Angioimmunoblastic T-cell lymphoma: nobody knows what to do...

Transcription

1 Angioimmunoblastic T-cell lymphoma: nobody knows what to do... Felicitas Hitz, Onkologie/Hämatologie St.Gallen SAMO Lucerne

2 : Problems PTCL are rare diseases with even rarer subgroups Difficulte pathologic definition of the disease Outcome analysis based on heterogeneous retrospective data

3 3 General clinical features summerized from 12 clinical series ; BJH 2009 Advanced stage III/IV 68 94% LDH > normal 46 85% Performance status > % B-Symptoms 52 86% Bulky mass 5 26% High risk IPI 38%

4 Clinical features: organ involvement summerized from 12 clinical series ; BJH 2009 Generalized lymphadenopathy % Bone marrow involvement 12-70% Hepatomegaly 25 83% Splenomegaly 51 73% Skin rash 38 58% Effusion/oedema/ascites 25 53% Polyarthritis/arthralgias 16 18% Lung involvement 10% Neurologic manifestation 10% Gastrointestinal involvement rare

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6 Laboratory Testing summerized from 12 clinical series ; BJH 2009 Anemia 40 88% Positive Coombs test 32 75% Lymphopenia 17 52% Thrombocytopenia 9 20% Hypereosinophilia 32 50% Hypergammaglobulinaemia 50 83%

7 Differential diagnosis of Infection Systemic inflammatory disease

8 Nobody knows what to do......but some try to overcome the problems!

9 Registry data International T-cell Project, Vose et al. JCO 2008

10 Registry data International T-cell Project, Vose et al. JCO 2008

11 Registry data International T-cell Project, Vose et al. JCO 2008

12 Pathology Distinctive features with Medium sized neoplastic cells Arborizing blood vessels Proliferation of follicular dendritic cells Scatered EBV pos. B-cell blasts Cell of origin in the germinal center: follicular helper T-cell (Tfh); virus have been enrolled in the transformation of the Tfh

13 Pathobiology Laurence de Leval et al BJH 2009

14 Gen expression profiling Iqbal et al: Blood Feb 2010 robust classifier for, ATLL, ALCL Classification PTCL-unclassifiable as Role of the microenvironment in Need for validation of molecular signature with more clinical Titel der samples Präsentation Pathways and therapeutic targets for new drugs

15 Trial results Registry data Retrospective analysis of PTCL Subgroup analysis of for consolidation of firstline therapy with autologous tx, allogenic tx Prospective Phase II trials with subgroup analysis of Phase III trial ACT-1 and ACT-2

16 Registry data International T-cell Project, Vose et al. JCO 2008

17 Registry data : Survival by histologic type and IPI International T-cell Project, Vose et al. JCO 2008

18 Registry data International T-cell Project, Vose et al. JCO 2008

19 Response and survival rates in pts with PTCL with anthracycline-based regimens: a meta-analysis AbouYabis et al Blood 2007 abstr 3452 subgroup analysis: CR 54 % Estimated 5-year OS: 37% Conclusion:future trials need to focus on subtype specific treatments for increasing and sustaining CR

20 Retrospective studies: Up-front high-dose therapy and autologous SCT for PTCL Hosing and Champlin Ann of Oncol 2011

21 High-dose therapy and autologus SCT in : EBMT data Kyriakou et al. JCO pts with BEAM (74%) and autologous SCT; median age 53 years Median follow-up of 31 months Cumulative incidence of non-relapse mortality 2 years OS 48 months Titel derofpräsentation Cumulative incidence relapse 48 months PFS for pts in CR 48 months vs 23% for chemotherapy-refractory disease Conclusion: CR at transplant is the major determinant outcome

22 Allogenic SCT is able to induce long-term remission in : EBMT data Kyriakou et al JCO pts with ; > 2 lines of chemo Median age 45 years Different conditioning regimen Non relapse mortality: 12 months Relapse rate: 3 years 66% 3 years, 64% 3 years

