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2 Follicular Lymphoma Overview Protocol * Review Histology,, complete staging and prognostic score, present at lymphoma MDM; enrol in clinical trial if available Follicular Lymphoma Grade 1 and 2 Staging FLIPI Hb < 120 LDH > ULN Ann Arbor Stage III / IV Number of nodal sites > 4 Age > 60 years Grade 3a* & b** Treat as DLBCL Stage I and II IF RT?Observation Relapsed Disease Watch and Wait RT if localised Chemotherapy options o R-CHOP o R-CVP o R-FM o R Chlorambucil Consider in CR2 autologous or RIC allogeneic transplant Rituximab maintenance (unfunded) Stage III and IV Watch and Wait until treatment indicated Chemotherapy options: Chlorambucil (especially in older patients) R-CHOP R-FM R- CVP Rituximab maintenance (unfunded) *Grade 3a FL can be treated on either DLBCL or FL protocol, at the discretion of the treating physician ** Grade 3b treated as DLBCL

3 Role of Rituximab Limited Stage disease Advanced Stage disease Role of Rituximab Relapsed disease Transformed disease Role of transplant Sub Topics

4 Follicular Lymphoma Overview Review Histology, complete staging and prognostic score refer below, present at lymphoma MDT, enrol in clinical trial if available FLIPI Factors Risk Group Number of factors 5 year overall survival - Hb <120 - LDH>ULN - Ann Arbor stage III/IV - Number of nodal sites >5* - Age >60 years - *Individual sites =right and left cervical; mediastinal; right and left axillary; right and left epitrochlear; mesenteric; paraaortic; right and left inguinal Buske Blood : Limited Stage Disease Stage I/II Options Involved field radiotherapy, 24-30Gy with lower dose preferred Very good 0, Good Poor 3,4, Advanced Stage Disease 10 year overall survival Stage III/IV Watch and Wait until treatment indicated (see below, GELF criteria for treatment) Options for chemotherapy when required: Chlorambucil +/- prednisone +/- rituximab R-CHOP R-CVP R-Fludarabine/Mitoxantrone R- Bendamustine (currently unfunded) Clinical trials with investigational agents Single agent rituximab GELF criteria * : High tumor bulk (see definition below) Presence of systemic symptoms Eastern Cooperative Oncology Group (ECOG) performance status > 1 Serum lactate dehydrogenase (LDH) or B2-microglobulin level above normal values High tumor bulk is defined with the following parameters: A tumor > 7 cm in diameter 3 nodes in 3 distinct areas each > 3 cm in diameter Symptomatic spleen enlargement Organ compression

5 Ascites or pleura effusion *Brice P, Bastion Y, Lepage E, et al. J Clin Oncol. 1997;15:1110- Diagnosis Requires an adequate biopsy, usually an excision lymph node biopsy where possible or, where not surgically accessible, then a core biopsy. All cases should be reviewed by an experienced haematopathologist and management discussed at a multidisciplinary lymphoma conference. Follicular lymphoma is derived from germinal centre B cells. It is graded from I-III depending on the proportion of large cells per high power field. Variants and subtypes Grade 1 & 2 should be treated identically. There is no evidence for a difference in outcome. Grade 3a: management is controversial. It should probably be treated in the same way as grade 1 & 2, but there may sometimes be concerns about distinguishing from grade 3b. Grade 3b should be treated as DLBCL. After anthracycline containing chemotherapy combinations, long term PFS is better than for grade 1-2, although some series still detect continuing relapse especially in those with advanced stage disease. Cutaneous follicular NHL: BCL2 negative: is considered a separate disease entity and is not included in this guideline. BCL2+ is likely to be associated with systemic follicular lymphoma and should be investigated and treated according to this guideline The median age of presentation is 60 years. Most cases present with advanced disease and 50% have bone marrow involvement at presentation % of cases present with stage I or II disease. Initial Investigations Full blood count, Na, K, Ca, PO 4, renal function, urate, liver function tests, LDH, immunoglobulins, Β2 microglobulin. Hepatitis B testing (surface Ag & core Ab)and consider HIV and hepatitis C testing. Bone marrow biopsy obtaining 20 mm of haematopoietic tissue (may not be needed if stage IA or IIA) CT scan chest, abdomen, pelvis +/- neck if lymph node palpable in the neck. Consider cardiac echocardiogram/gated heart scan for patients who are to receive an anthracycline. PET scan assessment should be considered where upstaging would lead to a change in management (i.e. stage I & II disease) Fertility discussions Staging Ann Arbor (Cotswold modification) staging system I II Involvement of a single lymph node or lymphoid structure (spleen, thymus, Waldeyer s ring) Two or more regions on the same side of the diaphragm

