sem informação100120th Congress of European-Hematology-Associationsem informaçã

Bullorsky, E.

Casanova, L.

De Riz, M.

Enrico, A.

Milone, J.

Moiraghi, B.

Navarro Cabrera, J.

Olivera, L. Enciso

Pagnano, K.

Pavlovsky, C.

Undurraga, M. S.

Haematologica

English

Repositorio da Producao Cientifica e Intelectual da Unicamp

UNIVERSIDADE ESTADUAL DE CAMPINAS
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REPOSITÓRIO DA PRODUÇÃO CIENTIFICA E INTELECTUAL DA UNICAMP
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Cidade Universitária Zeferino Vaz Barão Geraldo
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Background: The additional benefit of achieving major molecular response
(MMR) in patients with Complete Cytogenetic Response (CCyR) response is
still under debate, and therefore, patients with CCgR without MMR after 12
months of treatment are considered as a “warning” by European LeukemiaNet
(ELN) recommendations. Several clinical trials have shown how patients treat-
ed with imatinib front line and classified as late warning responders can benefit
from treatment changed to nilotinib in terms of improving molecular response.
However, there are no data regarding to treatment change to dasatinib in this
group of patients
Aims: To evaluate the efficacy and safety of treatment change to dasatinib in
patients treated with imatinib first line with late suboptimal response (patients
with CCyR without MMR after at least 18 months of treatment) by the ELN 09
recommendations
Methods: We are presenting preliminary results of the first 18 patients enrolled
in the phase II DASAPOST study (NCT01802450). Main inclusion criteria were
patients treated with late suboptimal response by the ELN09 (CCyR without
MMR after 18 months of treatment). Previous treatment with imatinib 600mg
(but not 800mg) was allowed. Median exposure to imatinib before dasatinib
was 5.1 years (1.8-12.2). Sokal risk groups % (L/I/H) was 22.5%, 55% and
22.5%. Median age was 56 years (34-77). Primary end point was the achieve-
ment of MMR after 6 months of dasatinib. Secondary endpoints were to assess
the efficacy of dasatinib in terms of depth and kinetics of molecular response,
as well as the relationship of response with lymphocyte alterations. Responses
evaluations were performed following indications of the ELN. All BCR-ABL/ABL
(IS) measurements were centralized in an EUTOS laboratory.
Results: Clinical: Eighteen patients have been enrolled in the study. Median
follow up at data cut-off was 262 days (21-380). Three out of 18 (16%) patients
had discontinued dasatinib due to side effects (pancreatitis, pleural effusion
and low grade, persistent side effects (fever, arthralgias, anemia and asthenia).
16/18 patients have been evaluated at 3 months, 12 at 6 months and 6 at 12
months. Cumulative incidences by ITT of MMR calculated by competing risks
by 3 and 6 months were 50 and 83%. However, for patients who reached the
6 months assessment frequencies of MMR and MR4.5 were 85% and 42%
respectively. No patient have lost CCyR while 1 patient in MR4.5 lost MMR. 1
patient had reduced dasatinib dose to 70mg due to congestive heart failure
(patient achieved and maintained undetectable molecular response). Immuno-
logical: Lymphocyte counts were done before and after dasatinib intake at
baseline, at 3 and 6 months, observing an increment of counts post intake in
most patients. At baseline the median increase post intake was 1,79 fold (
0,98-3,2). There was no significant association between this increment and
MMR at 3M (MMR at 6 months was not studied, as most patients obtained this
response at that timepoint).
Summary and Conclusions: Our study shows, for the first time to our knowl-
edge, that in patients treated with Imatinib and late suboptimal (warning)
