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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 784-789
Early Detection of Relapse by Prospective Reverse
Transcriptase-Polymerase Chain Reaction Analysis of the PML/RAR
Fusion Gene in Patients With Acute Promyelocytic Leukemia Enrolled
in the GIMEMA-AIEOP Multicenter "AIDA" Trial
By
Daniela Diverio,
Vincenzo Rossi,
Giuseppe Avvisati,
Silvia DeSantis,
Alessandra Pistilli,
Fabrizio Pane,
Giuseppe Saglio,
Giovanni Martinelli,
Maria Concetta Petti,
Alessandra Santoro,
Pier Giuseppe Pelicci,
Franco Mandelli,
Andrea Biondi, and
Francesco Lo Coco for
the GIMEMA and AIEOP Cooperative Groups
From the Dipartimento di Biotecnologie Cellulari ed Ematologia,
Università "La Sapienza", Rome; Clinica Pediatrica,
Ospedale S. Gerardo, Università di Milano, Monza; Istituto L.& A. Seràgnoli, Università di Bologna, Bologna;
CEINGE, Università Federico II, Napoli; Istituto Europeo di
Oncologia, Milano; Clinica Medica, Ospedale Maggiore, Novara; Divisione
di Ematologia, Ospedale V. Cervello, Palermo, Italy.
 |
ABSTRACT |
Although the majority of patients with acute promyelocytic
leukemia (APL) are potentially cured by treatments combining
all-trans retinoic acid (ATRA) and chemotherapy (CHT), a
sizable proportion (around 30%) will relapse during follow-up.
Retrospective molecular monitoring studies using reverse
transcriptase-polymerase chain reaction (RT-PCR) for the specific
PML/RAR fusion gene, have shown that a positive test usually
precedes the occurrence of hematologic relapse. Prospective RT-PCR
analyses were performed since 1993 at diagnosis and at preestablished
time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RAR+ APL enrolled in the multicenter
Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA)
trial AIDA (All-trans retinoic acid plus Idarubicin).
Treatment consisted of ATRA and idarubicin for induction followed by
three polychemotherapy courses as consolidation. The sensitivity level
of the RT-PCR assay for PML/RAR, as assessed by serial dilution
experiments, was 10 4. All patients were in hematologic
remission and tested PCR at the end of consolidation. Of
21 who converted to PCR-positive thereafter, 20 underwent hematologic
relapse at a median time of 3 months (range, 1 to 14) from the first
PCR+ result. Seventeen of these 21 (81%)
PCR+ conversions were recorded within the first 6 months
postconsolidation. Of 142 who tested persistently PCR in
 2 tests after consolidation, 8 had hematologic relapse and 134 remained in complete remission (CR) after a median follow-up of 18 months (range, 6 to 38) postconsolidation. Using a time-dependent Cox
model, the relative risk of hematologic relapse of patients who
converted to PCR+ was 31.8 (confidence
limits 95%, 12.9 to 78.3). Our results indicate that
conversion to PCR positivity for PML/RAR during remission is highly
predictive of subsequent hematologic relapse and highlight the
prognostic value of stringent molecular monitoring during the early
postconsolidation phase in APL. As a result of the present study,
salvage treatment in patients enrolled in the GIMEMA trial AIDA is now
anticipated at the time of molecular relapse, defined as the conversion
to PCR positivity in two successive BM samplings during follow-up.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
THE MAJORITY (up to 70%)
of patients with acute promyelocytic leukemia (APL) are currently
induced into long-term remission and potential cure with modern
treatment approaches combining all-trans retinoic acid (ATRA) and
chemotherapy. However, despite this progress, relapse occurs in 20% to
30% of patients receiving such therapy and still represents a major
obstacle to final cure.1-8
Although patients with relapsed APL have a good chance of
achieving second remission, disease recurrence is associated with higher frequency of refractory leukemia and with shorter
survival.1-2 Novel treatment approaches, including AM80 (a
synthetic retinoid) or arsenic trioxide seem effective in APL
relapse,9,10 but their use is still investigational.