6 III IV X E Two or more regions on both sides of the diaphragm Involvement of extranodal sites (such as liver, lung or marrow) not due to direct extension from a nodal site Bulky Disease 10 cm maximal dimension of a nodal mass, or Mediastinal mass > 1/3 internal transverse diameter of the thorax measured at the level of T5/6 intercostal space on PA CXR. Involvement of a single extranodal site, adjacent to a known nodal site. B Recurrent unexplained fever > 38º, or Recurrent unexplained drenching night sweats, or Unexplained weight loss (>10% from baseline in the previous six months). Risk Stratification Prognostic Factors ; 1. FLIPI see above 2. FLIPI 2 INDICES Age >60 years Hb <120 g/l Bone marrow involvement Elevated Β2 microglobulin Longest diameter largest involved node >6cm *Federico JCO 2009 Sep 20;27(27): Limited Stage Management At most, 10-15% of FL are detected at the early stages I and II. In these patients, radiotherapy is the treatment of choice and is applied as involved site, involved field or involved node irradiation. Where a PET scan result could lead to a change in radiation field that could lead to increased toxicity or change therapy from radiation to watch and wait or chemotherapy, biopsy confirmation is recommended where possible

7 Rationale Involved field radiotherapy delivering a dose of 24 Gy in multiple fractions is considered standard of care Observation of patients with early stage disease is acceptable if radiotherapy is thought to be undesirable or due to patient choice following discussion with a radiation oncologist or if the patient has had a complete excision of the involved node Includes; Stage III/IV Advanced Stage Management Options for chemotherapy include: Clinical trials with investigational agents R-CHOP R-CVP

8 R-Fludarabine/Mitoxantrone R-bendamustine (currently unfunded) Chlorambucil +/- prednisone +/- rituximab Single agent rituximab For the elderly or those with poor performance status, Chlorambucil +/- prednisone is a reasonable option. 7.1 Watch and Wait Advanced Stage Management Rationale Advanced stage follicular lymphoma is incurable, and a watch and wait approach until the disease becomes symptomatic has been recommended. Median survival is 8-10 years. No clear survival benefit has yet to be demonstrated for immediate vs expectant management. Therefore Observation and active monitoring is an appropriate strategy in patients with asymptomatic advanced stage FL. Criteria for Withholding Treatment lack of major symptoms (fatigue is a common associated symptom and it will be a matter of clinical judgment and patient preference whether to initiate treatment) no cytopenias due to lymphoma (neut >1.0; plts >100 Hb >10) no bulky disease (>7cm diameter; or >3x >3cm ) no compromised organ function due to lymphoma no raised LDH FLIPI is not a proven criterion for initiating treatment, but closer monitoring may be required patient agreement Rituximab with chemotherapy (such as CVP, CHOP, Bendamustine, Fludarabine, chlorambucil ) is considered the standard treatment of patients requiring treatment. Overall, there is not overwhelming evidence for benefit of one regimen over another, and either alkylator-based therapy or purine analogues can be used. The role of rituximab is discussed below (section 7.3). Chlorambucil is associated with an ORR of 50-70%. CVP is associated with a higher CR rate and PFS but no clear survival benefit. No randomized trial demonstrates an advantage with anthracycline-based chemotherapy, eg CHOP, over CVP. Fludarabine monotherapy is associated with a RR of 65-84% and in combination with cyclophosphamide 89% ORR, or in combination with mitoxantrone 91% ORR, 43% CR and 63% two year DFS. However, whilst FM is associated with a higher CR rate than CHOP, this has not been shown to translate into a better PFS or OS. Where autologous stem cell transplantation is an option, care should be given to the number of cycles of fludarabine due to concerns about future stem cell mobilization. Bendamustine, especially in combination with rituximab, has shown good efficacy and tolerability in FL but is currently not generally available in NZ outside a clinical trial. Studies have demonstrated that it is better tolerated than R-CHOP and associated with a longer PFS (54.8 months vs 34.8 months) For transformed disease, R-CHOP is a reasonable front line