responses, switch to Dasatinib induced MMR in 83% of the patients, although
16% discontinued treatment because of toxicity. No association was found
between lymphocyte “mobilization” post intake and response. Dasatinib
appears to have a good benefit/ risk ratio in this type of patients. More details
on the immunologic studies will be provided.
E1118
OPTIMIZATION OF THERAPEUTIC DOSES OF RADOTINIB FOR CHRONIC
MYELOID LEUKEMIA BASED ON EXPOSURE-RESPONSE RELATION-
SHIP ANALYSES
H. Noh1,2,* M.S. Park3,4, S.H. Kim5, H. Menon6, S. Jootar7, T. Saikia8,
J.Y. Kwak9, J.S. Park10, H.J. Kim11, S.J. Oh12, H. Kim13, D.Y. Zang14, S. Park15,
H.L. Park16, G.Y. Lee16, D.J. Cho16, J.I. Lee1,2,3,4, D.W. Kim15,17
1Department of Pharmacy, College of Pharmacy, Yonsei University, 2Yonsei
Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University,
3Department of Pharmaceutical Medicine and Regulatory Science, Colleges
of Medicine and Pharmacy, Yonsei University, Incheon, 4Department of Clinical
Pharmacology, Severance Hospital, Yonsei University Health Systems, Seoul,
5Department of Internal Medicine, Dong-A University Medical Center, Busan,
Korea, Republic Of, 6Leukemia and Lymphoma Unit, Department of Medical
Oncology, Tata Memorial Hospital, Mumbai, India, 7Department of Medicine,
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 8Department of
Medical Oncology, Prince Aly Khan Hospital, Mumbai, India, 9Department of
Internal Medicine, Chonbuk National University Hospital, Jeonju, 10Department
of Hematology-Oncology, Ajou University Hospital, Suwon, 11Department of
Hematology-Oncology, Hwasun Hospital, Chonnam National University, Hwa-
sun, 12Deparment of Internal Medicine, Kangbuk Samsung Hospital,
Sungkyunkwan University, School of Medicine, Seoul, 13Division of Hematology
and Cellular Therapy, Ulsan University Hospital, University of Ulsan College of
Medicine, Ulsan, 14Department of Hematology-Oncology, Hallym University
Sacred Heart Hospital, Anyang, 15Cancer Research Institute, The Catholic Uni-
versity of Korea, Seoul, 16Central Research Institute, IL-YANG Pharm. Co.,
Ltd., Yongin, 17Department of Hematology, Seoul St. Mary’s Hospital, The
Catholic University of Korea, Seoul, Korea, Republic Of
Background: BCR-ABL1 tyrosine kinase inhibitors (TKIs) have been admin-
istered as fixed doses for adult patients with chronic myeloid leukemia (CML).
However, due to the wide inter-individual variability in the pharmacokinetics of
TKIs and increasing evidence supporting the relationship between drug expo-
sure and the efficacy and toxicity of these agents, there may be potential ben-
efits of TKI dose individualization based on body size. Radotinib is a selective
second generation BCR-ABL1 TKI and a phase 2 study was previously con-
ducted in patients with TKI failed CP CML.
Aims: Using the data from the phase 2 study, radotinib exposure-efficacy and
-safety relationship analyses were conducted to explore the dosing methods
that will potentially improve the efficacy and safety profiles of radotinib.
Methods: The efficacy and safety data were collected for 12 months after the
initiation of radotinib therapy from a multi-center phase 2 study conducted in
77 CP CML patients resistant and/or intolerant to other TKIs. All patients
received radotinib 400 mg twice daily until a dose-limiting toxicity (DLT)
appeared, after which the dose was reduced to 300 mg twice daily. The rela-
tionships between the body weight-adjusted dose (Dose/wt) and the probability
of achieving major cytogenetic response or experiencing DLT were explored
using a logistic regression method. The analyses were repeated using body-
surface-area-adjusted dose (Dose/BSA). Upon a stratification of the patients
based on Dose/wt or Dose/BSA, time-to-first DLT curves were compared using
a Kaplan-Meier method.
