|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3015-3021
A Modified AIDA Protocol With Anthracycline-Based
Consolidation Results in High Antileukemic Efficacy and Reduced
Toxicity in Newly Diagnosed PML/RAR -Positive Acute
Promyelocytic Leukemia
By
Miguel A. Sanz,
Guillermo Martín,
Consuelo Rayón,
Jordi Esteve,
Marcos González,
Joaquín Díaz-Mediavilla,
Pascual Bolufer,
Eva Barragán,
María J. Terol,
José D. González,
Dolors Colomer,
Carmen Chillón,
Concha Rivas,
Teresa Gómez,
José M. Ribera,
Rafael Bornstein,
José Román,
María J. Calasanz,
Jesus Arias,
Carmen Álvarez,
Fernando Ramos, and
Guillermo Debén for the PETHEMA Group
From Hospital Universitario La Fe, Valencia, Spain; Hospital Central
de Asturias, Oviedo, Spain; Hospital Clínico San Carlos,
Madrid, Spain; Hospital Clínico Universitario, Valencia, Spain;
Hospital Insular de Las Palmas, Las Palmas, Spain; Hospital Clinic,
Barcelona, Spain; Hospital General, Alicante, Spain; Hospital U. Germans Trias i Pujol, Badalona, Spain; Complexo Hospitalario
Xeral-Calde, Lugo, Spain; Hospital Universitario, Salamanca, Spain;
Hospital de Cruces, Baracaldo, Spain; Complejo Hospitalario,
León, Spain; and Hospital Juan Canalejo, La Coruña, Spain.
 |
ABSTRACT |
The Spanish PETHEMA group designed a protocol for newly
diagnosed PML/RAR -positive acute promyelocytic leukemia
(APL) in which induction and consolidation followed the original
AIDA regimen, except for the omission of cytarabine and
etoposide from consolidation. Induction consisted of 45 mg/m2 all-trans retinoic acid (ATRA) daily until
complete remission (CR) and 12 mg/m2 idarubicin on days 2, 4, 6, and 8. Patients in CR received 3 monthly chemotherapy courses:
idarubicin 5 mg/m2/d × 4 (course no. 1), mitoxantrone 10 mg/m2/d × 5 (course no. 2), and idarubicin 12 mg/m2/d × 1 (course no. 3). Maintenance therapy consisted
of 90 mg/m2/d mercaptopurine orally, 15 mg/m2/wk methotrexate intramuscularly, and, intermittently,
45 mg/m2/d ATRA for 15 days every 3 months. Between
November 1996 and December 1998, 123 patients with newly diagnosed
PML/RAR-positive APL from 39 centers were enrolled. A total of 109 patients achieved CR (89%; 95% confidence interval [CI], 83 to 95),
12 died of early complications, and the remaining 2 were resistant.
Consolidation treatment was associated with very low toxicity and no
deaths in remission were recorded. Molecular assessment of response by reverse transcriptase-polymerase chain reaction (RT-PCR) showed conversion to PCR-negative in 48 of 99 (51%) and 82 of 88 patients (93%) after induction and consolidation, respectively. The 2-year Kaplan-Meier estimates of overall survival and event-free survival were
82% ± 4% and 79% ± 4%, respectively. For patients who achieved CR, the 2-year disease-free survival (DFS) was 92% ± 3%. These data
indicate that a significant reduction in toxicity might be obtained in
APL using a less intensive consolidation without apparently compromising the antileukemic effect. These results also suggest a
minor role for cytarabine and etoposide in the treatment of newly
diagnosed PML/RAR-positive APL patients.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
SINCE THE INTRODUCTION of
all-trans retinoic acid (ATRA), several issues appear critical
to the design of optimal front-line therapy in acute promyelocytic
leukemia (APL). (1) Sensitivity to ATRA is genetically determined by
the PML/RAR fusion that is formed as a consequence of the
t(15;17).1 Demonstration of the specific chromosome
abnormality or of its molecular counterpart might be considered a
mandatory criterion to start tailored therapy.2 (2) The
best therapy results, in terms of complete remission (CR) and
disease-free survival (DFS), have been obtained using ATRA and
chemotherapy for remission induction.3-9 As shown in a
randomized study,9 simultaneous combination is more
effective than sequential administration of ATRA and chemotherapy. (3)
The additional benefit, if any, provided by cytarabine administered in
induction and/or in consolidation remains unclear. In fact, although
randomized trials comparing different chemotherapy induction regimens
in APL have not been performed, the inclusion of cytarabine in addition to daunorubicin, with or without other chemotherapy agents (eg, thioguanine, etoposide), does not appear to significantly affect disease outcome,10 nor does it seem to provide better
results than those obtained with high-dose
daunorubicin11-14 or idarubicin alone.15,16 (4)
Detection of minimal residual disease at relatively low sensitivity
levels (10 4) during hematological CR (HCR)
postconsolidation is a strong predictor of relapse,17 and
the achievement of sustained molecular remission might be considered as
our best therapeutic goal at present. (5) The benefits of maintenance
therapy that contains ATRA have been shown in 2 large randomized
studies.7,9
Keeping the above considerations in mind, in 1996 the Spanish PETHEMA
group designed a protocol (LPA96) for the treatment of newly diagnosed
PML/RAR-positive APL patients. This protocol included an induction
phase with ATRA and idarubicin, as in the original AIDA regimen of the
Italian GIMEMA group.3 In contrast with the latter
treatment, however, we decided to omit cytarabine and etoposide from
consolidation therapy and used an anthracycline-based consolidation
with the same idarubicin and mitoxantrone dose/schedule adopted by the
Italian group. Our main objectives were to evaluate the toxicity of
this approach and its antileukemic efficacy in terms of molecular
response and DFS.
