Prevalence, Predictive Factors Therapy and Outcome of Patients with Follicular Lymphoma Refractory to First Line Immunochemotherapy

Abstract Background: Follicular lymphoma (FL) is the most frequent indolent lymphoma and is characterized by a high response to immunochemotherapy (ICT). However, patients refractory to first-line ICT have a worse prognosis. The objective of this study was to determine the prevalence of refractory FL, the factors that predict refractoriness as well as the salvage treatment and outcome. Patients and methods: This is a retrospective analysis including stage II-IV FL patients treated with first-line ICT in 3 Spanish institutions. The cohort was divided into ICT-refractory patients (less than partial response after induction or maintenance/consolidation therapy, as well as relapse or progression within 6 months of the last dose of therapy) and ICT-sensitive. Baseline features, therapy received and outcome were analyzed. Results: 283 patients were included, the median age was 58 years-old (range 28 to 85) and 53% were female. 200/231 (87%) had a good performance status (ECOG < 2), 260/295 (88%) presented with stages III and IV and 163/284 (57%) had bone marrow involvement. High-risk FLIPI score was seen in 108/256 (42%), high serum LDH in 78/263 (28%) and high serum B2-microglobulin in 138/253 (54%). RCHOP was administered to 226 (80%), RCVP to 36 (13%) and rituximab in combination with fludarabine or bendamustine-based therapy to 21 (7%). Seventeen patients received consolidation with radioimmunotherapy and 140 received maintenance with rituximab (n=137) or interferon (n=3). Sixteen patients received complementary radiotherapy. Forty-three (16%) patients were ICT-refractory (37 within 6 months of the completion of induction and 6 during or within 6 months of the completion of maintenance/consolidation therapy). On univariate analysis, high-risk FLIPI (OR 5.4, [95% CI 2.3-12.6]), high-risk FLIPI2 (5.4, [2.4-12.4]), B symptoms (3.2, [1.6-6.6]), ECOG ≥ 2 (4.6, [2-10.9]), involvement of > 4 nodal regions (2.3, [1.02-5.3]), hepatomegaly (7.5, [2.6-21.5]), splenomegaly (2.8, [1.4-5.9]), high B2-microglobulin (4, [1.7-9.5]), high serum LDH (3.9, [1.8-8]) and treatment with RCVP (compared with RCHOP, 2.8, [1.2-6.2]) were correlated with refractoriness. On multivariate analysis, high-risk FLIPI score (4.9, [2.1-11.7]) and treatment with RCVP (3.4, [1.2-9.4]) were the only variables associated with refractoriness. After exclusion of FLIPI, ECOG ≥ 2 (3, [1.1-8.4]) and high serum LDH (4.7, [2-11]) were correlated with refractoriness, in addition to RCVP therapy (4.5, [1.5-13.2]). Ten-year OS probabilities in ICT-sensitive and ICT-refractory patients were 83% (95% CI 76%-90%) and 33% (12%-54%), respectively (p<0.001) (Figure 1). ICT-refractory patients were more likely to be also refractory to second-line therapies than ICT-sensitive patients (21/31 [68%] vs 10/58 [17%], p<0.001). In addition, histological transformation was suspected by clinical or biological features or confirmed by tissue biopsy in 11/43 ICT-refractory and 8/240 ICT-sensitive (p<0.0001). Death among ICT-refractory patients was more frequently due to lymphoma than in ICT-sensitive patients (19/23 [83%] vs 14/28 [50%], p=0.033). Conclusions: In this series of FL treated with first-line ICT, the prevalence of refractoriness was low and occurred most frequently during or within 6 months of induction rather than maintenance/consolidation therapy. FLIPI score and RCVP treatment (compared to RCHOP) were predictive of refractoriness. The response rate of ICT-refractory FL patients to second-line therapy is low and the prognosis is poor. Supported in part by RD12/0036/0029 del RTICC, Instituto Carlos III. Figure 1. Overall survival in immunochemotherapy (ICT)-sensitive and ICT-refractory patients (p<001) Figure 1. Overall survival in immunochemotherapy (ICT)-sensitive and ICT-refractory patients (p<001) Disclosures Sancho: CELLTRION, Inc.: Research Funding. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.

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Activity of Idelalisib in High-Risk Follicular Lymphoma with Early Relapse Following Front Line Immunochemotherapy

Blood ◽

10.1182/blood.v126.23.2744.2744 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2744-2744 ◽

Cited By ~ 6

Author(s):

Ajay K Gopal ◽

Brad S Kahl ◽

Christopher Flowers ◽

Peter Martin ◽

Brian K Link ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Research Funding ◽

Progression Free Survival ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Free Survival ◽

