that up-front ATRA combined with
chemotherapy (CHT) results in long-lasting remission and a potential
cure in up to 70% of newly diagnosed cases. In particular, best
results have been obtained in patients with a genetically proven
diagnosis who received a simultaneous ATRA plus CHT
combination.3,5-7 Furthermore, 2 randomized studies have
demonstrated a substantial benefit by including an ATRA-containing
maintenance in the treatment program for APL.2,6 Despite
this progress, however, treatment failure still occurs in approximately
30% of patients receiving state-of-the-art therapy due to early death
or, more frequently, disease relapse.
Meanwhile, identification in the early 1990s of the
PML/RAR Although there is general agreement on the inclusion of ATRA for
remission induction in front-line therapy for APL, no consensus presently exists as to the type and intensity of CHT to be used during
induction and consolidation. Based on the long-established sensitivity
of APL to anthracyclines, some investigators have used idarubicin alone
for induction,3,7,12 whereas others have used conventional
acute myeloid leukemia-like protocols either for
induction2,4-6 or consolidation.6 Using ATRA
plus IdArubicin (AIDA) for remission induction and 3 CHT consolidation
courses, the Italian multicenter group GIMEMA reported, in a
preliminary analysis of their study,3 a 95% response rate
and a 2-year event-free survival (EFS) of 79%. The efficacy of such a
regimen was recently confirmed by the Spanish PETHEMA
group7 where an identical induction schedule was adopted.
However, different from GIMEMA, the PETHEMA treatment omitted
cytarabine and other non-intercalating drugs also from the
consolidation phase. Using RT-PCR tests with similar sensitivity
(10 Based on the above considerations, we have carried out a combined
analysis of the updated results of the GIMEMA and PETHEMA APL trials.
Our aims were to perform a better adjusted comparison between the 2 APL
regimens, which differ only in the inclusion or not of drugs other than
anthracyclines during consolidation; to identify prognostic factors for
relapse risk; and to build a predictive model for relapse to be used in
the design of improved risk-adapted protocols.
Patients
Laboratory studies
RT-PCR monitoring Details of the processing of bone marrow samples for RNA extraction and RT-PCR protocols for PML/RAR amplification have been given in previous reports.3,7 For the PETHEMA patients, RT-PCR tests were carried out by 12 different Spanish laboratories, involved in an external quality control program, which included interlaboratory exchange of samples, as reported elsewhere.19 In addition, PCR-positivity at the end of consolidation or during clinical remission was additionally checked in a reference laboratory (P.B., Valencia, Italy). For the GIMEMA patients, RT-PCR tests were performed by sample centralization in 2 reference laboratories as previously reported.11An identical schedule of pre-established time intervals for PCR monitoring was planned for each of the 2 studies. In brief, samples were collected at diagnosis, after induction, after consolidation, every 3 months during the first 2 years, and every 4 to 6 months thereafter. In cases of doubtful or positive PCR during hematologic complete remission (HCR) after the end of consolidation, an extra bone marrow sample was taken 2 to 4 weeks later to confirm the result.Treatment As shown in Figure 1, the treatment schedule of the GIMEMA and PETHEMA protocols was based on a common CHT backbone, including identical induction (ATRA plus idarubicin) and maintenance therapies (ATRA plus mercaptopurine and methotrexate), as well as the same dose schedule of intercalating drugs (idarubicin and mitoxantrone) for consolidation. The only difference was the omission of nonintercalating drugs from consolidation in the PETHEMA protocol. Details of the treatment schedules have been provided elsewhere.3,7
Definitions and study end points Hematologic complete remission and hematologic relapse were defined according to the criteria of the National Cancer Institute.14 Molecular remission was defined as the disappearance on an ethidium bromide gel of the PML/RAR -specific
band visualized at diagnosis, using an RT-PCR assay with a sensitivity
level of 10 4. Molecular relapse was defined as the
reappearance of PCR positivity in 2 consecutive bone marrow samples at
any time after consolidation therapy. For Kaplan-Meier actuarial
estimates, in which the event "relapse" was considered as an end
point, the relapse-free survival (RFS) was calculated in 2 ways.
Firstly, hematologic relapse was the only uncensored event considered;
in such cases, patients who were treated intensively because of a
molecular relapse were censored for survival analysis at the time
of salvage treatment. Secondly, hematologic and molecular relapses were
considered equally as uncensored events.
Statistical methods Chi-square and Fisher exact tests were used to analyze differences in the distribution of variables among patient subsets. For univariate comparison, unadjusted time-to-event analyses were performed using the Kaplan-Meier estimate,15 as well as log-rank tests and their generalizations.16-18 All survival estimates are reported ± 1 SE. The median duration of follow-up was 27 months (range, 4-68 months). To identify the most significant independent prognostic factors, additional multivariate analysis was performed using the Cox model.19 The variables for analysis are listed in Table 1. Patient follow-up was updated in January 2000. Computations were performed using 4F, 1L, and 2L programs from the BMDP statistical library (BMDP Statistical Software, Los Angeles, CA).