9 Response Assessment CT of involved sites 4 weeks after last cycle treatment. Documentation of symptoms and clinical examination. Bone marrow biopsy if involved at presentation. Role of Rituximab Four prospective randomized phase III studies investigating Rituximab plus chemotherapy vs chemotherapy alone demonstrate an increase in initial response, a prolongation of response duration and a longer OS. First time treatment immunochemotherapy phase III trials FLIPI (LR/IR/HR Regimen Phase Patients (n) ORR % Duration Reference 14/41/45 R-CHOP III year TTF, 85% Hiddemann et al (2005) -/42/46 R-CHOP BR III PFS: 46.7 months (FI), PFS: n.r. Rummel et al (2009) 7/37/56 R-MCP then IFN III PFS: n.r. (4 year PFS : 71%) Herold et al (2007) 19/41/40 R-CVP III TTP: 34 months Marcus et al (2005) 19/35/46 R-CVP +1FN III PFS: n.r. (5 year PFS: 53%) Salles et al (2008) The use of rituximab in first line therapy for follicular lymphoma is recommended. optimal number of cycles is not well established The Rituximab maintenance A number of studies have investigated the role of rituximab as maintenance. Induction chemotherapy regimens and the dosing schedule for rituximab have varied in these trials. A recent meta-analysis favours the use of rituximab as maintenance, suggesting a benefit despite prior use of

10 rituximab and with either dosing schedule of weekly infusions for four consecutive weeks every six months or a single infusion every 2-3 months. The results of the EORTC (PRIMA) study have demonstrated that rituximab maintenance for 2 years improves PFS (75% vs 58% after 3 years, p<0.0001) with an excellent safety profile. An improvement in overall survival has not yet been demonstrated and currently this therapy is not funded. Rituximab maintenance is associated with increased numbers of infections, some of which are serious. Possible mechanisms include rituximab-associated neutropenia and rituximab-induced hypogammaglobulinaemia. Rituximab maintenance is not currently funded. Autologous Transplant in CR1 HDT with autologous stem cell rescue is not recommended to consolidate first remission outside of clinical trials. To date, three published trials show mixed results with high rates of myelodysplastic syndrome reported (Table II).

11 Relapsed Disease A repeat biopsy and histopathological assessment is strongly recommended at the time of relapse to exclude disease transformation. There are no validated prognostic scores for relapsed disease. Relapsed disease is not necessarily an indication for therapy and patients can be managed expectantly. After relapse, both response rates and relapse-free survival after salvage decline. The median survival is 4-5 years after first relapse. The addition of rituximab in relapsed disease in patients who have not had prior treatment with rituximab, has shown benefit both with R-CHOP chemotherapy and R-FCM with regards to ORR, CR and PFS. Four cycles of rituximab are currently funded in relapsed follicular lymphoma. The treatment options for relapsed disease include: Clinical trials with novel agents Chemotherapy with the regimens listed above for initial therapy Radiotherapy for localized disease In select cases, myeloablative therapy with stem cell transplant after response to salvage chemotherapy Maintenance therapy in relapsed Follicular lymphoma In patients with relapsed and refractory disease maintenance rituximab improves PFS more than threefold when compared to observation. Two years of maintenance with rituximab shows prolonged PFS (44.2 vs 11.6 months with prior CHOP chemotherapy and 51.8 vs 23 months with prior RCHOP). Improvement in OS was not statistically significant. The duration of maintenance therapy is not yet established most trials have used two years of maintenance or until disease progression. Rituximab maintenance in relapsed disease is not currently funded.

12 Autologous Transplant in CR2 8.2 Autologous Stem Cell Transplant in Relapsed Disease The EBMTR-sponsored CUP study is the only prospective randomized trial of autologous transplant in relapsed disease but this study was carried out in the pre-rituximab era.. Its findings confirm smaller non-randomized series. The trial closed early due to slow accrual and only 89 patients were randomized. Patients enrolled in the study were <65 years with PS 0-1 in a CR or PR after re-induction chemotherapy and with <20% B cells on their bone marrow aspirates. The findings show that autologous transplantation results in a prolonged PFS and OS. There was no benefit to purging of the bone marrow graft. Schouten HC et al JCO 2003; 21: Transformed follicular lymphoma Histological transformation to diffuse large B-cell lymphoma (DLBCL) may occur at any stage of the disease; this may occur via a variety of different genetic mechanisms. The annual incidence of transformation is approx 2-3% - this rate appears to remain static for several years and may plateau with time. Transformation to DLBCL must be suspected when there is rapidly enlarging lymphadenopathy, high or rising LDH, hypercalcaemia, or sudden increase in symptoms. Biopsy is mandatory for confirmation. Transformation is an event that has historically been associated with poor prognosis (median survival approx 12 months) although this has improved with the introduction of rituximab. One recent study reported a median overall survival following transformation of 50 months. ( Link B, et al. JCO 2013) The evidence base concerning the role of autologous SCT in transformed FL is largely based on a small number ( n=6) of non-comparative studies mostly carried out in the pre-rituximab era. Despite these limitations, expert opinion and accepted clinical practice recommends consideration of this approach in selected patients with transformed FL (BBMT 2010;16: ). Such patients might include those with transformed disease at presentation and those with chemosensitive relapse, especially where both groups achieve PR as opposed to CR to rituximab containing therapy regimens and those where disease relapse occurs early after initial therapy. Patients with late disease transformation

