High-intermediateintermediate 3 43%

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1 Diffuse large B cell Lymphoma (DLBCL) Most comon NHL type (31%) Large cells with loss of follicular archtecture Clinics: aggressive; extranodal site (CNS, stomach, testis..) Median survival: weeks to months if not treated Diagnosis: typical immunophenotype: CD 20, CD22+; Curable in 50% or more of cases

2 International Prognostic Index (=IPI) for the aggressive non-hodgkin s lymphomas Prognostic Factors: Age > 60 LDH > 1x normal Performance status >1 Stage III or IV Number of extranodal sites >1 Risk Category: Factors 5 year OS Low 0 or 1 73% Low-intermediate 2 51% High-intermediateintermediate 3 43% High 4 or 5 26% 1. Gene expression profiling defines 3 subgroups of DLBCL 2. Gene expression profiling predicts survival

3 ESMO Treatment Recommendations THERAPY: 1. Young good-risk patients (aaipi 0,1): 6 x Rituximab (R)-CHOP 14 (Rituximab 8x) 2. Young poor-risk risk patients (aaipi 2,3): no current standard - clinical trials 3. Patients aged > 60 years: 8 x R-CHOP 21 RESPONSE EVALUATION: PET (positron emission tomography)

4 Relapsed and refractory DLBCL- role of transplantation 1. Salvage regimen: R-DHAP, R-ICE, R-ESHAP 2. Autologous stem cell transplantation: Standard of care in chemosensitive relapse; Future aspects: Radioimmunotherapy (Z-BEAM), Rituximab maintenance 3. Reduced intensity conditioning (RIC) allogeneic stem cell transplantation: after failure of autologous myeloablative hematopoietic stem cell transplantation; 3 year overall survival 31%!

5 Autologous stem cell transplantation autologous: patient s own stem cells Blood counts Chemotherapy associated complications why does it work: high dose chemotherapy! Day -7 Day 0 0 Day +14 Conditioning: Chemotherapy +/-Radiotherapy Infusion of autologous stem cells engraftment

6 Allogeneic stem cell transplantation allogeneic; stem cells from an (un)related donor Blood counts Chemotherapy associated complications Reduced intensity conditioning (RIC) / NST Graft versus host disease Day -7 Day 0 0 Day +14 why does it work: (Chemotherapy) Immunotherapy: graft versus lymphoma effect of the donor immune system! Conditioning: Chemotherapy +/-Radiotherapy Infusion of allogeneic stem cells engraftment NST = nonmyeloablative stem cell transplantation

7 Allogeneic stem cell transplantation: Graft versus host disease (GVHD) Alloreactive donor T-cells may attac recipients cells resulting in rush of the skin, diarrhea, lungand liver dysfunction Graft versus Lymphoma Effect!! Gut Liver Lung Skin

8 DLCBL: Emerging Agents Microenvironment: Bevacizumab Lenalidomide Surfacemarker/ Antibodies : Anti-CD20/ RIT Anti-CD22/ Epratuzumab Chemotherapy: Bendamustine Pixantrone RIC allogeneic SCT Pathways : Proteasome inhibitors: Bortezomib; HDAC inhibitors: Vorinostat, Panobinostat, Belinostat mtor inhibitors: Everolimus, Temsirolimus Bcl-2 family inhibitor: ABT-263, GX SYK inhibitors: Fostamatinib

9 Peripheral T-cell lymphoma (PTCL) PTCL represents 10%-15% 15% of new NHL cases per year PTCL is a heterogeneous group of mature T-cell lymphoma usually aggressive clinical course, often presents as extranodal, disseminated disease 30% refractory course of disease the incidence of PTCL is growing significantly (aging population) Rizvi, Blood 06

10 Peripheral T-cell lymphoma - most common PTCL subtypes Peripheral T-cell lymphoma is the most common subtype (Europe: 35%) Angioimmunoblastic lymphoma (29%) Anaplastic large cell lymphoma ALK+/ ALK- (16%) JM Vose, JCO 08