Patient characteristics The distributions of the main clinical and biologic presenting features for each series are summarized in Table 1. There were no significant differences between the 2 groups with respect to gender, white blood cell (WBC) and platelet counts, FAB subtype, or PML breakpoint. With respect to age, more pediatric (younger than 16 years) and fewer elderly patients (older than 60 years) were observed in the GIMEMA cohort; however, differences in age distribution were not statistically significant (P = .07). A slightly significant difference was observed between the 2 cohorts with respect to hemoglobin level, with more anemic patients (hemoglobin 10 g/dL)
in the GIMEMA series (P = .02).
Outcome As of January 2000, a total of 27 relapses (12.4%) were recorded, taking into account all types of disease recurrence (ie, hematologic, extramedullary, and molecular relapses) in both series. Eleven patients in the PETHEMA and 9 in the GIMEMA group had clinical relapse at a median interval of 11 and 16 months from the achievement of HCR, respectively. Four of these clinical relapses occurred primarily in the central nervous system, in 2 patients in the PETHEMA trial, and 2 in the GIMEMA. Seven additional patients (4 in PETHEMA and 3 in GIMEMA) had a molecular relapse in the bone marrow at intervals of 6 to 22 and 9 to 16 months, respectively.Depending on the assignation of molecular relapses as censored or
uncensored events, the 3-year Kaplan-Meier estimates of RFS for the
total series were 90 ± 2% and 86 ± 2%, respectively. Minor
differences observed between GIMEMA and PETHEMA were not statistically
significant (Figure 2).
Prognostic factors for remission duration Univariate analysis.
Table 2 summarizes the results of
univariate analysis for each separate group, as well as for the
combined GIMEMA and PETHEMA series. For the total series, as well as
in each study group, the only factor that had a significant
prognostic influence on remission duration (considering either
hematologic or hematologic plus molecular remission) was the WBC count
at presentation. Platelet count also showed a significant influence or
a trend in the total series and in each study group. Finally, the BCR
subtype showed a trend in the GIMEMA group only.
Multivariate analysis.
Because several cut-off points of platelet and WBC count had shown
discriminant value in the univariate analysis, we created by
transformation several categorized variables of platelet and WBC count.
Then, in addition to the remaining presenting features, all these
variables were simultaneously introduced in the multivariate analysis
(proportional hazards regression model). After selecting WBC count with
the cut-off point of 10 × 109/L in step 1 as the first
variable to enter into regression, the categorized platelet count with
the cut-off point of 40 × 109/L was selected in step 2. Table 3 shows the principal results of
the multivariate analysis, where the variables are listed in the order
entered by the forward stepwise modeling procedure. The only 2 characteristics selected were presenting WBC and platelet counts.
Figures 3 and
4 show the actuarial RFS according to
the different discriminating cut-offs for WBC and platelet counts, respectively. The classification of molecular relapse as a censored or
uncensored event did not change these results, except for the P value limit when entering platelet count into the
model (.05 and .07, respectively).
Development of a simplified predictive model for RFS.
Based on the above results, a simple predictive model was constructed
for defining the diagnosis risk groups of RFS. This permitted the
identification of the following patient categories: (1) low-risk group:
presenting WBC count below or equal to 10 × 109/L and
platelet count above 40 × 109/L; (2) intermediate-risk
group: presenting WBC and platelet counts below or equal to
10 × 109/L and 40 × 109/L, respectively;
and (3) high-risk group: presenting WBC greater than
10 × 109/L. The numerical distribution of patients in
the 3 above groups was as follows: low-risk 53 (24%), intermediate 115 (53%), and high-risk 49 (23%). The differences in RFS curves of the 3 risk groups (Figure 5) were highly
significant (P < .0001).