Line Therapy ◽

First Line Treatment

Abstract Background: Follicular lymphoma (FL) is the most common indolent NHL with a heterogenous natural history of disease and a median survival of 8 to 12 y, albeit ranging between 1 to 20 y. Casulo et al. (2015) identified a high-risk FL cohort of patients with progression of disease (POD) at ≤24 months following initiation of immunochemotherapy with R-CHOP. Idelalisib (Zydelig) is a first-in-class, highly selective, oral inhibitor of PI3Kd which is indicated for relapsed FL or SLL following receipt of at least two lines of systemic chemotherapy. Retrospective subgroup analysis of the idelalisib registrational trial NCT01282424 (101-09) of a cohort with early POD following immunochemotherapy was performed to assess possible activity of idelalisib in this population. Methods: A subset of 46 patients enrolled in study 101-09 were identified as having been diagnosed with FL and having received first-line immunochemotherapy, of which 37 experienced early POD, defined as starting second-line treatment within 24 months of initial first-line treatment. For the latter group, descriptive statistics of demographic and baseline characteristics and inter-treatment intervals in months as well as Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) following initiation of immunochemotherapy and idelalisib were calculated. Population: Demographic characteristics of these 37 patients included median (range) age at initiation of idelalisib of 64 (33-84) y and 18 (48.6%) females. Histologic grade at diagnosis included 33 (89.2%) with grades 1 or 2 as well as 4 (10.8%) with grade 3A, while 21 (56.8%) patients had a FLIPI score ≥3. The mean (s.d.) number of prior therapies was 3.4±1.4, with a range of 2 to 8, while first-line therapies included 21 (56.8%) patients who received R-CHOP-based regimens, 7 (18.9%) who received BR, and 5 (13.5%) who received R-CVP. Mean (s.d.) inter-treatment intervals included 12.5±6.1 months between first- and second-line for all patients, 9.7±9.3 months between second- and third-line for all patients, 11.9±12.0 months between third- and fourth-line for 24 (64.9%) patients, and 11.8±7.6 months between fourth- and fifth-line for 15 (40.5%) patients. Median (range) time from first-line therapy to idelalisib initiation was 30.3 (8.9-94.7) months; no patient received idelalisib as second-line therapy. Results: Best responses included 5 (13.5%) patients with CR, 16 (43.2%) with PR, 2 (5.4%) with SD, and 1 (2.7%) with PD; median duration of response for those with CR or PR was 11.8 months (95% CI: 3.8 months, not evaluable). There were 7 (18.9%) deaths and 21 (56.8%) PFS events in this group. Estimated probabilities of survival (s.e.) and progression-free status at 2 y following initiation of idelalisib were 79%±7% and 29%±10%, respectively. Median PFS was 11.1 months (95% CI: 5.5, 19.3 months). Estimated probability of survival (s.e.) at 5 years following initiation of first-line treatment was 79%±8%. Median overall survival from both initiation of first-line immunochemotherapy as well as with idelalisib was not reached during the course of this study. Conclusions: Idelalisib may have significant clinical activity in high-risk and doubly-refractive FL following early relapse status post first-line immunochemotherapy. Given the small size of the studied subset population which may not be representative, further characterization in additional patients is warranted to ensure the generalizability of this finding, including consideration of further investigational protocols featuring targeted therapies employed both as single agents and in combination. Figure 1. Overall Survival From Initiation of First-line Treatment Figure 1. Overall Survival From Initiation of First-line Treatment Figure 2. Overall Survival From Initiation of Idelalisib Figure 2. Overall Survival From Initiation of Idelalisib Figure 3. Progression-Free Survival From Initiation of Idelalisib Figure 3. Progression-Free Survival From Initiation of Idelalisib Disclosures Gopal: Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Flowers:Infinity Pharmaceuticals: Research Funding; Genentech: Research Funding; Spectrum: Research Funding; Millennium/Takeda: Research Funding; Seattle Genetics: Consultancy; Spectrum: Research Funding; Pharmacyclics: Research Funding; AbbVie: Research Funding; AbbVie: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Research Funding; Onyx Pharmaceuticals: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; OptumRx: Consultancy; Gilead Sciences: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Millennium/Takeda: Research Funding; Acerta: Research Funding; Infinity Pharmaceuticals: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding. Martin:Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Ye:Gilead: Employment. Koh:Gilead: Employment. Abella:Gilead: Employment. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Abbvie: Consultancy; Gilead: Consultancy. Salles:Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau.

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Thirty-Five Year Follow-up Analysis of Follicular Lymphoma Patients Treated through the Nebraska Lymphoma Study Group: Prognostic Factor Analysis and Outcomes

Blood ◽

10.1182/blood-2020-142743 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Amulya Yellala ◽

Elizabeth R. Lyden ◽

Heather Nutsch ◽

Avyakta Kallam ◽

Kai Fu ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Follicular Lymphoma ◽

