Transcript Dr. Ghazi Nsouli

European Society of Haematology
2010 Meeting
Non – Hodgkin's Lymphomas
Selected Abstracts
Ghazi M. Nsouli MD
COMBINATION OF RITUXIMAB WITH
CHLORAMBUCIL AS FIRST LINE TREATMENT
IN PATIENTS WITH MANTLE CELL
LYMPHOMA:
A HIGHLY EFFECTIVE REGIMEN
S SACHANAS,1 G PANGALIS,2 T VASSILAKOPOULOS,2 P KORKOLOPOULOU,3 F
KONTOPIDOU,2 C ATHANASOULIA,2 X YIAKOUMIS,1 S MASOURIDIS,2 C
KALPADAKIS,4 M MOSCHOYIANNIS,1 M SIAKANTARIS,2 P TSIRKIDINIS,5
S KOKORIS,2 V PAPPIS,2 M ANGELOPOULOU2
ABSTRACT 0826
Study Design
• 20 patients with MCL
• BMA and Bx and LGI endoscopy
• IgVH analysis and FISH for the detection of
t(11;14) translocation at dx & at reevaluation
• Induction :Rituximab (375mg/m2 Day 1 .
Chlorambucil 10mg/day 1-10 of each 28d
cycle. x8. followed by chlorambucil x4
additional cycles
• Maintainance: Rituximab q2m x 1y
Response
• After cycle 8: CR 65% PR 35%
• After cycle 12: CR 90% PR 5% PD 5%
• 13/18 patients had t(11;14) and 12 had
achieved molecular CR
• Median follow up 22m
• 2y PFS 82% with 2/18 CR pts relapsing at 14
and 20m
• Conlusion: well tolerated and effective
regimen
A GENETIC VARIANT OF MLH1, A GENE
INVOLVED IN DNA MISMATCH REPAIR,
IS AN INDEPENDENT PREDICTOR OF
OVERALL SURVIVAL IN DIFFUSE LARGE
B-CELL LYMPHOMA TREATED WITH RCHOP
ROSSI, D, DIVISION OF HEMATOLOGY, AMEDEO AVOGADRO
UNIVERSITY, NOVARA, ITALY(P) ET AL
Background
• DLBCL treatment rely on DNA damage for
tumor killing.
• Host genetic variability in genes repairing DNA
damage may affect response to drugs and
prognosis.
• Aims: to verify the impact of DNA repair
genes SNPs on prognosis of R-CHOP treated
DLBCL
Patients characteristics
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163 consecutive DLBCL treated with R-CHOP
Age >60 63.8% cases,
ECOG PS >1 12.9%,
Extra-nodal sites >1 25.2%
Ann Arbor stage III-IV 52.1%
Bulky in 28.2%
LDH elevation 46.0%
IPI >2 33.7%
Median follow-up was 48 months.
• Thirty-five SNPs from 18 genes were analyzed
on patients’ germline DNA. These included
SNPs affecting:
•
i) mismatch repair (MLH1rs1799977/rs1800734);
• ii) base excision repair (XRCC1rs1799782/rs25487,
OGG1rs1052133);
• iii) nucleotide excision repair (ERCC1rs3212986,
ERCC2rs1052555/rs13181/rs1799793/rs238406,
ERCC4rs1800067/rs3136038, ERCC5rs17655,
ERCC6rs2228528/rs2228529/rs3793784, XPArs1800975,
XPCrs222799/rs2228000/rs2607775/rs2228001);
• iv) double strand break repair
(BRCA1rs49868507rs17999507rs799917, BRCA2rs144848,
LIG4rs1805388, XRCC2rs3218536, XRCC3rs17997947rs861539,
XRCC4rs1805377, XRCC6rs5751129/rs132788);
• v) direct reversal (MGMTrs16906252/rs2308321/rs12917)
Results
• Univariate analysis controlled for multiple
comparisons identified MLH1rs1799977 as the
sole DNA repair SNP predicting OS in R-CHOP
treated DLBCL.
• Patients carrying the MLH1rs1799977 AG/GG
genotype displayed :
– an increased risk of death (HR:3.23; 4-years OS:
55.5%) compared to AA carriers (4-years OS:
80.9%) (p=.0002; q=.009)
Results
• Multivariate analysis selected MLH1rs1799977
(HR:3.14; p=.0004) as an independent
predictor of OS,
• along with IPI (HR:1.38; p=.0377) and
• bulky disease (HR:2.56; p=.0044).
