Tuscano, Joseph M.

The treatment landscape of B-cell lymphomas has significantly evolved in recent years with approval of novel targeted therapies. CD3 × CD20 bispecific antibodies and CD19-directed monoclonal antibodies and antibody–drug conjugates have demonstrated efficacy in relapsed/refractory follicular lymphoma (FL). Bruton tyrosine kinase (BTK) inhibitor–based regimens are emerging as effective treatment options for patients with TP53-mutated classical mantle cell lymphoma (MCL). Results from ongoing clinical trials suggest that the addition of CD3 × CD20 bispecific antibodies to chemoimmunotherapy improves outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, MCL, and DLBCL.

Novel targeted therapies (small molecule inhibitors, antibody–drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton’s tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Abstract Background: Patients with diffuse large B-cell lymphoma (DLBCL) not cured by first line R-CHOP chemotherapy or second line high-dose chemotherapy with autologous stem cell rescue have a poor prognosis and represent a clear unmet medical need. Lenalidomide (Revlimid®), an immunomodulatory drug, has activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory DLBCL. Methods: Patients with relapsed/refractory DLBCL with measurable disease after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test was conducted to investigate and characterize associations of prognostic variables with response. Results: Twenty-six patients with DLBCL lymphoma were enrolled. The median age was 66 (45–86) and 13 were female. Median time from diagnosis to lenalidomide was 2.4 (0.5–12) years and median number of prior treatment regimens was 3 (1–6). Three patients (12%) exhibited an objective complete response (1 complete response (CR) and 2 complete responses unconfirmed (CRu)). Two patients had a partial response (PR) for an overall response rate of 19% and 7 had stable disease (SD). Response to lenalidomide was associated with low disease burden (33% for < 50 cm2v 0% for ≥ 50 cm2, P=0.06) and longer time from rituximab to lenalidomide treatment (33% for ≥ 230 days v 0% for < 230 days, P=0.05). Patients with favorable values for both these prognostic factors (N = 10) had a 50% response rate [RR] (30% CR/CRu RR) compared with a 0% RR for patients with unfavorable values (N = 16; P < 0.004) and a progression free survival (ongoing) of 7.4 months v 1.9 months. Although there were no responses in the poor prognosis group, 4 patients exhibited stable disease with an ongoing median PFS of > 4.2 months (> 3.6 - > 6.2). Eight patients (31%) required at least one dose reduction with a median time to first dose reduction of 1.8 months (0.4–2.9). One patient each (4%) had Grade 4 anemia, cauda equinine syndrome, febrile neutropenia, intermittent rash, lymphopenia, neutropenia, pneumonitis and thrombocytopenia. Most common Grade 3 adverse events were neutropenia (19%), thrombocytopenia (15%) and leukopenia (12%). Conclusion: The prognostic factors of tumor burden and time from last dose of rituximab appear to identify relapsed/refractory DLBCL patients with a high likelihood of response to lenalidomide oral monotherapy.

Abstract Background: Mantle cell lymphoma (MCL) is a distinct type of non-Hodgkin’s Lymphoma characterized by being incurable with a low response rate and short progression free survival when treated with conventional chemotherapy agents. Lenalidomide (Revlimid®), an immunomodulatory drug, is approved for the treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a del(q5) cytogenetic abnormality. Lenalidomide has also shown activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide in relapsed/refractory MCL. Methods: Patients with relapsed/refractory MCL and measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Fifteen patients with MCL were enrolled. Median age was 67 (45–84) and 7 were female. Median time from diagnosis to lenalidomide was 5.1 (0.7–12.7) years and median number of prior treatment regimens was 4 (2–6). Eight patients (53%) exhibited an objective response (1 complete response (CR), 1 complete response unconfirmed (CRu) and 6 partial responses (PR)), 2 had stable disease (SD) and 5 had progressive disease (PD). All eight responses were in eleven patients having a tumor burden < 50 cm2 and a time since last rituximab therapy of ≥ 230 days. No responses were achieved in four patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of < 230 days. Four of 5 patients (80%) with a prior stem cell transplant responded. Progression free survival [PFS] is 5.7 months and ongoing. Seven patients (47%) required at least one dose reduction with a median time to first dose reduction of 2.3 months (1.2–4.9). Grade 4 adverse events were neutropenia (13%), thrombocytopenia (13%), and thromboembolism (13%). Most common Grade 3 adverse events were neutropenia (33%) and leukopenia (20%). Conclusion: Lenalidomide oral monotherapy produced a 53% response rate in relapsed/refractory MCL with manageable side effects.