Treatment Regimen ◽

Research Funding ◽

Study Group ◽

Secondary Malignancies ◽

Lymphoma Study Group

Background Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL) and most common of the clinically indolent NHLs. Although often considered an incurable disease, overall survival has increased significantly with refinement in diagnostic techniques and the addition of rituximab. The course of FL is quite variable and presence of symptoms, organ dysfunction, cytopenias, aggressiveness of tumor are all taken into consideration when deciding individual treatment. In this study, we evaluated a large patient cohort with FL treated over a 35 year period for progression free survival (PFS), overall survival (OS) based on FLIPI score, tumor grade, and treatment regimen and also looked at causes of late failures. Methods We evaluated 1037 patients (pts) from the Nebraska Lymphoma Study Group that were diagnosed with FL between the years of 1983-2020. Descriptive statistics were stratified according to age, histological subtype, treatment regimen, FLIPI category, presence and type of secondary malignancy. PFS was calculated from the time of diagnosis to progression or death and OS was the time from diagnosis to death from any cause. PFS and OS were plotted as Kaplan-Meier curves with statistically significant p<0.05. Results The median age at diagnosis and treatment was 61 years (yrs, range 17-91). A total of 9.1% were characterized as FLIPI high risk, 37.8% intermediate risk, and 33.6% low risk, 19.5% unavailable. Among the histological grade, 23.1% had FL- grade 1, 30.2% FL-2, 27.3% FL-3A, 2.5 % FL-3B and 16.9 % Composite Lymphoma. Anthracycline + rituximab was given in 24.5% of pts, whereas 43.8% of pts received an anthracycline based regimen without rituximab, 9.8% received rituximab without an anthracycline and 10.6% received neither of these agents. 6.75% (70 pts) were later found to have secondary malignancies of which 11 pts had myelodysplastic syndrome, 10 pts had acute leukemia and 9 pts had lung cancer. With a median follow up of 9.2 yrs and a maximum of 36 yrs, 29.7% (308 pts) had not relapsed. The median PFS across all groups was 4.6 yrs (Fig 1) and OS was 12.1 yrs. Median OS was significantly longer in patients that received rituximab at 16.1 yrs as compared to patients that did not receive rituximab at 9.89 yrs (Fig 2). PFS was 8.6 yrs, 3.6 yrs and 2.1 yrs and OS was 15.1 yrs, 11.7 yrs and 4.9 yrs in FLIPI low, intermediate and high risk groups respectively (p=<0.001) (Fig 3), suggesting that survival was influenced by FLIPI score. Median PFS in FL-3B and FL-3A was 9.2 yrs and 5.2 yrs respectively which is longer than 4.7 yrs and 4.2 yrs for FL-1 and FL-2 (p=0.24). OS in FL-3A and FL-3B subgroups was 10.8 yrs while it was 11.6 yrs and 14.3 yrs in FL-2 and FL-1 (P=0.081). PFS is significantly longer at 10.6 yrs in pts treated with both anthracycline and rituximab containing regimen as compared to 5.3 yrs in pts treated with rituximab alone and 3.05 yrs in pts that had only anthracycline based regimen (p=<0.001) (Fig 4). The median OS also was significantly higher in the combination regimen group at 18.8 yrs as compared to 11.3 yrs in rituximab only group and 9 yrs in anthracycline based regimen group (p=<0.001). When pts with FL-3A and FL-3B were grouped together and stratified according to treatment regimen, the group that received anthracycline and rituximab combination has highest PFS and OS at 13.3 yrs and 18.8 yrs (p<0.001). when pts with FL-3A were analyzed separately and stratified by treatment regimen, the results of PFS and OS were similar and statistically significant. However, of the 24 pts in FL-3B group, analysis revealed that PFS and OS was longer in anthracycline based regimen only group, however results were not statistically significant. Among the pts that relapsed/died after 10 years (n=190), the cause of death was relapsed lymphoma in 13.7%, unknown in 55.8%, secondary malignancies in 4.2%, treatment related in 2.6% and not related to disease in 23.7%. A total of 278 pts survived > 10 yrs, and of these pts, 119 (30%) had not relapsed at the last follow up. Conclusion The addition of rituximab to standard anthracycline based chemotherapy has resulted in significant improvements in the PFS and OS rates of FL. These results also support the prognostic value of the FLIPI in patients treated in the rituximab era. Late relapses after 10 yrs from disease can occur, but 11.5% of patients had not relapsed with long term follow up. Secondary malignancies are also an important consideration in the long term survivors. Disclosures Lunning: Acrotech: Consultancy; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; Verastem: Consultancy, Honoraria; ADC Therapeutics: Consultancy. Armitage:Trovagene/Cardiff Oncology: Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Consultancy; Ascentage: Consultancy. Vose:Bristol-Myers Squibb: Research Funding; Karyopharm Therapeutics: Consultancy, Honoraria; Seattle Genetics: Research Funding; Allogene: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding; Wugen: Honoraria; Novartis: Research Funding; Celgene: Honoraria; Incyte: Research Funding; Roche/Genetech: Consultancy, Honoraria, Other; Verastem: Consultancy, Honoraria; Miltenyi Biotec: Honoraria; Loxo: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Epizyme: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria.

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Lenalidomide Treatment For Lower Risk Non-Deletion 5q Myelodysplastic Syndromes Patients Yields Higher Response Rates When Used Prior To Azanucleosides

Blood ◽

10.1182/blood.v122.21.1507.1507 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1507-1507

Author(s):

Rami S Komrokji ◽

Maria G. Corrales-Yepez ◽

Najla H Al Ali ◽

Eric Padron ◽

Jeffrey E Lancet ◽

...

Keyword(s):

