Klinik och behandling av follikulära lymfom Ola Linden, Öl, Docent Skånes Onkologiska Kliniken

Follikulär lymfom klinik I Oöm körtelförstoring Lunghili ofta engagerade. Större mediastinalt engagemang sällsynt Större bukengagemang inte ovanligt. Kan vara asymptomatiskt eller ge upphov till postrenalt hinder eller subileus CNS engagemang är sällsynt Epiduralt växt och medullakompession av och till. Isolerat tunntarmsengagemang förekommer (duodenum), ofta bifynd

Pat med follikulärt lymfom grad 1

Follikulär lymfom klinik? II 250 i Sverige årligen Stadium*: (Grad I + II) I 20%, II 20%, III 20%, IV 40%. (Grad III) I 20%, II 20%, III 30%, IV 30%, LD-stegring 20% Transformationer 3% årligen ** *Svenska lymfomregistret, Rapport för 2000-2006 **Relander et al: JCO 2010

Follikulär lymfom klinik III Waxing and waning Spontanremissioner Botbart? Gastrointestinalt stadium IE och IIE har utmärt prognos även utan behandling

Spontaneous Regressions in Initially Untreated Patients with indolent Non-Hodgkin’s lymphoma No of Months to Months of patients regression regression median range median range Total 19/83 8 2 – 120 >13 >4 – >72 FSC/NLPD 13/44 30% 7 2 – 120 15 >4 – >72 FM/NM 3/18 17% 2 – 23 >4 – 12 SL/DLWD 3/21 14% 26 – 93 6 – >72 Median age 57 years. 77% had stage IV disease Five with initial symptoms Regressions were noted in moderate >3 cm or minimal adenopathy. S. J. Horning New Engl J Med 311 (23), 1984

Infektioner, Vaccinationseffekt Spontana remissioner kända sedan 1800-talet. W. Busch. Einfluβ von Erysipel. Berliner Klin Wschr 1866 Anton Tjechov kände också till sambandet Vaccinationseffekt vid förnyad behandling med enbart rituximab. Infektioner kan förlänga PFS

Andra gången Gillt Född 1950 Tidigare sjudomar: hypertoni 1999 Follikulärt lymfom, grad II, stadium III. Inkluderad i nordiska studien: R mot R + Interferon 2003 Återfall. Ånyo Rituximab 4 + 4 2019 i kontinuerlig remission sedan 2003

Patient född 42 2001 Follikulärt lymfom, grad III, stadium IV. 6 x CHOP-21 2002 Återfall. DHAP + högdosbehandling 2003 Återfall. Radioimmunterapi inom studie 2004 PD. Leukeran + rituximab 2006 Återfall. Leukeran + rituximab → Nästan CR 2007 underhållsbehandling med rituximab 2008 Pneumoni x 2. Andra gången: Pseudomonas, 4 veckors meronem 2009 Klagar sin nöd 2019 MDS

Kaplan–Meier curves. Kaplan–Meier curves. A, overall survival according to b-CD3 levels. B, time to next treatment according to b-CD8 levels. Wahlin B E et al. Clin Cancer Res 2011;17:4136-4144 ©2011 by American Association for Cancer Research

Follicular Lymphoma International Prognostic Index Ogynsam Faktor Parameter RR Ålder >60 år 2,38 Stadium III-IV, 2,0 Hb <120 g/l 1,55 S-LD >NVgränsen 1,5 Antal lymfknutestationer >4 1.39 FLIPI 2, inkluderar, förutom ålder och Hb (som ovan), beta2mikroglobulin, tumörbulk (> 6 cm) och benmärgs engagemang som riskfaktorer, men ej stadium, antal lymfknutestationer eller S-LD. Solal-Céligny P et al. Blood 2004;104:1258-1265

Follicular lymphoma Prognostic Index FLIPI2 1. Längsta diametern på största tumörmanifestationen > eller ≤ 6 cm 2. β2-mikroglobulin > eller ≤ övre referensområdesgränsen 3. Förekomst eller avsaknad av benmärgsengagemang 4. Hb < 120 g/L mot ≥ 120 g/L 5. Ålder ≥ 60 years jämfört med < 60 år  

Mannikin used for counting the number of involved areas. Mannikin used for counting the number of involved areas. See “Demographic characteristics and initial staging” in the text. Each rectangle corresponds to a nodal area. Solal-Céligny P et al. Blood 2004;104:1258-1265 ©2004 by American Society of Hematology

