• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
A. Stathis - New drugs in the treatment of lymphomas
 

A. Stathis - New drugs in the treatment of lymphomas

on

  • 2,191 views

 

Statistics

Views

Total Views
2,191
Views on SlideShare
2,190
Embed Views
1

Actions

Likes
0
Downloads
0
Comments
0

1 Embed 1

http://www.easoncology.net 1

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • The aim of this presentation is to summarize the several lines of evidence which demonstrated an etiopathogenic link between bacterial infections and certain types of lymphoma. The best known model is the one of H Pylori and gastric (MALT) lymphoma... The H Pylori and MALT lymphoma story has begun more than 10 years ago and has generated a fascinating model of tumor growth from the background of a chronic inflammation This story is also the example of how improvements in the biologic knowledge can be translated into novel therapeutic strategies.
  • To conclude…..

A. Stathis - New drugs in the treatment of lymphomas A. Stathis - New drugs in the treatment of lymphomas Presentation Transcript

  • Highlights 11- ICML Lugano 15-18 June 2011 Anastasios Stathis, MD Oncology Institute of Southern Switzerland CH-6500 Bellinzona
  • Topics
    • some general data
    • Mantle Cell Lymphoma
    • Follicular Lymphoma
    • DLBCL
    • T-cell lymphoma
    • new drugs
  • The role of the microenvironment in malignant lymphomas
    • Classic HL: cells in the microenvironment have an impact on outcome prediction
    • Nodular Sclerosing HL: increased macrophages in diagnostic biopsies predict for unfavorable survival following both primary and secondary therapies
    RD Gascoyne et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv47 (abs VII ) N=130
  • Hematological response to antiviral treatment in 94 patients with indolent B-NHL associated with HCV infection: studies of the FIL L. Arcaini et al. Ann Oncol 2011, 22 Suppl 4:iv129 (abs 138) 94 pts with iNHL and HCV infection 36 pts received IFN (in 26 with ribavirin) 57 received peg-IFN (in 53 plus ribavirin) 76 pts treated in 1st line 18 pts had AT in 2nd line CR 47%, PR 30 % in first line Lower response rate in 2nd line Similar responses between IFN and peg-IFN Better long term control of iNHL with peg-IFN PFS 5-yr OS 94%; 5-yr PFS 78% DOR > 3 yrs in 40% of pts
  • PET+ lesions at the end of chemotherapy for Hodgkin Lymphona Engert et al., Abstr. 45, ICML-11 728 advanced HL with residual disease after 6-8 BEACOPP 74% PET -  No RT  only 5% relapsed (NPV 94.6%) 26% PET +  RT Conclusion : PET - residual disease (after BEACOPP) do NOT need RT
  • HD16 R PET scan in low risk HL : The GHSD HD16 trial
  • PET scan in PMBCL: New IELSG protocol
    • in previous study: ~ ⅔ PET- after induction
    • PET - after induction
    • activated at ICML-11
    RT 0 /
  • DA-EPOCH-R for Burkitt’s lymphoma and PMBCL 30 Burkitt at 5y median FU EFS 97%, OS 100% 40 PMBCL at 4y median FU EFS 95%, OS 100% only 3/40 needed RT/surgery for PET+ Dunleavy et al., Abstr. 71, ICML-11 Dunleavy et al., Abstr. 150, ICML-11
  • Topics
    • some general data
    • Mantle Cell Lymphoma
    • Follicular Lymphoma
    • DLBCL
    • T-cell lymphoma
    • new drugs
  • Centrocytic lymphoma -Described by K. Lennert more than 30 year ago -Accepted as a separate entity in the 1990s
  • The hallmark of mantle cell lymphoma is the t(11;14)(q13;q32) Mantle cell lymphoma
  • MCL frequency at the IOSI Diffuse Large B-cell Lymphoma 37% Follicular Lymphoma 20 % CLL/SLL 15 % MALT lymphoma 7% Mantle Cell Lymphoma 6.5 %