Overall Survival ◽

Myelodysplastic Syndromes ◽

Lower Risk ◽

Research Funding ◽

Response Rates ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy

Abstract Introduction Lenalidomide (LEN) is the standard of care for treatment of transfusion dependent lower risk myelodysplastic syndromes (MDS) with chromosome 5q deletion (del 5q). In the MDS-002 study, 26% of lower risk transfusion dependent MDS patients became red blood cell transfusion independent after LEN treatment. National Comprehensive Cancer Network (NCCN) clinical guidelines list LEN as a second line treatment alternative for transfusion dependent anemia in lower risk non-del 5q MDS after azanucleosides failure. The response rate to LEN after azanucleosides failure, however, is not known given that the MDS-002 study preceded FDA approval of azanucleosides. To address the best sequence of LEN to optimize response potential in lower risk MDS, we examined the response rates to LEN in non-del 5q lower risk MDS when offered as first line after (erythroid stimulating agents) ESA's or after azacitidine failure. Methods This was a retrospective study conducted using the Moffitt Cancer Center (MCC) MDS database. We identified patients with lower risk MDS who received both LEN and azacitidine as first or second line therapy after erythroid stimulating agents. Lower risk MDS was defined according to the international prognostic scoring system (IPSS) Low or intermediate-1 (int-1) risk groups. The primary endpoint was to compare rates of erythroid hematological improvement (HI-E) between the group of patients who received LEN as first line therapy followed by azacitidine as second line (LEN 1st line group) and those who received LEN as second line therapy after azacitidine (LEN 2nd line group). HI was defined according to international working group criteria (IWG 2006). Chi- square test was used for categorical variables, T-test was used for continuous variables, and Kaplan Meier estimates for overall survival. All analyses were conducted using SPSS statistical software (IBM version 21) Results We identified 63 patients who received both azacitidine and LEN as first and second line where 37 patients were in group 1 (LEN 1st line) and 26 patients were in group 2 (LEN 2nd line). Baseline characteristics between the two groups are summarized in Table-1. There were no statistically significant differences between the 2 groups in terms of mean age at diagnosis, gender, WHO subtype, revised IPSS, or mean blood counts. The majority of patients had refractory cytopenia with multilineage dysplasia (RCMD) and had low risk revised IPSS . The rate of HI-E was 38% (n=14) among LEN 1st line group compared to 12% (n=3) in LEN 2nd line group. (p=0.04). There was no difference in overall survival (OS) among the two groups with a median OS of 104 months and 87 months, respectively, p=0.55. There was no difference in AML transformation rate, 5.4% (n=2) and 11% (n=3) among the two groups, respectively, p=0.33. There were no differences in response rates to azacitidine among the two groups. Among the Len 1st line group response to 2nd line azacitidine was 38% (n=14) compared to 35% (n=9) among those who received azacitidine as first line followed by LEN as 2nd line. (p=0.69). Conclusion LEN yields a higher rate of HI-E in non-del 5q lower risk MDS when used as first line therapy. If validated in a larger cohort, LEN should be considered for 1st line therapy after ESAs rather than after azacitidine failure. Responses to azacitidine were similar among the two groups, indicating no adverse effect of LEN on azacitidine response. Disclosures: Komrokji: Celgene: Research Funding, Speakers Bureau. Off Label Use: use of lenalidomide in non del 5q. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.

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Baseline Suvmax Did Not Predict Histological Transformation from Follicular Lymphoma to Aggressive Lymphoma in the Phase III GALLIUM Study

Blood ◽

10.1182/blood-2018-99-116686 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4160-4160 ◽

Cited By ~ 4

Author(s):

Farheen Mir ◽

Sally F Barrington ◽

Michel Meignan ◽

Helen Brown ◽

Tina Nielsen ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

Research Funding ◽

Performance Status ◽

Bone Marrow Involvement ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Phase Iii ◽

Aggressive Lymphoma ◽

Histological Transformation

Abstract Introduction: Follicular lymphoma (FL) generally has an indolent clinical course, but there is a 1-2% annual rate of histological transformation (HT) into aggressive lymphoma. Nodal HT sites have a higher maximum standardized uptake value (SUVmax) than non-transformed sites, and patients with HT typically show greater variation in SUVmax between sites. Upfront identification of patients at high risk of HT would allow physicians to consider treatment intensification. The objective of this analysis was to assess the relationship between baseline SUVmax (bSUVmax) and HT in the GALLIUM study (NCT01332968). Methods In the randomized, phase III GALLIUM study, 1202 previously untreated patients with grade 1-3a FL were randomized to receive induction with either obinutuzumab (GA101; G)- or rituximab (R)-based immunochemotherapy. Patients who responded received maintenance therapy with the same antibody. The primary endpoint of investigator-assessed progression-free survival was significantly improved in the G arm relative to the R arm (hazard ratio 0.66; p=0.001). As an exploratory endpoint, the degree of 18-fluorodeoxyglucose (FDG)-avidity expressed by SUVmax was assessed in patients with baseline FDG positron emission tomography (FDG-PET) scans by an independent review committee. Results: Among 522 patients with available bSUVmax data, 13 (2.5%) experienced biopsy-confirmed HT to diffuse large B-cell lymphoma or Grade 3b FL after a median follow-up of 59 months. Patients with HT were older (median age 61 vs 56 years), and were more likely to have a poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status 2: 15.4% vs 2.6%), present with high-risk Follicular Lymphoma International Prognostic Index (FLIPI; 61.5% vs 40.3%), and have bone marrow involvement (76.9% vs 52.9%) than those without. More than 65% of patients showed bSUVmax >10, but only a minority of these experienced HT. Median (range) bSUVmax in patients with versus without HT was 12.4 (8.14, 27.95) versus 11.8 (3.05, 64.43), respectively. Median (range) baseline SUVrange (bSUVrange), defined as the difference between bSUVmax of the most and least FDG-avid lymphoma sites, was 6.6 (1.08, 23.91) versus 7.14 (0.00, 59.81), respectively (Figure). Conclusions: bSUVmax >10 is common in patients with previously untreated FL and is rarely associated with early HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting there may be little benefit in re-biopsy of lesions to exclude HT before commencing therapy. Better markers for identification of FL patients at risk of transformation are needed. Disclosures Mir: F. Hoffmann-La Roche: Employment. Barrington:F.Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees; Department of Health (England): Research Funding; MRC: Research Funding; CRUK: Research Funding; EPSRC: Research Funding; National Institute of Health Research: Research Funding. Meignan:F. Hoffman-La Roche Ltd: Honoraria. Brown:PAREXEL, external business partner with Roche Products Ltd, Welwyn, UK: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sahin:F. Hoffman-La Roche Ltd: Other: Ownership interests PLC. Trotman:F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding.

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Effects of the sequential administration of GEMOX followed by FOLFIRI in cholangiocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.348 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 348-348

Author(s):

Sihem Sebbagh ◽

Chantal Dreyer ◽

Armand De Gramont ◽

Olivia Hentic ◽

Pascal Hammel ◽

...

