FOLLICULAR LYMPHOMA Lymphoma Management Course Oxford 2018

Dr Fiona Miall Leicester Outline

• Epidemiology • Clinical Features • Pathology • Diagnosis and staging • Treatment options upfront • Prognosis • Keeping your patient at the centre of this process What 3 words sum up Follicular lymphoma to you? Patient story : What 3 words sum up Follicular lymphoma to you?

“Lucky” “Straightforward” “Lucky” “Straightforward”

AG: 55 years old when diagnosed. Well, very active, successful male professional who woke up one Sunday with back pain and told he had cancer by Wednesday Diagnosed FL grade 1, advanced stage and treated with oral chemotherapy 10 years without treatment on very active monitoring At relapse treated on clinical trial and has just completed 4 years maintenance Rituximab 16 years since diagnosis in CR 2. “Complications” “Devastating” “Complications” “Devastating”

NS: 47 years old when diagnosed. Well, successful female doctor with 4 children (4yrs – 16 yrs) Noted by colleagues to have bulky neck nodes after losing weight ++ Diagnosed FL grade 2, advanced stage and treated with immunochemotherapy to CMR Then maintenance Rituximab, discontinued early due to infections . Epidemiology UK 16% (HMRN) Hong USA 20%-40% Kong 8%

Follicular lymphoma is the 2nd most common lymphoma worldwide (after DLBCL)

Variability in incidence across the world Non-Hodgkin Lymphoma (C82-C86): 1993-2014 European Age-Standardised Incidence Rates per 100,000 Population, by Sex, UK

Incidence of FL has increased alongside the 39% increase in NHL since the early 90’s

Prevalence has increased more so due to improved treatment

Source: cruk.org/cancerstats You are welcome to reuse this Cancer Research UK statistics content for your own work. Credit us as authors by referencing Cancer Research UK as the primary source. Suggested style: Cancer Research UK, full URL of the page, Accessed [month] [year]. Age-specific rates per 100 000 by subtype: FL Median age 50-59 Haematological Malignancy Research Network (HMRN) 2004–2012. Male=female

Lymphoma incidence, survival and prevalence 2004–2014: sub-type analyses from the UK’s Haematological Malignancy Research Network A Smith, S Crouch, S Lax, J Li, D Painter, D Howell, R Patmore, A Jack and E Roman British Journal of Cancer 2016 US lymphoid malignancy statistics by World Health Organization subtypes

CA: A Cancer Journal for Clinicians Volume 66, Issue 6, pages 443-459, 12 SEP 2016 DOI: 10.3322/caac.21357 http://onlinelibrary.wiley.com/doi/10.3322/caac.21357/full#caac21357-fig-0002 Clinical Features

• Most patients with FL have widespread nodal disease at diagnosis, with ~ 2/3 being stage III/IV at diagnosis

• Often feel relatively well

• ~ 1/3 B symptoms

• Large mediastinal masses rare, retroperitoneal and mesenteric masses causing obstructive nephropathy much more common Clinical Features

• Pure extranodal presentations uncommon (<10%)

• Commonest sites of extranodal involvement are liver and bone marrow (BM involved in ~ 40%)

• Overt leukaemic phase uncommon at presentation

• Next commonest extranodal sites are • Spleen • Waldeyers ring • GI tract (most often duodenum and small bowel) Care to exclude specific • Skin subtypes = see later Clinical Features • A minority of patients have indolent disease with little or no progression over several decades. • The nodes can wax and wane • Patients may enter spontaneous and prolonged remissions • Some patients are on ‘Watch and Wait’ will never require systemic treatment • 20–30% of patients will die following transformation of their disease to high-grade lymphoma (much commoner early after diagnosis) • Prognostic indices do not yet discriminate well on an individual basis

“Not knowing is very difficult” Pathology • Pathologically distinctive • FL cells have morphologic, immunophenotypic, and genetic features of the lymphoid germinal centre

• The genetic hallmark of FL t(14;18)(q32;q21) results in the constitutive overexpression of the bcl 2 protein, which impairs the normal germinal centre apoptotic process

• A disease-specific microenvironment with interaction facilitating survival: FL cells with macrophages, follicular dendritic cells, fibroblasts, endothelial cells and T lymphocytes (CD4/8) and T-regs Pathology

