European Society of Haematology2010 Meeting

Non – Hodgkin's LymphomasSelected Abstracts

Ghazi M. Nsouli MD

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

COMBINATION OF RITUXIMAB WITH CHLORAMBUCIL AS FIRST LINE TREATMENT IN PATIENTS WITH MANTLE CELL LYMPHOMA: A HIGHLY EFFECTIVE REGIMEN

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

ROSSI, D, DIVISION OF HEMATOLOGY, AMEDEO AVOGADRO UNIVERSITY, NOVARA, ITALY(P) ET AL

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 R-CHOP

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• 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.

CZUCZMAN, MYRON, ROSWELL PARK CANCER INSTITUTE, BUFFALO, UNITED STATES OF AMERICA(P)

LENALIDOMIDE MONOTHERAPY IS CLINICALLY ACTIVE IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL): A POOLED ANALYSIS OF DATA FROM 2 PHASE II STUDIES (NHL-002/003)

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 glyco-engineered 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 rituximab-refractory 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 IMMUNOCHEMO-THERAPY: 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;

• 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% (observa-tion) and 22% (R-maintenance) of patients (with neutropenia 1% vs. 4%; and infections 1% vs. 4%, respectively).