Keyword(s):

Overall Survival ◽

Univariate Analysis ◽

Locally Advanced ◽

Progression Free Survival ◽

Median Number ◽

Severe Toxicity ◽

Second Line ◽

First Line ◽

Free Survival ◽

Sequential Administration

348 Background: Advanced cholangiocarcinoma are benefiting from platinum-based therapy (Valle et al, NEJM) but no validated option is available as second line systemic therapy. Methods: Objective : Explore the effect of 2 consecutive lines of chemotherapy in patients with cholangiocarcinoma fitted to receive sequential administration of received gemcitabine and oxaliplatin (GEMOX) followed by FOLFIRI. A retrospective study was conducted among patients who received GEMOX in first line followed by FOLFIRI in second line from January 2005 and September 2013 at Beaujon hospital (France). Overall survival, progression free survival and prognostic factors were determined by the Kaplan-Meier method and univariate analysis. Results: Thirty-four patients were included in the cohort. Eighteen patients (53%) presented intrahepatic cholangiocarcinoma (ICC) and 16 (47%) presented extrahepatic cholangiocarcinoma (ECC). At diagnosis, tumors were localized in 4 patients (12%), locally advanced in 13 patients (38%) and metastatic in 17 patients (50%). Among 10 patients with prior surgery, 7 received GEMOX adjuvant chemotherapy. The median overall survival time was 20.6 months in all patients and 17.1 months in patients who received GEMOX followed by FOLFIRI in the advanced setting. The median first line progression-free survival (PFS) was 5.7 months with a median number of 8 cycles of GEMOX. The median second line PFS was 2.9 months with a median number of 5 cycles of FOLFIRI. Patients who received >8 cycles of GEMOX in first line survived longer than those who received ≤ 8 cycles (23.1 vs 15.1 months; hazard ratio (HR) 5.22, P=0.009). The PFS of second line FOLFIRI was not different in patients who received more than 8 cycles of GEMOX (HR=1.72 P=0.26). Univariate analysis showed no correlation between age, sex, localization of primary, stage, and surgery with overall survival. No severe toxicity was reported related to GEMOX-FOLFIRI sequential combination in this study. Conclusions: Sequential administration of GEMOX followed by FOLFIRI is feasible for fitted patients with cholangiocarcinomas, yielding overall survival over 1 year.

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The impact of PBRM1 mutations on overall survival in greater than 2,100 patients treated with immune checkpoint blockade (ICB).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.666 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 666-666 ◽

Cited By ~ 3

Author(s):

A. Ari Hakimi ◽

Yasser Ged ◽

Jessica Flynn ◽

Douglas R Hoen ◽

Renzo G Di Natale ◽

...

Keyword(s):

Overall Survival ◽

Cox Regression ◽

Univariate Analysis ◽

Second Line ◽

Loss Of Function ◽

First Line ◽

Vegf Inhibitors ◽

Cell Renal Cell Carcinoma ◽

Cox Regression Analysis ◽

The Impact

666 Background: PBRM1 is the second most commonly mutated gene in clear cell renal cell carcinoma (ccRCC). We have previously shown favorable outcomes in PBRM1-mutated ccRCC tumors treated with vascular endothelial growth factor (VEGF) inhibitors. Recent data suggested PBRM1 mutations may sensitize ccRCC and non RCC malignancies to ICB therapy. We queried the impact of PBRM1 loss on overall survival (OS) across 2,152 patients treated with ICB. Methods: PBRM1 mutations were assessed in metastatic ccRCC patients who received first line (n = 82) or second line (n = 61) ICB or ICB/VEGF combinations. Additionally, 41 cohorts of non-RCC malignancies treated with ICB and combination (n = 2,009) were analyzed. Mutations were assessed by next generation targeted sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) and adjusted for tumor mutation burden (TMB), copy number alterations (CNA), loss of function(LOF) mutations (non RCC cohort) and IMDC risk (for ccRCC patients). Results: PBRM1 mutations were not associated with improved OS in ICB the entire ccRCC cohort (HR 1.37; CI 0.79-2.4; p = 0.265), the first line (p = 0.624) or second line setting (p = 0.39) or as combination with VEGF inhibitors (p = 0.2). Several RCC subgroups were investigated (see Table at bottom). In the non-RCC cohorts (n = 2,009) PBRM1 mutations were not significantly associated with OS on univariate analysis (HR = 0.73, p = 0.22 for LOF and HR = 0.84,p = 0.34 for non LOF), and remained insignificant after adjusting for TMB, total CNA, and drug class (CTLA4, PD-1/PDL-1 and combinations) (HR = 1.07, p = 0.78 for LOF and HR = 1.08,p = 0.67 for non LOF). Conclusions: Neither in ccRCC nor in the pan-cancer cohort did PBRM1 mutations appear to be associated with improved overall survival with ICB therapy.[Table: see text]

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Phase II Study with R-FND Followed by 90-Y Ibritumomab Tiuxetan Radioimmunotherapy and Rituximab Maintenance for Untreated High-Risk Follicular Lymphoma

Blood ◽

10.1182/blood.v118.21.99.99 ◽

2011 ◽

Vol 118 (21) ◽

pp. 99-99

Author(s):