Survival of the 1795 patients according to risk group as defined by the Follicular Lymphoma International Prognostic Index. . Survival of the 1795 patients according to risk group as defined by the Follicular Lymphoma International Prognostic Index. Solal-Céligny P et al. Blood 2004;104:1258-1265 ©2004 by American Society of Hematology

FLIPI I+II FLIPI III FLIPI III+IV Overall survival according to treatment regimen, by follicular lymphoma international prognostic index (FLIPI) score. FLIPI I+II FLIPI III Overall survival according to treatment regimen, by follicular lymphoma international prognostic index (FLIPI) score. (A) FLIPI 1 to 2. The overall P value for all curves is P = .009. (B) FLIPI 3. The overall P value for all curves is P < .0001. (C) FLIPI 4 to 5. The overall P value for all curves is P = .02. R, rituximab; FND, fludarabine, mitoxantrone, and dexamethasone; IFN, interferon alfa; ATT, alternating triple therapy with cyclophosphamide, doxorubicin, vincristine, dexamethasone, and bleomycin, with etoposide, methylprednisolone, cytarabine, and cisplatin, with mitoxantrone, vincristine, prednisone, and procarbazine with IFN maintenance; CHOP-Bleo, cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin. FLIPI III+IV Liu Q et al. JCO 2006;24:1582-1589 ©2006 by American Society of Clinical Oncology

D-vitamin koncentration i blod hos SWOG och PRIMA studier R-CHOP ± underhåll vid follikulära lymfom Prima-studien Median européer 17 ng/ml ~ 42,5 nM vitamin D Follow-up efter median 4,5 år significantly inferior OS (HR 3.8, p=0.02) för under denna nivå first quartile (25 nM), PFS and OS were significantly inferior for those with lower values (PFS HR 1.73, p=0.0086; OS HR 2.7, p=0.03). OS HRs indicating a magnitude of association at or greater than the individual FLIPI prognostic factors

Was ist denn schon normal? Melior (ref i region Skåne) 75 nM De flesta ense om att 50 nM tarvas för muskuloskeletal hälsa Uptodate ansvarig editor för Vitamin D: 75 nM Oumbärliga medarbetare inom lymfom/sarkom i Lund: 25 till 101 nM 35 nM förenligt med tjänst i Lund upp t.o.m. ÖL:s nivå

Strålbehandling

Återfallsfrihet efter strålbehandling för patienter med follikulärt lymfom Stadium I+II, yngre än 60 (1) och de ≥ 60 år (2) Mac Manus, Hoppe JCO, 1996

 Återfallsfrihet efter Strålbehandling för follikulärt lymfom Stadium I och II Wilder et al.  (2001) Long-term results with radiotherapy for stage I-II follicular lymphomas.  Int J Radiat Oncol Biol Phys51:1219–1227.

Progression-free survival in terms of maximal size of patient’s follicular lymphoma at start of RT. Each tick mark indicates duration of progression-free survival for 1 patient.

Strålbehandling 24 mot 30 Gy

Strålbehandling 24 mot 30 Gy

Volume 15, Issue 4, Pages 457-463 (April 2014) 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial  Prof Peter J Hoskin, FRCR, Amy A Kirkwood, MSc, Bilyana Popova, MSc, Paul Smith, MSc, Martin Robinson, FRCR, Eve Gallop-Evans, FRCR, Stewart Coltart, FRCR, Prof Timothy Illidge, FRCR, Krishnaswamy Madhavan, FRCR, Caroline Brammer, FRCR, Patricia Diez, MSc, Prof Andrew Jack, FRCPath, Isabel Syndikus, FRCR  The Lancet Oncology  Volume 15, Issue 4, Pages 457-463 (April 2014) DOI: 10.1016/S1470-2045(14)70036-1 Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 1 Trial profile All numbers refer to randomised sites, not patients. *All radiotherapy target sites are included in the analysis of local progression (the primary endpoint). The Lancet Oncology 2014 15, 457-463DOI: (10.1016/S1470-2045(14)70036-1) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 2 Progression-free survival for all sites (A) and overall survival for one site per patient (B) The Lancet Oncology 2014 15, 457-463DOI: (10.1016/S1470-2045(14)70036-1) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 2 Progression-free survival for all sites (A) and overall survival for one site per patient (B) Peter J Hoskin , Amy A Kirkwood , Bilyana Popova , Paul Smith , Martin Robinson , Eve Gallop-Evans , Stewart Colt... 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial The Lancet Oncology, Volume 15, Issue 4, 2014, 457 - 463 http://dx.doi.org/10.1016/S1470-2045(14)70036-1

