Indolent Lymphomas. Dr Ram Malladi

Transcription

1 Indolent Lymphomas Dr Ram Malladi

2 Follicular lymphoma is commonest indolent lymphoma INDOLENT LYMPHOMA % of all NHL Follicular Lymphoma 22 Small lymphocytic lymphoma 6 Marginal zone lymphoma 6 Lymphoplasmacytic lymphoma 1

3 General Characteristics Often present with few or no symptoms Present in the elderly Indolent growth pattern relapsing, remitting course of disease High grade transformation Some patients may not need treatment for many years Generally incurable

4 Follicular lymphoma is of germinal centre B-cell origin Tiacci et al Nature Reviews Cancer, 2006

5 Characteristics of Follicular Lymphoma 6 th Decade Male=Female 50% advanced stage Bone marrow involvement: 40-70% t(14;18)(q32;q21) 90% cases overexpression of bcl-2 Prognosis of t(14;18)+/- cases similar Often asymptomatic

6 Follicular Lymphoma:duration of successive remissions Johnson PW et al, 1995

7 Histological Features of Follicular Lymphoma CD20 staining CD10 +, BCL2 +, BCL6 +, sig + MUM1 - Grade 1-2 Grade 3 Grade 3A Grade 3B Grading Definition 0-15 Centroblasts per hpf >15 centroblasts per hpf Centrocytes present Solid sheets of centroblasts

8 Aims of a Prognostic Index In each patient, to help determine the most appropriate treatment for a given clinical course To allow comparison of clinical trials in the literature To allow the design of prospective clinical trials in a relatively homogeneous subgroups of patients

9 Follicular Lymphoma International Risk group Prognostic Index (FLIPI) No Factors Disttribution of patients 5-year overall survival, % 10-year overall survival Low Intermediate High Based on 4000 patients ( ) Age Serum LDH Nodal areas >4 Haemoglobin <12g/dl Solal-Celigny P, et al. Blood 2004

10 FLIPI2 Limitations of original FLIPI Built before the era chemoimmunotherapy Some important clinical and biological parameters were not included eg size of largest mass, serum β 2 -microglobulin Designed with Overall Survival as endpoint FLIPI2 Tumour >6cm Serum β 2 -microglobulin Marrow involvement Hb <12 Age >60 Risk group No Factors Distribution of patients 3-year PFS, % 5-year PFS, % Low Intermediate High

11 Management of Limited Stage Follicular Lymphoma Radiotherapy is treatment of choice Stage I disease or contiguous Stage II disease Involved Field/Involved Site 24Gy in 12 fractions recommended Princess Margaret Cancer Centre, Toronto Abstract 062, ICML 12, Lugano Stage I-II disease 526 patients, received radiotherapy alone CR/CRu=98.7% Relapse Risk at 10 years=51.3% OS at 10 years =65%

12 Advanced Stage Follicular Lymphoma: Immediate Treatment Vs Watch and Wait Standard of care is watch and wait management unless bulk disease, compressive symptoms, system symptoms, marrow failure, organ failure by infiltration, rapidly enlarging adenopathy 104 patients with advanced stage indolent lymphoma randomised between watch and wait Vs immediate Treatment with ProMACE-MOPP + TNI (Young et al Seminars in Hematology, 1988) 56% of expectant arm did not receive treatment 44% patients crossed-over to chemo/tni arm (median 34 months) No difference in Overall survival between the two arms Newly diagnosed follicular NHL randomised (n=193): no treatment Vs Prednimustine Vs Interferon alpha (Bastion et al, JCO 1997 (GELF)) Median FFT= 24 months vs 40 months vs 45 months (Median f/up of 45 months) Overall survival (5 years)= 78% vs 70% vs 84% Newly diagnosed with advanced stage Follicular NHL (n=309) randomised to receive watch and wait (+crossover for progression) Vs chlorambucil (Ardeshna et al, Lancet 2003 (BNLI)) Median overall survival= 6.7 years vs 5.9 years (median f/up=16 years)

13 Ardeshna et al, Lancet 2003 Time to 1 st systemic treatment in Observation Group (A)Overall Survival (B) Cause-specific survival Time to 2 nd chemotherapy in both Groups

14 Criteria for treatment (BNLI/GELF criteria) Bulky disease : nodal/extranodal mass > 7cm B symptoms Raised B2-microglobulin/LDH Bone marrow failure Rapidly progressive disease over any 3 6 month period Involvement of 3 nodal sites (>3 cm) Splenic enlargement Compression syndrome Pleural/peritoneal effusion

15 Intensification of upfront chemotherapy in Follicular Lymphoma Overall survival according to treatment group 1:Cyclophosphamide 2:CHOP-Bleomycin Peterson BA et al JCO, 2003