• Unlike the normal germinal-centre cells, the neoplastic cells do not remain confined to the germinal centre but migrate to other follicles within the lymph node and others, to peripheral blood, and bone marrow

• Looking at the lymph node: the follicles often extend beyond the capsule, sometimes with fibrosis

• Morphology of the cut node shows excesses of centrocytes, and a variable proportion of centroblasts – it is this which leads to the grading of FL This reactive germinal center contains normal centrocytes and centroblasts; follicular dendritic cells are often binucleate and identified by their oval to round nuclei with pale chromatin and small distinct eosinophilic nucleoli (arrows)

Neoplastic follicle in low-grade FL contains centroblasts and centrocytes, similar to those in the reactive germinal centers; however, the follicles have a more monomorphous appearance because of the predominance of centrocytes. Arrows indicate follicular dendritic cells. In the right hand panel, the Giemsa stain shows off the rare centroblasts in low grade FL

In FL grade 3A (left), centroblasts are numerous, but centrocytes are still present; with persistence of follicular dendritic cells. In FL grade 3B / ~ DLBCL (right), there are solid aggregates of centroblasts. • Previous and following slide adapted from: Follicular Lymphoma Chapter 18, 321-352.e8. Haematopathology 2nd edition 2017 • Laurence de Leval, Abner Louissaint and Nancy Lee Harris Grade Definition † Grade 1 to 2 (low grade) * 0-15 centroblasts/hpf † 40-60% Grade 1 0-5 centroblasts/hpf † 15 is the 25-35% Grade 2 6-15 centroblasts/hpf prognostically † Grade 3 >15 centroblasts/hpf important cut-off Grade 3A Centrocytes present Grade 3B Solid sheets of centroblasts Reporting of Pattern Proportion Follicular (%)

Follicular >75 ‡ Follicular and diffuse 25-75 ‡ Focally follicular <25 § Diffuse 0 Diffuse areas containing >15 centroblasts/hpf are reported as diffuse large B-cell lymphoma ‡ with follicular lymphoma (grade 1 to 2, 3A, or 3B) Pathology

+ + + + − − • Ig CD19 CD20 CD22 • CD43 CD5 + + + • CD79a PAX5 CD10 + + • BCL2 BCL6 Often stronger staining than in normal follicles • nodular+ meshworks+ of CD21 CD23 follicular dendritic cells The FL cells won’t be universally +ve, so less staining • Immunoglobulin genes than in normal follicles rearranged, mutated • t(14;18)(q23;q32) and IGH/ BCL2 rearranged PCR or FISH for BCL2 -IGH rearrangement should be considered in cases suggestive of FL who are BCL2 –ve by IHC How was the diagnostic process?

Everything stopped

The wait over Christmas and New Year was so hard.. It has changed my clinical practice with my own patients Diagnosis and Staging

• Always aim for an excision lymph node in a patient presenting with suspected follicular lymphoma

• Work up: • Contrast CT scan of (neck) T,A,P and a Bone Marrow A & T ? • Viral screen (Hep B, C, HIV) • Igs and paraprotein screen • LDH and beta-2M • Pregnancy test if fertile female Diagnosis and Staging – discussion points

• 1. Widespread LNs, no organomegaly / bulk – when to do a BM?

• 2. Patient with palpable neck but also mesenteric and retroperitoneal nodes on CT

• Would you do a trucut biopsy or an excision biopsy in your hospital?

• When might a trucut biopsy be appropriate? PET CT

• – not recommended by NICE in the work up of FL other than in localised disease by CT … But… Bone marrow involvement

Tip: @ v low power look for Confirmatory flow and paratrabecular infiltrate – it won’t always be this obvious immunohistochemistry: • ?

courtesy of Ed Uthman at flickr Bone marrow involvement

Tip: @ v low power look for Confirmatory flow and paratrabecular infiltrate – it won’t always be this obvious immunohistochemistry: Flow on BM will usually show: CD 5 - and CD 10 +

Along with +ve pan-B markers: CD19, 20, CD79a, PAX5 & surface immunoglobulin with light chain restriction

courtesy of Ed Uthman at flickr Follicular lymphoma involving the bone marrow 2

Image ID: 60428 Authors: Joo Y. Song, MD

Category: Lymphoma: Mature B-cell neoplasms > Low-grade B-cell lymphoma > Follicular Lymphoma