Results
• Multivariate analysis identified MLH1rs1799977
(HR:1.66; p=.0498) as an independent predictor
of EFS, along with IPI (HR:1.61; p<.0001) and
bulky disease (HR:1.84; p=.0215).
• Patients carrying the MLH1rs1799977 AG/GG
genotype displayed an increased risk of failing
second line platinum-based regimens (HR: 3.04;
4-year OS from salvage: 16.0%) compared to AA
carriers (4-year OS from salvage: 57.3% p=.0050)
• By bivariate analysis, MLH1rs1799977
predicted OS from salvage independent of
having (p=.0020) or having not (p=.0480)
consolidated with SCT
Conclusion
• i) MLH1rs1799977 is a non-synonymous SNP causing
the I219V amino acidic substitution on MLH1, a gene of
the mismatch repair pathway;
• ii) in silico, MLH1rs1799977 is predicted to have
deleterious consequences;
• iii) in vitro, the G variant allele of MLH1rs1799977
associates with reduced MLH1 protein expression;
• iv) loss of MLH1 in tumor cells is known to induce
refractoriness to doxorubicin and platinum
compounds.
• Consistently, DLBCL carriers of the MLH1rs1799977
AG/GG genotypes displayed poor OS possibly due to
altered MLH1 expression.
LENALIDOMIDE MONOTHERAPY IS
CLINICALLY ACTIVE IN PATIENTS WITH
RELAPSED/REFRACTORY DIFFUSE LARGE BCELL LYMPHOMA (DLBCL): A POOLED
ANALYSIS OF DATA FROM 2 PHASE II STUDIES
(NHL-002/003)
CZUCZMAN, MYRON, ROSWELL PARK CANCER INSTITUTE,
BUFFALO, UNITED STATES OF AMERICA(P)
Patient population
• Subset analysis of patients with DLBCL from
the NHL-003 and NHL-002 study evaluating
the clinical utility of lenalidomide in patients
with relapsed/refractory DLBCL.
• Defined as : DLBCL, mantle cell lymphoma,
transformed lymphoma, and follicular
lymphoma grade 3, with measurable disease
(≥2 cm), and ≥1 prior treatment
Patients and Results
• Primary end point : ORR
• NHL-002 Rx lenolidamide 25 mg d1-21/28 for 52
m and NHL-003 till progression.
• 134 patients (26 NHL-002 and 108 NHL-003)
• Age: m 66y median Dx time : 2.3 y
• Failed Rx 3 (1-10)
• ORR: 26% CR/CRu 9%
• 15 pts with SCT (28.8) responded
• Median Response duration for responders: 10.4
m
PHASE II STUDY OF SMILE
CHEMOTHERAPY FOR NEWLY-DIAGNOSED
STAGE IV, RELAPSED OR REFRACTORY
EXTRANODAL NK/T-CELL LYMPHOMA,
NASAL TYPE: NKTSG STUDY
Kwong, YL, University of Hong Kong, Hong Kong, China
Medications
• SMILE [Steroid=dexamethasone 40 mg/day
d2-4 IV, Methotrexate 2 g/m2 d1 6hr IV,
Ifosfamide 1.5 g/m2 d2-4 IV, L-asparaginase
6000 U/m2 d8,10,12,14,16,18,20 IV, and
Etoposide 100 mg/m2 d2-4 IV; every 28 days]
showed promising results (Cancer Sci, 2008)
• age: 16-67 years (median 47);
male:female=21:18; newly-diagnosed stage IV
disease in 21; first relapse in 13; and primary
refractory disease in 5
PROMISING EFFICACY WITH THE NEW
ANTI-CD20 ANTIBODY GA101 IN HEAVILY
PRE-TREATED PATIENTS – FIRST RESULTS
FROM A PHASE II STUDY IN PATIENTS
WITH RELAPSED/REFRACTORY INDOLENT
NHL (INHL)
Salles, A, Hospices Civils de Lyon, Lyon, France(P)
• GA101 is the first fully humanized and glycoengineered type II monoclonal anti-CD20
antibody .