Nathan H. Fowler ◽

Sattva S. Neelapu ◽

Michelle A. Fanale ◽

Maria A. Rodriguez ◽

Barbara Pro ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Stage Iii ◽

Ibritumomab Tiuxetan ◽

Advisory Committees ◽

Rituximab Maintenance

Abstract Abstract 99 Background: Follicular lymphoma (FL) patients (pts) with high-risk features using the FL International Prognostic Index (FLIPI) have an expected 5-year survival of approximately 50% with conventional chemotherapy. The incorporation of anti-CD20 monoclonal antibody therapy has improved results in this poor risk subgroup. (Buske, Blood 2006;108:1504) We have previously demonstrated that R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone) is an effective regimen for indolent lymphoma, capable of inducing molecular remissions. (McLaughlin, ASCO 2003;102:564). Both extended dosing of rituximab following induction, and consolidation of first remission with 90-Y ibritumomab tiuxetan radioimmnotherapy (RIT) can improve complete response rates and progression free survival (PFS) rates for patients with advanced FL. (Morschhauser, JCO 2008;32:5156; Salles, Lancet 2011;377:42) This is the first report of a chemoimmunotherapy approach followed by both RIT consolidation and rituximab maintenance. Methods: Untreated patients with FL (grade 1–3), with high risk disease (FLIPI score ≥ 3) who had adequate hematologic function and extensive stage (III/IV) disease were eligible for study entry. Patients received rituximab (375mg/m2 days 1 and 8 of cycle 1, and day 1 of subsequent cycles) fludarabine (25mg/m2 days 1–3), mitoxantrone (10mg/m2 day 1), and dexamethasone (20mg days 1–5) for four 28 day cycles. RIT was given 12–16 weeks following R-FND pending hematologic recovery. Six weeks following RIT, patients received rituximab 375mg/m2 every two months for one year. The primary objective of the study was to determine the PFS rates based on 1999 International Working Group criteria. The secondary objectives included assessing the safety and tolerance of RIT and maintenance rituximab after R-FND, assessing the CR and overall response rates, and determining the overall survival following treatment. Results: Forty nine patients were enrolled and 47 received treatment between October 2004 and April 2009. Forty-six patients were eligible for efficacy analysis. The median age was 61 (37–78), 80% had bone marrow involvement, and all had stage III/IV disease. Twenty four (51%) patients had bulky disease (>5cm) and 42 (91%) had elevated β2M. Thirty six patients completed all planned courses of treatment. Eight patients did not receive RIT, two due to neutropenia after R-FND. One patient had progressive disease while on treatment. Following R-FND, the complete (CR + CRu) and partial response rates were 87% and 13%. With RIT consolidation, the CR rate increased to 91%. At a median follow up of 50 months, the projected five year overall survival and PFS rates were 93% and 74%. Toxicity was mainly hematologic. Grade ≥ 3 neutropenia and thrombocytopenia occurred in 57% and 35% of patients respectively. Thirty seven patients required growth factors and 17 patients required transfusions. The median time to hematologic recovery following RIT was 10 weeks. The most common non-hematologic adverse events (≥Gr 3) were fatigue (17%), dypsnea (13%), and myalgia (11%). There were 3 cases of myelodysplasia (MDS), one in a patient who did not receive RIT. Conclusions: The combination of R-FND followed by RIT intensification and rituximab maintenance results in OS and PFS outcomes that are better than traditional combinations in this high risk population. Given the potential for serious toxicity (eg. MDS) seen in this trial and other intensive treatment strategies, this approach may be most appropriate in high-risk FLIPI patients whose outlook with standard therapy is poor. Acknowledgments: This study was sponsored by Genentech and Spectrum. Disclosures: Fowler: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Younes:Genentech, SBIO, Seattle Genetics, Syndax, Sanofi-Aventis: Honoraria, Research Funding.

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Impact Of Rituximab Maintenance Schedule On Prognosis In First Line Treatment Of Follicular Lymphoma. Retrospective Analysis From Czech Lymphoma Group (CLG) Database

Blood ◽

10.1182/blood.v122.21.4387.4387 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4387-4387

Author(s):

Andrea Janikova ◽

Zbynek Bortlicek ◽

Vit Campr ◽

Leos Kren ◽

David Belada ◽

...

Keyword(s):

Overall Survival ◽

Follicular Lymphoma ◽

Retrospective Analysis ◽

Research Funding ◽

Statistical Significance ◽

Induction Treatment ◽

Line Treatment ◽

First Line ◽

Rituximab Maintenance ◽

First Line Treatment

Abstract Introduction Results of randomized studies showed benefit of maintenance therapy with monoclonal anti-CD20 antibody (rituximab) in terms of time to progression (PFS) and overall survival (OS) in follicular lymphoma (FL). General recommendation, based on large clinical trial, is to give 2 years of rituximab maintenance á 375mg/m2every 2 months (12 doses) in first line setting. On the other hand, there are various rituximab maintenance schedules; however, the clear comparison of clinical efficacy is missing. Our retrospective analysis compared two different schedule of rituximab maintenance in first-line treatment of FL used in university centers participating on CLG registry. Methods Data were recruited from 1702 FL patients registered in the prospectively maintained multicentric database (Czech Lymphoma Group; CLG). For the analysis, patients with stage II-IV of new diagnosed FL (grade 1-3a) responding (complete or partial remission) to 6-8 cycles first-line RCHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) followed with rituximab maintenance (RM) were included. Completed planned maintenance was inclusion criterion. Patients with previous watch and wait or additional first line therapy (radiotherapy, other chemotherapy, transplant therapy) were excluded. Results Totally, 168 evaluable FL patients with median age 57ys (range 28-82) including 70 (41.7%) men treated with RCHOP + RM were found in CLG database. 52/168 patients received totaly 8 doses of rituximab maintenance every 3 months for 2 years (RM8 arm), whereas 47/168 patients were treated with totaly 12 doses (RM12 arm) of rituximab maintenance every 2 months for 2 years. All patients in both subgroups completed planned RM therapy. There was no difference in distribution of age, gender, FLIPI, grade, B-symptoms, bone marrow involvement, performance status, LDH and beta2microglobuline level between both arms. Induction treatment in terms of administered cycles CHOP (6xCHOP in 41/52 and 35/45 pts., for RM8 and RM12 arm) and rituximab doses (8xR in 48/52 and 41/45 pts., for RM8 and RM12 arm) was similar between arms (ns). There were 4/52 (7.7%) and 5/47 (10.6%) relapses in subgroups RM8 and RM12, with no statistical significance. Median PFS was 3.8 (2.1-5.8) years vs. 3.9 (2.4-7.8) years in RM8 and RM12 arms (not significant), and median OS 3.91 (2.2-6.94) years vs. 3.1 (2.48-8.6) years also with no statistical significance. Conclusion Our results show, that rituximab maintenance given every 2 or every 3 months for two years in first line treatment brings similar benefit to the FL patients in terms of remission duration and overall survival. Despite the fact, that presented data are retrospective observation, this is the first report comparing two different rituximab maintenance regimens in FL. Further prospective study and longer follow up are needed to confirm our preliminary data. This work was supported by grant NT/12193-5 and MHCZ-DRO (FNBr 65269705) Disclosures: Mayer: Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Trneny:Roche: Honoraria, Research Funding.