This study shows that, in patients with newly diagnosed APL receiving up-front AIDA, the use of an anthracycline-based consolidation omitting cytarabine and other nonintercalating agents seems to be equally effective as a more intensive regimen including these drugs. In addition, in this study we have defined a simple model that permits the easy identification at diagnosis of 3 distinct prognostic groups among patients receiving AIDA-derived treatments. This, in turn, provides a rationale for the design of risk-adapted protocols aimed at further improving treatment outcome for this type of leukemia. With regard to the first issue, our findings extend and strengthen a recently reported preliminary observation from the PETHEMA group.7 The comparison of updated results of that study with those obtained from the GIMEMA trial for patients receiving more intensive consolidation indicates that similarly high RFS rates are obtained with either regimen. Our results are also in line with the study of Estey and colleagues12 who reported a disease-free survival (DFS) at 1 year of 87% using an AIDA-like regimen for induction, followed by a postremission therapy including idarubicin and alternating cycles of mercaptopurine, vincristine, methotrexate, and prednisone. Taken together, these findings open new important perspectives in the treatment of APL; with respect to the risk of relapse, they strongly suggest that omission of cytarabine from consolidation might permit better adaptation to the ATRA/anthracycline combination. The remarkable similarity in patient characteristics, protocol design, and response to therapy between the PETHEMA and GIMEMA studies prompted us to analyze prognostic factors influencing RFS in the 2 groups combined. Minor differences in the 2 series, such as age and hemoglobin levels, appeared irrelevant for the purpose of our study. In fact, these 2 variables were not associated with an increased relapse risk in the present study, or in previous ones.4-7 Although prognostic factors have been analyzed in only a marginal way in the majority of recent studies on APL, there is general agreement on the prognostic impact of WBC count in remission response,5-7,20 EFS,3,5,7 DFS, and relapse risk.3,7 To the best of our knowledge, no other clinical presenting factors, except for platelet count, correlate consistently with relapse risk. In fact, a long-term follow-up report of the APL 1991 trial from the European APL Group found a significantly higher incidence of relapse for patients who had fewer than 50 × 109/L platelets at presentation.21 Importantly, in our study, this factor retained its prognostic value in the multivariate analysis. Although the significance of such a finding is presently unclear, it may be speculated that platelet number at diagnosis somehow reflects a level of residual polyclonal hematopoiesis spared by the leukemic process. PCR positivity after consolidation deserves a separate mention as an index with predictive value for relapse; however, this biologic parameter is not available at the time of diagnosis.5,11 Interestingly, our prognostic model that includes only WBC and platelet counts permits the identification of a patient subset with an extremely low relapse risk, in which the use of the less intensive postinduction regimen adopted by the PETHEMA trial seems most appropriate. On the other hand, patients assigned to intermediate-risk and especially to high-risk categories would potentially benefit from intensification of postremission therapy aimed at obtaining greater efficacy in eradicating minimal residual leukemia. The use of combined ATRA and CHT has led to striking improvements in
the outlook for APL, as reported by a number of recently published
studies conducted at the multi-institutional level.1-7 Therefore, it is important that our proposed prognostic model be
validated in an independent patient series, in particular for those
patients where the ATRA plus CHT combination indicates a greater
therapeutic efficacy. In the meantime, we firmly believe that such a
model should be reproducible for PML/RAR
Submitted February 25, 2000; accepted April 12, 2000.
Supported in part by grants no. 96/1734 and 99/0806 from the Fondo de Investigación Sanitaria (FIS), Ministerio de Sanidad of Spain; grant FIJC PETH-99 from the International José Carreras Leukemia Foundation; grant no. HI1998-0147 from Ministerio de Educación y Cultura of Spain; MURST Azioni Integrate Italia-Spagna, AIRC (Associazione Italiana per la Ricerca sul Cancro); and ROMAIL (Associazione Italiana contro le Leucemie, Sezione di Roma).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Presented in part at the 41st meeting of the American Society of Hematology, New Orleans, LA, December 3-7, 1999. Reprints: Miguel A. Sanz, Servicio de Hematología, Hospital Universitario La Fe, Av. Campanar 21, 46009 Valencia, Spain; e-mail: msanz{at}uv.es.
1. Soignet S, Fleischauer A, Polyak T, Heller G, Warrell RP Jr. All-trans retinoic acid significantly increases 5-year survival in patients with acute promyelocytic leukemia: long-term follow-up of the New York study. Cancer Chemother Pharmacol. 1997;40(suppl):S25-S29. 2. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337:1201-1208.
3.
Mandelli F, Diverio D, Avvisati G, et al.
Molecular remission in PML/RAR 4. 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. 1998;6:78-85.
5.
Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH, 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.
1999;93:4131-4143
6.
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.
1999;94:1192-1200
7.
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
8.
Lo Coco F, Diverio D, Falini B, Biondi A, Nervi C, Pelicci PG.
Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia.
Blood.
1999;94:12-22 9. Grimwade D. The pathogenesis of acute promyelocytic leukemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. Br J Haematol. 1999;106:591-613[Medline] [Order article via Infotrieve].
10.
Estey EH, Giles FJ, Kantarjian H, et al.
Molecular remission induced by liposomal-encapsulated all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia.
Blood.
1999;94:2230-2235
11.
Diverio D, Rossi V, Avvisati G, et al.
Early detection of relapse by prospective RT-PCR analysis of the PML/RAR
12.
Estey E, Thall PF, Pierce S, Kantarjian H, Keating M.
Treatment of newly diagnosed acute promyelocytic leukemia without cytarabine.
J Clin Oncol.
1997;15:483-490
13.
Falini B, Flenghi L, Fagioli M, et al.
Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the anti-PML monoclonal antibody PG-M3.
Blood.