  • R-CHOP vs R-FC followed by maintenance with Rituximab or IFN First results of a RCT for elderly patients with Mantle cell lymphoma H Kluin-Nelemans et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv86 (abs 016 )
    • Feasible
    • Induction with R-CHOP results in better outcome than R-FC
      • Less progression during induction (5 vs 15%)
      • More overall responses (87 vs 78%)
      • Improved survival at 3 years; 71 vs 55%
    • 6 cycles of R-FC caused too much toxicity
    • R-CHOP followed by maintenance therapy with rituximab should become the gold standard to which new induction regimens have to be compared
    R-CHOP R-FC OS European MCL Network
  • R-CHOP vs R-FC followed by maintenance with Rituximab or IFN First results of a RCT for elderly patients with Mantle cell lymphoma
    • R maintenance longer remission than IFN maintenance (51 vs 24 months; p = 0.012)
    • R-CHOP maintenance 3-year survival 83% (R-FC maintenance 67%)
    • R-CHOP foloowed by R maintenance the new standard for elderly patients?
    Abstract 16, 11-ICML
  • Oral lenalidomide plus 4 doses of rituximab induced prolonged remissions in relapsed/refractory MCL: a phase I/II clinical trial Wang M et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv119 (abs 109)
    • lenalidomide 10, 15, 20 and 25 mg orally daily 3 weeks on and 1 week off, every 28 days.
    • Rituximab 375 mg/m2 IV weekly X 4, cycle 1 only
    • 2 patients experienced a DLT (in cycle 1) at 25 mg dosage level:
        • Grade 3 hypercalcemia, hyperuricemia, and elevation of creatinine
        • Grade 4 non-neutropenic fever, hypotension, and sepsis
    • Oral lenalidomide plus 4 doses of rituximab is effective and induced high quality and durable remissions in relapsed/refractory MCL
    • This combination had a very favourable toxicity profile
    Response N=46 (%) ORR 26 (57) CR 15 (33) PR 11 (24) SD 10 (21.5) PD TTFR 10 (21.5) 2 (2-8)
  • Outcomes of patients (n =640) with MCL undergoing autologous versus RIC allogeneic transplantation
    • Early in the disease course, Auto and Allo: favorable long term survival
    • Later in the disease, no apparent benefit to Allo
    • Relapse/progression may be lower with Allo in Early MCL
    • TRM and Allo: 20-30% at 2 yrs
    • For most patients, Auto appears to be the preferred choice if feasible, but no plateau
    TS Fenske et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv87 (abs 018) „ Early MCL“
  • Topics
    • some general data
    • Mantle Cell Lymphoma
    • Follicular Lymphoma
    • DLBCL
    • T-cell lymphoma
    • new drugs
  • High response rates with Lenalidomide plus Rituximab for untreated indolent B cell NHL N Fowler et al. 11-ICML (Lugano 2011) – Ann Oncol 2011, 22 Suppl 4:iv128 (abs 137) PFS Lenalidomide 20mg Days 1-21 Cycles 1-6* 1 2 3 4 5 6 7 8 9 10 11 12 If clinical benefit, can proceed to 12 cycles R= RESTAGING Lenalidomide 20mg Days 1-21 Cycles 7-12
    • Lenalidomide and R in indolent NHL: RR 90%, CR 66%
    • CR in FL: 87%
    • Mild toxicity profile Lenalidomide/R
    Months Rituximab 375mg/M 2 Day 1 of Cycles 1-6 R Rituximab 375mg/M 2 Day 1 of Cycles 7-12 R R R
  • Inotuzumab Ozogamicin (CMC-544) in patients with indolent B-cell NHL refractory to Rituximab, Rituximab plus chemotherapy, or radioimmunotherapy
    • ORR of 57% in refractory indolent lymphoma;
    • ORR of 67% in follicular lymphoma