Watch and Wait

Randomised study of watch and wait versus immediate systemic treatment in asymptomatic patients with indolent lymphoma. Time to second chemotherapy in both groups P =0.01 Ardeshna et al: Lancet 362:516-522, 2003

W and W mot R-induktion och R-underhåll hos pat utan behandlingsindikation Ardeshna Lancet Oncology 2014

Patienter med behandlingsindikation Symtomgivande sjukdom Cytopeni(er) Leukemiserat lymfom Massiv eller symtomgivande splenomegali Annan organpåverkan Bulkig sjukdom (> 6 cm enligt FLIPI-2) eller stor sjukdomsbörda Kontinuerlig eller snabb progress

Overall survival (OS) and failure-free survival (FFS) in 580 assessable stage IV follicular lymphoma patients in five consecutive studies spanning 25 years. Overall survival (OS) and failure-free survival (FFS) in 580 assessable stage IV follicular lymphoma patients in five consecutive studies spanning 25 years. Liu Q et al. JCO 2006;24:1582-1589 ©2006 by American Society of Clinical Oncology

Relative Överlevnad för pat med follikulärt lymfom Junlén et al. Leukemia 2015

EFS and OS in DLBCL and follicular lymphoma (FL) based on statin use. C är EFS för follikulärt lymfom Kaplan-Meier plots for event-free survival (EFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) based on statin use. Statin use during rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy did not affect (A) EFS and (B) OS in patients with DLBCL. (C) Statin use was associated with prolonged EFS in patients with FL. Nowakowski G S et al. JCO 2010;28:412-417 ©2010 by American Society of Clinical Oncology

Antikroppar mot CD20 Tositumomab, en musantikropp, 131I-tositumomab ingick i Bexxar Rituximab, en chimärantikropp Obinutuzumab, en humaniserad antikropp Rituximab gavs första gången 1997

Antikroppar mot CD20 Type I, CDC: rituximab, ofatumomab Type II: direkt apoptosinducerande: obinotuzumab, Tositumomab Båda I och II kan ge god ADCC

Type I och II

Whole-blood B-cell depletion mediated by GA101 (black squares), rituximab (open diamonds), and ofatumumab (open triangles) in heparin-treated whole-blood samples: F/F donor (A), F/V donor (B), V/V donor (C). Whole-blood B-cell depletion mediated by GA101 (black squares), rituximab (open diamonds), and ofatumumab (open triangles) in heparin-treated whole-blood samples: F/F donor (A), F/V donor (B), V/V donor (C). The average B-cell depletion and SDs were calculated from the triplicates of each experiment. The data from one of three independent experiments for each genotype are shown. Average values of triplicates corresponding to EC50 values, percentage maximal killing and statistical analysis conducted for each donor and genotypes (3 donors/genotype, total of 9 experiments) are included in the Supplementary Table S1. Sylvia Herter et al. Mol Cancer Ther 2013;12:2031-2042 ©2013 by American Association for Cancer Research

Först linjens Behandling av Follikulärt lymfom grad I-IIIA Begränsad samsyn R-Kemo (R-CHOP, R-Bendamustin, R-CVP) Antikroppar (rituximab) enbart Lenalidomid +rituximab Strålbehandling (Såväl kurativ som palliativ) (Radioimmunterapi, Kemo enbart (chlorambucil)

Figure 2 Kaplan-Meier estimates of progression-free survival (A), time to next antilymphoma treatment (B), time to next chemotherapy (C), and overall survival (D) from randomisation with rituximab maintenance versus observation HR=hazard ratio. ... Gilles Salles , John Francis Seymour , Fritz Offner , Armando L?pez-Guillermo , David Belada , Luc Xerri , Pierre ... Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial The Lancet Volume 377, Issue 9759 2011 42 - 51 http://dx.doi.org/10.1016/S0140-6736(10)62175-7

