Update on Follicular Lymphoma. Brad Kahl, M.D.

Update on Follicular Lymphoma Brad Kahl, M.D.

Follicular Lymphoma: 25% of NHL Cases Other subtypes (9%) T and NK cell (12%) Burkitt (2.5%) Diffuse large B cell (DLBCL) (30%) Mantle cell (6%) Follicular (25%) Lymphoplasmacytic (< 2%) Small lymphocytic (7%) MALT-type marginal-zone B cell (7.5%) Nodal-type marginal-zone B cell (<2%)

Indolent NHL Follicular NHL Small Lymphocytic Lymphoma Marginal Zone NHL nodal Marginal Zone NHL splenic MALT lymphoma

Follicular Lymphoma Second most common NHL (2%) Typically advanced stage at presentation Often asymptomatic Median survival of about 12+ years Noncurable with conventional therapy Transformation to aggressive lymphoma can occur (3%/year) Winter JN, et al. Hematology Am Soc Hematol Educ Program. 2004;203-220.

Follicular Lymphoma Immunophenotype CD10, 19, 20, 22, 79a (+) Cytogenetics t(14;18)(q32;q21) occurs in >80% of cases of FL Bcl-2 juxtaposition into the IgH heavy chain locus Grading Grade 1: 1-5 centroblasts/high-power field Grade 2: 6-15 centroblasts/high-power field Grade 3: >15 centroblasts/high-power field Grade 3a: >15 centroblasts, but centrocytes are present Grade 3b: centroblasts form solid sheets Winter et al. Hematology Am Soc Hematol Educ Program. 2004;203.

Spanning the Continuum of Care: Optimizing Patient Outcomes in NHL clinicaloptions.com/oncology Pathophysiology of Follicular Lymphoma Staudt LM, et al. N Engl J Med. 2007;356:741-742.

Spanning the Continuum of Care: Optimizing Patient Outcomes in NHL clinicaloptions.com/oncology The Follicular Lymphoma International Prognostic Index (FLIPI) FLIPI score used to predict outcomes of therapy based on adding number of risk factors (each factor = 1 point) Older than 60 yrs of age Ann Arbor stage III/IV disease LDH > ULN > 4 involved nodal sites Hb < 12 g/l FLIPI Risk Group Risk Factors, n Patients, % 5-Yr OS, % 10-Yr OS, % Relative Risk Low 0-1 36 90.6 70.7 1.0 Intermediate 2 37 77.6 50.9 2.3 High 3 27 52.5 35.5 4.3 Solal-Céligny P, et al. Blood. 2004;104:1258-1265.

Spanning the Continuum of Care: Optimizing Patient Outcomes in NHL clinicaloptions.com/oncology Predictive Factors in FL: Gene Expression in Tumor-Infiltrating Normal Immune Cells Dave SS, et al. N Engl J Med. 2004;351:2159-2169.

Probability of Survival Spanning the Continuum of Care: Optimizing Patient Outcomes in NHL clinicaloptions.com/oncology Predictive Power of Gene Expression in FL: Survival Predictor Score Survival predictor score based on immune response-1 and -2 signatures Significantly associated with survival in both training and test sets (P <.001 for both) High SPS associated with poor outcome 1.0 0.9 0.6 Quartile of SPS Median, Yr Survival 5 Yr, % 10 Yr, % 0.4 0.2 0 P <.001 0 3 6 9 12 15 Yrs 1 13.6 86 51 2 11.1 86 58 3 10.8 69 54 4 3.9 38 29 Dave SS, et al. N Engl J Med. 2004;351:2159-2169.

Survival probability Survival Probability Spanning the Continuum of Care: Optimizing Patient Outcomes in NHL clinicaloptions.com/oncology Prognostic Factors in FL: Lymphocyte- Associated Macrophage Content 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 OS Median n OS, Yrs LAM < 15/hpf 87 16.3 LAM > 15/hpf Low LAM 12 5.0 PFS Median n OS, Yrs LAM < 15/hpf 87 7.05 LAM > 15/hpf 12 Low LAM 0.3 High LAM 0.2 High LAM P <.001 0.1 P =.001 0 0 5 10 15 20 0 5 10 15 20 Yrs Yrs 1.0 0.9 0.8 0.7 0.6 0.5 0.4 1.69 Farinha P, et al. Blood. 2005;106:2169-2174.

FL Treatment Disease generally incurable Prognosis generally good Lots of treatment options Can make decision making difficult

Patients (%) Spanning the Continuum of Care: Optimizing Patient Outcomes in NHL clinicaloptions.com/oncology Survival in Indolent Lymphoma: The Stanford Experience (1960-1996) 100 80 1987-1996 1976-1986 1960-1975 60 40 20 0 0 5 10 15 20 25 30 Yr Adapted from Horning SJ. Semin Oncol. 1993;20(suppl 5):75-88.