Results: Efficacy. No significant associations were found between radotinib
Dose/wt or Dose/BSA and major cytogenetic response at Months 1, 3 and 6.
Safety. Positive correlations were observed between radotinib Dose/wt and
the probabilities of first DLT occurrence at Months 3 (p=0.002), 6 (p=0.003), 9
(p=0.004), and 12 (p=0.007). Similar positive correlations were observed for
Dose/BSA. Statistically significant differences were evident in the Kaplan-Meier
curves of DLT between various Dose/wt groups, particularly between the
groups of Dose/wt <6 mg/kg and Dose/wt ≥6 mg/kg (p=0.008) with the median
time to first DLT being 259 and 83 days, respectively. At the cut-off of 6 mg/kg,
the patient weighs 66.7 kg. A 2-tier weight-based dosing method was recom-
mended to reduce the probability of DLT: radotinib 300 mg or 400 mg twice
daily for patients weighing ≤65 kg or >65 kg, respectively.
Summary and Conclusions: The probability of DLT increased without
improvement in efficacy as the Dose/wt or Dose/BSA of radotinib increased.
Therefore, a lower initial radotinib dose of 300 mg twice daily is recommended
for CP CML patients weighing ≤65 kg. A randomized clinical trial would be
needed to confirm the efficacy and safety of this alternative dosing regimen.
E1119
EFFICACY AND SAFETY OF DASATINIB VS. IMATINIB IN LATIN AMERI-
CAN SUBPOPULATION FROM THE DASISION TRIAL IN PATIENTS WITH
NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA (CML) IN CHRONIC
PHASE (CP)
A. Enrico1,* J. Milone1, B. Moiraghi2, L. Casanova3,4, M.S. Undurraga5,
L. Enciso Olivera6,7, E. Bullorsky8, J. Navarro Cabrera9, K. Pagnano10,
M. De Riz11, C. Pavlovsky12
1Hospital Italiano La Plata, La Plata, 2Hospital J. M. Ramos Mejía, CABA,
Argentina, 3Department of Medical Oncology, Instituto Nacional de Enfer-
medades Neoplásicas, 4Department of Medical Oncology, Clínica Oncológica
Miraflores, Lima, Peru, 5Hospital del Salvador, Santiago, Chile, 6Instituto
Nacional de Cancerología Bogotá, 7; Universidad Nacional de Colombia,
Bogotá, Colombia, 8Hospital Británico Buenos Aires, CABA, Argentina, 9Hos-
pital Nacional Edgardo Rebagliati Martins, Lima, Peru, 10Hemocentro-Unicamp,
Universidade Estadual de Campinas, Campinas-SP, Brazil, 11Medical Depart-
ment, Bristol-Myers Squibb, Buenos Aires, 12FUNDALEU, CABA, Argentina
Background: Kantarjian et al. reported in the phase 3 DASISION TRIAL that
519 patients with newly diagnosed CML-CP from 108 centers in 26 countries
were randomized to receive dasatinib (n=259) or imatinib (n=260). Of these,
23 % (120) were from the Latin America (LA) region (23 % Argentina, 9 %
Chile, 3 % Colombia, 15 % Peru, 19 % Brazil and 30% Mexico).
Aims: The main objective was to evaluate if LA results from DASISION TRIAL
can be considered similar to those obtained in the overall study.
Methods: DASISION (CA180-056; NCT00481247) is a signed IC 60 month-
Open Label Multinational randomized phase 3 trial comparing dasatinib 100
mg QD versus imatinib 400 mg QD in patients with CML-CP diagnosed within
3 months who had not received previous treatment for CML. All exposure, safe-
ty, and efficacy results described here were analyzed on the 120 LA patients
(all randomly assigned to receive dasatinib (n=63) or imatinib (n=57)) in com-
parison to the total patients treated (including Latin American patients), here
referred to as “all randomized”. The efficacy and safety were assessed by using
data obtained during the initial 3 years period of the trial.
Statistical Methods: Comparison of the rates was performed for p=0.05 (two-
tailed). Response (efficacy variables) and AEs rates were estimated with their
95% confidence intervals (CIs) when needed. The difference in rates between
the 2 treatment groups was tested by using Pearson Chi square Test. PFS and