PRIMA : Progression Free Survival at 10 years Oral Session - Abstract #486 59th ASH Annual Meeting, Atlanta, GA, December 9-12, 2017 PRIMA : Progression Free Survival at 10 years (from randomization) Median: 10.5 y Median: 4.1 y P<.0001 HR=0.61 (95%CI) 0.52-0.73 PRIMA 10 YEARS

PRIMA : Progression Free Survival at 10 years Oral Session - Abstract #486 59th ASH Annual Meeting, Atlanta, GA, December 9-12, 2017 PRIMA : Progression Free Survival at 10 years (from randomization) Median: 10.5 y Median: 4.1 y P<.0001 HR=0.61 (95%CI) 0.52-0.73 PRIMA 10 YEARS

PRIMA : Progression Free Survival at 10 years Oral Session - Abstract #486 59th ASH Annual Meeting, Atlanta, GA, December 9-12, 2017 PRIMA : Progression Free Survival at 10 years (from randomization) Median: 10.5 y Median: 4.1 y P<.0001 HR=0.61 (95%CI) 0.52-0.73 PRIMA 10 YEARS

•PFS efter 10 år: 51% (underhåll) vs 35% (obs) PriMA Ph3 R maintenance PFS at 10 y in FL (MO18264) SallesG.A, et al. Abstract: [486] STUDY DESIGN •Patients:FL with high tumorburden, who have responded first-line R-chemotherapy•Arms:Observation (n=513) vs R-maintenance (n=505), 7-year follow up RESULTS •Median PFS: 10.49 yrs(R-underhåll) vs 4.06 ys(obs) p<0.0001; HR=0.61) •PFS efter 10 år: 51% (underhåll) vs 35% (obs) •Signifikant vinst med R-underhåll för PFS i planerade analyser •Mors: 84 pts (observation) vs 88 pts (R-underhåll) • OS efter 10 år i båda armar (80%);

Bendamustin Cave allopurinolum

R-bendamustin mot R-CHOP PFS Rummel et al. ASCO 2012

StiL NHL7-2008 MAINTAIN Ph3 BR followed by 2 or 4 yR maintenance in 1L FL RummelM.J, et al. Abstract: [483] STUDY DESIGN Patients: stage II (bulky disease >7 cm), III, or IV disease; Induction therapy: 1L treatment with 6 cycles of BR plus 2 additional cycles R (N=612); Maintenance treatment (in responders): R 375 mg/m2every 2 mons for 2 vs 4 yrs(N=351) •90% responded to induction therapy with 33% achieving CR •PFS appears superior with 4 yrsvs 2 yrsof R-maintenance, HR= 0.63 (95% CI 0.36–1.11) •Historical comparison for PFS between responding pts given 2 yrsof R-maintenance & from StiLNHL1 study who received BR only appears to favorR-maintenance, HR= 0.78 (95% CI 0.54–1.04) •261 pts discontinued induction therapy or first 2 yrsof maintenance; including PD (33%), toxicity or infections (11%) , R intolerance (5%), death (4%) with median age of 70 yrs& 5 pts died from infections •One patient died from a PML (randomized to 4 yrsof R)

ASH #1267 från University at Buffalo: Obinutuzumab mot Rituximab, Analys av CLL11 med en farmakokinetisk och farmakodynamisk modell O bättre än R med avseende på CR och PFS Studie av antikroppsmängder och tumörceller Cell-kill var 5 falt högre för O EC50 var 15 falt lägre för Obinutuzumab

Gallium R-kemo mot Obinutuzumab-kemo 2 års underhåll i båda armar Gängse dosering av rituximab Obinutuzumab 1000 mg per administration till stor som liten

Kaplan–Meier Estimates of Investigator-Assessed Progression-free Survival and Overall Survival among Patients with Follicular Lymphoma. Figure 1 Kaplan–Meier Estimates of Investigator-Assessed Progression-free Survival and Overall Survival among Patients with Follicular Lymphoma. Tick marks indicate censored data. Marcus R et al. N Engl J Med ;377:1331-1344

Vikt och Utfall

AE i form av mors i Galliumstudien Obinutuzumab armen 4% Rituximab armen 3,4%

Relevance: R mot R-kemo Obehandlade follikulära lymfom 1 till 1 randomisering R gavs under 6 + 6 cykler och R upp till 2 år Kemo gavs under 6 cykler och R underhåll upp till 2 år

F Morschhauser et al. N Engl J Med 2018;379:934-947. Progression-free Survival and Overall Survival in the Intention-to-Treat Population. Figure 1. Progression-free Survival and Overall Survival in the Intention-to-Treat Population. Panel A shows estimates of progression-free survival as assessed by an independent review committee, and Panel B shows estimates of overall survival. F Morschhauser et al. N Engl J Med 2018;379:934-947.