16 Rituximab Monoclonal antibody therapy CD20 Transmembrane phosphoprotein with a single extracellular loop Function unknown Expressed on (most) B cell cancers Rituximab is a chimeric monoclonal anti-cd20 antibody Complement fixation Antibody Dependent Cellular Cytotoxicity (ADCC) Apoptosis Relapsed indolent lymphoma Overall response 50-60% (McLaughlin et al JCO 1998) Median Progression-free survival of responders=13 months Treatment naïve indolent lymphoma Overall response 73%

17 R-Chemo upfront therapy improves Time to treatment failure and Overall Overall Survival Survival: R-CVP vs CVP Time to treatment failure Marcus et al JCO, 2008

18 Initial Treatment for Follicular Lymphoma Enrollment in clinical trials Elderly patients: Chlorambucil *TRANSFORMED FOLLICULAR LYMPHOMA* Chemotherapy + rituximab CVP + Rituximab CHOP + Rituximab Fludarabine + Cyclophosphamide + Rituximab Bendamustine + Rituximab (Rummell et al 2009, Median PFS 69 vs 31 months BR vs CHOP-R Improved TTF/PFS with rituximab addition Longer term studies may show OS benefits Radioimmunotherapy: See later Autologous stem cell transplant 3 Phase III randomised studies comparing chemotherapy alone (NO RITUXIMAB) with chemotherapy consolidated with high dose therapy None show a benefit in overall survival x2 show significant improvements in PFS (Lenz et al, Blood 2004 & Deconinck et al Blood 2005.) x1 shows no benefit in PFS (Sebban et al, Blood 2006)

19 PRIMA study: Rituximab consolidation in Follicular Lymphoma (Salles et al, Lancet 2011) Tested the benefit of maintenance rituximab in previously untreated patients with follicular lymphoma needing systemic therapy 1217 patients enrolled Following standard rituximab-containing chemotherapy, patients in PR or CR were randomised to receive 2 years of maintenance rituximab or not (375mg/m 2 every 8 weeks) Improvement in PFS for maintenance (75% vs 57%, median f/up 36 months) No difference in overall survival between groups

20 Treatment of relapsed Follicular Lymphoma Asymptomatic patients may not need treatment Non-cross reacting chemotherapy (R-CHOP, R-DHAP, R-ICE, R-IVE, R-ESHAP, R-Benda) Maintenance Rituximab (Von Oers JCO 2010) improves PFS compared to no maintenance (median PFS 3.7years vs 1.7years) Ibritumomab tiuxetan (Zevalin) Ytriuum-labelled anti-cd20 antibody (β-emitter) Overall response 75% Complete remission 15% neutropenia/thrombocytopenia at 4-8 weeks Option in patients with poor performance score or elderly FIT Study (Not a relapse study)-morschhauser et al JCO CR/PR after upfront chemo (with or without R) randomised to Zevalin Consolidation (single dose) or not. Significant improvement in median PFS (37 months vs 13 months) No change in OS Trial done in pre-rituximab era 131 I-tositumomab (Bexxar) β- and γ-emitter Allogeneic transplant Considered in selected individuals RIC conditioing Curative potential

21 Freedman et al, Blood 1999 Kaplan-Meier estimate of FFR after ABMT for 113 informative patients who were either PCR or PCR+ after ex vivo purging.

22 Benefit for autograft: 4 year OS= 46% vs 71% vs 77% CUP Study:Schouten et al, JCO 2003 PFS OS

23 EBMT Lym-1 Study In vivo purging alone has no benefit Maintenance alone has benefit in PFS at 10years (54% vs 37%) Maintenacne + purging has benefit in PFS (62% vs 37%) No effects on OS Pettengell et al. JCO 2013.

24 A change to watch and wait strategy for Follicular lymphoma? Asymptomatic Stage II-IV Follicular NHL with adequate marrow reserve (Ardeshna et al, ASH 2010) randomised (n=462) to watch & wait vs rituximab x4 vs rituximab x4 + rituximab maintenance rituximab x4 alone arm discontinued early because of perceived undertreatment Median time to initiation of new treatment was 33 months vs Not reached Progression free survival at 3 years= 30% vs 75%

25 The future management options for follicular lymphoma Role of PET-adapted therapy for follicular lymphoma PET neg CR at end of induction R-Chemo associated with increased PFS Incorporation of novel agents upfront and at relapse Lenalidomide (+rituximab = R 2 ) Idelalisib (PI3 kinase δ inhibitor) Gopal et al NEJM 2014 Incorporation of novel antibody therapy Obinutuzumab (GA101) Salles et al JCO 2013 (single agent) & Radford et al Blood 2013 (with chemo)-phase II studies Likely more active than rituximab Subcutaneous rituximab Salar et JCO 2014