The identification during hematologic remission of
patients at highest risk of relapse is relevant to adjust treatment
choices and may allow us to anticipate salvage therapy. We and others have shown that reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of the PML/RAR fusion gene derived from the t(15;17) may enable the detection of residual leukemic cells during remission in APL patients.11-21 Using PCR assays with a
sensitivity threshold ranging between 103 and
104, several retrospective studies reported that
patients who remain (or convert to) PCR+ after
consolidation are very likely to relapse within a few months, whereas
patients in long-term remission and potentially cured show no
PCR-detectable residual disease.11-21
Following these observations, the Italian Gruppo
Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) and
Associazione Italiana Ematologia e Oncologia Pediatrica
(AIEOP) groups initiated in 1993 a trial for newly
diagnosed APL ("AIDA" [All-trans retinoic acid plus Idarubicin]
0493), which included serial prospective PCR evaluations. The recently
reported interim results indicate that 60% and 96% of patients
convert to PCR after induction and consolidation,
respectively.5 However, because  20% of patients
achieving molecular remission relapsed during follow-up, it appears
that PCR tests performed at the end of consolidation fail to identify
all patients at risk.5
We report here the results of a prospective PCR monitoring
study in 163 PML/RAR+ patients enrolled in the AIDA
trial. Our findings, which indicate that conversion to PCR positivity
after consolidation is almost uniformly followed by hematologic
relapse, prompted us to anticipate salvage therapy at the time of
minimal disease recurrence.
| |
MATERIALS AND METHODS |
Patients and sample collection.
As of July 1997, 519 patients with a genetically confirmed diagnosis of
APL were eligible to enter the Italian GIMEMA "AIDA" trial. Of
these, 479 (92%) were characterized by RT-PCR as
PML/RAR+. After the end of consolidation treatment, 312 of 324 (96%) tested PCR and 12 (4%) PCR+.
These latter 12 cases received allogeneic transplant from HLA-identical or unrelated donor, or alternative treatments at the physician's discretion and are not included in this monitoring analysis. Of the 312 patients who tested PCR, 163 with 6 months
postconsolidation follow-up, and in which at least two bone marrow (BM)
samples were collected at the scheduled time intervals and sent to
referral laboratories, are included in the present study.
All investigators of participating institutions (see Appendix) were
requested to prepare locally Ficoll-Hypaque (Nycomed
Pharma AS, Oslo, Norway) isolated mononuclear cells collected from BM aspirates, wash cells twice in sterile phosphate-buffered saline (PBS),
and then store samples at  20°C in a 4-mol/L guanidium thiocyanate (GTC) solution. According to the study design, BM aspirates
for molecular monitoring analyses were called at diagnosis, after
induction, at the end of consolidation, every 3 months during the first
and second year, and then every 6 months during the third and fourth
year after consolidation. GTC aliquots were provided to peripheral
institutions by the two central laboratories. Specific recommendations
were made for the use of RNAase-free disposable materials during cell
manipulation. Cryopreserved GTC samples were sent in dry ice to two
referral molecular biology laboratories (Hematology, University "La
Sapienza" of Rome and Clinica Pediatrica, University of
Milano-Monza) where RT-PCR analyses were performed.
RT-PCR of PML/RAR.
Total RNA was extracted by the method of Chomczynsky and
Sacchi.22 To assess the integrity of RNA, samples were run
after extraction on a formaldehyde minigel. Cases showing partial or total RNA degradation were not processed further and a new sample was
requested in such cases to the peripheral Center. RT-PCR amplification of the PML/RAR hybrid gene was performed as reported
elsewhere,12,13 with two modifications: the annealing
temperature was raised to 56°C and, starting from April 1996, the
Amplitaq Gold enzyme (Roche Molecular Systems Inc, Branchburg, NJ) was
used as Taq polymerase in both laboratories. In addition to the
amplification of the hybrid gene in patient RNA, each RT-PCR experiment
included the coamplification of: (1) RNA from the NB4 cell line as
positive control; (2) all reagents plus water and no RNA as negative
control; and (3) a cDNA fragment containing RAR exons 2 and 3 obtained from the same patient under analysis (internal control) to
further verify RNA integrity and to assess the efficiency of the RT
step.
The sensitivity of the RT-PCR assay was determined by amplifying
serially diluted RNA mixtures of a diagnostic sample with 100% of
blasts and the t(15;17)-negative myeloid cell line GF-D8, as
reported.12 The PML/RAR transcript was still detectable in the presence of 0.1 ng total RNA, that is a final dilution of
104. Such detection level was repeatedly obtained in
several new experiments performed using Amplitaq Gold as DNA
polymerase. The use of the latter apparently increased either the
specificity or the sensitivity of the assay. However, in only two of
nine experiments performed using Amplitaq Gold, were we able to
visualize on the ethidium bromide gel a 105
dilution, whereas a 104 dilution was constantly
detected.