Kaminski et al: N Engl J Med, Feb 3, 2005 Progressionsfri överlevnad for patienter med follikuärt lymfom, behandlade med Radioimmunterapi, (Bexxar, 131I-tositumomab). Kaminski et al: N Engl J Med, Feb 3, 2005

Obinutuzumab plus benda followed by obinutuzumab maintenance prolongs OS compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma: updated results of the GADOLIN study Bruce D Cheson,1 Marek Trněný,2 Kamal Bouabdallah,3 Greg Dueck,4 John Gribben,5 Pieternella J Lugtenburg,6 Oliver Press,7 Gilles Salles,8 Günter Fingerle-Rowson,9 Federico Mattiello,9 Elisabeth Wassner-Fritsch,9 Laurie H Sehn10 1Georgetown University Hospital, Washington, DC, USA; 2Charles University, Prague, Czech Republic; 3University Hospital of Bordeaux, CHU Haut-Leveque, Bordeaux, France; 4British Columbia Cancer Agency, Kelowna, BC, Canada; 5Queen Mary University of London, London, United Kingdom; 6Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 7Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 8Hospices Civils de Lyon, Université Claude Bernard Lyon-1, Lyon, France; 9F. Hoffmann-La Roche Ltd, Basel, Switzerland; 10British Columbia Cancer Agency and the University of British Columbia, Vancouver, BC, Canada

CD20-positive rituximab-refractory iNHL Study design Open-label, multicenter, randomized, Phase III study in rituximab-refractory iNHL pts Induction Maintenance* CD20-positive rituximab-refractory iNHL Patients were aged ≥18 yrs with documented rituximab- refractory iNHL and an ECOG performance status of 0–2 Target enrolment: 410 G G 1000mg IV every 2 months for 2 years G-B B 90mg/m2 IV (D1, D2, C1–C6) and G 1000mg IV (D1, D8, D15, C1; D1, C2–6), q28 days B B 120mg/m2 IV (D1, D2, C1–C6), q28 days Randomized 1:1 Data cut-off: 1 April 2016 Rituximab-refractory definition: Failure to respond to, or progression during any prior rituximab- containing regimen (monotherapy or combined with chemotherapy), or progression within 6 months of the last rituximab dose, in the induction or maintenance settings Endpoints considered in current analysis: PFS (INV), OS, TTNT, safety *Patients in the G-B arm without evidence of progression following induction received G maintenance

Baseline patient and disease characteristics in the iNHL population Characteristic, % (n) G-B, n=204 B, n=209 Mean age, years (range) 62.0 (34–87) 61.9 (21–87) Mean time from diagnosis to randomization, years (range) 4.2 (0.3–32.1) 4.2 (0.3–29.9) Male 56.9 (116) 58.4 (122) ECOG performance status at baseline 0–1 2 95.6 (195) 4.4 (9) 95.1 (196)* 4.9 (10)* Bone marrow involvement at baseline 32.5 (64/197) 35.9 (70/195) Extranodal involvement 55.4 (113) 49.5 (103)† Bulky disease at baseline (6cm) 34.3 (70) 35.9 (74)* FLIPI at diagnosis (FL pts only) Low (0–1) Intermediate (2) High (3) Unknown 25.6 (42)‡ 31.1 (51)‡ 39.0 (64)‡ 4.3 (7)‡ 20.6 (35)§ 35.3 (60)§ 40.6 (69)§ 3.5 (6)§ 80.4% (164 patients) in the G-B arm and 81.8% (171 patients) in the B arm had a FL diagnosis; characteristics were similar to the iNHL population *n=206; †n=208; ‡n=164; §n=170; FLIPI, Follicular Lymphoma International Prognostic Index