We report here a study on 123 newly diagnosed PML/RAR positive
patients enrolled in this trial. Besides the expected important reduction of treatment-related toxicity, we found that high molecular remission and DFS rates might be achieved in APL using this less intensive treatment.
| |
MATERIALS AND METHODS |
Eligibility Criteria
Eligibility criteria included: (1) confirmed genetic diagnosis by
demonstration of the t(15;17) and/or PML/RAR rearrangement; (2) no
prior chemotherapy; (3) normal hepatic and renal function; (4) Eastern
Cooperative Oncology Group (ECOG) performance status of 0 to 3; (5)
serum creatinine <2.5 mg/dL, serum alkaline phosphatase, bilirubin,
and aspartate amino transferase (AST) <3 times the normal upper
limit; (6) no cardiac contraindications to anthracycline chemotherapy;
(7) negative pregnancy test; and (8) informed consent.
Protocol Design
Induction therapy consisted of oral ATRA 45 mg/m2/d,
divided into 2 doses administered every 12 hours, until HCR and for a maximum of 90 days, and 4 intravenous (IV) bolus (15 to 30 minutes) of
idarubicin 12 mg/m2 on days 2, 4, 6, and 8. In patients
younger than 15 years, ATRA doses were adjusted to 25 mg/m2. Treatment was started as soon as a diagnosis of APL
(M3 or M3 variant) was established by morphocytochemical criteria
according to the French-American-British (FAB) classification. For
patients in whom diagnosis was not confirmed by genetic studies, ATRA
was withdrawn and alternative chemotherapy given at the physician's discretion. Patients in HCR received 3 monthly consolidation courses consisting of idarubicin 5 mg/m2 IV daily for 4 days
(course no. 1), mitoxantrone 10 mg/m2 IV daily for 5 days
(course no. 2), and idarubicin 12 mg/m2 IV on only 1 day
(course no. 3). After completion of consolidation, patients who tested
polymerase chain reaction (PCR)-negative for the PML/RAR hybrid gene
were started on maintenance therapy with mercaptopurine 90 mg/m2/day orally, methotrexate 15 mg/m2/week
intramuscularly, and intermittently ATRA 45 mg/m2/d for 15 days every 3 months. Doses of mercaptopurine and methotrexate were
decreased by 50% if the white blood cell (WBC) count was lower than
3.5 × 109/L and discontinued if lower than 2.5 × 109/L. Maintenance therapy was given for 2 years.
Supportive therapy.
All patients were admitted to the hospital for remission induction,
while consolidation courses were always given on an outpatient basis.
IV antibiotic therapy, usually consisting of
 -lactamic/aminoglycoside associations, was initiated in case of
fever. This standard regimen was modified thereafter according to the
results of appropriate cultures. Treatment of coagulopathy during
induction was based on fresh frozen plasma and/or fibrinogen
transfusion, as well as on platelet support to maintain the platelet
counts above 30 × 109/L until disappearance of
significant coagulopathy. The use of heparin, tranexamic acid, and
other measures was optional. Once the coagulopathy was under control,
platelet transfusions were only used in patients with infectious or
hemorrhagic manifestations or when the platelet count dropped below 20 × 109/L. At the first signs of suspected ATRA
syndrome, ATRA was discontinued and patients were given 10 mg
dexamethasone every 12 hours as recommended by Frankel et
al.18 Prophylactic dexamethasone, using the same doses, was
also administered in cases where the WBC count was greater than 5 × 109/L. The use of hydroxyurea was not recommended
for patients with hyperleukocytosis.
Laboratory Studies
Bone marrow samples were collected at diagnosis, after induction, after
consolidation, at 2 months during the first year, every 3 months during
the second year, and every 4 to 6 months after this period. Besides
morphological evaluation, samples were processed for RNA extraction and
reverse transcriptase (RT)-PCR of PML/RAR. In case of doubtful or
positive PCR during HCR, an extra bone marrow sample was required in 2 to 4 weeks time to confirm the result. RT-PCR tests were performed 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. and E.B., Valencia, Spain). Most laboratories followed the method of Biondi et al,20
and a minor group used the method described by Borrow et
al.21 Immunophenotypic and cytogenetic analyses were
systematically performed at diagnosis only. Since May 1998, for rapid
diagnostic refinement and patient enrollment into the protocol, we have
occasionally used the immunohistochemical analysis of PML protein
distribution, using monoclonal antibody PG-M3 (kindly provided by B. Falini, Institute of Hematology, University of Perugia, Perugia,
Italy22).