• 40 patients were randomized to receive GA101 in
a low-dose (LD, n=18) or a high dose (HD, n=22)
cohort. GA101 was given on d1, d8, d22 and q21
days for total of 9 infusions (6 months).
• In the LD cohort, GA101 was given 400mg all
infusions; in the HD cohort, d1 and d8 at 1600mg
and 800mg thereafter.
• Primary endpoint was response rate, with
secondary endpoints of safety and
pharmacokinetics
• 75% of patients completed all scheduled 9
infusions
• 38/40 patients were evaluable for end of
treatment response (EOR), evaluated 4 weeks
after last infusion, 44 weeks after treatment start.
• EOR was 17% (3 PR, 6 SD, 7 PD, 2 UNK) in the LD
cohort, and 55% (2 CR, 10 PR, 6 SD, 4 PD) in the
HD cohort. Of note, 7/24 rituximab-refractory
patients (6 HD, 1 LD) responded, with 4 in HD and
1 in LD with an ongoing response
• Responses occurred across all FcγIIIR
genotypes in both cohorts
• In this group of heavily pre-treated iNHL
patients, single-agent GA101 was safe with a
high response rate in HD cohort (55%), and
responses also observed in rituximabrefractory patients (HD 55% [6/11]),
supporting a possible dose-response
relationship.
RITUXIMAB MAINTENANCE FOR 2-YEARS
SIGNIFICANTLY IMPROVES THE OUTCOME
OF PATIENTS WITH UNTREATED HIGH
TUMOR BURDEN FOLLICULAR LYMPHOMA
AFTER RESPONSE TO IMMUNOCHEMOTHERAPY: RESULTS OF THE PRIMA STUDY
Salles, G, Hospices Civils de Lyon & Université
Claude Bernard, Pierre-bénite, France(P)
Design
• 2-years of rituximab (R) maintenance in
follicular lymphoma (FL) patients responding
to first line immunochemotherapy, consisting
of either
• 8 cycles of R-CVP, or
• 6 cycles of R-CHOP or
• R-FCM (plus 2 additional rituximab infusions)
Patient characteristics
• median age 56 years [range
22–87];
• 52% male;
• 90% Ann Arbor stage III-IV;
• 56% bone marrow
involvement;
• 4% ECOG performance
status >1;
• 33% B symptoms;
• 34% elevated LDH;
• 32% β2-microglobulin
>3mg/L;
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FLIPI score 0-1 (21%),
FLIPI 2 (36%),
FLIPI 3-5 (43%).
Patients received induction
immunochemotherapy with
– R-CHOP (75%),
– R-CVP (22%) or
– R-FCM (3%).
• Response status at the time
of randomization was
CR=39%;
• CRu=32% and
• PR=28%
• 1018 eligible patients responding to induction
therapy were randomized (stratified by
regimen and response to induction) to
observation or R-maintenance, 375 mg/m2 i.v.
every 8 weeks for 2 years.
Planned Interim Analysis
• ITT: 513 observation, 505 rituximab
maintenance,
• median follow-up of 25 months from
randomization, a significant (P<.0001)
improvement in PFS (the 1ry endpoint) seen
in the rituximab maintenance arm (2-year
PFS= 82%; 95%CI [78-86%] vs to 66% [61-70%]
in the observation arm; hazard ratio
(HR)=0.50; 95%CI [0.39-0.64])
• PFS benefit among sub-groups for age (<60
and >60), FLIPI score and response after
induction. Time to next anti-lymphoma
treatment (HR=0.58 [0.44-0.77]) and time to
next chemotherapy (HR=0.60 [0.44-0.81])
were also significantly improved
• Response status at the end of maintenance or
observation was better in the R-maintenance
arm (CR/CRu 67% versus 48%, respectively
Results
• At the time of data cut-off, only 34 patients
(3.3%) had died and longer follow-up is required
to evaluate the effects of rituximab maintenance
on overall survival in this study.
• The most common AEs were infections (22%
observation, 37% R-maintenance).
• Grade 3-4 AEs were reported in 16% (observation) and 22% (R-maintenance) of patients (with
neutropenia 1% vs. 4%; and infections 1% vs. 4%,
respectively).