Treatment history in the iNHL population Characteristic, % (n) G-B, n=204 B, n=209 Median prior regimens, n (range) 2 (1–7) 2 (1–10) Median time since completion of last regimen, months (range) 3.9 (0.1–128.4) 3.9 (0.5–64.0) Patients refractory to last regimen 92.2 (188) 92.3 (193) Patients rituximab-refractory to 0 regimen 1 regimen 2 regimens 3 regimens 4 regimens 1.5 (3) 80.9 (165) 16.2 (33) 1.0 (2) 0.5 (1) 0.0 (0) 77.5 (162) 17.7 (37) 4.3 (9) Patients double refractory to rituximab and an alkylating agent overall 77.5 (158) 81.3 (170) Treatment history was similar in the FL population

INV-assessed PFS in the FL population Kaplan-Meier plot of INV-assessed PFS by treatment arm (FL) 1.0 G-B, n=164 B, n=171 Pts with event, n (%) 93 (56.7) 125 (73.1) Median PFS (95% CI), mo 25.3 (17.4, 36.0) 14.0 (11.3, 15.3) HR (95% CI), p-value* 0.52 (0.39, 0.69), p<0.0001 0.8 0.6 Probability 0.4 B (N=171) G-B (N=164) Censored 0.2 + Median follow-up (FL): 31.2 months (vs 21.1 months in primary analysis) 6 12 18 24 30 36 42 48 54 60 Time (months) No. of patients at risk B G-B 171 164 141 138 84 107 45 86 32 67 18 49 15 40 9 26 4 15 4 *Stratified analysis; stratification factors: prior therapies, refractory type, geographical region

TTNT in the iNHL population Kaplan-Meier plot of TTNT by treatment arm (iNHL) 1.0 G-B, n=204 B, n=209 Pts with event, n (%) 100 (49.0) 139 (66.5) Median TTNT (95% CI), mo 40.8 (28.3, NR) 19.4 (16.2, 24.3) HR (95% CI)* 0.59 (0.45, 0.77) 0.8 0.6 Probability 0.4 B (N=209) G-B (N=204) Censored 0.2 + Median follow-up (iNHL): 31.8 months (vs 21.1 months in primary analysis) 6 12 18 24 30 36 42 48 54 60 66 Time (months) No. of patients at risk B G-B 209 204 178 179 133 147 100 122 74 109 59 88 42 67 33 50 21 31 11 17 3 7 NR, not reached *Stratified analysis; stratification factors: iNHL subtype, prior therapies, refractory type, geographical region

TTNT in the FL population Kaplan-Meier plot of TTNT by treatment arm (FL) 1.0 G-B, n=164 B, n=171 Pts with event, n (%) 82 (50.0) 121 (70.8) Median TTNT (95% CI), mo 33.6 (25.3, NR) 18.0 (15.4, 21.3) HR (95% CI)* 0.57 (0.43, 0.75) 0.8 0.6 Probability 0.4 B (N=171) G-B (N=164) Censored 0.2 + Median follow-up (FL): 31.2 months (vs 21.1 months in primary analysis) 6 12 18 24 30 36 42 48 54 60 66 Time (months) No. of patients at risk B G-B 171 164 147 141 107 117 78 95 55 84 43 66 31 51 22 37 15 22 7 13 3 7 NR, not reached *Stratified analysis; stratification factors: prior therapies, refractory type, geographical region

Kaplan-Meier plot of OS by OS in the FL population Kaplan-Meier plot of OS by treatment arm (FL) 1.0 G-B, n=164 B, n=171 Pts with event, n (%) 39 (23.8) 64 (37.4) Median OS (95% CI), mo NR (NR, NR) 53.9 (40.9, NR) HR (95% CI), p-value* 0.58 (0.39, 0.86), p=0.0061 0.8 0.6 Probability 0.4 B (N=171) G-B (N=164) Censored 0.2 + Median follow-up (FL): 31.2 months (vs 21.1 months in primary analysis) 6 12 18 24 30 36 42 48 54 60 66 Time (months) No. of patients at risk B G-B 171 164 159 147 137 141 122 129 103 111 84 90 65 71 49 56 32 38 13 20 7 12 NR, not reached *Stratified analysis; stratification factors: prior therapies, refractory type, geographical region

