Follicular Lymphoma. Aruna K. Reddy, MD. Hematology& Oncology Peace Health Southwest Medical Center

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1 Follicular Lymphoma Aruna K. Reddy, MD Hematology& Oncology Peace Health Southwest Medical Center

2 Follicular Lymphoma Malignant neoplasm resulting from clonal proliferation of malignant B-cells Second most common lymphoma in US Median age at Dx 60 yrs

3 Lymphoma Classification Older Classifications: Rappaport, Kiel, International working formulation REAL: Classification based on cell of origin (B, T or NK), includes morphology, immunophenotype, genetic and clinical features. Current: WHO classification

4 Follicular Lymphoma:Epidemiology 1-3 cases / annually in 1950 s Incidence increasing: 5-7/ Increased incidence with age. Median age at diagnosis: 60 Predisposing factors: Unknown Variations in racial incidence Male /Female ratio---1:1.7 Incidence is low in China and Japan Incidence higher in people of Jewish ancestry In the US incidence is 2-3 times higher in whites compared to African Americans or Asians.

5 Pathogenesis Incompletely understood. ~85 percent of patients have t(14;18) which results in the overexpression of B cell leukemia/lymphoma 2 (BCL-2), an oncogene that blocks programmed cell death (apoptosis), leading to prolonged cell survival. Multiple genetic events are required for the development of FL since the t(14;18) translocation can be identified in normal individuals and patients with diffuse large B-cell lymphoma.

6 Presentation & work up Asymptomatic adenopathy Waxing and waning adenopathy B-Symptoms: 20% Bone marrow involvement: 70% at diagnosis. Symptomatic in some patients. Increased LDH 20% at diagnosis Excision biopsy preferred CBC, CMP, LDH B2 microglobulin Hepatitis panel, HIV if appropriate SPEP CT chest abdomen pelvis Bone marrow biopsy PET/CT in some situations

7 Diagnosis Excision biopsy: is preferred to show nodal architecture (follicular vs diffuse) Pathology: Morphology Flow cytometry Immunohistochemistry FISH/cytogenetics

8 Pathology/Diagnosis Morphology: Most notable morphologic feature: nodular growth pattern, which recapitulates the normal germinal centers (GC) of secondary lymphoid follicles

9 Reactive follicle versus Follicular lymphoma

10 Warnke et al Follicular Lymphoma Grading Counting centroblasts/hpf is used to determine the tumor grade Grade I 0-5 centroblasts/hpf Grade II 6-15 centroblasts/hpf Grade III >15 centroblasts/hpf Centrocytes Mixed Centroblasts Small cleaved follicle cells large blastic follicle cells

11 Follicular Lymphoma 85% have t(14;18) that generates a BCL2-IGH fusion gene that results in overexpression of BCL-2 protein (blocks apoptosis)

12 IHC/Flow cytometry/molecular analysis Tumor cells express monotypic immunoglobulin light chain, CD20 (or CD19), CD10, and BCL-6 and are negative for CD5 and CD23. >85 percent of tumors express BCL-2, as a result of a t(14;18) which can be detected by fluorescence in situ hybridization (FISH) or by polymerase chain reaction (PCR).

13 Ann Arbor Staging

14 FLIPI Age> or equal to 60 yrs Ann Arbor Stage III-IV Hemoglobin Level <12g/dl Serum LDH > ULN Number of Nodal sites >4 Risk Groups Low :0-1 Intermediate: 2 High : > or = 3 The index was able to separate 3 risk groups with different long-term prognosis. 10 Year OS: 71%, 51%, 36% respectively for low, intermediate and high risk groups

15 FLIPI and Survival Solal-Céligny P et al. Blood 2004; by American Society of Hematology

16 FLIPI versus FLIPI 2 FLIPI Age> or equal to 60 yrs Ann Arbor Stage III-IV Hemoglobin Level <12g/dl Serum LDH > ULN Number of Nodal sites >4 FLIPI 2 Age over 60 Bone marrow involvement Hemoglobin level less than 12 g/dl Beta2-microglobulin (B2M) higher than the upper limit of normal Longest diameter of the largest involved node (LoDLIN) of more than 6 cm