To verify the reproducibility of results between the two reference
laboratories, 66 RNA samples including diagnostic and remission specimens, were divided in two aliquots and blindly analyzed in parallel. The results showed 100% concordance as regarding both the
presence or absence of the fusion mRNA and the type of transcript in
positive cases.
Treatment plan.
The AIDA protocol consists of an induction phase combining oral ATRA
given daily until complete remission (CR) and four doses of intravenous
idarubicin, followed by three polychemotherapy consolidation courses.
At the end of consolidation, PCR patients were
randomized into four arms including chemotherapy alone with
6-mercaptopurine and methotrexate (arm 1), ATRA alone (arm 2),
alternating chemotherapy and ATRA (arm 3), or observation (arm 4).
Patients who tested PCR+ after consolidation underwent, if
eligible, allogeneic BM transplantation in first CR or received
alternative therapy at the physician's discretion. Detailed drug doses
and schedule of the protocol have been reported
elsewhere.5,23
Criteria for hematologic and molecular response.
Hematologic remission was defined as a normal BM cellularity with less
than 5% leukemic promyelocytes and normalization of peripheral blood
counts. PCR negativity was defined as the absence, on ethidium
bromide-stained electrophoresis gel, of the specific PML/RAR
amplification band detected at diagnosis, in the presence of RNA
integrity as evaluated by minigel visualization, and successful amplification of the internal control. PCR positivity in follow-up studies was defined as the reappearance on ethidium bromide-stained gel
of the same amplification band detected at diagnosis. A second BM
sample was requested in all cases who converted to PCR+ and
the assay repeated to avoid false positivity due to contamination or
amplification of nonspecific PCR products. Hematologic relapse was
defined as the reappearance of 5% leukemic promyelocytes in the BM.
Statistical analysis.
Relapse probability was calculated from the end of consolidation to the
time of hematologic relapse or last follow-up, according to the
Kaplan-Meier method.24 Patients PCR in
the BM at the time of isolated extrahematologic relapse were considered
as censored in the relapse curves. The relative risk and 95%
confidence limits were estimated using a time-dependent proportional
hazard Cox model.25
| |
RESULTS |
A total of 163 patients who tested PCR at the end of
consolidation are included in this molecular monitoring analysis. A
minimum potential follow-up of 6 months after consolidation and at
least two scheduled and evaluable PCR tests were considered for patient inclusion in the present evaluation. The remaining 149 of the 312 patients who tested PCR after consolidation were
excluded due to protocol violation, because it was too early for
evaluation, or, as a main cause (115 cases), because less than two
scheduled and evaluable BM samples were received by referral
laboratories.
A mean of 5 (range, 2 to 11) BM samples per patient collected during
postconsolidation follow-up were analyzed. In the vast majority of
cases, specimens were processed and the results obtained within 3 weeks
from receipt. The appropriate oligonucleotide set, using the PML
external primer (M4, located on PML exon 3) for patients initially
characterized as having the short or bcr3 isoform or, alternatively,
the PML internal primer (M2, for patients initially characterized as
having the long type or bcr1-2 isoform) was adapted to each case during
monitoring analyses to visualize a single PML/RAR amplification band
and to avoid the resolution of multiple bands due to PML alternative
splicing. Morphologic examinations of BM smears and PCR tests were
always done independently avoiding any exchange of information between
cytology reviewers and molecular biologists to minimize interpretation
bias. Clinical updates, including written reports of marrow appearance
and PCR data, were timely and independently sent to the GIMEMA data
center by local clinical institutions and by referral molecular biology
laboratories.
Twenty-one of the 163 patients tested PCR+ at least once
during follow-up. BM morphologic reports documented hematologic
remission in all 21 cases at the time of conversion to
PCR+. Of these 21, 20 (95%) underwent subsequent
hematologic relapse within a median time of 3 months (range, 1 to 14)
from the time of first conversion to PCR+. In 8 of these 20 patients, at least one further BM sample was analyzed and found
positive before overt relapse. Seventeen of the 21 (81%)
PCR+ conversions were recorded within the first 6 months,
ie, on the first or second scheduled sampling collected
postconsolidation. Detailed characteristics of these 20 patients who
converted to PCR+ and underwent hematologic relapse are
reported in Table 1. One patient showed a
transient PCR-positivity 16 months after the end of consolidation, with
a subsequent analysis performed 3 weeks later showing again
PCR-negativity. This patient remained in remission after 2 months.