1997;90:4046-4053 14. Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol. 1990;8:813-819[Abstract]. 15. Kaplan EL, Meier P. Nonparametric estimations from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 16. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50:163-170[Medline] [Order article via Infotrieve]. 17. Harrington D, Fleming TR. A class of rank test procedures for censored survival data. Biometrika. 1982;69:133-143. 18. Harrington D, Fleming TR. Counting Processes and Survival Analysis. New York, NY: John Wiley & Sons; 1991. 19. Cox DR. Regression models and life tables (with discussion). J R Stat Soc B. 1972;34:187-220. 20. Di Bona E, Avvisati G, Castaman G, et al. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol. 2000;108:689-695[Medline] [Order article via Infotrieve]. 21. Fenaux P, Chastang C, Castaigne S, et al. Long term follow-up confirms the superiority of ATRA combined with chemotherapy (CT) over CT alone in newly diagnosed acute promyelocytic leukemia. Blood. 1997;90(suppl 1):331a.
The authors thank Luis Benlloch (from PETHEMA) and Paola Fazi, Maria Luce Vegna, and Marco Vignetti (from GIMEMA) for data collection and management. The following institutions and personnel participated in PETHEMA trial: Hospital Universitario La Fe, Valencia (M.A. Sanz, G. Martín, P. Bolufer, E. Barragán); Hospital Central de Asturias, Oviedo (C. Rayón); Hospital Clínico San Carlos, Madrid (J. Díaz-Mediavilla, A. Villegas); Hospital Clínico Universitario, Valencia (M.J. Terol, I. Marugán); Hospital Insular de Las Palmas, Las Palmas (J.D. González); Hospital Clinic, Barcelona (J. Esteve, D. Colomer); Hospital General, Alicante (C. Rivas); H.U. Germans Trias i Pujol, Badalona (J.M. Ribera); Complexo H. Xeral-Calde, Lugo (J. Arias); Hospital Universitario, Salamanca (M. González, C. Chillón); Hospital de Cruces, Baracaldo (M.C. Alvarez); Complejo Hospitalario, León (F. Ramos); Hospital Juan Canalejo, A Coruña (G. Debén); H. Ntra Sra del Pino/Sabinal, Las Palmas (R. Mataix, T. Gómez); Hospital Reina Sofia, Córdoba (S. Tabares, J. Román); Hospital Clínico Universitario, Valladolid (F. Fernández); H. Universitario Vall D'Hebron, Barcelona (J. Bueno); Hospital Son Dureta, Palma de Mallorca (A. Novo); Hospital Xeral de Galicia, Santiago de Compostela (M. Pérez); Hospital Ramón y Cajal, Madrid (J. Odriozola, C. Ferro); Hospital do Meixoeiro, Vigo (C. Loureiro); Hospital Severo Ochoa, Leganés (P. Sánchez); Hospital Dr. Peset, Valencia (M.J. Sayas); Hospital 12 de Octubre, Madrid (J. De la Serna, R. Bornstein); Hospital General de Murcia, Murcia (J.M. Moraleda); H.U. Virgen de la Victoria, Málaga (I. Pérez); H.U. Puerta del Mar, Cádiz (F.J. Capote); H. San Pedro de Alcántara, Cáceres (J.M. Bergua); Basurtuko Ospitalea, Basurto (J.M. Beltrán de Heredia); Hospital Rio Hortega, Valladolid (M.J. Peñarrubia); H. General Jerez de la Frontera, Jerez de la Frontera (A. León); Hospital General, Albacete (J.R. Romero); Hospital Xeral Cíes, Vitoria (C. Poderós); Hospital Txagorritxu, Vitoria (J.M. Guinea); Hospital San Pau, Barcelona (S. Brunet); H. General Oncología Pediátrica, Alicante (C. Esquembre); Hospital Rio Carrión, Palencia (F. Ortega); H.U. Marqués de Valdecilla, Santander (E. Conde, C. Richard); H.U. La Fe (Hospital Infantil), Valencia (V. Castell); Universidad de Navarra, Pamplona (M.J. Calasanz). The following institutions participated in the AIDA 0493 trial: Ematologia, Universita' "La Sapienza", Roma (F. Mandelli, G. Avvisati, D. Diverio, F. Lo Coco, M.C. Petti, M.L. Vegna); Divisione di Ematologia, Ospedale S. Martino, Genova (E. Damasio, R. Cerri); Istituto di Ematologia L. e A. Seragnoli, Universita', Bologna (S. Tura, G. Visani, G. Martinelli); Divisione di Ematologia, Ospedale S. Bortolo, Vicenza (F. Rodeghiero, E. Di Bona); Divisione di Ematologia, Policlinico S. Matteo, Pavia (C. Bernasconi, M. Lazzarino); Divisione di Medicina E, Opedale S. Giovanni, Torino (L. Resegotti, M. Falda); Divisione di Ematologia, Policlinico Careggi, Firenze (P. Rossi Ferrini, F. Leoni); Divisione di Ematologia, Ospedali Riuniti, Bergamo (T. Barbui, A. Rambaldi); Divisione di Ematologia, Ospedale Civile, Pescara (G. Fioritoni, A. Recchia); Servizio di Ematologia, Policlinico, Bari (V. Liso, G. Specchia); Divisione di Ematologia, Ospedale A. Businco, Cagliari (G. Broccia, W. Deplano); Servizio di Ematologia, Ospedale