OS by treatment group were estimated via the Kaplan-Meier product-limit
method. Due to the fact that the 120 LA patients is a subset of the planned
total enrolled population, every statistical analysis of LA was considered
exploratory.
Results: Treatment was discontinued due to disease progression in 4,8 % and
446 | haematologica | 2015; 100(s1)
20thCongress of the European Hematology Association
7% of the cases, unacceptable toxicity in 3,2% and 8,8% of the cases in dasa-
tinib and imatinib groups respectively. Baseline characteristics and demograph-
ics of LA patients were relatively well balanced between the two treatment
groups and were similar to the overall study data with exception of baseline
high Hasford risk score in LA patients that was higher in both (dasatinib and
imatinib) treatment groups. At 36 months the rates of cumulative cCCyR, MMR
and PFS, OS and AEs rates for patients in either arm in LA patients and in all
randomized patients can be seen in Table below. AEs in LA and in all random-
ized patients will be described.
Table 1.
Summary and Conclusions: The results reported here suggest that the effi-
cacy profiles of dasatinib vs. imatinib in LA patients are similar to those seen in
the analysis of all patients worldwide. Exploratory comparisons of efficacy in
LA patients of dasatinib vs. imatinib arms yielded similar trends as observed in
all patients, having numerically higher rates of cumulative long-term response
rate values of cCCyR and MMR in dasatinib treatment Group. Both treatment
groups also experienced high rate values of PFS and OS after a 3-year follow-
up. Since small sample size in LA limits the strength of conclusions for efficacy
and safety, further exploration is needed to confirm any potential differences
compared with the total treated population in order to increase accuracy.
Acknowledgment: The authors thank all study sites for Bristol-Myers Squibb
(BMS)-sponsored study CA180-056, Milayna Subar Group Medical Director
WW Hematology-BMS and Medical Writing/Stat Ricardo Glancszpigel and Mar-
iana Glancszpigel from 3Eff Co, funded by BMS.
E1120
THE EFFICACY AND SAFETY OF GENERIC IMATINIB IN PATIENTS WITH
CHRONIC MYELOID LEUKEMIA (CML) AFTER SWITCHING FROM
GLIVEC: UPDATED DATA FROM CERRAHPAŞA CML COHORT
T. Soysal1, A.E. Eskazan1,* S. Sadri1, I. Erdogan1, S. Berk1, F.F. Yalniz1,
T. Elverdi1, A. Salihoglu1, M.C. Ar1, S. Ongoren Aydin1, Z. Baslar1, N. Tuzuner2,
U. Ozbek3, Y. Aydin1
1Department of Internal Medicine, Division of Hematology, 2Department of
Pathology, Istanbul University Cerrahpasa Faculty of Medicine, 3Department
of Genetics, Istanbul University Institute of Experimental Medicine (DETAE),
Istanbul, Turkey
Background: Imatinib is the standart of care in patients with chronic myeloid
leukemia (CML). Generic imatinib (GI) has been approved in the treatment of
CML in many countries including Turkey. We previously published our experi-
ence regarding the efficacy and safety of GI in patients with CML who started
tyrosine kinase inhibitor (TKI) treatment with original imatinib (OI) [Glivec] but
then had to switch to GI due to reimbursement policy [Eskazan AE, et al. Leuk
Lymphoma. 2014;55:2935-7]. Among our patient cohort, the efficacy and safety
of GI were comparable to those of OI. However the median duration of GI expo-
sure in that study was 12 months, shorter than the OI treatment duration prior
to switching.
Aims: The aim of this study was to update the efficacy and safety data of GI
among our chronic phase CML (CML-CP) patient cohort when used sequentially
after OI treatment with an extended follow-up. 
Methods: Our study cohort consisted of one hundred and forty-five patients
with CML-CP who were followed under OI with a median of 55 months (Figure
1). Patients on OI first switched to GI due to reimbursement policy after August