17 Case Presentation 55 year old female patient with a right preauricular mass of a years duration, slight discomfort in last 3-4 months. No rapid change in size, no other local symptoms. PMH: HTN, hyperlipidemia FH: No cancers ROS: No fevers, chills, sweats, weight loss. Positive fatigue, continues to work part time. PE: Preauricular mass 3x4 cm, bilateral axillary adenopathy. CBC, CMP normal Biopsy: Follicular lymphoma low grade CT chest abdomen pelvis: PE, diffuse adenopathy both sides of diaphragm, no bulky disease, largest node 3.6 cm, suspicion for splenic involvement. BM biopsy not done LDH: 208 U/L, B2 microglobulin: Normal, HIV neg, Hepatitis panel negative,spep normal,tsh normal FLIPI= 3 FLIPI 2=0 ( BM not done) or 1

18 Treatment Options for Follicular Lymphoma Observation Clinical Trial Local Radiotherapy Systemic chemotherapy oral agents: Chlorambucil, Cytoxan and Prednisone IV agents: Cytoxan, Fludarabine, Mitoxantrone, Vincristine, Adriamycin, Bendamustine, CHOP, CVP, FCM with or without Rituximab Antibody therapy: Rituxan, Bexxar, Zevalin. Stem cell transplant Novel Therapies

19 Treat or Wait???&Worry Stage Constitutional symptoms Anatomic obstruction Organ dysfunction Cosmetic considerations Painful lymph nodes Cytopenias Patient preference Physician preference

20 Early StageTreatment 10-15% present with Stage I or II disease potentially curable local radiotherapy Adjuvant chemo after radiation is not beneficial Observation is an option in select situations

21 Radiotherapy Advani et al JCO patients were identified (11 stage I, 32 stage II), with a median age of 58 years. Reasons for no initial therapy: physician choice (n = 20) large abdominal radiation field required (n = 10) advanced age (n = 7) concern for xerostomia (n = 4), patient refusal (n = 2). At a median follow-up of 86 months, 27 patients (63%) had not been treated. The median time to treatment in the remaining 16 patients was 22 months. 4/16 patients transformed to a higher-grade lymphoma. 9 patients died-six due to progressive lymphoma. Estimated survivals at 5, 10, and 20 years were 97%, 85%, and 22%, respectively.

22 Radiotherapy only Local radiotherapy (RT) alone was compared with radiotherapy plus continuous oral chlorambucil (RT+CHL) for the treatment of localized, low grade non-hodgkins lymphoma (NHL) in a prospective randomized study of 148 patients. After 18 years follow up there was no significant difference in overall survival or disease free survival between the two treatment groups.

23 Advanced Stages:Chemotherapy Chlorambucil, Cytoxan, either as single agents or in combination with Prednisone Combination regimens (used alone or with Rituxan) CVP (Cytoxan, Vincristine, Prednisone) CHOP (CVP +Adriamycin) FND (Fludarabine, Mitoxantrone, Dexamethasone) FCM: (Fludarabine, Cytoxan, Mitoxantrone) Bendamustine +-Rituximab

24 R-CVP versus CVP Marcus et al JCO 2008 Previously untreated patients 8 cycles of CVP plus rituximab (R-CVP; n = 162) or CVP (n = 159). R-CVP: Overall and complete response rates were 81% and 41% CVP : 57% and 10% (P <.0001). At a median follow-up of 30 months, patients treated with R-CVP had a very significantly prolonged time to progression (median 32 months versus 15 months for CVP; P <.0001). Median time to treatment failure was 27 months in patients receiving R-CVP and 7 months in the CVP arm (P <.0001). Rituximab did not add significantly to the toxicity of CVP.

25 R-CHOP versus CHOP 428 patients with untreated, advanced-stage FL were randomly assigned for therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone (n = 205) or CHOP combined with rituximab (R-CHOP) (n = 223). R-CHOP Vs CHOP: overall response rate (96% vs 90%; P =.011) R-CHOP significantly prolonged the time to treatment failure (P <.001). R-CHOP superior overall survival (P =.016), with 6 deaths in the R- CHOP group compared with 17 deaths in the CHOP group within the first 3 years. Severe granulocytopenia was more frequently observed after R- CHOP (63% vs 53%; P =.01). Severe infections: R-CHOP and CHOP (5% and 7%).