Civile, Avellino (E. Volpe, N. Cantore); Divisione di Ematologia, Ospedale A. Pugliese, Catanzaro (A. Peta, F. Iuliano); Divisione di Ematologia, Ospedale S. Gerado, Monza (E. Pogliani, G. Corneo); Ematologia, Ospedale Generale e Regionale, Bolzano (P. Coser, P. Fabris); Sezione di Ematologia Spedali Civili, Brescia (T. Izzi, G. Rossi); Cattedra di Ematologia, Universita', Catania (E. Cacciola, F. Di Raimondo); Cattedra di Ematologia, Universita', Parma (V. Rizzoli, C. Almici); Cattedra di Ematologia, Universita', Verona (G. Perona, D. Veneri); Cattedra di Ematologia, Universita', Genova (M. Gobbi, M. Clavio); Divisione di Ematologia, Ospedale Cardarelli, Napoli (R. Cimino, F. Ferrara); Divisione di Ematologia, Osp. Nuovo Pellegrini, Napoli (R. De Biasi, E. Miraglia); Divisione di Ematologia, T.E.R.E., Napoli (L. De Rosa, V. Mettivier); Cattedra di Ematologia, Universita' Tor Vergata, Roma (S. Amadori, G. Aronica); Clinica Pediatrica, Ospedale S. Gerardo, Monza (G. Masera, A. Biondi, A. Luciano); Divisione di Ematologia, Universita' Cattolica, Roma (G. Leone, S. Sica); Divisione di Ematolgia, Ospedali Riuniti, Reggio Calabria (F. Nobile, B. Martino); Sezione di Ematolgia, Ospedale S. Croce, Cuneo (E. Gallo, A. Gallamini); Divisione di Ematologia, Ospedale S.Maria Goretti, Latina (L. Deriu, A. Cherichini); Sezione di Ematologia, CTMO, Cremona (A. Porcellini, S. Morandi); Divisione di Ematologia, Nuovo Policlinico, Napoli (B. Rotoli, C. Selleri); Cattedra di Ematologia, Università, Perugia (M.F. Martelli, A. Tabilio); Clinica Medica, Universita', Palermo (A. Cajozzo, M. Musso); Divisione di Ematologia, Ospedale V.Cervello, Palermo (F. Caronia, S. Mirto, A. Santoro); Divisione di Ematologia, Ospedale B.Gesù, Roma (G. De Rossi, M. Caniggia); Istituto di Ematologia, Nuovo Ospedale Torrette, Ancona (P. Leoni, M. Montillo); Centro di Riferimento Oncologico, Aviano (S. Monfardini, V. Zagonel); Patologia Medica, Universita', Genova (R. Ghio, E. Balleari); Clinica Medica, Policlinico S. Matteo, Pavia (E. Ascari, R. Invernizzi); Divisione di Ematologia, Universita', Pisa (B. Grassi, M. Petrini); Ematologia, Ospedale S.S. Annunziata, Taranto (P. Mazza, G. Lazzari); Cattedra di Ematologia, Universita', Udine (M. Baccarani, A. Candoni); Ematologia Pediatrica, Universita', Catania (G. Schiliro', A.M. Ippolito); Ematologia, IV Divisione Pediatrica, Genova (L. Massimo, C. Micalizzi); Cinica Pediatrica, Universita', Pavia (F. Severi, F. Locatelli); Ematologia, Ospedale Regionale A. Di Summa, Brindisi (G. Quarta, A. Melpignano); Cattedra di Ematologia, Universita', Ferrara (G. Castoldi, F. Lanza); Semeiotica Medica, Universita', Genova (F. Patrone, M. Sessarego); Divisione di Ematologia, Ospedale Niguarda, Milano (E. Morra, A.M. Nosari); Ematologia, Ospedale S. Raffaele, Milano (C. Bordignon, L. Camba); Ematologia ed Autotrapianto Ospedale S.Martino, Genova (A.M. Carella, F. Frassoni); Sezione di Ematologia, Ospedale S. Francesco, Nuoro (A. Gabbas, G. Latte); Cattedra di Ematologia, Policlinico, Palermo (P. Citarella, S. Grisanti); Divisione di Ematologia, Ospedale S. Salvatore, Pesaro (G. Lucarelli, G. Sparaventi); Sezione di Ematologia, Ospedale S. Carlo, Potenza (F. Ricciuti, M. Pizzuti); Divisione di Ematologia, Ospedale S. Camillo, Roma (A. De Laurenzi, L. Pacilli); Div. di Ematologia, Casa Sollievo della Sofferenza, S.G. Rotondo (M. Carotenuto, L. Melillo); Divisione di Ematologia, Ospedale A.Sclavo, Siena (E. Dispensa, A. Bucalossi); Clinica Pediatrica, Ospedale G. Salesi, Ancona (P. Giorgi, L. Felici); Clinica Pediatrica I, Policlinico, Bari (F. Schettini, N. Santoro); Onco-Ematologia Pediatrica, Ospedale Regionale, Cagliari (P. Biddau); II Divisione Pediatrica, Ospedale Pausilipon, Napoli (V. Poggi, M.F. Pintà); Clinica Pediatrica I, Universita', Napoli (M.T. Di Tullio, M. Giuliano); Clinica Pediatrica II, Universita', Padova (L. Zanesco, M. Pilon); Clinica Pediatrica III, Universita', Pisa (P. Macchia, C. Favre); Clinica Pediatrica, Universita', Torino (E. Madon, R. Miniero); Department of Hematology, University, Nijmegen (NL) (T. de Witte, P. Muus); Medizinische Klinik III, University, Munich (D) (U. Jehn); Department of Hematology, University, Leiden (NL) (R. Willemze); Department of Hematology, University, Ankara (TK) (M. Beksac); Az Middelheim, AfdelingHemato-Oncologie, Antwerpen (B) (R. De Bock).