Of the 142 patients who tested persistently PCR in
2 postconsolidation tests, eight (5.6%) underwent hematologic
relapse at a median time of 1.5 months (range, 1 to 23). In seven of
these eight cases, a BM specimen collected within 3 months before
hematologic relapse could be analyzed and tested negative, whereas no
sample was sent at such scheduled time in the other patient. The
remaining 134 patients in this group are in hematologic remission at a
median postconsolidation follow-up of 18 months (range, 6 to 38).
Figure 1 shows the probability of
hematologic relapse according to the results of molecular monitoring.
Two patients who tested PCR in the BM at the time of
isolated extramedullary relapse were censored in the relapse curves.
Considering that conversion to PCR+ is observed at variable
times during follow-up, the relapse risk analysis to compare positive and negative patients was performed using a time-dependent Cox model.
The relative risk of developing hematologic relapse for patients who
converted to PCR+ at any time during follow-up compared
with patients who remained persistently PCR was 31.8 (confidence limits 95%, 12.9 to 78.3).
| |
DISCUSSION |
In recent years, a number of studies have highlighted the relevance of
PML/RAR detection in the clinical management of
APL.1,2,11-21 At diagnosis, such importance relies on the
possibility of identifying virtually 100% of patients responsive to a
specific therapy including ATRA. After treatment, longitudinal
retrospective studies of minimal residual disease (MRD) monitoring have
shown that PCR amplification of this hybrid gene is prognostically
informative because overt relapse is usually (but not uniformly)
preceded by a positive test and, conversely, long-term survivors test
PCR.11-21 These findings further
distinguish APL from all other acute leukemia subsets in which
associations with a specific genetic lesion are never equally
consistent and where MRD studies have yielded more controversial
results.26 On the other hand, several investigators have
pointed out the technical difficulties of the RT-PCR assay for
PML/RAR, which are mainly related to the low amount and instability
of the fusion transcript, resulting in a less sensitive test compared
with the amplification of other well-characterized leukemia associated
fusion genes such as, for example, BCR/ABL and
AML1/ETO.27,28 It seems, however, that this relatively poor
sensitivity (most studies report detection levels between
103 and 104) results in a
clinically useful threshold, whereby patients who test positive during
remission have been reported to be at highest risk of developing
hematologic relapse.11-21
The present study was performed prospectively in a large number of
patients characterized at diagnosis as having PML/RAR-positive APL
and enrolled in a single treatment protocol. According to the design of
our trial,5 one of the aims of molecular monitoring was to
identify at the end of consolidation patients at risk of relapse to
adjust further treatment choices (including allogeneic transplantation
in patients still positive at such time). The exceedingly high fraction
of PCR cases observed after consolidation (96%)
compared with the hematologic relapse rate at 2 years (20%, data
not shown), indicate that a sizable proportion of patients at risk are
not identified at this time. By contrast, we found that the results of
subsequent postconsolidation analyses are extremely relevant in terms
of outcome prediction. In fact, 20 of 21 patients who converted to PCR+ during follow-up underwent successively overt relapse,
whereas only 8 of 142 who tested 2 times negative after consolidation relapsed thereafter. Because they are obtained prospectively, these
data provide compelling and definite evidence that PCR positivity during hematologic remission predicts relapse in APL.
With respect to the sensitivity of the assay, we observe that although
our method allowed us to reach clinically useful conclusions, a greater
degree of standardization is needed to enable better reproducibility in
large clinical trials. Future studies should be aimed at determining
whether a given amount of the PML/RAR transcript correlates with a
clinical remission status and, conversely, which copy number detection
would anticipate the occurrence of impending relapse in individual
patients. It is expected that newly developed automated methods, such
as Taqman quantitative PCR, will be of considerable help for this
purpose, ensuring more reliable comparison among different studies.
As to the time elapsed between the first molecular evidence of MRD and
hematologic relapse, the majority of patients in the present study had
overt disease recurrence within a few months from the first
PCR+ test, although a rather heterogeneous behavior was
observed considering the whole group (range, 1 to 14 months). It is
presumed that intrinsic biologic diversity related to the clonogenic
capacity of leukemia cells may account for such variability.
Alternatively, this heterogeneous clinical evolution may simply be
related to differences in the amount of MRD, which are undetected using
a nonquantitative assay. With respect to a potential influence of
maintenance treatment, we found no significant correlations between
treatment type and time elapse from PCR positivity to disease
recurrence (Table 1).