13 after initial therapy may be considered for R-CHOP type salvage without consideration of autologous SCT. Allogeneic Transplant Allogeneic stem cell transplantation is the only potentially curative option for advanced stage follicular lymphoma. This is in part due to the graft versus lymphoma effect. There are also other beneficial aspects to allogeneic SCT including a dose response effect from conditioning therapy; the ability to harvest HSCs from a normal donor and the fact that these HSCs are normal ie not affected by tumour contamination or MDS from prior therapy. There is a high TRM but low relapse risk seen with ablative regimens which are only suitable for younger patients. RIC regimens can be applied to older patients with acceptable low rates of TRM and with good long term survival although there is are high rates of chronic GVHD. The largest report of allogeneic transplant following myeloablative therapy is a retrospective analysis of 176 patients by the IBMTR which confirms findings in smaller studies that there is a low recurrence rate of 19% but a substantial non-relapse mortality rate of 30%. There is some heterogeneity of the results, but most of the published series report a relapse rate of around 20% and a 3 year TRM of 30-40%. The largest series reported for RIC transplant is 188 patients by the EBMTR of which only 52 patients had follicular lymphoma. They report a 5 year OS and PFS of 60% but follow up is relatively short. Outcomes after RIC Allo Transplant for follicular lymphoma Series 3 year TRM 3 year RR 3 year OR 3 year % % % EPS/PFS Robinson et al (2002)* Morris et al (2004) /49 Vigoroaux (2005) Resvani et al (2008) Khouri et al (2008) NR NR Hari et al (2008) Ingram et al (2008) Thomson et al (2010) tt TRM : Transplant Related Mortality. RR : Relapse Risk. OS : Overall Survival. EPS: Event Free Survival. PFS: Progression Free Survival. NR : Not Reported.

14 * At 2 years. At 4 years. tt Current PFS The MDACC experience of RIC allosct in 47 selected patients with chemosensitive relapse incorporating conditioning with fludarabine, cyclophosphamide and rituximab is impressive and this protocol has been adopted by the US BMT Clinical trials Network as a formal phase II clinical trial protocol. ( Blood 2008;111: ). See figure below. Fit patients less than 65 years of age with chemosensitve disease with an available donor should be considered for RIC allogeneic transplant. Cases should be discussed at the transplant advisory committee. References Hiddemann W, Buske C, Dreyling M. Current management of follicular lymphomas. BJH 2006; 136: Gribben J. How I treat indolent lymphoma. Blood 2007; 109: Zinzani P, Pulsoni A Perrotti A et al. Fludarabine and mitoxantrone with or without rituximab versus CHOP with or without rituximab as front line treatment of patients with follicular lymphoma. JCO2004; 22:12: Vidal L, Frafter-Gvili A, Leibovici L et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomised trials. J Natl Cancer Inst 2009; Van Oers M, Klasa R, Marcus R et al. Rituximab maintenance improves clinical outcome in relapsed/resistant follicular NHL in patients with and without rituximab during induction: results of a prospective randomised phase 3 intergroup trial. Blood 2006; 108: Schouten H, Qian W, Kvaloys S et al. High dose therapy improves PFS and survival in relapsed follicular NHL. Results from the randomized European CUP trial. J Clin Onc 2003; 21:

15 Wirth A, Foo M, Seymour JF et al. Impact of FDG PET on staging and management of early stage follicular NHL. Int J Radiat Oncol Biol Phys 2008; 71(1): Oliansky DM, Gordon LI, King J et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of follicular lymphoma: an evidence-based review. Biol Blood Marrow Transplant Apr;16(4): Epub 2010 Jan 28 PRIMA BRIGHT McNamara C, Davies J, Dyer M, et al Guidelines on the investigation and management of follicular lymphoma BJH 2011; 156, Ghielmini M et al; ESMO guidleines consensus conference on malignant lymphoma. Annals of oncology 24: Friedberg J, Myrtek, M, et al Effectivenes of First Line Management strategies for Stage 1 Follicular Lymphoma: Analysi of the National LymphoCare Study. Federico M et al R-CVP vs R-CHOP vs R-FM for the initial treatment of Advances Stage Follicular Lymphoma: Results of the FOLL05 Trial JCO 31: Link B, Maurer M, Nowakowski G, et al Rates and Outcomes of Transformation in the Immunochemotherapy era: JCO 31(26)3272 Villa D et al 2013 Autologous and Allogeneic Transplant for transformed follicular lymphoma; A report of the Canadian Blood and Bone Marrow Transplant group JCO 31(9) Tan D et al 2013 Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood 122(6) 981

16 Algorithm for Dx & Rx FL