Abstract Background: High dose chemotherapy with stem cell transplant is currently employed in relapsed/refractory aggressive Non-Hodgkin’s Lymphoma (NHL). Lenalidomide (Revlimid®), an immunomodulatory drug, has shown activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory aggressive NHL following stem cell transplant (SCT). Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Fourteen (29%) of the 49 patients enrolled into the study had a prior SCT. Median age was 61 (23–76) and 5 were female. Histology was diffuse large B-cell lymphoma [DLBCL] (n=5), follicular center lymphoma grade 3 [FL] (n=2), mantle cell lymphoma [MCL] (n=5) and transformed [TSF] (n=2). Median time from diagnosis to lenalidomide was 3.9 (1.1–31.4) years and median time from SCT to study entry was 1.9 (0.5–11.7) years. The median number of prior treatment regimens was 5 (2–8). Seven patients (50%) exhibited an objective response (1 complete response unconfirmed (CRu), and 6 partial responses (PR)), 5 had stable disease (SD) and 2 patients had progressive disease (PD). Six responses were in eight patients having a tumor burden < 50 cm2 and a time since last rituximab therapy of ≥ 230 days. One response was achieved in six patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of < 230 days. Four of 6 (67%) patients who had SCT as their last treatment prior to lenalidomide [median time from SCT to lenalidomide = 0.8 (0.5–4.8) years] responded. Progression free survival [PFS] is 4.5 months and ongoing. Six patients (43%) required at least one dose reduction with a median time to first dose reduction of 1.6 months (0.4–4.9). Two patients each (14%) had Grade 4 adverse events of neutropenia and thrombocytopenia. The most common Grade 3 adverse events were neutropenia (36%), thrombocytopenia (21%), and leukopenia (14%). Conclusion: Lenalidomide produced a 50% response rate with manageable side effects in relapsed/refractory aggressive NHL following stem cell transplant.

Abstract Background: Lenalidomide (Revlimid®) has been reported to show activity in non-Hodgkin’s Lymphoma (NHL). However, prognostic factors predicting an individual patient’s response were unavailable. Aim: To investigate prognostic factors for lenalidomide response in patients with relapsed/refractory aggressive NHL. Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1-21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test and multivariate analyses using logistic regression were conducted to investigate associations of prognostic variables with response. Results: Forty-nine patients received lenalidomide oral monotherapy. The median age was 65 (23-86) and 24 were female. Histology was diffuse large B-cell lymphoma (n=26), follicular center lymphoma grade 3 (n=5), mantle cell lymphoma (n=15) and transformed (n=3). Median time from diagnosis was 2.7 (0.4-32) years and median number of prior treatment regimens was 4 (1-8). Forty-five (92%) of the patients had received prior rituximab and 63% were rituximab-refractory. Seventeen patients (35%) exhibited an objective response (2 complete responses, 4 complete responses unconfirmed and 11 partial responses). Response to lenalidomide was the same for patients who were refractory to rituximab (30%) and those who were not (31%). Three of 4 patients who were rituximab naive responded. Multivariate analysis including IPI, ECOG PS, stage, LDH, # of extranodal sites, age, sex, # of prior regimens and time from diagnosis identified only time since last rituximab and tumor burden as correlated with response. Response to lenalidomide was associated with low tumor burden (52% for <50 cm2v 0% for ≥50 cm2, P=0.033, odds ratio=10.9) and longer time from rituximab to lenalidomide treatment (52% for ≥ 230 days v 6% for <230 days, P=0.031, odds ratio=6.6). Rituximab depletes normal host B-cells and the kinetics for their loss and recovery are consistent with the timing of lenalidomide activity following rituximab. This may be a basis for this effect. However other tumor/host biological factors may also play a role. Patients with favorable values for both prognostic factors (N=24) had a 67% response rate [RR] compared to a 4% RR for patients with unfavorable values (N=25; P< 0.001) and a progression free survival (ongoing) of 7.5 months v 1.9 months. Although absolute lymphocyte count was not selected as a prognostic indicator of response in the multivariate setting, a trend was evident in the univariate analysis (42% for > 0.6 × 109/L v 9% for ≤0.6 × 109/L, P=0.071). Conclusion: Tumor burden and host immune competence may determine the response of relapsed/refractory aggressive NHL to lenalidomide monotherapy.