26 R-CHOP versus R-Bendamustine Rummel et al ASH untreated patients were randomized to receive Rituximab 375 mg/m2 (day 1) plus either Bendamustine(B) 90 mg/m2 (days 1+2) every 28 days or the standard CHOP-R regimen every 21 days for a maximum of 6 cycles. Median follow up 32 months ORR: BR vs CHOP-R--- 93%, 93% CR: BR Vs CHOP-R 40%, 30% Median PFS:54.8 mos Vs 34.8 mos No OS difference BR regimen better tolerated. Significant differences in hematologic toxicities were observed for neutropenia grade 3+4 (BR 10.7% vs CHOP-R 46.5%; p<0.0001) G-CSF was more often used in CHOP-R treated pts (20% of all cycles) than it was used in the B-R group (4%) (p<0.0001).

27 Radioimmunotherapy: first line Anti-CD20 Immunotherapy 85% of NHL s are of B cell origin and CD 20 expressed in >90% of all B cell NHL s Two FDA approved anti-cd20 radiolabelled antibodies Bexxar, tositumomab, iodine 131 Beta and Gamma emitter, half life of 8 days, tissue penetration ~ 1 mm effective half life is much less. Zevalin, Ibritumomab, yttrium 90 Beta emitter, half life of 64h, tissue penetration ~ 5 mm

28 First Line Therapy RIT Kaminski et al NEJM patients with stage II - IV Follicular Lymphoma Single course of Rx with Iodine 131 Tositumomab(Bexxar) A dosimetric dose of Tositumomab followed by a therapeutic dose with Iodine 131labelled Tositumomab delivering 75cGy of radiation to the total body. Results: 95% response, 75% complete response At a median follow up 5.1 years: PFS 59% Rate of relapse decreased progressively with time First year: 25%, second year 13%, Third year 12%, 4.4% per year subsequently.

29 Progression-free and Overall Survival for All Patients RIT: First Line therapy Kaminski, M. et al. N Engl J Med 2005;352:

30 Responders Survival

31 First Line Consolidation: Options Radioimmunotherapy Rituximab Maintenance Possible similar efficacies Not compared in randomized trials.

32 Chemo+RIT: Link et al JCO patients received CVP followed by I -131 Tositumomab Response Rate: 100% Complete Response 93% 15/17 patients with BM involvement confirmed CR Median follow up 8 years 5 Year PFS 56%, 5 year OS 83% Two patients developed MDS/AML

33 CHOP+RIT Press et al JCO 2007(SWOG study) 90 patients with untreated, advanced-stage FL Six cycles of CHOP followed 4 to 8 weeks later by tositumomab/iodine I-131 tositumomab The ORR: 91%,CR rate: 69% Median follow-up time of 5.1 years The estimated 5-year overall survival (OS) rate was 87%, and the progression-free survival (PFS) rate was 67%. The 5-year estimates of OS and PFS were each 23% better (absolute difference) than the corresponding figures for patients treated on previous SWOG protocols with CHOP alone.

34 First-line Consolidation(RIT) Zevalin 414 responding patients to front line chemotherapy were randomly assigned to receive 90Y-ibritumomab tiuxetan (rituximab 250 mg/m2 on day 7 and day 0 followed on day 0 by 90Y-ibritumomab tiuxetan 14.8 MBq/kg; maximum of 1,184 MBq) or no further treatment (control). The primary end point was progression-free survival (PFS) Consolidation significantly prolonged median PFS (after a median observation time of 3.5 years) in all patients (36.5 v 13.3 months in control arm ( <.0001) regardless of the type of initial response or FLIPI score. 77% of patients in PR after induction converted to CR/CRu, resulting in a final CR rate of 87%. The most common toxicity with 90Y-ibritumomab tiuxetan was hematologic, and grade 3 or 4 infections occurred in 8% of patients.