© 2000 by The American Society of Hematology.
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  P. Montesinos, J. Diaz-Mediavilla, G. Deben, V. Prates, M. Tormo, V. Rubio, I. Perez, I. Fernandez, M. Viguria, C. Rayon, et al. Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis Haematologica, September 1, 2009; 94(9): 1242 - 1249. [Abstract] [Full Text] [PDF]
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 C. Kelaidi, S. Chevret, S. De Botton, E. Raffoux, A. Guerci, X. Thomas, A. Pigneux, T. Lamy, F. Rigal-Huguet, S. Meyer-Monard, 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., June 1, 2009; 27(16): 2668 - 2676. [Abstract] [Full Text] [PDF]
|
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 |
|
 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]
|
|
|
|
|
|
F. Ravandi, E. Estey, D. Jones, S. Faderl, S. O'Brien, J. Fiorentino, S. Pierce, D. Blamble, Z. Estrov, W. Wierda, et al. Effective Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid, Arsenic Trioxide, and Gemtuzumab Ozogamicin J. Clin. Oncol., February 1, 2009; 27(4): 504 - 510. [Abstract] [Full Text] [PDF]
|
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P. Montesinos, J. M. Bergua, E. Vellenga, C. Rayon, R. Parody, J. de la Serna, A. Leon, J. Esteve, G. Milone, G. Deben, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors Blood, January 22, 2009; 113(4): 775 - 783. [Abstract] [Full Text] [PDF]
|
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C. Santamaria, M. C. Chillon, R. Garcia-Sanz, A. Balanzategui, M. E. Sarasquete, M. Alcoceba, F. Ramos, T. Bernal, J. A. Queizan, M. J. Penarrubia, et al. The relevance of preferentially expressed antigen of melanoma (PRAME) as a marker of disease activity and prognosis in acute promyelocytic leukemia Haematologica, December 1, 2008; 93(12): 1797 - 1805. [Abstract] [Full Text] [PDF]
|
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 S. D. Gore, L. Morris, I. Gojo, M. P. Devetten, K. Jamieson, M. A. Sekeres, R. J. Arceci, R. L. Redner, T. Dauses, E. L Schachter-Tokarz, et al. Minimizing Therapy for Patients with Acute Promyelocytic Leukemia: Efficacy of Single Cycle of Arsenic-Based Consolidation Therapy. Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 1932 - 1932. [Abstract]
|
|
|
|
|
|
B. Paiva, M.-B. Vidriales, J. Cervero, G. Mateo, J. J. Perez, M. A. Montalban, A. Sureda, L. Montejano, N. C. Gutierrez, A. G. de Coca, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation Blood, November 15, 2008; 112(10): 4017 - 4023. [Abstract] [Full Text] [PDF]
|
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M. A. Sanz, P. Montesinos, E. Vellenga, C. Rayon, J. de la Serna, R. Parody, J. M. Bergua, A. Leon, S. Negri, M. Gonzalez, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group Blood, October 15, 2008; 112(8): 3130 - 3134. [Abstract] [Full Text] [PDF]
|
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L. Ades, M. A. Sanz, S. Chevret, P. Montesinos, P. Chevallier, E. Raffoux, E. Vellenga, A. Guerci, A. Pigneux, F. Huguet, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results Blood, February 1, 2008; 111(3): 1078 - 1084. [Abstract] [Full Text] [PDF]
|
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 M. S. Tallman and J. K. Altman Curative Strategies in Acute Promyelocytic Leukemia Hematology, January 1, 2008; 2008(1): 391 - 399. [Abstract] [Full Text] [PDF]
|
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R. H. Jacomo, R. A. M. Melo, F. R. Souto, E. R. de Mattos, C. T. de Oliveira, E. M. Fagundes, H. N. d. S. Bittencourt, R. I. Bittencourt, T. C. Bortolheiro, E. J.A. Paton, et al. Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines Haematologica, October 1, 2007; 92(10): 1431 - 1432. [Abstract] [Full Text] [PDF]
|
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|
N. Asou, Y. Kishimoto, H. Kiyoi, M. Okada, Y. Kawai, M. Tsuzuki, K. Horikawa, M. Matsuda, K. Shinagawa, T. Kobayashi, et al. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RAR{alpha} transcript after consolidation therapy: The Japan Adult Leukemia Study Group (JALSG) APL97 study Blood, July 1, 2007; 110(1): 59 - 66. [Abstract] [Full Text] [PDF]