The times are changing 3 retrespective studies showing patients are more likely to be alive at 5-10 years compared to earlier periods SEER Database SWOG MD Anderson

My approach to a patient with newly diagnosed with FL Symptoms absent Low Tumor Burden Watch/Wait vs. single agent rituximab High Tumor Burden R-chemo +/- MR vs. Watch/Wait Symptoms present Single agent rituximab vs. R-chemo R-chemo +/- MR

GELF Criteria 3 nodes greater than 3 cm Single node greater than 7 cm Systemic symptoms or any symptoms Compression or risk of compression of vital organ Leukemic phase Cytopenias due to marrow infiltration Splenomegaly greater than 16 cm

Symptomatic, High Tumor Burden FL Symptoms absent Low Tumor Burden Watch/Wait vs. single agent rituximab High Tumor Burden R-chemo +/- MR vs. Watch/Wait Symptoms present Single agent rituximab vs. R-chemo

Overcoming Barriers to Optimal Treatment of Non-Hodgkin s Lymphoma clinicaloptions.com/oncology First-line Combined Immunochemotherapy in Untreated FL Regimen N Time PFS, % OS, % R-chemo Chemo R-chemo Chemo CHOP [1] 428 1.5yr 82* 64 95* 90 CHVP- IFN [2] 358 8yr 44* 28 79 70 CVP [3] 321 4yr 38* 14 83* 77 MCP [4] 201 6yr 71* 40 80* 65 *Statistically significant improvement for R-chemo vs chemo. 1. Hiddeman W, et al. Blood. 2005;106:3725.-3732. 2. Salles G, et al. Blood. 2008;112:4824-4831. 3. Marcus R, et al. J Clin Oncol. 2008;26:4579.-4586. 4. Herold M, et al. J Clin Oncol. 2007;25:1986-1992.

Which chemo backbone? R-CHOP vs. R-CVP vs. R-FM No OS difference R-CHOP and R-FM better PFS than R-CVP 3 yr - 60% vs 47% R-CHOP better safety profile than R-FM Fewer infections What about R-bendamustine? ASCO 2012: Abstract #135 and #6.

Bendamustine-Rituximab (B-R) vs CHOP-R StiL NHL 1-2003 Follicular Waldenström s Marginal zone Small lymphocytic Mantle cell (elderly) R Bendamustine- Rituximab - Bendamustine 90 mg/m 2 day 1+2 - Rituximab 375 mg/m 2 day 1 CHOP-Rituximab - Cyclophosphamide 750 mg/m 2 day 1 - Doxorubicin 50 mg/m 2 day 1 - Vincristine 1.4 mg/m 2 day 1 - Prednisone 100 mg days 1-5 - Rituximab 375 mg/m 2 day 1

Entities 549 patients randomized. 514 patients evaluable for response and toxicity B-R CHOP-R Age (median) Total n 261 253 64 Follicular 54 % 139 140 60 Mantle cell 18 % 45 48 70 Marginal zone 13 % 37 30 66 Waldenströms 8 % 22 19 64 SLL 4 % 10 11 68 Unclassifiable 2 % 7 5 69 MJR

PFS: follicular (n=279) 1.0 0.9 0.8 Median (months) B-R n. y. r. CHOP-R 40.9 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Hazard ratio, 0.61 (95% CI 0.42-0.87) p = 0.0072 0.0 0 12 24 36 48 60 72 84 96 months MJR

Toxicities (all CTC-grades) B-R (n=261) CHOP-R (n=253) (no. of pts) (no. of pts) P value Alopecia - +++ < 0.0001 Paresthesias 18 73 < 0.0001 Stomatitis 16 47 < 0.0001 Skin (erythema) 42 23 = 0.0122 Allergic reaction (skin) 40 15 = 0.0003 Infectious complications 96 127 = 0.0025 - Sepsis 1 8 = 0.0190

Conclusions R-bendamustine appears to be a reasonable alternative to R-CHOP Study still unpublished Data quality issues BRIGHT trial done in North America Presented at ASH 2012 Regimens appear comparable Toxicity tradeoff

What about maintenance rituxmab (MR)? Lancet, Jan 1, 2011.

PRIMA background MR beneficial in terms PFS after frontline CVP chemotherapy (E1496) 3 yr PFS 68% vs 33% (HR 0.4)» Hochster et al, JCO 2006 MR beneficial in terms of PFS after 2 nd line R-CHOP/CHOP Median PFS 3.7 vs. 1.3 yrs (HR 0.37)» Van Oers et al, JCO 2010 What about MR after frontline R-chemo?

GELA PRIMA: Study Schema Endpoints 1º = PFS 2º = EFS, OS Previously untreated grades I, II, or III FL (N=1200) CHOP x6 + Rituximab x8 CVP x8 + Rituximab x8 FCM x6 + Rituximab x8 CR, PR R A N D O M IZ E D Maintenance Rituxan 375 mg/m 2 q2 mos x 2 yrs Observation High tumor burden by GELF criteria.