11 Peripheral T-cell lymphoma (PTCL) Geographic variability of PTCL International Prognostic Index (=IPI) is a valuable tool for risk stratification PTCL versus DLBCL: anthracycline-based chemotherapy is less effective in most PTCL while outcome has improved for B-cell lymphomas, PTCL outcomes have remained poor

12 Current treatment options First-line therapy: NCCN guidelines: clinical trials preferred! CHOP is the most commonly prescribed regimen as initial treatment: CHOP-EG,EPOCH, Hyper CVAD, First-line consolidation: all patients except low-risk (aaipi) should be consolidated with high dose therapy and autologous stem cell transplantation Exception: Anaplastic large cell lymphoma ALK+ is a subtype with good prognosis Prospective studies of frontline autologous stem cell transplantation: CR : 47%-61%; OS (3y) : 39%-75% Allogeneic RIC SCT: EBMT survey: 39% PFS at 4 years, no relaps after 2 years also refractory patients benefit Rizvi, Blood 06

13 New agents in Peripheral T-cell lymphoma Antimetabolite: Proteasome inhibitors: Bortezomib; Pralatrexate HDAC inhibitors: Surfacemarker/ Antibodies : Anti-CD 52/ Alemtuzumab Anti-CD CCR4 Anti-CD CD 30 Immunotoxins/ Denileukin diftitox Depsipeptide Vorinostat,

14 Chronic lymphocytic leukemia (CLL) leukemic, lymphocytic lymphoma 11% of all hematologioc neoplasms most common form of adult leukemia median age of 58 years (range = ) heterogenous course of disease Complications of progressive CLL: Bone marrow failure Immunosuppression Severe infections Transformation (Richter s T.) Autoimmune cytopenia immediate treatment of early stage patients no survival advantage! standard management in newly diagnosed early stage CLL: active monitoring

15 Chronic lymphocytic leukemia (CLL) Staging system Rai: Stage 0 : Lymphocytosis Low risk : 12.5 years Stage I : + Lymphadenopathy Intermediate risk : 7 years Stage II : + Hepato- and/or Splenomegaly Stage III : + Anemia (Hb < 11g/dl) Stage IV : + Thrombopenia (< /µl) High risk : 1.5 years Staging system Binet: Stage A: < 3 enlarged lymphnodes-areas Stage B: 3 enlarged lymphnodes-areas Stage C: Anemie (Hb < 10g/dl) or Thrombopenia (< /µl)

16 Treatment in CLL: Revised indications 1. BINET stage C or Rai stage III-IV disease 2. Early stage active disease: Progessive anemia or thrombocytopenia Progressive, symptomatic splenomegaly (> 6cm) or lymphadenopathy (> 10cm) Progressive lymphocytosis : > 50% in 2 months or ALC doubling time: < 6months Refractory autoimmune anemia or thrombocytopenia Fever, night sweats, fatigue or weight loss NCI-WG 2008

17 Proposed alogorithm for first line therapy Asymptomatic BINET A-B or Rai O-2 None (except high risk pts in clinical trials) Binet C or Rai III-IV or active disease (any stage) Good physical condition Relevant comorbidities Fludarabine Cyclophosphamide Rituximab (=FCR) Chlorambucil or Fludarabine Deletion 17: FCR; Alemtuzumab allogeneic stem cell transplantation Hallek Blood 2009

18 Allogeneic stem cell transplantation in CLL Autologous stem cell transplantation is not curative! Allogeneic stem cell transplantation: evidence for graft versus CLL activity! EBMT consensus: In summary long term disease free survival and possibly cure seem to be possible in one third to two-thirds thirds of patients undergoing allo-sct for poor risk CLL EBMT criteria for poor risk disease: Purine analogue refractoriness Early relapse after purine analogue combination therapy or auto SCT (within 24 months) Deletion17 requiring therapy (Richter transformation) Progression free survival : 37% in deletion 17 pts; no late relapse after 4 years! Dreger, Leukemia 2007

19 Selected novel agents in CLL Chemotherapy: Bendamustine Immunmodulatory Agents: Lenalidomide Antibody : Ofatumumab Antibody: Lumiliximab CDK inhibitor: Flavopiridol Polychemotherapy: OFAR,CFAR,R-FCM FCM..

20 Thank you for your attention