35 Maintenance Rituxan: PRIMA Trial (First Line Consolidation) 1,217 patients with untreated FL, stage III or IV, were initially treated with rituximab plus CHOP (75%), CVP (22%), or FCM (3%). Responders (n = 1,018) were randomized to observation(o) alone or maintenance rituximab(rm) infusions every 2 months for 2 years. Median follow-up: 25 months RM Vs O arm:progression-free survival(pfs):82%vs 66%(P<.0001) RM Vs O arm:recurrence rate: 18% Vs 34% Benefits were observed across all subgroups, including age, disease severity, and type of induction chemotherapy received. Therapy was well tolerated. Grade 3 and 4 adverse events :RM arm Vs O arm(23% vs 16%) grade 2 infections RM Vs O(37% vs 22%) Quality of life was similar in both arms.

36 Relapsed Follicular Lymphoma Biopsy to confirm relapse and rule out transformation Salvage Treatment: depends on efficacy of prior regimens early(<12 months) versus late relapse Rituximab could be re-added if the previous remission was greater than 6 mos Chemoimmunotherapy used in first line setting based on previous response and duration FCMR or combination regimens not used previously Radioimmunotherapy

37 Relapse therapy: Consolidation Options Second line consolidation: Rituximab Maintenance High dose therapy with autologous transplant or Allogeneic transplant Rituximab maintenance prolongs PFS and OS in relapsed disease Short lived first remissions with chemo+r in first line setting: Consider transplant after reinduction.

38 EORTC CHOP Vs R-CHOPX 6 cycles (N=465) Responders(N-364)-Rituximab Maintenance(RM) Vs Observation(O) Results: CR (O Vs RM): 15.6% Vs 29.5% (P <.001). ORR (O Vs RM) 72.3% Vs 85.1% (P <.001) Median follow-up from second random assignment was 6 years, and 75% followed for at least 5 years. Median PFS : 3.7 years in RM arm 1.3 years in O arm (P <.0001) CHOP: Median PFS RM arm:3.1 yrs Vs 1 yr in O arm( P <.001) R-CHOP: Median PFS RM arm: 4.4 yrs Vs1.9 yrs in O arm(p=.043) RM arm: 5-year OS rate 74.3% O arm : 5-year OS rate 64.7% (P =.07)

39 EORTC

40 Rituximab maintenance (RM) Vidal et al ASH 2010 Meta-analysis of 8 randomized trials(n=2283)med follow up (25mos-9.5yrs) End Points: Overall Survival(OS) and Progression Free survival(pfs) RM Vs O: significantly better OS (HR for death 0.75, 95% (CI) Refractory or relapsed (i.e., previously treated) significant OS survival benefit(hr for death 0.72, 95% CI 0.57 to 0.91,(N=909 ) Previously untreated patients (First line no OS survival benefit did not (HR for death 0.83, 95% CI 0.56 to 1.23, 1374 patients). RM Vs O: significantly better PFS(HR % CI 0.48 to 0.61) RM after first induction therapy (HR 0.53, 95% CI 0.44 to 0.63, n=1374) RM after two or more inductions (HR 0.63, 95% CI 0.50 to 0.79, n=804) RM after different therapies: Rituximab alone (HR 0.54, 95% CI 0.40 to 0.73, n=240) Rhemotherapy alone (HR 0.49, 95% CI 0.37 to 0.66, n=308) Rituximab-chemotherapy (HR 0.58, 95% CI 0.48 to 0.70, n=1352)

41 Retreatment with RIT Kaminski et al JCO patients 56% ORR 25% CR (median duration 35 months) Responses longer with retreatment 6 patients with MDS/AML

42 Transplantation High dose chemo with stem cell support improves PFS and OS in relapsed patients Should be considered in patients especially with short lived remissions after R containing chemo regimens Role has to be redefined in the Rituximab era. In selected patients Allogeneic transplant may provide a curative option in the relapse setting.

43 Other treatments Epratuzumab anti CD 22 antibody Rituximab + Epratuzumab in untreated patients: ORR 84% Ofatumumab, also known as HuMax- CD20) is a human monoclonal antibody. Ofatumumab targets an epitope different from rituximab.