Because this study was performed in the context of a multicenter
clinical trial involving more than 70 institutions (listed in the
Appendix), some considerations on the logistic and technical difficulties encountered may be of interest. Molecular monitoring data
could be obtained in approximately half of the patients with an
evaluable follow-up. The main reasons for failure to analyze the
remaining patients were related to poor compliance from some local
institutions as regarding scheduled samplings or inadequate shipment
and late receipt of samples resulting in poor RNA yield after
extraction. We remark, however, that the vast majority of PCR+ conversions were recorded in our study within the
first 6 months after the end of consolidation. This observation
emphasizes the prognostic value of a stringent molecular assessment of
MRD performed in the early posttherapy period. Thus, despite the
logistic and technical difficulties, we strongly recommend that all
efforts are made to warrant this monitoring analysis during the first 6 months after consolidation treatment.
Based on the findings reported here, the GIMEMA and AIEOP groups have
recently adopted an amendment in the AIDA protocol. According to this,
patients who convert to PCR+ at any time after
consolidation are tested again in a new BM sample collected within 2 to
4 weeks after the first one, and therapy of relapse is anticipated
after confirmation of PCR positivity in the second BM specimen. Such
repeated sampling certainly provides the most adequate experimental
condition to rule out false positivity due to PCR contamination.
To the best of our knowledge, this is the first report on acute
leukemia showing that MRD results are translated into operationally active medical decisions. Whether the anticipation of treatment at the
time of MRD recurrence will improve the outcome of APL relapsed
patients remains to be established. However, we presume that at least
some significant advantages will be obtained, such as the disappearance
or minimization of early deaths due to hemorrhage or ATRA syndrome, and
the possibility of outpatient-based treatment. Together with the
important recent advances in the front-line therapy of APL, early
identification and treatment of relapse might represent a further step
towards the final cure of all patients with this disease.
| |
FOOTNOTES |
Submitted February 17, 1998;
accepted March 26, 1998.
Supported by ROMAIL (Associazione Italiana contro le Leucemie, Sezione
di Roma), CNR Project "Biotecnologie" and Fondazione Tettamanti,
Monza.
Presented in part at the 39th Annual Meeting of the American Society of
Hematology, held in San Diego, CA, December 5-9, 1997.
Address reprint requests to Francesco Lo Coco, MD,
Dipartimento di Biotecnologie Cellulari ed Ematologia, Università
"La Sapienza", Via Benevento 6, 00161 Rome, Italy; e-mail:
lococo{at}bce.med.uniroma1.it.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We are grateful to Dr M. L. Vegna for statistical analysis.
| |
APPENDIX |
The following clinical departments participated in the AIDA 0493 trial: Ematologia, Università "La Sapienza",
Roma, F. Mandelli, G. Avvisati, D. Diverio, A.M. Testi, 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,
Università, 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, Università,
Catania, E. Cacciola, F. Di Raimondo; Cattedra di Ematologia,
Università, Parma, V. Rizzoli, C. Almici; Cattedra di Ematologia,
Università, Verona, G. Perona, D. Veneri; Cattedra di Ematologia,
Università, 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, Università Tor Vergata, Roma, S. Amadori,
G. Aronica; Clinica Pediatrica, Ospedale S. Gerardo, Monza, G. Masera,
A. Biondi, A. Luciano; Divisione di Ematologia, Università
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, Università, Palermo, G. Mariani, 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, Università, Genova, R. Ghio, E. Balleari;
Clinica Medica, Policlinico S. Matteo, Pavia, E. Ascari, R. Invernizzi; Divisione di Ematologia, Università, Pisa, B. Grassi, M. Petrini; Ematologia, Ospedale S.S. Annunziata, Taranto, P. Mazza, G. Lazzari; Cattedra di Ematologia, Università, Udine, M. Baccarani, A. Candoni; Ematologia Pediatrica, Università, Catania, G. Schilirò, A.M. Ippolito; Ematologia, IV Divisione Pediatrica,
Genova, L. Massimo, C. Micalizzi; Cinica Pediatrica, Università,
Pavia, F. Severi, F. Locatelli; Ematologia, Ospedale Regionale A. Di
Summa, Brindisi, G. Quarta, A. Melpignano; Cattedra di Ematologia,
Università, Ferrara, G. Castoldi, F. Lanza; Semeiotica Medica,
Università, 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, Università, Napoli, M.T. Di Tullio, M. Giuliano; Clinica Pediatrica II, Università, Padova, L. Zanesco,
M. Pilon; Clinica Pediatrica III, Università, Pisa, P. Macchia,
C. Favre; Clinica Pediatrica, Università, 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, Afdeling Hemato-Oncologie, Antwerpen (B), R. De Bock.
| |
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Abstract
Introduction
Abstract