Image ID: 13837 Authors: Peter Maslak

Category: Lymphoma: Mature B-cell neoplasms > Low-grade B-cell lymphoma > Follicular Lymphoma

In the BM aspirate or in blood the FL cells may look cleaved

• Stage IA Radiotherapy

• Stage IIA NICE: • Offer local radiotherapy as first-line treatment • Consider 'watch and wait' (observation without therapy) as first-line treatment for people with stage IIA follicular lymphoma who are asymptomatic and for whom treatment with a single radiotherapy volume is not suitable. • Offer the same treatments that might be offered to people with advanced-stage (stages III and IV) symptomatic follicular lymphoma to people with stage IIA follicular lymphoma who are symptomatic and for whom radiotherapy is not suitable. Treatment options – Advanced stage asymptomatic FL NICE guideline

• Offer rituximab induction therapy to people with advanced-stage (stages III and IV) follicular lymphoma who are asymptomatic. Treatment options – Advanced stage symptomatic FL NICE guideline

• Rituximab, in combination with: • cyclophosphamide, vincristine and prednisolone (CVP) • cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) • mitoxantrone, chlorambucil and prednisolone (MCP) • cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α (CHVPi) or • chlorambucil is recommended as an option for the treatment of symptomatic stage III and IV follicular lymphoma in previously untreated people.

• New 2018: Obinutuzumab is recommended as an option for untreated advanced follicular lymphoma in adults (first as induction treatment with chemotherapy, then alone as maintenance therapy), only if FLIPI score is 2 or more Treatment options – Advanced stage – UK practice 2017-8

• Treating advanced-stage asymptomatic follicular lymphoma • Rituximab induction therapy ..in practice used little, though an option • Watch and Wait (Ardeshna 2003 Chl v W&W no OS diff)

• Treating advanced-stage symptomatic follicular lymphoma • Rituximab, in combination with: • cyclophosphamide, vincristine and prednisolone (CVP) • cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) • mitoxantrone, chlorambucil and prednisolone (MCP) • cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α (CHVPi) or • chlorambucil

• Plus Bendamustine used and available via CDF then bluteq Treatment options – Advanced stage – UK practice BSH guideline

• Rituximab - chemotherapy should be used in patients with newly diagnosed, symptomatic advanced stage FL. There is currently no strong evidence to support one chemotherapy regimen over another.

• Observation remains an appropriate approach in patients with asymptomatic, advanced stage FL in an attempt to delay the need for chemotherapy. This is particularly the case for patients over 70 years of age.

• Patients with grade 3b FL should be treated as if they have DLBCL. • Autologous stem cell transplantation has no role in first line therapy for FL (without histological transformation). Treatment options / dilemmas –UK practice 2018

Treating advanced-stage symptomatic follicular lymphoma

• Rituximab- chemo • Obinutuzumab – chemo

• Which chemo with which antibody?

• Maintenance afterwards?

• PETREA study PETReA: Phase 3 evaluation of PET-guided, Response- Adapted therapy in patients with previously untreated, high tumour burden follicular lymphoma

Version 2 01 March 2018 (Protocol Version 2, 26 September 2017) LCTU 35 Liverpool Clinical Trials Unit Study Design

Aim to recruit: 840 patients over 53 months from approx. ~100 centres throughout the UK

Following induction treatment, patients who achieve an anatomical CR or PR will be allocated into PET +ve or –ve groups and treated as below:

Group 1: PET +ve - randomised (1:1 ratio) Arm A: Rituximab maintenance Arm B: Rituximab + lenalidomide (R2)

Group 2: PET –ve - randomised (1:1 ratio) Arm A: Rituximab maintenance Arm B: No further treatment

LCTU 36 Liverpool Clinical Trials Unit Treatment options – Advanced stage

• Whatever option you chose, aiming for ~ 90% ORR ie few who don’t respond upfront WhWho to start with watch & wait? None of the following ..