8533 Background: Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma (NHL) with poor prognosis. The immunomodulatory agent lenalidomide shows consistent activity with tolerable safety in multiple phase II studies of relapsed/refractory aggressive NHL (NHL-002 and NHL-003) and MCL post-bortezomib (MCL-001). This pooled analysis further examined the efficacy and safety of single-agent lenalidomide in patients with relapsed/refractory MCL. Methods: Single-agent lenalidomide was given 25 mg/d PO on days 1-21 of 28-day cycles as tolerated for 52 weeks (NHL-002) or until disease progression (NHL-003 and MCL-001). All MCL patients received ≥1 prior treatment, including bortezomib in MCL-001. Efficacy data were examined by independent central review for MCL-001 and NHL-003 and by investigators for NHL-002. Results: 206 patients with relapsed/refractory MCL were studied. The median age was 67 y (range 33-84; 63% ≥65 y), 91% stage III/IV disease and 51% had received ≥4 prior regimens (76% prior bortezomib). Overall response rate (ORR) with lenalidomide was 32% (10% CR/CRu), with a median time to response of 2.1 months and median duration of response (DOR) of 16.6 months (not yet reached in patients with CR/CRu; Table). Kaplan-Meier estimates for median PFS and OS were 5.4 and 23.9 months, respectively. Mean daily dose of lenalidomide was 21 mg. Grade 3/4 AEs included neutropenia (44%), thrombocytopenia (29%), anemia (11%), and fatigue (7%). Other any-grade AEs included tumor flare reaction (7%), venous thromboembolic events (7%), and invasive second primary malignancies (3%). Conclusions: Lenalidomide produced rapid and durable responses in patients with relapsed/refractory MCL, and exhibited a predictable safety profile among 3 phase II studies of lenalidomide in heavily pretreated patients, including prior treatment with bortezomib. Clinical trial information: MCL-001: NCT00737529; NHL-002: NCT00179660; NHL-003: NCT00413036. [Table: see text]

8052 Background: Lenalidomide (Revlimid), an immunomodulatory drug of the IMiDs class, is approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. This study was designed to assess the safety and efficacy of lenalidomide in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). Methods: Patients with relapsed/refractory aggressive NHL with measurable disease after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: As of enrollment cut-off, 50 patients were enrolled and 49 received drug. Forty-one patients were evaluable for response. The median age was 65 (46–84) and 18 were female. Histology was diffuse large B-cell lymphoma [DLBCL] (n=21), follicular center lymphoma grade 3 [FL] (n=3), mantle cell lymphoma [MCL] (n=14) and transformed [TSF] (n=3). Median time from diagnosis to lenalidomide was 3.2 (0.4–32) years and median number of prior treatment regimens was 3 (1–7). Fourteen patients (34%) exhibited an objective response (5 complete responses unconfirmed (CRu) and 9 partial responses (PR)), 12 had stable disease (SD) for a tumor control rate (TCR) of 63% and 15 progressive disease (PD). Responses were seen in each of the aggressive histologic subtypes studied: DLBCL (5/21), MCL (6/14), FL (2/3), and TSF (1/3). Five of 11 patients (45%) with a prior stem cell transplant responded. Progression free survival although ongoing is currently > 239 (>191 - >373) days in patients experiencing CRu and > 160 (>54 - >251) days in patients with PR. Most common Grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%) while most common Grade 3 adverse events were neutropenia (22%), leukopenia (14%) and thrombocytopenia (12%). Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory aggressive NHL. No significant financial relationships to disclose.

