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

obtained in low (Sokal) risk patients. This allows a more suitable comparison
with other published series. METHODS Clinical and anagraphical
data were collected through a web-based system. Peripheral blood
samples for quantitative molecular analysis (RT-Q-PCR, Bcr-Abl/Abl x
100 - Taqman) were centralized in Bologna. RESULTS Overall, between
Jan 2004 and Jan 2006, 55 italian centers enrolled 217 low Sokal risk
newly diagnosed CML pts . Median age was 50 yrs (range 18-84), 136
(63%) males and 81 (37%) females. 217 patients were evaluable for
response at 3 months, 181 at 6 months and 118 at 12 months. Median
observation time is 12 months. At 6 months, 86% of evaluable cases
obtained a complete cytogenetic response (100% Ph-neg, CCgR). A
major molecular response (MMolR) defined as a Bcr-Abl/Abl x 100 ratio
< 0.05%, was shown in 54% of CCgR pts. At 12 months, the CCgR rate
was 88% and the MMolR rate in CCgR pts was 60%. With this short
observation period, only 4 pts (1,8%) progressed to accelerated/blastic
phase.CONCLUSIONS 201 low Sokal risk pts were enrolled in the IRIS
trial: at 12 months CCgR and MMolR (reduction of Bcr-Abl/Bcr ratio level
> 3 logs) rates were 76% and 66%, respectively (T. Hughes et al.,
NEJM 349:15, 2003). Our multicentric study confirms and reinforce the
results of the IRIS trial in the same Sokal risk category, showing that imatinib
is highly effective and manageable outside of academical structures
as well as in strictly monitored trials. ACKNOWLEDGMENTS COFIN
2003, FIRB 2001, AIRC, Fondazione del Monte di Bologna e Ravenna,
European Leukemia Net, BolognaAIL.
0550
IMATINIB HIGH DOSE (800 MG) IN INTERMEDIATE SOKAL RISK PATIENTS CML IN
CHRONIC PHASE: RESULTS OF A PHASE II TRIAL OF THE GIMEMA CML WORKING PARTY
G. Rosti, 1 F. Castagnetti, 1 M. Amabile, 1 S. Luatti, 1 F. Palandri, 1
A. Poerio, 1 P. Giannoulia, 1 M. Breccia, 2 F. Stagno, 3 G. Specchia, 4
C. Bigazzi, 5 F. Iuliano, 5 F. Pane, 6 G. Martinelli, 1 G. Saglio, 7
M. Baccarani1
1 2 Institute of Hematology Seràgnoli, BOLOGNA; Chair of Hematology, Università
La Sap, ROMA; 3Chair Of Hematology, Università di Cata, CATANIA;
4 5 Chair of Hematology, Università di Bar, BARI; Hematology Unit, ASCOLI
PICENO; 6CEINGE, Università di Napoli, NAPOLI; 7Patologia Medica,
Orbassano, TORINO, Italy
Background. Imatinib has become the treatment of choice for CML.
The standard dose (SD) for chronic phase (CP) CML is 400 mg daily:
results are less favourable in pts at high or intermediate Sokal risk vs low
Sokal risk ones. In intermediate Sokal risk patients, the IRIS trial (Hughes
et al NEJM 349:15, 2003 ) reported at 12 mos a complete cytogenetic
response (CCgR- 0% Ph-pos) rate of 67% and a major molecular response
(MMolR) rate of 45%. Pre-clinical and clinical data suggest that high doses
(HD - 800 mg daily) of imatinib may be more effective. AIMS The
GIMEMA CML Working party is conducting a phase II, multi-istitutional
prospective study (serial n. CML/021) to investigate the effects of imatinib
HD in intermediate Sokal risk. Between Jan , 2004 and May, 2005,
25 centers enrolled 78 pts ; median age 56 yrs (26-79) (24% were aged 65
years or more at enrollment). The median observation time is 18 mos.
RESULTS At 6 mos, 81% obtained a CCgR and 54% of CCgR pts a
MMolR (Bcr-Abl/Abl x 100 ratio < 0.05%). At 12 mos, the CCgR rate was
88% and the MMolR rate was 56%. Two patients progressed to accelerated/blastic
phase. The compliance to HD treatment was good: at 3, 6 and
12 mos 56%, 53% and 54% of the pts received a median daily dose of
imatinib equal or superior to 600 mg . Non hematopoietic AEs accounted
for the great majority of dose reductions. CONCLUSIONS The results
of this trial further indicate that imatinib HD induces higher and more rapid
responses in intermediate Sokal risk CML pts in early chronic phase,
being superior to the results obtained with SD (IRIS) and in the range of
the MD Anderson results (Kantarjian et al Blood 2004 103:2873).