23 prospective studies: Up-front high-dose therapy and autologous SCT for PTCL Hosing and Champlin Ann of Oncol 2011

24 Dose-dense induction followed by autologous SCT: phase II study Nordic Lymphoma Group Lauritzsen et al ICML pts /166 pts (19%) CHOEP-14, BEAM, autologous SCT 87 % CR after 6 courses; 80% after ASCT 67% BEAM and ASCT with 4 year OS 50% ; PFS 47% Conclusion: high-dose therapy with ASCT is effective in previousely untreated PTCL although early progression remains a problem

25 Conclusions from prospective transplant studies % are candidates for tx 1/3 of failure occured before tx 1/4-1/5 of failure occured after tx Improve induction efficacy Efficent consolidation strategy CR 59% - 81% after ASCT % long-term responders

26 Phase III: European Intergroup trial for primary T-cell NHL ACT-1: Inclusion: patients < 60 years Treatment: CHOP-14 vs CHOP-14 + alemtuzumab; consolidation with autologous SCT Act-2: Inclusion: patients > 60 years Treatment: CHOP-14 vs CHOP-14 + alemtuzumab

27 Biologic targets for new drugs? Monoclonal antibodies Antivascular endothelial growth factors Immunmodulators Immunosuppressants (microenvironment)

28 Phase II PTCL: new substance + CHOP Bevacizumab: antivascular endothelial growth factor Complete remission in a pts with --> ECOG: Bevacizumab + CHOP --> high incidence of cardiac events Advani et al Blood 2009 Alemtuzumab: anti-cd52 specific antibody OR: 90%; median duration of follow-up:29months Median OS and EFS: 27and 10 months Adverse events: neutropenic fever, CMV reactivation, EBV related lymphoma! Conclusion: effectiv but not durable regimen with serious adverse events Kluin-Nelemans Ann of Oncol 2011

29 Phase II PTCL: new substance + CHOP Zanolimumab: anti CD-4 monoclonal antibody 21 pts with ORR: 24% 5 PR: 2 ALTL, 3 2 CR: 1 PTCL nos; 1 Conclusion: active and well tolerated D Amore et al Blood 2007 abstract 3409

30 Phase II : fludarabin, cyclophosphamid, followed by thalidomide First prospective trial in Untreated Flu 40mg/m2; Cyclo 250mg/m2 x3d every 4 weeks plus ThalTitel forder6präsentation mo Start 2009, slow recruiting Aim 37 patients

31 Phase II PTCL: lenalidomide Lenalidomide: immun-modulator Inclusion: relapsed/refractory PTCL ORR: 30%, ALTL, PTCL nos PFS: 95 days Toxicities: neutropenia 20%, thrombocytopenia 33% Conclusion: clinical activity with low toxicity profile

32 Case reports : lenalidomide Rentschler et al ICML 2011 Abstract 249 Case 1: relapse after CHOP; PR after 2line therapy Lenalidomde 25mg --> 10mg CR after 5 cycles Duration of response 519 days Case 2: Prior 5 lines of therapy Lenalidomide 25mg Progressive disease

33 Phase II : treatment experience with ciclosporin CyS: inhibits nuclear factor of activated Tcell transcription complex Interrupting T-cell activation 12 pts with 8/10 pts with response: 3CR, 5PR Advani et al. Leuk Lymphoma 2007 Phase II ECOG trial: closed because of slow accrual

34 Phase I : treatment experience with LMB-2 LMB-2: anti-cd25 monocloncal antibody Clinical activity in phase II trials, especially in Kreitman et al JCO 2000 Clinical response but rapid tumor progression Phase II planned with LMB-2 after chemotherapy

35 Conclusions Registries are important data containers to guide further prospective trials GEP defines biologic characteristics and microenvironment of Consolidation of firstline treatment with autologous SCTTitel isder effective Präsentation in CR but not for pts with chemo-refractory disease Prospective trials of PTCL and subentities are warranted Further investigations of biologic targets