PRIMA conclusions MR for 2 years after R-Chemo significantly prolongs PFS and time to next treatment 3 yr PFS 75% vs 58% (HR 0.55) Effect consistent in all subgroups Slight increase in infections Although no effect on Ig levels No difference in QOL No effect on OS to date

Remaining questions Is PFS and time to next chemo benefit enough? Does QOL need to be improved by MR? Do infections cause concerns? Will patients respond less well to rituximab based regimens later? What to tell patients? I discuss pros and cons. I find most (but not all) patients choose MR

Asymptomatic, High Tumor Burden FL Symptoms absent Low Tumor Burden Watch/Wait vs. single agent rituximab High Tumor Burden Symptoms present Single agent rituximab vs. R-chemo R-chemo +/- MR

Asymptomatic, High Tumor Burden Generally recommend R-chemo followed by MR Likely to recommend BR induction MR optional as before Some patients barely qualify as HTB Reasonable to start on W&W but monitor closely for progression

Asymptomatic, Low Tumor Burden Symptoms absent Low Tumor Burden High Tumor Burden R-chemo +/- MR vs. Watch/Wait Symptoms present Single agent rituximab vs. R-chemo R-chemo +/- MR

Asymptomatic, Low Tumor Burden Watch and wait remains a reasonable standard 3 RCTs failed to demonstrate any overall survival advantage for immediate therapy All in the pre-rituximab era No trials of R-chemotherapy in this patient population One trial of rituximab vs. watch and wait

R A N D O M I S A T I O N ARM A Watch and Wait ARM B Rituximab Induction ARM C Rituximab Induction & maintenance Progressive disease requiring therapy stops protocol treatment Compulsory CT scan Clinic visits CT scan only if clinical CR Compulsory CT scan Continued follow up Bone marrow for histology and MRD only if CT shows CR

How to interpret? PFS and TTNT benefit without an OS benefit Does that warrant routine rx with rituximab? What endpoints do you and your patients value? Is there a QOL benefit for associated with remission?

Quality of Life Assessments QoL assessed in 456/463 randomised patients Before & after randomisation If no new Rx initiated further assessments at 1 mo after randomisation then 2 monthly for 2 yr then 6 monthly for 2 yr

QoL instruments Functional Assessment of Cancer Therapy- General (FACT-G) Hospital Anxiety and Depression Scale (HADS) Mental Adjustment to Cancer Scale -3 questions Impact of Event Scale Revised Illness Impact Bank -5 questions Illness Coping Style -4 questions

ENDPOINTS PRIMARY To determine whether at 7 months after randomization. immediate treatment with rituximab results in increased functional well-being deferring treatment results in increased anxiety and depression Increased attendances and the S/E related to the administration of rituximab impacts negatively on well being SECONDARY The same at month 13, 25 and 37

QOL Results A minority of patients suffered from anxiety and depression (13% and 3%) Patients assigned to rituximab had less anxiety than those on W&W Most patients functioned quite well and adapted to their illness over time

My conclusions Given lack of OS advantage, perfectly acceptable to W&W Some benefits to rituximab PFS and TTNT Discuss with patients For a minority of patients with significant anxiety and coping issues, rituximab has benefit Try and ascertain who these folks are Some patients better served by rituximab

ECOG 4402 (RESORT) Accruing 389 patients with low-tumor-burden stage III/IV FL Rituximab 375 mg/m 2 qw 4 CR or PR R A N D O M I Z E Rituximab maintenance 375 mg/m 2 q12w Rituximab re-treatment at progression 375 mg/m 2 qw 4 Primary end point: time to rituximab failure Secondary end point: time to first cytotoxic therapy http://www.clinicaltrial.gov/ct/show/nct00075946?order=2. Accessed May, 2005.

E4402 Results No difference in time to treatment failure Slight benefit in time to first chemo 95% vs 86% chemo free at 3 yrs Came at a cost of 3.5x more rituximab Both arms well tolerated Slightly more toxicity on maintenance Conclusion Retreatment is our preferred strategy

Symptomatic, Low Tumor Burden Symptoms absent Low Tumor Burden Watch/Wait vs. single agent rituximab High Tumor Burden R-chemo +/- MR vs. Watch/Wait Symptoms present R-chemo +/- MR

Symptomatic, Low Tumor Burden CC is usually fatigue Make sure not some other cause Single agent rituximab seems reasonable Low risk experiment R-chemo >95% response rate

Summary

Recurrent Follicular NHL Fact that indolent NHL is rarely cured Patients exhibit pattern of continuing relapse Necessary to have wide variety of treatment options to deal with successive relapses Goal of retreatment: to establish a quality remission My definition of a quality remission: One that is - durable achieved without excessive toxicity

Recurrent Follicular Lymphoma: Recommended Treatment Conventional strategies Rituximab + maintenance Chemo-immunotherapy + maintenance Radioimmunotherapy External beam XRT Autologous transplant Allogeneic transplant Novel strategies Novel monoclonal antibodies Drug/Ab conjugates Bortezomib (Velcade ) Bendamustine (Treanda ) Lenalidomide (Revlimid ) B cell receptor signaling CAL 101 Ibrutinib Bcl-2 antagonists ABT-199 NCCN. 2006. Available at: http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf

Questions?