12th Congress of the European Hematology ... - Haematologica

12 th Congress of the European Hematology Association
Acute lymphoblastic leukemia - Clinical
0371
HIGH INTERLEUKIN-15 EXPRESSION LEVELS IN INITIAL DIAGNOSTIC LEUKEMIC CELLS
OF CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA ARE ASSOCIATED WITH
SUBSEQUENT RELAPSE INVOLVING THE CENTRAL NERVOUS SYSTEM
G. Cario, 1 S. Izraeli, 2 A. Teichert, 3 P. Rhein, 4 J. Skokowa, 3 A. Möricke, 1
M. Zimmermann, 3 A. Schrauder, 1 W.D. Ludwig, 4 K. Welte, 3
H. Schünemann, 5 B. Schlegelberger, 3 M. Schrappe, 1 M. Stanulla3 1 University Hospital Schleswig-Holstein, KIEL, Germany; 2 Chaim Sheba Medical
Center, Tel-Hashomer, TEL-AVIV, Israel; 3 Hannover Medical School, HAN-
NOVER, Germany; 4 Robert-Rössle-Clinic, Charite, BERLIN, Germany; 5 Italian
National Cancer Institute, ROME, Italy
Background. Central nervous system (CNS)-targeted therapy as part of
treatment for childhood acute lymphoblastic leukemia (ALL) is highly
effective in the prevention of CNS relapse, but is associated with significant
toxicity. The intensity of CNS-targeted treatment is adjusted
according to the risk of ALL relapse originating from the CNS, the most
important risk factor being overt CNS involvement at diagnosis. However,
most ALL relapses involving the CNS occur in patients classified
as CNS-negative at initial diagnosis. Although there are some known
risk factors for CNS involvement of ALL such as T-cell-precursor
immunophenotype and high initial white blood cell (WBC) count, the
underlying biology leading to CNS disease is poorly understood. Aims.
To improve patient characterization and to explore potential distinct
biological properties of leukemic cells that migrate into the CNS by
comparing gene expression profiles of childhood ALL patients with initial
CNS involvement to CNS-negative patients. Methods. Leukemic gene
expression profiles from bone marrow of 17 CNS-positive patients and
26 CNS-negative patients frequency-matched for risk factors associated
with CNS involvement were analyzed using microarrays containing
more than 39,000 distinct cDNA clones (SFGF, Stanford CA). Data were
analyzed applying Significance Analysis of Microarrays (PNAS 2001,
98, 5116-5121). Results were confirmed by real-time quantitative polymerase
chain reaction analysis and validated using independent patient
samples. Results. Our analytical approach identified several differentially
expressed genes. To control for possible T-cell contamination of the
samples, we purified leukemic cells from four samples and repeated the
analysis. Interleukin 15 (IL-15) was one of the genes for which differential
expression could be confirmed with an up to 10-fold higher expression
in CNS-positive patients. The high expression of IL-15 in patients
with CNS involvement was validated in an independent set of 13 CNSpositive
and 26 CNS-negative patients by quantitative RT-PCR in a similar
range as described above (P Mann-Whitney U-Test ″0.001). In multivariate
analysis, IL-15 expression levels above the median were associated
with CNS involvement compared to expression equal to or below
the median (odds ratio (OR) = 10.70, 95% confidence interval (CI) 2.95-
38.81). Diagnostic likelihood ratios for CNS-positivity were 0.09 (95%
CI 0.01-0.65) for the first and 6.93 (95% CI 2.55-18.83) for the fourth IL-
15 expression quartile. Next, we compared IL-15 expression at initial
diagnosis of CNS-negative patients subsequently relapsing with CNS
involvement (n=22) to those without CNS disease and being in longterm
remission (n=44). In patients CNS-negative at diagnosis, IL-15 levels
above the median were associated with subsequent CNS relapse
compared to expression equal to or below the median (OR=13.80, 95%
CI 3.38-56.31). Conclusions. We conclude that measurement of IL-15
expression levels could serve as an additional tool to further tailor CNSdirected
therapy in children newly diagnosed with ALL. Additional studies
are needed to finally elucidate the role of IL-15 in the pathogenesis
of CNS disease in childhood ALL.
0372
FINAL RESULTS OF THE TREATMENT OF ADOLESCENTS AND YOUNG ADULTS WITH
STANDARD-RISK ALL WITH THE PEDIATRIC-BASED PROTOCOL PETHEMA ALL-96
J.M. Ribera, 1 J.M. Ribera, 1 A. Oriol, 1 M.A. Sanz, 2
P. Fernandez-Abellan, 2 E. Del Potro, 2 E. Abella, 2 J. Bueno, 2 C. Grande, 2
C. Calvo, 2 C. Bethencourt, 2 J. Fernandez-Calvo, 2 J.M. Martí, 2 I. Heras, 2
R. Parody, 2 E. Feliu, 2 J.J. Ortega2 1 2 Institut Català d'Oncologia- Hospital Ge, BADALONA; PETHEMA Group,
BARCELONA, Spain
Background. Recent retrospective comparative studies have shown
134 | haematologica/the hematology journal | 2007; 92(s1)
that adolescents and young adults with standard-risk (SR) ALL are better
managed with pediatric-based than adult-based chemotherapeutic
schedules. Aims. To report the final results of the PETHEMA ALL-96, a
pediatric-based protocol, in adolescents and young adults with SR ALL.