study design: Randomized double blind phase III trial ≤ 12 cycles or until PD, relapse, or intolerability R-lenalidomide (R2) Rituximab: 375 mg/m2 d1, 8, 15, 22 of cycle 1; d1 of cycles 2-5 Lenalidomide: 20 mg/d*, d1-21/28 (12 cycles) 5-year follow-up for OS, SPMs, subsequent treatment, and histological transformations Relapsed/refractory FL and MZL (N = 358) 1:1 *10 mg if CrCl between 30 to 59 mL/min. R-placebo Rituximab: 375 mg/m2 d1, 8, 15, 22 of cycle 1; d1 of cycles 2-5 Placebo: matched capsules (12 cycles) Stratification Prior rituximab (yes vs no) Time since last therapy (≤ 2 vs > 2 y) Histology (FL vs MZL) Key eligibility criteria MZL or FL (grades 1-3a) in need of treatment ≥ 1 prior chemotherapy, immunotherapy or chemoimmunotherapy Not rituximab refractory Prophylactic anticoagulation / antiplatelet Rx recommended for at risk patients Growth factor use was allowed per ASCO/ESMO guidelines1,2 Primary endpoint: PFS by IRC (2007 IWG criteria w/o PET) NCT01938001 1. Crawford et al. Ann Oncol. 2010;21 Suppl 5:248-251. 2. Smith et al. J Clin Oncol. 2015;33:3199-3212.

Primary endpoint: progression-free survival (ITT, IRC) PFS by IRC* Median follow up: 28.3 months Median PFS R2 (n = 178) R-placebo (n = 180) HR (95% CI) P Value By IRC, mo (95% CI) 39.4 (22.9-NE) 14.1 (11.4-16.7) 0.46 (0.34-0.62) < 0.0001 By investigator, mo (95% CI) 25.3 (21.2-NE) 14.3 (12.4-17.7) 0.51 (0.38-0.69) *Censoring rules based on FDA guidance. Data cutoff June 22, 2018.

overall survival in patients with fl (prespecified subgroup analysis) Median follow up: 28.3 months 35 total deaths (11 R2, 24 R-placebo) 2-year OS was 95% (95% CI, 90%-98%) for R2 and 86% (95% CI, 79%-91%) for R-placebo Data cutoff June 22, 2018.

Tumor response to idelalisib therapy. Tumor response to idelalisib therapy. Waterfall plot of maximum change from baseline of the sum of the products of the greatest perpendicular diameters (SPD) of lymph nodes for early-early PD (<12 months) and late-early (12-24 months) FL patients. The black dashed line represents a change of −50% and is a criterion for lymphadenopathy response.8 Ajay K. Gopal et al. Blood 2017;129:3037-3039 ©2017 by American Society of Hematology

PFS and OS. (A) PFS from initiation of idelalisib in early PD patients. PFS and OS. (A) PFS from initiation of idelalisib in early PD patients. Kaplan-Meier curve showing PFS results in early-early PD (≤12 months) or late-early (12-24 months) FL patients treated with idelalisib. PFS (months) = (minimum [date of PD, date of death] − date of first dose of idelalisib + 1)/30.4375. (B) OS from initiation of idelalisib in early PD patients. The Kaplan-Meier survival curve shows the results of idelalisib treatment in early-early PD (≤12 months) or late-early (12-24 months) FL patients. OS (months) = (date of death − date of first dose of idelalisib +1)/30.4375. HR, hazard ratio. Ajay K. Gopal et al. Blood 2017;129:3037-3039 ©2017 by American Society of Hematology

Överlevnad hos 693 högdosbehandlade patienter med follikulärt lymfom, uppdelade efter konditionering.  Montoto, Canals, Rohatiner et al:Leukemia (2007) 21, 2324–2331

(a) Progression-free survival in 693 patients who received HDT (a) Progression-free survival in 693 patients who received HDT. (b) Progression-free survival according to disease status at HDT

Allogen Transplantation av Follikulärt lymfom (A) Överlevnad (B) Icke återfallsbetingad dödlighet efter donator typ (A) Overall survival and (B) nonrelapse mortality stratified by donor type. The unrelated group includes patients with HLA-matched or one allele–mismatched unrelated donors (n = 19), whereas the mismatched (MM) unrelated group contains patients mismatched at the one-antigen level or greater (n = 9). Rezvani A R et al. JCO 2008;26:211-217 ©2008 by American Society of Clinical Oncology

Follikuärt lymfom Stadium III B Behandlas som DSBCL. R-CHOP x 6 “Follicular lymphoma grade 3B: is it a real disease”?* *Harris et Kluin Haematologica 2011