26 Marginal Zone Lymphomas Three subtypes (based on clinical differences in behaviour) Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma): more common Nodal marginal zone lymphoma Splenic marginal zone lymphoma Much less common All subtypes share a common cell of origin (Marginal zone B-cell) Marginal zone of lymphoid tissues is a distinct microanatomic compartment of the B-cell follicle Well developed in organs with abundant influx of antigens

27 MALT lymphomas Arises in organs that normally lack lymphoid tissue Stomach, lung, salivary and lachrymal glands These organs accummulate B-cells due to chronic antigenic stimulation: chronic infection/autoimmune disease Genotoxic effect on B cells Free-radical release by attracted neutrophils Prolonged B cell proliferation Lead to abnormalities of NFkB pathway (Constitutive activation)

28 Organisms associated with MALT lymphomas Organism Helicobacter pylori Helicobacter heilmannii Campylobacter jejuni Borrelia burgdorferi Chlamydia psittaci Lymphoma Gastric MALT lymphoma Immunoproliferative Small Intestinal Disease (IPSID) Cutaneous MALT lymphoma Orbital MALT lymphoma Splenic Marginal Zone Lymphoma

29 Gastric MALT lymphoma H.pylori survives gastric acid and colonises the gut wall Triggers lymphoid infiltration t(11;18) in 10-50% of cases: AP12-MALT1 rearrangements More resistant to H.pylori eradication

30 Clinicopathological features of Marginal Zone Lymphomas MALT lymphomas Generally present as Stage IE Bone marrow involvement is uncommon Sites affected include the stomach, salivary glands, thyroid, intestine, conjunctiva, lachrymal gland, skin. Splenic Marginal Zone Lymphomas Typically presents in the elderly Splenomegaly associated with blood and marrow involvement Nodal Marginal Zone Lymphomas Typically present with abdominal/pelvic lymphadenopathy with marrow involvement

31 Histological features of Marginal Zone Lymphomas MALT Neoplastic cells invade and destroy epithelium Heterogeneous in cell composition CD20

32 Histological features of Marginal Zone Lymphomas (2) Nodal In initial stages expansion of the follicular marginal zone is seen with or without attenuated follicular mantle zones In later stages expansion of neoplastic marginal zone B-cells causes colonization of follicles with diffuse effacement of nodal architecture Thin arrow shows remaining germinal centres Thick arrow shows diffuse architecture of cortex Positive for sig, CD20, CD79a Negative for CD5 and Cyclin D1

33 Treatment of Marginal Zone Lymphomas (1) MALT Gastric Eradication of H.pylori is treatment of choice for localised disease (Antibiotics + PPI therapy):70% CR rate Very few patients relapse from a complete response No benefit for consolidation chemotherapy clarithromycin 500 mg twice a day with amoxicillin 1000 mg twice a day/or metronidazole 500 mg twice a day plus a proton pump inhibitor for 14 days is a well accepted treatment of first choice In non-responders or H.pylori negative disease Chlorambucil + rituximab: >90% CR with few relapses Local radiotherapy to stomach

34 Treatment of Marginal Zone Lymphomas (2) Other MALT lymphoma sites Stage I presentation is a common feature Involved field radiotherapy is often curative in >80% patients Nodal involvement at presentation requires consideration of combination of chemotherapy +/- rituximab

35 Treatment of Marginal Zone Lymphomas (3) Splenic Splenectomy is treatment of choice for symptomatic splenomegaly and/or pancytopenias Other second line therapies: Fludarabine/cyclophosphamide +/- rituximab Nodal No consensus treatment protocol Response rates are lower with combination chemotherapy compared to other forms of marginal zone lymphomas

36 Lymphoplasmacytic lymphoma WHO 2008 definition A neoplasm of small B cells, and plasma cells, usually involving bone marrow and sometimes lymph nodes and spleen, which does not fulfill the criteria for any of the other small B cell lymphoid neoplasma Median age is in 60s Majority have IgM paraprotein (sometimes with cryoglobulin activity)

37 Clinical Presentation of Lymphoplasmacytic Lymphoma Fatigue due to anaemia Other cytopenias Hyperviscosity syndrome Fevers, night sweats and weight loss Rarer presentations Cryoglobulins Neuropathy Cold agglutinins amyloid

38 Treatment of Lymphoplasmacytic Lymphoma No consensus on treatment Options are Single agent Chlorambucil Fludarabie Combination Fludarabine, Cyclophosphamide +/- rituximab (ORR 75%) CHOP +/- rituximab ORR (90% vs 60%)

39 Summary of follicular lymphoma Limited/early stage Radiotherapy alone Advanced stage (low tumour burden) Watch and wait Advanced stage (high tumour burden) R-chemo or R-novel agents + maintenance R Relapsed disease R-Chemo or R-novel agent + autograft + maintenance R