ACKNOWLEDGMENTS COFIN 2003, FIRB 2001, AIRC, CNR, Fondazione
del Monte di Bologna e Ravenna, European LeukemiaNet, AIL.
0551
MULTIPLE ANALYSES AFFIRM THE INDEPENDENT ADVERSE INFLUENCE OF ABL/BCR
BREAKPOINT SPANNING DELETIONS ON SURIVAL IN CHRONIC MYELOID LEUKEMIA
M. Pfirrmann, 1 S. Kreil,2 C. Haferlach, 3 K. Wagdorn, 2 A. Chase, 2
R. Hehlmann, 4 A. Reiter, 4 A. Hochhaus, 4 N.C.P. Cross2 1 University of Munich, MUNICH, Germany; 2 University of Southampton, SAL-
ISBURY, United Kingdom; 3 MLL Münchner Leukämielabor, MUNICH, Germany;
4 Med. Fakultät MA, Universität Heidelberg, MANNHEIM, Germany
Background. Deletions at or encompassing the ABL/BCR junction on
12 th Congress of the European Hematology Association
the derivative chromosome 9 [(der(9)] are seen in 10-15% of patients
with chronic myeloid leukemia (CML). However whether deletions are
genuinely associated with an adverse prognosis on survival remains controversial.
We investigated the prognostic significance of der(9) deletions
in 339 patients enrolled in three randomized German CML trials and
allocated to receive interferon-α (IFN). Initial univariate analysis showed
no significant survival difference between 59 deleted and 280 non-deleted
patients. Only the 21 patients with breakpoint-spanning deletions
had a significantly poorer survival compared to patients without deletions.
Aims. We sought to investigate whether der(9) deletion status (no
deletion vs. one-sided deletions vs. deletions spanning the ABL/BCR
breakpoint) provided independent prognostic information with regard
to survival when additional factors (age, spleen enlargement, white blood
cell count hemoglobin, and the proportions of blasts, eosinophils, and
basophils in peripheral blood) were also considered. Methods. Deletions
were defined using a novel DNA-based deletion screen based on multiplex
ligation-dependent probe amplification. Associations between the
candidate variables and survival were assessed with multiple Cox regression.
In order to attribute survival probabilities to IFN treatment, survival
times were censored at the start of imatinib therapy or the date of an allogeneic
stem cell transplantation for patients still in chronic phase. Results.
Firstly, we examined the prognostic value of deletion status in a common
Cox model with the Hasford score (Hasford et al., JNCI 1998; 90:850-
858) which was developed and validated to differentiate three prognostic
groups with regard to survival after start of IFN treatment. Of 338
patients with deletion status and score available, 131 had died. Patients
without deletions (n=279, 83%) had a median survival of 6.8 years.
Whilst the 21 cases (6%) with deletions at the whole breakpoint showed
a median survival of 6.1 years, the 38 patients (11%) with one-sided
deletions (whether ABL or BCR was concerned made no difference in
survival) had a six-year survival probability of 0.74. Of the 12 patients
observed beyond that time, nobody died. The Hasford low-risk group
contained 132 patients (39%, median survival: 8.6 years), intermediaterisk
group 166 (49%, median survival: 6.8 years), and the high-risk group
40 patients (12%, median survival: 5.6 years). For both Hasford score and
deletions status, the logrank test indicated a statistically significant discrimination
of survival probabilities. As prognostic factors in a common
model, deletion status and Hasford score kept their statistical significance
(p=0.007 and p=0.011). In a second approach, all candidate variables
were entered into the model. Backward elimination yielded a final
model with three independent variables: deletion status (p=0.007), age
(p=0.018), and spleen enlargement (p5%) and/or high likelihood of incurring incremental
costs for medical treatment/monitoring. The full ranges for the incidence
of AEs (if available) were summarized from publication to provide
ranges for sensitivity analyses in future economic analyses. The nilotinib
median duration of exposure was 8.1 months while the median
treatment duration of dasatinib was 5.6 months. Results. The Grade 3/4
hematologic AEs are the most common AEs (table below) and are
approximately twice as high for dasatinib compared to nilotinib. Common
Grade 3/4 biochemistry abnormalities include hyperglycemia in
haematologica/the hematology journal | 2007; 92(s1) | 205