Definitions and Study Endpoints
HCR and hematological relapse were defined according to the National
Cancer Institute criteria.23 Failures were classified as
resistant leukemia and early death. Early death was defined as death
occurring during induction therapy or during the period of aplasia
after chemotherapy. 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 104. Molecular relapse was defined as the
reappearance of PCR-positivity in 2 consecutive bone marrow samples at
any time after consolidation therapy. Chromosomal abnormalities were
described according to the International System for Human Cytogenetics
Nomenclature. Toxicity was graded according to the World Health
Organization (WHO) grading system. According to Frankel et
al,5 ATRA syndrome was defined as: definitely present in
the presence of the 5 characteristic signs or symptoms of this
syndrome18: fever, dyspnea, pleural and/or pericardial
effusion, pulmonary infiltrates, and unexplained weight gain greater
than 5 kg; indeterminate when 2 to 4 of the above-mentioned signs and
symptoms occurred; and definitely absent in the remaining patients.
Duration of neutropenia and thrombocytopenia was defined as the time,
in days, from the start of chemotherapy until the day of the first
measurement of absolute neutrophil count >1 × 109/L
and platelets >50 × 109/L, respectively. Overall
and event-free survival (OS and EFS) were calculated from the date of
starting induction therapy, while relapse-free survival (RFS) and DFS
were calculated from the day of HCR achievement. Failure to achieve HCR
(defined above), relapse, and death in HCR were considered the
"events," whichever occurred first, to analyze, when applicable,
as censored data in EFS, RFS, and DFS.
Statistical Methods
Unadjusted time-to-event analyses were performed using the Kaplan-Meier
estimate,24 log-rank tests, and their
generalizations.25-27 Univariate analysis for induction
response was performed using Pearson's  2 test or, if
applicable, Fisher's exact test, and the 95% confidence intervals
(CI) for difference in proportion were calculated. Variables included
in the analysis are listed in Table 1.
| |
RESULTS |
Accrual and Patient Characteristics
Between November 1996 and January 1999, 136 consecutive patients from
39 Spanish institutions (see Appendix) were registered, based on a
morphocytochemical diagnosis of AML-M3 according to the FAB
classification. Of these, 13 patients (10%) were subsequently excluded: 10 because of absence of the genetic hallmark upon
cytogenetic and molecular analysis, 2 because of poor medical condition
(ECOG grade 4 at admission due to cerebral hemorrhage, leading to death before the start of therapy), and 1 because of protocol violation. All
of the remaining patients were genetically diagnosed by demonstration of the specific translocation (2), the PML/RAR hybrid gene (36) or
both (85). The main clinical and biological characteristics of the 123 newly diagnosed PML/RAR-positive APL patients who were considered
eligible are shown in Table 1.
Induction Therapy
Hematological and molecular response.
Of the 123 eligible patients, 109 achieved HCR (89%; 95% CI, 83 to
95), and the remaining 14 were considered as failures due to either
therapy-related mortality (12) or induction resistance, which was
observed in 2 patients of 41 and 71 years, respectively. Of the 12 early deaths, 3 were due to infection (occurred from day +18 through
day +31), 8 to cerebral, intestinal, or pulmonary hemorrhage (days +1
through +23), and the remaining 1 to ATRA syndrome (day +28).
PML/RAR RT-PCR tests were available in 99 cases at the end of
induction and/or before consolidation. Fifty-one patients (51%) tested
PCR-positive and 48 (49%) PCR-negative at this time point.
Univariate analysis demonstrated no significant relationships among
clinical-biological characteristics at diagnosis and PCR status after
induction therapy. However, presenting WBC count and age clearly
influenced the HCR rate. A poorer response rate was, in fact, observed
in older age patients and in those with higher WBC count, with the more
discriminant cut-off values being 70 years and 50 × 109/L, respectively (Table 1).
Toxicity.
Apart from the above-mentioned 12 toxic deaths that occurred during
induction therapy, other minor hematological and nonhematological toxicities are listed in Table 2. Due to
presumed ATRA syndrome, ATRA was discontinued early for 35 patients
(28%) at a median time of 9 days of treatment (range, 1 to 25). A
definitely present ATRA syndrome was diagnosed in 7 patients (6%), 1 of whom died, whereas an indeterminate ATRA syndrome was reported in 25 cases (20%).
Supportive care and hospitalization.
The median hospital stay was 36 days (range, 5 to 70). During this
period, the median time on antibiotics was 27 days (range, 5 to 67).
Median red blood cell (RBC) and platelet concentrates transfused per
patient were 10 U (range, 2 to 49) and 36 U (range, 3 to 138),
respectively. The median time to attain 1 × 109 PMN/L
and a platelet count greater than 50 × 109/L was 24 days (range, 5 to 57) and 19 days (range, 6 to 45), respectively.