|
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C. Santamaria, M. C. Chillon, C. Fernandez, P. Martin-Jimenez, A. Balanzategui, R. Garcia Sanz, J. F. San Miguel, and M.-G. Gonzalez Using quantification of the PML-RAR{alpha} transcript to stratify the risk of relapse in patients with acute promyelocytic leukemia Haematologica, March 1, 2007; 92(3): 315 - 322. [Abstract] [Full Text] [PDF]
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L. Ades, S. Chevret, E. Raffoux, S. de Botton, A. Guerci, A. Pigneux, A. M. Stoppa, T. Lamy, F. Rigal-Huguet, A. Vekhoff, 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., December 20, 2006; 24(36): 5703 - 5710. [Abstract] [Full Text] [PDF]
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E. Estey, G. Garcia-Manero, A. Ferrajoli, S. Faderl, S. Verstovsek, D. Jones, and H. Kantarjian Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia Blood, May 1, 2006; 107(9): 3469 - 3473. [Abstract] [Full Text] [PDF]
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D. Douer ATO: the forefront of APL treatment? Blood, April 1, 2006; 107(7): 2588 - 2589. [Full Text] [PDF]
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V. Mathews, B. George, K. M. Lakshmi, A. Viswabandya, A. Bajel, P. Balasubramanian, R. V. Shaji, V. M. Srivastava, A. Srivastava, and M. Chandy Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity Blood, April 1, 2006; 107(7): 2627 - 2632. [Abstract] [Full Text] [PDF]
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 E. J. Jabbour, E. Estey, and H. M. Kantarjian Adult Acute Myeloid Leukemia Mayo Clin. Proc., February 1, 2006; 81(2): 247 - 260. [Abstract] [Full Text] [PDF]
|
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M. A. Sanz Treatment of Acute Promyelocytic Leukemia Hematology, January 1, 2006; 2006(1): 147 - 155. [Abstract] [Full Text] [PDF]
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 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]
|
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J. J. Ortega, L. Madero, G. Martin, A. Verdeguer, P. Garcia, R. Parody, J. Fuster, A. Molines, A. Novo, G. Deben, et al. Treatment With All-Trans Retinoic Acid and Anthracycline Monochemotherapy for Children With Acute Promyelocytic Leukemia: A Multicenter Study by the PETHEMA Group J. Clin. Oncol., October 20, 2005; 23(30): 7632 - 7640. [Abstract] [Full Text] [PDF]
|
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M. S. Tallman, D. G. Gilliland, and J. M. Rowe Drug therapy for acute myeloid leukemia Blood, August 15, 2005; 106(4): 1154 - 1163. [Abstract] [Full Text] [PDF]
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A. M. Testi, A. Biondi, F. L. Coco, M. L. Moleti, F. Giona, M. Vignetti, G. Menna, F. Locatelli, A. Pession, E. Barisone, et al. GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children Blood, July 15, 2005; 106(2): 447 - 453. [Abstract] [Full Text] [PDF]
|
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E. Estey, C. Koller, A. M. Tsimberidou, S. O'Brien, M. Beran, J. Cortes, M. Tirado-Gomez, G. Lopez-Berestein, and H. Kantarjian Potential curability of newly diagnosed acute promyelocytic leukemia without use of chemotherapy: the example of liposomal all-trans retinoic acid Blood, February 1, 2005; 105(3): 1366 - 1367. [Full Text] [PDF]
|
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M. A. Sanz, E. Vellenga, C. Rayon, J. Diaz-Mediavilla, C. Rivas, E. Amutio, J. Arias, G. Deben, A. Novo, J. Bergua, et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia Blood, December 1, 2004; 104(12): 3490 - 3493. [Abstract] [Full Text] [PDF]
|
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M. A. Sanz, G. Martin, M. Gonzalez, A. Leon, C. Rayon, C. Rivas, D. Colomer, E. Amutio, F. J. Capote, G. A. Milone, 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, February 15, 2004; 103(4): 1237 - 1243. [Abstract] [Full Text] [PDF]
|
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E. Raffoux, P. Rousselot, J. Poupon, M.-T. Daniel, B. Cassinat, R. Delarue, A.-L. Taksin, D. Rea, A. Buzyn, A. Tibi, et al. Combined Treatment With Arsenic Trioxide and All-Trans-Retinoic Acid in Patients With Relapsed Acute Promyelocytic Leukemia J. Clin. Oncol., June 15, 2003; 21(12): 2326 - 2334. [Abstract] [Full Text] [PDF]