GELF criteria, modified: • BNLI criteria : • High tumor bulk (see definition below) • Rapid, generalized disease progression in the • Presence of B symptoms preceding 3 months • ECOG performance status > 1 • Serum LDH or beta 2-microglobulin level above • Life-threatening organ involvement normal values • Renal infiltration • Macroscopic liver involvement High tumor bulk is defined with the following parameters: • Bone lesions • A tumor >7 cm in diameter • Presence of systemic symptoms • Three nodes in three distinct areas, each >3 cm in 9 diameter • Hemoglobin < 100 g/L or WBC < 1.5 x 10 /L, 9 • Symptomatic spleen enlargement or platelet count < 100 x 10 /L; related to • Organ compression bone marrow involvement • Ascites or pleural effusion Bendamustine-Rituximab (B-R) vs CHOP-R in Untreated Indolent Lymphoma

StiL NHL 1-2003 Bendamustine-R (4-week cycle) • Indolent NHL - Bendamustine 90 mg/m2 day 1+2 – FL - Rituximab 375 mg/m2 day 1 q – Lymphoplasmacytic (Waldenström’s) R – Marginal-zone CHOP-R (3-week cycle) – Small lymphocytic - Cyclophosphamide 750 mg/m2 day 1 • Mantle-cell (elderly) - Doxorubicin 50 mg/m2 day 1 - Vincristine 1.4 mg/m2 (max 2 mg) day 1 - Prednisone 100 mg/day on days 1–5 - Rituximab 375 mg/m2 day 1

NCT00991211. Clinical study report available at https://clinicaltrials.gov/ct2/show/NCT00991211?term=NCT00991211&rank=1. Rummel MJ et al. Lancet.2013;381:1203-1210. 10 year StiL data Rummel ASCO 2017 – iNHL 10 year StiL data Rummel ASCO 2017 – No OS difference PRIMA: Rituximab Maintenance vs Observation in Patients With FL

Stratified by response to induction, chemotherapy regimen, and geographic location prior to 1:1 randomization Rituximab maintenance Induction 375 mg/m2 q8w for Untreated Immunochemotherapy 2 yrs patients with 8 cycles high tumor Response* (n = 505) (N = 1019) 5-yr burden follicular R-CHOP or follow-up lymphoma R-CVP or R-FCM Observation (n = 513)

*Only patients with CR/CRu/PR randomized to maintenance therapy; 1 patient died during randomization.

Salles GA, et al. ASCO 2010. Abstract 8004. PRIMA results @ median follow-up of 73 months

• Rituximab maintenance resulted in a significant prolongation of PFS • 59.2% v 42.7% of patients without maintenance (p < 0.0001) • The beneficial effect of R-maintenance was seen across all ages and the FLIPI groups • an increase in the CR rate at the end of the 2-year maintenance PRIMA results @ median follow-up of 9.7 years (ASH 2017)

• 607 patients were available for follow-up • Median PFS: 4.1 observation vs 5 years R-maintenance (P < 0.0001; HR=0.61, 95% CI, 0.52–0.73) • 10-year estimated disease-free progression: 35% observation vs 51% R- maintenance • Time-to-next-treatment median time was not reached for the R- maintenance group vs 6 years with observation (P < 0.001; HR=0.66, 95% CI 0.55–0.78) • OS not significantly different : 80% R-maintenance vs 80% observation (P = 0.795; HR=1.04, 95% CI 0.77–1.40) Pooled estimates of overall survival with rituximab maintenance therapy for patients with follicular lymphoma compared with observation or rituximab at disease progression.

Liat Vidal et al. Blood 2010;116:1798

• Offering Rituximab after R-chemo, particularly R-CVP and R-CHOP is standard • Need to explain PFS v OS • Many patients will not complete maintenance • Watch for infections, particularly RTIs, sinus infections and fall in Igs • Rarer – neutropenia

• So offer and discuss … but what about maintenance O? Treatment – maintenance R

Like the rhythm of it Like the monitoring Very tired and tearful on day 4 Tough with the infections Next day I know I’ll be fine A hurdle to me working But.. I would have it again if I thought it would keep me It’s a reminder there's a tiger waiting to bite your leg alive for longer Also read results of the Bright study iNHL and MCL R Benda v R CHOP/R CVP updated at ASCO 2017 Flinn et al – maintenance R not mandated

Marcus et al NEJM 2017 Survival data at 34.5 months f-up

Estimated 3-year rate of progression-free survival, 80.0% O vs. 73.3% R Marcus et al NEJM 2017 Survival data at 34.5 months f-up