Consolidation Therapy
Molecular response.
Of the 109 patients who achieved HCR, 92 have at present completed the
3 consolidation courses and 17 are still on treatment. PML/RAR
RT-PCR tests were performed in 88 cases at the end of consolidation. Of
these, 82 (93%) tested PCR-negative and 6 (7%) PCR-positive. All of
the 40 patients found to be PCR-negative after induction and who were
tested after consolidation remained in molecular remission. Of 40 patients PCR-positive after induction and who were tested after
consolidation, 35 converted to PCR-negative, and 5 remained
PCR-positive. Of 8 patients who were analyzed at the end of
consolidation, but not after induction, 7 tested PCR-negative and 1 positive. Three of the 6 patients PCR-positive after consolidation converted to PCR-negative during maintenance. Of the remaining 3, 1 received high-dose chemotherapy and autologous stem cell transplantation (ASCT), 1 is on a waiting list for ASCT, and the confirmatory PCR is pending in the third case.
Toxicity.
All patients were able complete the 3 courses of chemotherapy as
scheduled, and no deaths occurred in HCR. The incidence and type of
toxicity associated with each consolidation course are reported in
Table 3. A higher rate of severe and
prolonged neutropenia and thrombocytopenia was observed with course no.
2, although only 63 patients had neutropenic fever during this cycle.
The median number of transfused platelet and RBC units was 9 (range, 1 to 82) and 4 (range, 1 to 19), respectively.
Maintenance Therapy
All 92 patients who received full consolidation therapy proceeded to
maintenance therapy as scheduled. Cytopenias, especially neutropenia,
and slight liver function test abnormalities were commonly observed in
this phase, often requiring dose reduction or temporary discontinuation
of chemotherapy. In only 1 patient, who promptly developed severe acute
pancreatitis associated with mercaptopurine treatment, was this drug
definitely withdrawn. No deaths in CR occurred during maintenance.
Outcome.
As of February 1999, 5 patients had clinical relapse at 4 to 15 months
from the achievement of HCR. Conversion to PCR-positive had been
documented in 2 of them 1 and 6 months before clinical relapse,
respectively. Two clinical relapses primarily occurred in the central
nervous system (CNS). Of these 2 patients, 1 is alive and
well, while the other 1 died of disease progression. The remaining 3 patients relapsed in the bone marrow and were treated with a
simultaneous combination of ATRA, mitoxantrone, and cytarabine; 2 achieved second HCR, and 1 died during marrow aplasia. Both patients
who attained second HCR underwent ASCT and died due to
transplant-related toxicity and subsequent relapse, respectively.
Three additional patients relapsed at the molecular level at +5, +7,
and +12 months postconsolidation. They were given intensification with
ATRA plus EMA (etoposide, mitoxantrone, and cytarabine) before developing clinically overt disease. Two of these patients died early
due to fungal infection, while the remaining 1 is alive and
PCR-negative.
The 2-year Kaplan-Meier estimates of OS and EFS are 82% ± 4% and 79% ± 4%, respectively. For patients who
achieved HCR, the 2-year DFS is 92% ± 3%
(Fig 1). Univariate analysis showed that only presenting WBC count had a significant prognostic influence on
both DFS and EFS (Fig 2), while age had an
influence only on the EFS (Fig 3).
| |
DISCUSSION |
This study shows that use of an anthracycline-based regimen omitting
cytarabine and etoposide for the treatment of newly diagnosed APL
results in high molecular remission, DFS, and OS rates, as well as in
substantially lower therapy-related toxicity.
Based on the established notion that response to ATRA correlates with
PML/RAR presence in leukemic cells, we decided to enroll in this
study only patients with genetically proven APL. For this purpose, the
systematic use of RT-PCR in conjunction with conventional cytogenetics
provided here the additional advantage of defining targets for the
sensitive assessment of response at the molecular level. In line with
the results of other multicenter trials in which genetic diagnosis was
routinely performed,3,5,6 10% of patients initially
registered in our study based on morphologic criteria subsequently
tested PML/RAR-negative and were excluded from the trial.
Our protocol was designed taking into consideration the main advances
derived from some recent clinical studies, especially those reported by
the European APL group9 and the Italian GIMEMA group.3 These have clearly shown that the best treatment
results are obtained with simultaneous ATRA treatment and chemotherapy. In addition, using idarubicin alone in combination with ATRA, the
GIMEMA group reported3 impressive induction results, which are comparable to those obtained by others using induction regimens containing cytarabine.4,6,8,9 Leaving unmodified the first
part of the AIDA protocol, our induction results were, as expected,
similar to those reported by Mandelli et al,3 and are
consequently comparable to the above-mentioned studies. In fact, all of
these studies, which reported CR rates around 90%, showed that their
results overlap when the confidence intervals are taken into account.
Minor differences in response rates might also be explained by subtle
differences in patient characteristics with potential prognostic impact
(eg, morphological and/or molecular subtype, age, WBC count, etc).