    42 SAEs were reported in 17 patients; the majority of SAEs (55%) were not considered to be related to the study treatment Goy A et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv105 (abs 069) 57% n = 35 26% n = 16 67% n = 35 31% n = 16
  • 702 FL patients (EBMT + CIBMTR) Sureda et al., Abstr. 037, ICML-11 Half of relapsed FL are rescued by allo BMT Sibling Unrelated 3y PFS 60% 49% P= 0.02 3Y OS 69% 54% P < 0.01
  • Topics
    • some general data
    • Mantle Cell Lymphoma
    • Follicular Lymphoma
    • DLBCL
    • T-cell lymphoma
    • new drugs
  • Treatment of limited-stage DLBCL can be effectively tailored using a PET-based approach LH Sehn et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv91 (abs 028) N=134 Majority of limited stage patients will be PET negative after 3 cycles of R-CHOP and have excellent outcome with systemic therapy alone PET positive patients who complete treatment with IFRT have a high rate of distant relapse, and alternative approaches may be necessary OS N=134
  • R-CHOP 14 vs 21 x 8 in elderly (ASH 2009, Abstract 406, Delarue et al, GELA) ICML update: all 600 patients analysed, 2nd interim analysis. (interim analysis – 200/600 pat.) Delarue et al., Abstr. 106, ICML-11 R-CHOP 14 R-CHOP 21 RR 72% 75% 3y EFS 57% 60% 3y OS 70% 73%
  • A randomized multicentre Phase III study for first-line treatment of young patients with high risk (AAIPI 2-3) Diffuse Large B-Cell Lymphoma: Rituximab plus Dose-Dense chemotherapy CHOP14/ MegaCHOP14 with or without intensified HDC and ASCT. Results of DLCL04 FIL Trial Vitolo U et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv106 (abs 072) CR/PR CR/PR Off study R-MegaCHOP14 x 4 R-CHOP14 x 4 R-MAD x 2 + BEAM + ASCT NR RANDOMIZATION R-MegaCHOP14 x 4 R-CHOP14 x 4 R E S T A G I N G 188 Pts 188 Pts R-MegaCHOP14x2 R-CHOP14 x 4 Off study NR *Patients at risk of CNS recurrence (SIE guidelines 2006): IT Mtx 4 or 6 doses
  • Vitolo U et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv106 (abs 072) 2-year PFS: median follow-up 24 months
      • R-dose-dense chemotherapy followed by R-HDC and BEAM with ASCT significantly reduced the risk of progression compared to standard dose-dense
      • A greater benefit was seen in those treated with RCHOP14x4 followed by R-HDC+ASCT compared to standard RCHOP14
      • An intensified RCHOP14 regimen (RMegaCHOP14) did not improve the outcome and increased toxicity
      • So far there is no difference in overall survival between HDC+ASCT and no ASCT and a more mature follow-up is needed to analyze this point
    p=0.0128 0.00 0.25 0.50 0.75 1.00 0 12 24 36 48 Months R-HDC+ASCT R-dose dense 71% 59% p=0.0762 0.00 0.25 0.50 0.75 1.00 0 12 24 36 48 Months R -CHOP+HDC+ASCT R -megaCHOP+HDC+ASCT R-CHOP R-megaCHOP
  • Randomized Phase II study of R-CHOP+ Enzastaurin vs R-CHOP in the first-line treatment of patients with intermediate and high-risk DLBCL. Preliminary analysis   Hainsworth JD et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv107 (abs 074)
    • An improvement in PFS was observed in patients treated with R-CHOP + ENZ, No difference in OS
    • Toxicity profiles were comparable between treatment arms
    First-line Therapy Maintenance Therapy Randomization (3:2) Single-agent ENZ 500 mg daily up to 3 years Observation Arm A: R-CHOP + ENZ 500 mg daily × 6 cycles of 21 days N=57 Arm B: R-CHOP alone × 6 cycles of 21 days N=43 CR, CRu or PR Stratified by IPI (2 vs 3, 4, 5) and age (≤60 vs >60 years)
  • Combination of Lenalidomide with R-CHOP (R2CHOP) as an initial therapy for aggressive B cell lymphomas - a Phase I/II study Nowakowski GS et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv119 (abs 110)