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Sequential RCHOP, Radioimmunotherapy and Rituximab Maintenance Improves Early Outcomes in Advanced Stage Follicular Lymphoma: 5 Year Outcomes from SWOG 0801

Blood ◽

10.1182/blood.v128.22.614.614 ◽

2016 ◽

Vol 128 (22) ◽

pp. 614-614

Author(s):

Paul M. Barr ◽

Hongli Li ◽

Richard Burack ◽

Michael LeBlanc ◽

Sonali M. Smith ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Maintenance Therapy ◽

Follicular Lymphoma ◽

Research Funding ◽

Progression Free Survival ◽

Advanced Stage ◽

Secondary Malignancies ◽

Free Survival ◽

Grade 3

Abstract Background: Despite an abundance of effective therapeutic options, advanced stage follicular lymphoma (FL) remains incurable. Further, prospective trials consistently demonstrate that 20% of patients relapse within 2 years and ultimately have an inferior survival (Casulo 2015). Maintenace rituximab following chemoimmunotherapy induction is able to delay disease progression but has not demonstrated a benefit in overall survival (Salles 2011). Additionally, radioimmunotherapy (RIT) is one of the most effective single agent options in FL but is not commonly utilized as part of upfront treatment. As such, the role of both remains unclear. Based on results demonstrated with RIT consolidation in SWOG 0016 and the efficacy of rituximab maintenance, SWOG 0801 was designed as a phase 2 single arm trial, conducted to evaluate the utility of consolidative RIT and sequential maintenance rituximab following chemoimmunotherapy induction. Methods: Eligible patients (pts) with treatment naïve stage III/IV or bulky stage II FL received RCHOP for 6 cycles (without rituximab for the last 2 cycles) followed by iodine-131 tositumomab and subsequent rituximab administered every 3 months for up to 4 years. The primary endpoint was progression-free survival (PFS) at 3 years. Secondary endpoints included 5-year overall survival (OS), overall response rate (ORR), and safety. Results: Of 87 pts registered to this study, 85 were deemed eligible following central pathologic review. One additional patient withdrew consent and received no treatment on protocol. Of the 84 evaluable patients, the median age was 52 years (range 29 - 80) ) and 18%, 40%, and 42%had low, intermediate and high risk FLIPI scores, respectively. Seventy-three pts completed RCHOP and I-131 tositumomab. Grade ≥3 AEs occurring ≥5% of pts included neutropenia (57%), leukopenia (40%), thrombocytopenia (20%), febrile neutropenia (17%), fatigue (10%), neuropathy (8%), anemia (7%) and hyperglycemia (5%). Reasons for discontinuation included refusal of tositumumab (6 pts), prolonged myelosuppression (2 pts), ascites (1pt), inability to provide tositumumab (1 pt), and an unrelated lower extremity wound (1 pt). Following induction and RIT, 59 complete responses and 23 partial responses were observed, for a ORR of 99% (95% CI: 93.5%, 99.9%) Sixty nine eligible patients registered to maintenance therapy with 42 completing the 4 year treatment plan. The only grade ≥3 AE that occurred in ≥5% of pts was leukopenia (5%). Twenty-seven pts discontinued maintenance therapy, including 11 in the first 2 years and 16 in the last 2 years, due to the following reasons: infection (8 pts), patient preference (8 pts), deaths (2 pts), treatment delay (2 pts), secondary solid tumors (2 pts), bowel perforation (1 pt), joint pain (1 pt), hepatic transaminase elevation (1 pt), insurance refusal (1 pt), and dose error (1 pt). Four additional secondary malignancies were reported following completion of therapy including solid tumors (3 pts) and AML (1 pt). To date, 9 deaths have occurred due to secondary malignancies (3 pts), unknown etiology (3 pts), cardiac arrest (2 pts) and non-alcoholic cirrhosis (1 pt). After median follow-up of 5.6 years (range 3-7 years), 17 events have occurred including 9 pts experiencing progressive FL resulting in a progression free survival of 90% (95% CI: 81.9%, 95.1%) at 3 years and 84%(95% CI: 74.5%, 90.6%) at 5 years (Figure). Three-year overall survival is 96% (95% CI: 89.3%, 98.8%) and 5-year overall survival is 94% (95% CI: 86.2%, 97.5%). Conclusions: SWOG 0801 demonstrates near universal responses following chemoimmunotherapy and RIT. This sequential therapeutic strategy appears to improve early outcomes as 94% of pts are without disease progression at 2 years, consistent with the best results ever demonstrated for FL in the National Clinical Trials Network. However, the majority of discontinuations occurred during maintenance suggesting that rituximab over a 4-year span is not feasible for many patients due to cumulative toxicity. Future studies investigating precision strategies in high-risk FL may consider an aggressive chemoimmunotherapy induction and RIT consolidation platform to overcome early FL progression given these promising outcomes. Support: NIH/NCI grants CA180888, CA180819, and in part by GlaxoSmithKline. Figure. Progression-Free Survival and Overall Survival Figure. Progression-Free Survival and Overall Survival Disclosures Barr: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Smith:Amgen: Other: Educational lecture to sales force; Juno: Consultancy; Pharmacyclics: Consultancy; AbbVie: Consultancy; Portola: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; TGTX: Consultancy. Gopal:Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy. Persky:Merck: Research Funding; Gilead: Speakers Bureau. Press:Roche / Genentech: Consultancy, Research Funding. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Other: Data Safety Monitoring Committee.