The current consensus on treatment requirements of APL has led us to
consider tailored therapeutic approaches differing from those used for
the rest of the AMLs as regards induction and maintenance only. With
very few exceptions,16 the consolidation phase has never
been substantially different from that commonly used for other AMLs. In
fact, even in the most recent trials,3,6-9 postremission treatment included cytarabine, usually combined with anthracyclines, and other drugs such as etoposide. All of these studies reported important toxicity during consolidation, leading to a variable, but
sizable, number of patients to receive less treatment than scheduled,
as well as to a death rate in remission of up to 10%, which
significantly increased in elderly patients.3,8,9 Our
approach to consolidation resulted in a rate of molecular remission,
which is remarkably high, and is similar to that reported by the
GIMEMA3 and the updated results of the Medical Research Council (MRC) trial,28 but which is
associated with significantly reduced toxicity and related morbidity
and mortality. In fact, all patients in the present study were able to
complete the 3 consolidation courses and no deaths in remission were
recorded. Combined with the preliminary findings reported by Estey et
al,16 who also omitted cytarabine from postremission
therapy, our study strengthens the view that this drug has little
therapeutic effect in APL and suggests that patients might be spared
the risks associated with intensive consolidation containing
cytarabine. Although in light of the short median follow-up, we cannot
establish at present the effectiveness of our treatment approach in the
long-term, the molecular response rate after consolidation and the
actuarial 2-year DFS rate are comparable with the best results reported thus far. Nevertheless, the low short-term relapse rate recorded in our
series might also be partially due to the administration of ATRA during
maintenance, which has proven to confer better DFS in two large
randomized studies.7,9
Despite considerable improvement in diagnosis and management of APL, a
proportion of patients who receive state-of-the-art treatment will
eventually die of early complications during induction or of disease
recurrence. Thus, two minor, but sizable, subsets should be considered
for individualized therapeutic approaches. Identification of patients
at highest risk of early death would allow prompt reinforcement of
adequate supportive care and, perhaps, less intensive induction
treatment. Conversely, patients at highest risk of relapse might
benefit from distinct postremission intensification, such as increased
anthracycline dosage and/or hematopoietic stem cell transplantation.
The adjusted definition of these two risk groups is one of the major
challenges for future clinical investigations in APL.
| |
APPENDIX |
The following clinical departments and personnel participated in this
trial (number of patients included in parentheses): Hospital
Universitario La Fe, Valencia, Sanz MA, Martín G (13); Hospital
Central de Asturias, Oviedo, Rayón C (8); Hospital
Clínico San Carlos, Madrid, Díaz-Mediavilla J (6);
Hospital Clínico Universitario, Valencia, Terol MJ (6);
Hospital Insular de Las Palmas, Las Palmas, González JD (6);
Hospital Clinic, Barcelona, Esteve J (6); Hospital General, Alicante,
Rivas C (5); Hospital U. Germans Trias i Pujol, Badalona, Ribera JM
(5); Complexo Hospitalario Xeral-Calde, Lugo, Arias J (4); Hospital
Universitario, Salamanca, González M (4); Hospital de Cruces,
Baracaldo, Alvarez MC (4); Complejo Hospitalario, León, Ramos F
(4); Hospital Juan Canalejo, La Coruña, Debén G (4);
Hospitales Ntra Sra del Pino/Sabinal, Las Palmas, Mataix R (3);
Hospital Reina Sofia, Córdoba, Tabares S (3); Hospital
Clínico Universitario, Valladolid, Fernández F (3);
Hospital Universitario Vall D'Hebron, Barcelona, Bueno J (3); Hospital
Son Dureta, Palma de Mallorca, Novo A (3); Hospital Xeral de Galicia,
Santiago de Compostela, Pérez M (2); Hospital Ramón y
Cajal, Madrid, Odriozola J (2); Hospital do Meixoeiro, Vigo, Loureiro C
(2); Hospital Severo Ochoa, Leganés, Sánchez P (2);
Hospital Dr. Peset, Valencia, Sayas MJ (2); Hospital 12 de Octubre,
Madrid, De la Serna J (2); Hospital General de Murcia, Murcia, Moraleda
JM (2); H. Universitario Virgen de la Victoria, Málaga,
Pérez I (2); H.U. Puerta del Mar, Cádiz, Capote FJ (2);
Hospital San Pedro de Alcántara, Cáceres, Bergua JM (2); Hospital Materno-Infantil de Las Palmas, Las Palmas, Lodos JC (1);
Basurtuko Ospitalea, Basurto, Beltrán de Heredia JM (1); Hospital
Rio Hortega, Valladolid, Peñarrubia MJ (1); Hospital Clínico Universitario Lozano Blesa, Zaragoza, Palomera L (1); Hospital General Jerez de la Frontera, Jerez de la Frontera, León A (1); Hospital General, Albacete, Romero JR (1); Hospital Xeral Cíes, Vitoria, Poderós C (1); Hospital Txagorritxu,
Vitoria, Guinea JM (1); Hospital San Pau, Barcelona, Brunet S (1);
Hospital General (Oncología Pediátrica), Alicante,
Esquembre C (1); Hospital Rio Carrión, Palencia, Ortega F (1);
Hospital U. Marqués de Valdecilla, Santander, Conde E (1); H. Universitario La Fe (Hospital Infantil), Valencia, Castell V (1).