Current upfront treatment dilemma- for FL requiring treatment – (FLIPI ≥2) - personal • R-CHOP +/- R maint • R-CVP +/- R maint • R-Benda ( paucity of evidence for maintenance) • O-CHOP +/- O maint • O-CVP +/- O maint • O-Benda +/- O maint (>5% deaths from AEs on Gallium)

• Careful discussion, consider patient factors for infective risk, infective prophylaxis, • Local delivery issues – sc Ritux v iv Obin infusion times; slight ↑IRRs with O though manageable and less than seen in CLL Prognosis FLIPI - Follicular Lymphoma International Prognostic Index

Characteristic RR (Death) Older than 60 yrs of age 2.38 Stage III-IV 2.00 Hemoglobin < 12.0 g/dL 1.55 Elevated LDH 1.50 Nodal sites > 4 1.39 FLIPI and OS

Risk Group Risk Factors, n 5-Yr OS, % 10-Yr OS, % Low 0-1 91 71 Intermediate 2 78 51 High ≥ 3 53 36

Solal-Céligny, et al. Blood. 2004;104:1258-1265. Downsides to the FLIPI

. Many important factors not used . May not agree with other indices . Not all 5 prognostic factors have same relative risk . Assumes that FL-3 behaves like FL-1 and FL-2 . Data come from the pre-rituximab era FLIPI 2

FLIPI 2 score used to predict outcomes of therapy based on adding number of risk factors (each factor = 1 point) – Longest diameter of largest • Hb < 12 g/dL involved node > 6 cm • Older than 60 yrs of age – Bone marrow involvement • β2-microglobulin > ULN

FLIPI2 Risk Patients, % 3-Yr PFS, % 5-Yr PFS, % HR Risk Group Factors, n Low 0-1 20 90.9 79.5 1.00 Intermediate 2 53 69.3 51.2 3.19 High 3-5 27 51.3 18.8 5.76 High vs int 1.81 Federico M, et al. J Clin Oncol. 2009;27:4555-4562.

Predictive Power of Gene Expression Signature in Follicular Lymphoma

Expression Signature (Prognosis) RR of Death P Value Immune response 1 (favorable) 0.15 < .0001 Immune response 2 (unfavorable) 9.35 < .0001

Dave SS, et al. N Engl J Med. 2004;351:2159-2169. Incorporating Genetic Risk and Performance Status Improves Prognostic Accuracy

• m7-FLIPI risk score incorporates non- silent mutations in genes associated Genes associated with with progression risk in FL as well as progression risk in FL FLIPI and ECOG PS

• m7-FLIPI score was a significantly EZH2 better predictor than FLIPI alone of ARID1A • 5-year failure-free survival MEF2B • Overall survival EP300 • Early treatment failure FOXO1 CREBBP CARD11

1. Pastore A et al. Lancet Oncol. 2015 2. Jurinovic V et al. Blood. 2016 Prognosis – after 1st line therapy

• Increasing data to suggest early treatment failure is a key poor prognostic factor

• FLIPI / FLIPI2 not prognostic at relapse Outcome of FL Patients According to Durability of Response to R-CHOP National LymphoCare Study Group

OS OS (validation set) 1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4 Survival (probability) Survival Survival (Probability) Survival 0.2 Early POD 0.2 Early POD Reference Reference 0 6 24 36 48 60 72 84 96 0 6 24 36 48 60 72 84 96 Time from risk-defining events (months) Time from risk-defining events (months) No. at risk: Early POD 110 82 66 56 50 42 32 14 3 Reference 420 408 387 363 344 253 145 34 0

R-CHOP = rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; POD = progression of disease.

Casulo C et al. J Clin Oncol 2015;33:2516-2522. • In the lymphocare study of the >500 patients receiving R-CHOP the 20% who progressed within 2 years had a 5 year OS of 50%, compared to 90% without progression.

• This is the group needing new treatment options Ongoing Treatment options

• More immunochemotherapy – alternate regimen (or same) depending on TTTF • O-Benda if fulfil Gadolin criteria • High dose therapy and ASCT • Allo SCT • Treatment on clinical trial with new agents FL variants

• In situ follicular neoplasia • Duodenal-type FL • Paediatric FL (boys, head and neck presentation) • Cutaneous Any Qs