|
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|
|
M. Beaumont, M. Sanz, P.M. Carli, F. Maloisel, X. Thomas, L. Detourmignies, A. Guerci, N. Gratecos, C. Rayon, J. San Miguel, et al. Therapy-Related Acute Promyelocytic Leukemia J. Clin. Oncol., June 1, 2003; 21(11): 2123 - 2137. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 W. Y. Au, A. K. W. Lie, C. S. Chim, R. Liang, S. K. Ma, C. H. Chan, Y. K. Mak, Y. T. Chen, C. C. So, Y. M. Yeung, et al. Arsenic trioxide in comparison with chemotherapy and bone marrow transplantation for the treatment of relapsed acute promyelocytic leukaemia Ann. Onc., May 1, 2003; 14(5): 752 - 757. [Abstract] [Full Text] [PDF]
|
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E. L. Sievers, B. J. Lange, T. A. Alonzo, R. B. Gerbing, I. D. Bernstein, F. O. Smith, R. J. Arceci, W. G. Woods, and M. R. Loken Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia Blood, May 1, 2003; 101(9): 3398 - 3406. [Abstract] [Full Text] [PDF]
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D. Douer, W. Hu, S. Giralt, M. Lill, and J. DiPersio Arsenic Trioxide (Trisenox(R)) Therapy for Acute Promyelocytic Leukemia in the Setting of Hematopoietic Stem Cell Transplantation Oncologist, April 1, 2003; 8(2): 132 - 140. [Abstract] [Full Text] [PDF]
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R. E. Gallagher, B. Y. Yeap, W. Bi, K. J. Livak, N. Beaubier, S. Rao, C. D. Bloomfield, F. R. Appelbaum, M. S. Tallman, J. L. Slack, et al. Quantitative real-time RT-PCR analysis of PML-RARalpha mRNA in acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129 Blood, April 1, 2003; 101(7): 2521 - 2528. [Abstract] [Full Text] [PDF]
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B. Lowenberg, J. D. Griffin, and M. S. Tallman Acute Myeloid Leukemia and Acute Promyelocytic Leukemia Hematology, January 1, 2003; 2003(1): 82 - 101. [Abstract] [Full Text] [PDF]
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M. S. Tallman, J. W. Andersen, C. A. Schiffer, F. R. Appelbaum, J. H. Feusner, W. G. Woods, A. Ogden, H. Weinstein, L. Shepherd, C. Willman, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol Blood, December 15, 2002; 100(13): 4298 - 4302. [Abstract] [Full Text] [PDF]
|
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E. H. Estey, F. J. Giles, M. Beran, S. O'Brien, S. A. Pierce, S. H. Faderl, J. E. Cortes, and H. M. Kantarjian Experience with gemtuzumab ozogamycin ("mylotarg") and all-trans retinoic acid in untreated acute promyelocytic leukemia Blood, May 13, 2002; 99(11): 4222 - 4224. [Abstract] [Full Text] [PDF]
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M. S. Tallman, C. Nabhan, J. H. Feusner, and J. M. Rowe Acute promyelocytic leukemia: evolving therapeutic strategies Blood, February 1, 2002; 99(3): 759 - 767. [Abstract] [Full Text] [PDF]
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R. Latagliata, M. C. Petti, S. Fenu, M. Mancini, M. A. A. Spiriti, M. Breccia, G. A. Brunetti, G. Avvisati, F. L. Coco, and F. Mandelli Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem Blood, February 1, 2002; 99(3): 822 - 824. [Abstract] [Full Text] [PDF]
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F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian Acute Myeloid Leukemia Hematology, January 1, 2002; 2002(1): 73 - 110. [Abstract] [Full Text]
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J. G. Jurcic, S. D. Nimer, D. A. Scheinberg, T. DeBlasio, R. P. Warrell Jr, and W. H. Miller Jr Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia Blood, November 1, 2001; 98(9): 2651 - 2656. [Abstract] [Full Text] [PDF]
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J. F. San Miguel, M. B. Vidriales, C. Lopez-Berges, J. Diaz-Mediavilla, N. Gutierrez, C. Canizo, F. Ramos, M. J. Calmuntia, J. J. Perez, M. Gonzalez, et al. Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to postinduction treatment stratification Blood, September 15, 2001; 98(6): 1746 - 1751. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