2012, and 80 patients switched to GI whereas sixty preferred to receive OI and
pay the price difference from their own pockets. After a median follow-up of 12
months, the data was first analyzed in October 2013, and the generics were
found to be at least non-inferior to the OI regarding efficacy and tolerability
when used subsequently [Eskazan AE, et al. Leuk Lymphoma. 2014;55:2935-
7]. We updated the data of this study after an additional follow-up of 16 months
in February 2015.
Results: Since the first analysis, 74 patients received GI with a median duration
of 15.5 months, and there were four patients who switched to 2nd generation
TKIs (2GTKIs) due to resistance and 4 patients were lost to follow-up. The
median of GI exposure in these patients after the first switch was 27 months
(range, 6-32 months). In the OI group, 60 patients received Glivec with a median
of 61 months and 13 months after the first switch and the first analysis, respec-
tively. There were 3 patients who switched to 2GTKIs (2 due to resistance, one
due to grade IV hepatitis), one patient was lost to follow-up, and one patient
quit OI due to a planned pregnancy. Twenty-seven patients receiving OI
switched to GI during the follow-up after a median of 10 months, and at the
time of the analysis, the study cohort consisted of 121 patients of which 28
were still on OI whereas ninety-three were receiving GI. All of these 121 patients
had durable major molecular respose (MMR), and none of the 27 patients who
switched from OI to GI lost their responses during the follow-up. There were no
imatinib dose reductions due to toxicities in both arms, and 4 patients had non-
hematological adverse events (AEs) (myalgia in 3 and gastrointestinal in one)
in the GI group whereas in the OI group there were 3 patients (myalgia in 2 and
one patient had both myalgia and hepatitis) with non-hematological AEs. Among
the twenty-seven patients who switched from OI to GI, two had grade I myalgia
after the switch.
Figure 1.
Summary and Conclusions: With an extended follow-up, generics were still
found to be comparable to Glivec regarding both efficacy and safety when used
subsequently. 
E1121
GENERIC IMATINIB IN NEWLY DIAGNOSED CHRONIC MYELOID
LEUKEMIA (CML) PATIENTS IN CHRONIC PHASE: UPDATED DATA FROM
A TURKISH CML COHORT 
A.E. Eskazan1,* M. Ayer2, B. Kantarcioglu3, N. Demirel3, D. Aydin3, F. Aydinli4,
O. Yokus4, S. Sadri1, I. Erdogan1, S. Berk1, F.F. Yalniz1, T. Elverdi1,
A. Salihoglu1, M.C. Ar1, S. Ongoren Aydin1, Z. Baslar1, Y. Aydin1, N. Tuzuner5,
U. Ozbek6, T. Soysal1
1Department of Internal Medicine, Division of Hematology, Istanbul University
Cerrahpasa Faculty of Medicine, 2Department of Hematology, Haseki Training
and Research Hospital, 3Department of Hematology, Okmeydani Training and
Research Hospital, 4Department of Hematology, Istanbul Training and
Research Hospital, 5Department of Pathology, Istanbul University Cerrahpasa
Faculty of Medicine, 6Department of Genetics, Istanbul University, Institute of
Experimental Medicine (DETAE), Istanbul, Turkey
Background: Generic imatinib (GI) has been approved in the treatment of
patients with chronic myeloid leukemia (CML)in many countries including
Turkey. Since there were limited data and some concerns about the efficacy of
haematologica | 2015; 100(s1) | 447
Vienna, Austria, June 11 – 14, 2015


Efficacy and safety of dasatinib vs. Imatinib in Latin american subpopulation from the dasision trial in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP)

http://repositorio.unicamp.br/jspui/bitstream/REPOSIP/353193/2/000361204903101.pdf

Efficacy and safety of dasatinib vs. Imatinib in Latin american subpopulation from the dasision trial in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP)

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