Patients and therapy. Criteria for SR-ALL: age 15-30 yr., WBC count
10% of BM blast
cells on day 14) 10 pts, early death 2, resistance 2, relapse 18 (1 CNS, 17
BM isolated or combined, 6 during therapy), death 16 pts (2 induction,
1 C2, 13 relapse/progression). With a median follow-up of 35 mo. 5-yr
(95%CI) OS and DFS probabilities were 74% (63-85) and 66% (54-78).
No pretreatment variables influenced CR, DFS and OS. The slow
response to therapy was the only prognostic factor for CR (80% vs.
99%, p=0.04) and survival (40% vs. 85%, p=0.001). Overall toxicity was
acceptable, although there were dose modifications or delay in therapy
in 10% pts in induction, 26% pts in C1, 15% in C2, 22% in M1 and 21%
in M2. Conclusions. The results of the pediatric-based PETHEMA ALL-
96 study for adolescents and young adults with SR ALL treated in adult
hematology units are identical to those reported in national series from
pediatric centers. Slow response to therapy was the only prognostic factor
for remission and survival.
Supported in part with Grant P-EF-06 from Jose Carreras Leukemia Foundation.
0373
TWO DECADES OF PROGRESS IN ADOLESCENTS WITH ACUTE LYMPHOBLASTIC
LEUKEMIAS TREATED IN THE FRALLE PROTOCOLS: ADOLESCENCE IS NO MORE A BAD
PROGNOSTIC FEATURE IF AN INTENSIVE CHEMOTHERAPY IS APPLIED
A. Baruchel, 1 M.F. Auclerc, 2 Y. Perel, 3 F. Mechinaud, 4 A. Auvrignon, 5
C. Schmitt, 6 C. Piguet, 7 O. Lejars, 8 C. Berthou, 9 F. Demeocq, 10
P. Schneider, 11 V. Gandemer, 12 G. Michel, 13 J.M. Cayuela, 14 T. Leblanc, 15
G. Leverger, 5 F. Fralle Group14 1 AP-HP, Paris 7 University, PARIS; 2 INSERM, PARIS; 3 CHU Bordeaux, BOR-
DEAUX; 4 CHU Nantes, NANTES; 5 Hôpital Trousseau, PARIS; 6 CHU Nancy,
NANCY; 7 CHU Limoges, LIMOGES; 8 CHU Tours, TOURS; 9 CHU Brest,
BREST; 10 CHU Clermont-Ferrand, CLERMONT-FERRAND; 11 CHU Rouen,
ROUEN; 12 CHU Rennes, RENNES; 13 CHU Marseille, MARSEILLE; 14 Hôpital
Saint-Louis, PARIS; 15 Hôpital St-Louis, PARIS, France
Adolescence has been claimed since the seventies to be associated to
a a bad prognosis in childhood ALL. Out of 4658 patients with ALL, 258
adolescents (15-20 year old)(5.5%) were treated in the successive
FRALLE 83, FRALLE 87-89, FRALLE 92 (pilot phase), FRALLE 93 and
FRALLE 2000 protocols. The main characteristics were: a sex ratio of 1.8
(M/F), a B-lineage in 71% of the cases vs T lineage in 29%, and a median
WBC of 12 G/L (9-1000). Translocation and fusion transcripts were
searched for in 120 evaluable BCP-ALL: t(9;22)/BCR-ABL, 8 pts (6%);
t(1;19)/E2A-PBX1, 12 pts (10%); t(4;11)/MLL-AF4, 4 pts (3%). Out of 75
evaluable pts t(12;21)/TEL-AML1 was found in only 4 pts (3%). 242 out
of 258 adolescents were in CR at the end of induction therapy (EOI)
(94%) without any significant difference according to the era. Nevertheless
a major difference in the 3y and 5y EFS was found ans is shown in
Table 1. The main modification introduced in the nineties was the adoption
of a double delayed intensification for the good early responders.
Autologous BMT or allogenic BMT were indicated in bad early responders
(D8 poor prednisone response, D21 marrow M3 response) and/or
unfavourable cytogenetics. The better results of the 2000 protocol can
mainly be explained by the intensification of chemotherapy in most
phases and especially between induction and delayed Intensification 1
and before delayed Intensification 2. These better results were obtained
despite decreasing the indications of allo BMT (6 performed vs 20 in the
nineties) and of CNS irradiation (100% in the nineties vs 35% in the current
era, including the TBI for BMTs). ABMT was no more indicated.
Conclusions. 1) excellent results can now be achieved in adolescents with
ALL 2) this works emphasizes again the need to treat adolescents according
to pediatric intensive protocols and not adult type protocols, as we