Abstract Background Survival rates for older pts with advanced HL (aged ≥60 yrs) were historically poor with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Reasons may include decreased tolerance of therapy, increased toxicity (particularly with bleomycin), comorbidities, and disease biology. The pivotal phase 3 ECHELON-1 study demonstrated superior 2-yr modified progression-free survival (mPFS) with frontline brentuximab vedotin + doxorubicin, vinblastine and dacarbazine (A+AVD) vs ABVD in pts with stage III/IV cHL (Connors JM et al, NEJM 2018). The study allowed entry of older pts, with no upper age limit. Alternative dosing schedules of the A+AVD regimen have been studied (e.g., sequential brentuximab vedotin before and after AVD; NCT01476410, Evens AM et al, J Clin Oncol 2018). We report efficacy and safety results from ECHELON-1 for older pts with cHL and compare these with those for pts aged <60 yrs. Methods mPFS per independent review facility (IRF) for pts ≥60 years was a prespecified subgroup analysis of ECHELON-1. Additional exploratory safety and efficacy analyses were also assessed and compared with younger pts (<60 yrs). The study was not powered for age-based subgroup analyses; p-values are descriptive without multiplicity adjustment. Results 14% (186/1334) of pts in the intent-to-treat (ITT) population were aged ≥60 yrs (A+AVD, n=84; ABVD, n=102) and included in the sub analyses. Median age (range) of older pts was: A+AVD, 68.0 yrs (60-82); ABVD, 66.0 yrs (60-83). Baseline pt and disease characteristics in older pts were similar in both arms. ECOG PS scores were 0 (36% vs 36%), 1 (52% vs 54%), and 2 (12% vs 10%) in A+AVD and ABVD arms, respectively. Pts received a median of 6 cycles with mean relative dose intensities for each drug (%) in older pts of: A+AVD, 92.3, 96.6, 93.3, and 97.9; ABVD, 97.3, 88.7, 93.3, and 95.9. With median follow-up of ~25 months, 2-yr mPFS per IRF was similar in both arms for older ITT pts (A+AVD 70.3% [95% CI: 58.4, 79.4] vs ABVD 71.4% [95% CI: 60.5, 79.8]; HR=1.00 [95% CI: 0.58, 1.72]; p=0.993). An exploratory analysis of standard PFS per investigator (INV) showed HR=0.85 ([95% CI: 0.49, 1.48]; p=0.576) (Table 1). For older pts with stage IV cHL (A+AVD n=51; ABVD n=67), there was an increase in 2-yr PFS per INV with A+AVD vs ABVD (74.0% [95% CI: 59.5, 84.0] vs 59.9% [95% CI: 45.6, 71.5]; HR, 0.66 [95% CI: 0.34, 1.26]; p=0.20); mPFS per IRF improvement with A+AVD in older stage IV pts was lower (HR=0.80; [95% CI: 0.42, 1.53]). In younger stage III/IV pts (<60 yrs) 2-yr mPFS per IRF and PFS per INV were also higher compared with older pts in both arms (Table 1). 66 of 83 older A+AVD pts required ≥1 dose modification of brentuximab vedotin, reasons were: dose reduction (n=27), dose held (n=4), dose delayed (n=51), brentuximab vedotin discontinued (n=17). In older pts, grade (G) 3/4 AEs occurred in 88% of A+AVD pts vs 80% ABVD pts; for younger pts, rates were 82% (A+AVD) vs 63% (ABVD) (Table 2). In older pts there were 3 (4%) on-study deaths in the A+AVD arm (1 each: hemophagocytosis, neutropenic sepsis, and myocardial infarction) and 5 (5%) with ABVD (all pulmonary-related). In pts <60 yrs, there were 6 on-study deaths (1%) with A+AVD vs 8 (1%) with ABVD. G3 neutropenia in older pts was (70%) A+AVD pts vs (59%) ABVD pts, and febrile neutropenia (FN) in 31 (37%) vs 17 (17%) pts. In older pts who had G-CSF primary prophylaxis (PP) neutropenia was seen in 4/10 (40%) A+AVD pts vs 1/9 (11%) ABVD pts (on-study FN in 3 [30%] vs 2 [22%] pts). In older pts, treatment-emergent peripheral neuropathy (PN) was reported in 54 (65%) of A+AVD pts vs 42 (43%) of ABVD pts (G≥3 in 15 [18%] vs 3 [3%] pts), respectively. In pts <60 yrs PN was reported in 388 (67%) A+AVD pts vs 244 (43%) ABVD pts (G≥3 in 55 [9%] vs 8 [1%] pts), respectively. In older pts at last follow-up, 65% (35/54) of A+AVD pts and 60% (25/42) of ABVD pts had complete resolution (A+AVD, 39%; ABVD, 38%) or improvement (A+AVD, 26%; ABVD, 21%) of PN events. 2% older A+AVD pts had pulmonary AEs (both G1/2 pulmonary infiltration) vs 13% older ABVD pts. Conclusions For older ECHELON-1 pts, mPFS and PFS were similar in both arms. In the larger subgroup of younger pts, mPFS and PFS were improved vs older pts. As expected, incidence of treatment-emergent AEs was higher in older pts, with regimen-specific AEs seen, including fatal pulmonary events in ABVD pts. The high incidence of FN in older A+AVD pts points to the need for G-CSF PP. Disclosures Evens: Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Tesaro: Research Funding; Novartis: Consultancy. Connors:Merck: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Roche Canada: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Seattle Genetics: Honoraria, Research Funding; Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; Bayer Healthcare: Research Funding; Cephalon: Research Funding; Bristol Myers-Squibb: Research Funding; Lilly: Research Funding; Genentech: Research Funding. Younes:Sanofi: Honoraria; Merck: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria; Incyte: Honoraria; Seattle Genetics: Honoraria; Bayer: Honoraria; Novartis: Research Funding; Curis: Research Funding; J&J: Research Funding; Genentech: Research Funding; Takeda: Honoraria; Roche: Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; BMS: Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding. Radford:Takeda: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Celgene: Research Funding; BMS: Consultancy, Speakers Bureau. Feldman:Seattle Genetics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Portola: Research Funding; KITE: Speakers Bureau. Tuscano:Takeda: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Oki:Seattle Genetics: Research Funding; Takeda Millenium: Honoraria, Research Funding; Jazz Pharmaceuticals: Employment. Grigg:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pocock:Kent & Canterbury Hospital: Employment. Dlugosz-Danecka:Roche: Consultancy; Servier: Consultancy. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Engley:Seattle Genetics: Employment. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jolin:Takeda Pharmaceuticals International Co.: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gallamini:Takeda: Consultancy, Speakers Bureau.