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The PRIMA-Prognostic Index (PI) Is Valid in Follicular Lymphoma (FL) Patients with Rituximab Chemo-Free First-Line Treatment

Blood ◽

10.1182/blood-2018-99-114866 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4150-4150 ◽

Cited By ~ 1

Author(s):

Eva Kimby ◽

Sandra Lockmer ◽

Harald Holte ◽

Björn E Wahlin ◽

Hans Hagberg ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Risk Group ◽

Bone Marrow Involvement ◽

First Line ◽

Advisory Committees

Abstract Background: Follicular lymphoma (FL) is a heterogenous disease. The optimal timing, sequence and choice of therapy remain matters of debate and there is no optimal prognostic tool. The FLIPI (Follicular Lymphoma International Prognostic Index) is based on five bio-clinical parameters and is widely used, but not as guide for choice of treatment. Recently a new prognostic score (PRIMA-PI), based solely on two parameters, bone marrow involvement and serum beta2 microglobulin (ß2m) was proposed for patients treated with immunochemotherapy (Bachy E., Blood 2018). The Nordic Lymphoma Group (NLG) performed two randomized trials including patients with symptomatic/progressive indolent CD20+ lymphoma, with rituximab monotherapy or rituximab in combination with interferon (IFN)-α2a as primary treatment, without maintenance (Kimby E., 2008, 2015). The 10 years follow-up of these patients showed a good survival with no major safety issues and no need for later chemotherapy in 38% of FL patients (Lockmer S, JCO 2018). Aim/Purpose: To evaluate two different prognostic systems (the new PRIMA-PI and the FLIPI), for overall survival (OS) and time to treatment failure (TTF) in a cohort of symptomatic/progressive FL patients treated with a rituximab-containing first-line regimen without chemotherapy. Methods: Previously untreated patients with a confirmed FL diagnosis (n=269) or indolent lymphoma not otherwise specified (n=22, most FLs with insufficient material for grading), treated in the NLG randomized trials with two cycles rituximab (375 mg/m2 x 4 weeks), with or without IFN-α2a, were classified into the three PRIMA-PI categories: high-risk: ß2m> 3mg / L, intermediate-risk: ß2m ≤ 3 mg / L with bone marrow involvement and low-risk: ß2m ≤ 3 mg / without bone marrow involvement. The FLIPI scores were also assessed. TTF, defined as the interval between randomization and either initiation of new lymphoma therapy due to relapse or intolerance, or death from any cause, as well as OS were estimated using the Kaplan Meier method. The log-rank test was used for comparison between risk groups. Results: Out of 291 patients, 252 had complete data on PRIMA-PI and FLIPI (at the time of randomization in the original trials) and were available for analyses of TTF and OS. Patient characteristics are shown in Table 1. PRIMA-PI seemed to identify a true high-risk group of 47 patients, 32 of them being high risk also according to FLIPI, while a larger patient group (n=117) was classified as FLIPI high-risk. After a long follow-up time, median 9.9 years (0.4 -18.8) from randomization, median 10.6 years for the 214 patients (74%) still alive, 76 patients (26%) were failure-free and 108 (37%) without need of any chemotherapy, Patients with PRIMA-PI high showed a shorter TTF compared to PRIMA-PI intermediate and low (Fig 1a), whereas the FLIPI risk-groups were not significantly separated (Fig 1b). Evidence of transformation to aggressive disease was seen in 55 patients, with no significant difference in frequency between the PRIMA-PI groups, nor between FLIPI groups. Both PRIMA-PI and FLIPI were of significant value for predicting OS, most evident after a long follow-up time (Fig 1c and d). In 41 patients the cause of death was progressive disease or therapy complications, regarded as lymphoma-related death, whereas 21 died of other causes. The lymphoma-specific survival was related to the PRIMA-PI (log-rank p=0.03), but not to the FLIPI (n.s). Prognosis was worse for the PRIMA-PI high-risk group than the for the low-risk, also when adjusted for sex, high age (>60 years), diagnosis, stage, ECOG and FLIPI risk-group; TTF HR 1.82 (95% CI 1.16-2.85, p=0.01) and OS HR 2.3 (95% CI 1.00-5.38, p=0.05). Conclusion: FL patients included in two NLG trials with complete clinical data and a median follow-up of >10 years after randomization have been assessed for validation of different prognostic indices. In these patients, all with chemo-free first-line therapy, the PRIMA-PI was shown a valid predictor of both TTF and OS and seemed more useful than the FLIPI. The PRIMA-PI high risk identified a group of patients (19% of all) with true poor prognosis. Disclosures Kimby: Roche: Honoraria; Roche: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding. Wahlin:Roche: Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Hagberg:Roche: Honoraria.

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