The following laboratories and personnel participated in this trial:
Hospital Universitario La Fe, Valencia, Bolufer P, Barragán E;
Hospital Universitario, Salamanca, González M, Chillón C; Hospital Clinic, Barcelona, Colomer D; Hospitales Ntra Sra del Pino/Sabinal, Las Palmas, Gómez T; Hospital Reina Sofia,
Córdoba, Román J; Universidad de Navarra, Pamplona,
Calasanz MJ; Hospital 12 de Octubre, Madrid, Bornstein R; Hospital
Clínico San Carlos, Madrid, Villegas A; Hospital
Clínico Universitario, Valencia, Marugán I; Hospital
Ramón y Cajal, Madrid, Ferro C; Hospital do Meixoeiro, Vigo,
Loureiro C; Hospital U. Marqués de Valdecilla, Santander, Richard C.
| |
ACKNOWLEDGMENT |
The authors thank Francesco Lo Coco and Guillermo F. Sanz for helpful
discussion and critical reading of the manuscript. We are also grateful
to Luis Benlloch for data collection and management.
| |
FOOTNOTES |
Submitted March 17, 1999; accepted June 28, 1999.
Supported in part by Grant No. 96/1734 from the Fondo de
Investigación Sanitaria (FIS), Ministerio de Sanidad of Spain,
and by Grant FIJC PETH-99 from the International José Carreras
Leukemia Foundation.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Presented in part at the 40th meeting of the American Society of
Hematology, Miami Beach, FL, December 4-8, 1998.
Address reprint requests to Miguel A. Sanz, MD, Servicio
de Hematología, Hospital Universitario La Fe, Av. Campanar 21, 46009 Valencia, Spain; e-mail: msanz{at}uv.es.
| |
REFERENCES |
1.
Miller WH Jr, Kakizuka A, Frankel SR, Warrell RP Jr, DeBlasio A, Levine K, Evans RM, Dmitrovsky E:
Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia.
Proc Natl Acad Sci USA
89:2694, 1992[Abstract/Free Full Text]
2.
Slack JL:
Recent advances in the biology and treatment of acute promyelocytic leukemia. Educational Book of the 34th Meeting of the American Society of Clinical Oncology Los Angeles, CA, 1998, p 54
3.
Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willenze R, Muus P, Pelicci PG, Biondi A, Lo Coco F:
Molecular remission in PML/RAR-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy.
Blood
90:1014, 1997[Abstract/Free Full Text]
4.
Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, Huebner G, Bauters F, Fegueux N, Fey M, Sanz MA, Lowenberg B, Maloisel F, Auzanneau G, Sadoun A, Gardin C, Bastion Y, Ganser A, Jacky E, Dombret H, Chastang C, Degos L, and the European APL 91 Group:
Effect of all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial.
Blood
82:3241, 1993[Abstract/Free Full Text]
5.
Frankel SR, Eardley A, Heller G, Berman E, Miller WH Jr, Dmitrvsky E, Warrell RP Jr:
All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York study.
Ann Intern Med
120:278, 1994[Abstract/Free Full Text]
6.
Burnett AK, Goldstone AH, Gray RG, Wheatley K, on behalf of the UK MRC Adult Leukemia Working Party:
All-trans retinoic acid given concurrently with induction chemotherapy improves the outcome of APL: Results of the UK MRC ATRA trial.
Blood
90:330a, 1997 (abstr)
7.
Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman CL, Bloomfield CD, Rowe JM, Wiernick PH:
All-trans retinoic acid in acute promyelocytic leukemia.
N Engl J Med
337:1201, 1997
8.
Asou N, Adachi K, Tamura J, Kanamuru A, Kageyama S, Hiraoka A, Omoto E, Akiyama H, Tsubaki K, Saito K, Kuriyama K, Oh H, Kitano K, Miyawaki S, Takeyama K, Yamada O, Nishikawa K, Takahashi M, Matsuda S, Ohtake S, Suzushima H, Emi N, Ohno R, for the Japan Adult Leukemia Study Group:
Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.
J Clin Oncol
16:78, 1998[Abstract/Free Full Text]
9. Fenaux P, Chastang C, Sanz MA, Dombret H, Archimbaud E, Jacky E,
Fey M, Rayón C, Huguet F, Sotto JJ, Gardin C, Reiffers J, Travade
P, Solary E, Fegueux N, Bordessoule D, San Miguel J, Link H, Desablens
B, Tilly H, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L
for the European APL Group: 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 (in
press)
10.
Head D, Kopecky KJ, Weick J, Files JC, Ryan D, Foucar K, Montiel M, Bickers J, Fishleder A, Miller M:
Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia.
Blood
85:1717, 1995
11.
Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon MF:
Acute promyelocytic leukemia: Results of treatment by daunorubicin.