    • No DLT seen in phase I (N=10)
    • Len 25 mg days 1-10 taken to phase II
    • (N=30)
    Overall response rate 100% Complete response rate 83% The clinical benefit appears to be equal in non-GCB vs GCB (lenalidomide overcomes poor outcome in non-GCB?) Agent Dose Route Day of Cycle Lenalidomide daily po 1-10 R-CHOP 375 mg/m 2 IV over 4-8 hours 1 Pegfilgrastin 6 mg SC 2 Aspirin 81 mg po daily Toxicity Grade 3 4 Hematological Neutropenia Thrombocytopenia 13% 16% 75% 25% Infection Neutropenic fever 9% 0% Vascular Venous Thrombosis 6% 0% Constitutional Fatigue Dehydration 6% 6% 0% 0%
  • Topics
    • some general data (including HL and PMBCL)
    • Mantle Cell Lymphoma
    • Follicular Lymphoma
    • DLBCL
    • T-cell lymphoma
    • some new drugs and other matters
  • Immunotoxin: brentuximab vedotin SGN-35 = anti CD30 AB + monomethyl auristatin E (anti-microtubule) 58 ALCL relapsed or refractory (50%) 72% ALK negative ORR 86% CR 53% Duration of response (1wk - 1 year), median not reached Shustov et al., Abstr. 125, ICML-11
  • Preliminary results from a multicenter, Phase II study of Bendamustine in refractory or relapsed T-cell Lymphoma „The BENTLY Trial“
    • Bendamustine: active in refractory and relapsed T-cell lymphoma
    • acceptable toxicity
    • high RR in highly pretreated poor risk patients (ORR 42%; CR 23%)
    • median response duration time: 5.5 mo
    G Damay et al 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv125 (abs 126)
  • Topics
    • some general data
    • Mantle Cell Lymphoma
    • Follicular Lymphoma
    • DLBCL
    • T- and NK-cell lymphoma
    • new drugs
  • Further interesting new antibodies Abstracts, 66, 144, 67, 145, 64, 68 Name Target Activity GA101 CD20 indolent + aggressive NHL lucatumumab CD40 FL dacetuzumab CD40 DLBCL KW-0761 CCR4 ATL blinatumomab CD3/CD19 DLBCL + MCL
  • Phase I study of SB1518, a novel oral JAK2 inhibitor, in relapsed lymphoma: clinical and biologic activity in multiple lymphoma subtypes A. Younes et al. 11-ICML (Lugano 2011) - Ann Oncol 2011, 22 Suppl 4:iv136 (abs 157)
    • SB1518:
    • well tolerated in relapsed lymphomas at doses up to and including 600 mg/d
    • MTD for SB1518 not identified
    • encouraging activity in relapsed lymphomas: PR at dose of 300 mg/d and greater
    • recommended dose for Phase II study is 400 mg/d
  • JP Leonard et al. 11-ICML (Lugano 2011) – Ann Oncol 2011, 22 Suppl 4:iv137 (abs 158 ) Kahl, Abstract 350, 11-ICML)
      • CAL-101 (100 or 150 mg BID) with Bendamustine or Rituximab:
      • active in indolent NHL and CLL/SLL, with high RR even in patients with unfavorable prognostic characteristics
      • manageable adverse event profile
      • RR single agent 66% RR with Benda or Rituximab ~ 90%
    A Phase I study of CAL-101, an Isoform-selective inhibitor of Phosphatidylinositol 3‑Kinase P110  , in combination with anti-CD20 monoclonal antibody therapy and/or Bendamustine in previously treated B-NHL N=49 Progression-Free Survival 0 2 4 6 8 10 12 0 10 20 30 40 50 60 70 80 90 100 iNHL: CAL-101 + B (N=15) iNHL: CAL-101 + R (N=12) CLL: CAL-101 + B (N= 9) CLL: CAL-101 + R (N=13) Cycle (28 days) % Progression Free
  • 12-ICML June 19-22, 2013 12th INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA Lugano, Switzerland Deadlines : ABSTRACT SUBMISSION: February 28, 2013 EARLY REGISTRATION: or on before March 15, 2013 LATE REGISTRATION: from March 16, 2013 (up to 3000 attendees) For information and on-line registration: www.lymphcon.ch