Blood
41:489, 1973[Abstract/Free Full Text]
12.
Sanz MA, Jarque I, Martín G, Lorenzo I, Martínez J, Rafecas J, Pastor E, Sayas MJ, Sanz G, Gomis F:
Acute promyelocytic leukemia. Therapy results and prognostic factors.
Cancer
61:7, 1988[Medline]
[Order article via Infotrieve]
13.
Petti MC, Avvisati G, Amadori S, Baccarani M, Guarini AR, Papa G, Rosti GA, Tura S, Mandelli F:
Acute promyelocytic leukemia: Clinical aspects and results of treatment in 62 patients.
Haematologica
72:151, 1987[Medline]
[Order article via Infotrieve]
14.
Marty M, Ganem G, Fischer J, Flandrin G, Berger R, Schaison G, Degos L:
Leucémie aigue promyelocitaire: étude retrospective de 119 malades traités par daunorubicine.
Nouv Rev Fr Hematol
26:371, 1984
15.
Avvisati G, Mandelli F, Petti MC, Vegna ML, Spadea A, Liso V, Specchia G, Bernasconi C, Alessandrino EP, Piatti C, Carella AM:
Idarubicin (4-demethoxydaunorubicin) as single agent for remission induction of previously untreated acute promyelocytic leukemia: A pilot study of the Italian cooperative group GIMEMA.
Eur J Haematol
44:257, 1990[Medline]
[Order article via Infotrieve]
16.
Estey E, Thall PF, Pierce S, Kantarjian H, Keating M:
Treatment of newly diagnosed acute promyelocytic leukemia without cytarabine.
J Clin Oncol
15:483, 1997[Abstract/Free Full Text]
17.
Diverio D, Rossi V, Avvisati G, DeSantis S, Pistilli A, Pane F, Saglio G, Martinelli G, Petti MC, Santoro A, Pelicci PG, Mandelli F, Biondi A, Lo Coco F:
Early detection of relapse by prospective RT-PCR analysis of the PML/RAR fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial.
Blood
92:784, 1998[Abstract/Free Full Text]
18.
Frankel SR, Eardley A, Lauwers G, Weiss M, Warrel RP Jr:
The `retinoic acid syndrome' in acute promyelocytic leukemia.
Ann Intern Med
117:292, 1992
19.
Bolufer P, Barragán E, Sanz MA, Martín G, Bornstein R, Colomer D, Delgado MD, González M, Marugán I, Román J, Gómez MT, Anguita E, Diverio D, Chomienne Ch, Briz M:
Preliminary experience in external quality control of RT-PCR PML/RAR detection in promyelocytic leukemia.
Leukemia
12:2024, 1998[Medline]
[Order article via Infotrieve]
20.
Biondi A, Rambaldi A, Pandolfi PP, Rosi V, Giudici G, Alcalay M, Lo Coco F, Diverio D, Pogliani EM, Lanzi EM:
Molecular monitoring of the myl/retinoic acid receptor- fusion gene in acute promyelocytic leukemia by polymerase chain reaction.
Blood
80:492, 1992[Abstract/Free Full Text]
21.
Borrow J, Goddard AD, Gibbons B, Katz F, Swirsky D, Fioretos T, Dube I, Windfield DA, Kingston J, Hagemeijer A:
Diagnosis of acute promyelocytic leukaemia by RT-PCR: Detection of PML-RAR and RAR-PML fusion transcripts.
Br J Haematol
82:529, 1992[Medline]
[Order article via Infotrieve]
22.
Falini B, Flenghi L, Fagioli M, Lo Coco F, Cordone I, Diverio D, Pasqualucci L, Biondi A, Riganelli D, Orleth A, Liso A, Martelli MF, Pelicci PG, Pileri S:
Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the anti-PML monoclonal antibody PG-M3.
Blood
90:4046, 1997[Abstract/Free Full Text]
23.
Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ:
Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.
J Clin Oncol
8:813, 1990[Abstract]
24.
Kaplan EL, Meier P:
Nonparametric estimations from incomplete observations.
J Am Stat Assoc
53:457, 1958
25.
Mantel N:
Evaluation of survival data and two new rank order statistics arising in its consideration.
Cancer Chemother Rep
50:163, 1966[Medline]
[Order article via Infotrieve]
26.
Harrington D, Fleming TR:
A class of rank test procedures for censored survival data.
Biometrika
69:133, 1982
27.
Harrington D, Fleming TR:
Counting Processes and Survival Analysis. New York, NY, Wiley, 1991
28.
Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH:
Presenting white cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: Results of the randomized MRC trial.
Blood
93:4131, 1999[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
F. Lo-Coco, E. Ammatuna, and M. A. Sanz
Current treatment of acute promyelocytic leukemia
Haematologica,
March 1, 2007;
92(3):
289 - 291.
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
A. Ghavamzadeh, K. Alimoghaddam, S. H. Ghaffari, S. Rostami, M. Jahani, R. Hosseini, A. Mossavi, E. Baybordi, A. Khodabadeh, M. Iravani, et al.
Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy
Ann. Onc.,
January 1, 2006;
17(1):
131 - 134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Sanz
Treatment of Acute Promyelocytic Leukemia
Hematology,
January 1, 2006;
2006(1):
147 - 155.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
M. A. Sanz, M. S. Tallman, and F. Lo-Coco
Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia
Blood,
April 15, 2005;
105(8):
3019 - 3025.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kim, J. Lim, Y. Kim, K. Han, S. Lee, and C. K. Min
Acute Promyelocytic Leukemia with +der(17)t(15;17) Detected by Fluorescence In Situ Hybridization (FISH)
Ann. Clin. Lab. Sci.,
April 1, 2005;
35(2):
195 - 198.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. de Botton, A. Fawaz, S. Chevret, H. Dombret, X. Thomas, M. Sanz, A. Guerci, J. San Miguel, J. de la Serna, A.M. Stoppa, et al.
Autologous and Allogeneic Stem-Cell Transplantation As Salvage Treatment of Acute Promyelocytic Leukemia Initially Treated With All-Trans-Retinoic Acid: A Retrospective Analysis of the European Acute Promyelocytic Leukemia Group
J. Clin. Oncol.,
January 1, 2005;
23(1):
120 - 126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
M. Battistella, L. D Burry, and J. T Seki
Retinoic acid syndrome after one dose of all-transretinoic acid
Journal of Oncology Pharmacy Practice,
September 1, 2004;
10(3):
149 - 154.
[Abstract]
[PDF]
|
|
|
|
|
|
|
S. de Botton, V. Coiteux, S. Chevret, C. Rayon, E. Vilmer, M. Sanz, J. de La Serna, N. Philippe, A. Baruchel, G. Leverger, et al.
Outcome of Childhood Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid and Chemotherapy
J. Clin. Oncol.,
April 15, 2004;
22(8):
1404 - 1412.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
R. M. Stone, M. R. O'Donnell, and M. A. Sekeres
Acute Myeloid Leukemia
Hematology,
January 1, 2004;
2004(1):
98 - 117.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
W. Kern, T. Haferlach, C. Schoch, H. Loffler, W. Gassmann, A. Heinecke, M. C. Sauerland, W. Berdel, T. Buchner, and W. Hiddemann
Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial
Blood,
January 1, 2003;
101(1):
64 - 70.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
G. Avvisati, M. C. Petti, F. Lo-Coco, M. L. Vegna, S. Amadori, M. Baccarani, N. Cantore, E. Di Bona, F. Ferrara, G. Fioritoni, et al.
Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up
Blood,
October 16, 2002;
100(9):
3141 - 3146.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pulsoni, L. Pagano, F. Lo Coco, G. Avvisati, L. Mele, E. Di Bona, R. Invernizzi, F. Leoni, F. Marmont, A. Mele, et al.
Clinicobiological features and outcome of acute promyelocytic leukemia occurring as a second tumor: the GIMEMA experience
Blood,
August 28, 2002;
100(6):
1972 - 1976.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
G. Specchia, F. Lo Coco, M. Vignetti, G. Avvisati, P. Fazi, F. Albano, F. Di Raimondo, B. Martino, F. Ferrara, C. Selleri, et al.
Extramedullary Involvement at Relapse in Acute Promyelocytic Leukemia Patients Treated or Not With All-Trans Retinoic Acid: A Report by the Gruppo Italiano Malattie Ematologiche dell'Adulto
J. Clin. Oncol.,
October 15, 2001;
19(20):
4023 - 4028.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.S. Chim, R. Liang, C.Y.Y. Tam, and Y.L. Kwong
Methylation of p15 and p16 Genes in Acute Promyelocytic Leukemia: Potential Diagnostic and Prognostic Significance
J. Clin. Oncol.,
April 1, 2001;
19(7):
2033 - 2040.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. R. Appelbaum, J. M. Rowe, J. Radich, and J. E. Dick
Acute Myeloid Leukemia
Hematology,
January 1, 2001;
2001(1):
62 - 86.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Bruserud, B. T. Gjertsen, and T.-s. Huang
Induction of Differentiation and Apoptosis-- A Possible Strategy in the Treatment of Adult Acute Myelogenous Leukemia
Oncologist,
December 1, 2000;
5(6):
454 - 462.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. A. Sanz, F. L. Coco, G. Martin, G. Avvisati, C. Rayon, T. Barbui, J. Diaz-Mediavilla, G. Fioritoni, J. D. Gonzalez, V. Liso, 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,
August 15, 2000;
96(4):
1247 - 1253.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Ferrara, F. Morabito, B. Martino, G. Specchia, V. Liso, F. Nobile, P. Boccuni, R. Di Noto, F. Pane, M. Annunziata, et al.
CD56 Expression Is an Indicator of Poor Clinical Outcome in Patients With Acute Promyelocytic Leukemia Treated With Simultaneous All-Trans-Retinoic Acid and Chemotherapy
J. Clin. Oncol.,
March 13, 2000;
18(6):
1295 - 1300.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
