PURPOSE Ibrutinib has shown activity in non–germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non–germinal center B-cell DLBCL. PATIENTS AND METHODS Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%). CONCLUSION The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.

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www.clinicaltrials.gov (NCT00824265).

Introduction DLBCL is an aggressive disease that can be classified by immunohistochemistry (IHC) into GCB and non-GCB or by gene expression profiling (GEP) into GCB, activated B-cell (ABC), and unclassified subtypes. RCHOP is the standard frontline treatment (tx) for DLBCL with a 60% cure rate. Ibrutinib (ibr), an oral covalent Bruton's tyrosine kinase inhibitor, showed activity in relapsed/refractory ABC DLBCL. This study aimed to analyze if the addition of ibr to RCHOP would improve efficacy in previously untreated patients (pts) with non-GCB DLBCL or the ABC subtype. Methods Pts with centralized IHC-confirmed non-GCB DLBCL were randomized 1:1 to standard RCHOP with either ibr (560 mg/d, po) or placebo (pbo) on a 21-day cycle for 6 or 8 cycles. Pts were stratified by revised International Prognostic Index, region (US/Western Europe vs rest of world), and number of prespecified RCHOP cycles (6 or 8). ABC DLBCL was retrospectively identified using GEP (HTG EdgeSeq cell of origin assay). Primary end point was event-free survival (EFS), defined as time from randomization to progression, relapse from complete response (CR), initiation of tx for PET-positive or biopsy-proven residual disease after ≥ 6 cycles of RCHOP, or death, in the intent-to-treat (ITT) or ABC population. Secondary end points included progression-free survival (PFS), CR rate, overall survival (OS), and safety. Results Overall, 838 pts were randomized to ibr + RCHOP (n = 419) or pbo + RCHOP (n = 419). Median age was 62 years (yrs) with 58.5% < 65 yrs; 67.7% had ABC subtype. Baseline prognostic factors were balanced; slightly more pts ≥ 65 yrs in the ibr + RCHOP arm (45% vs 38%). In the ibr + RCHOP and pbo + RCHOP arms, 80.8% and 90.7% of pts received ≥ 6 cycles of RCHOP; 22.4% and 13.6% discontinued tx (all drugs) with adverse event (AE) being the most common reason (12.2% vs 5.3%). All deaths rate was 16.5% vs 17.2% in the ibr + CHOP vs pbo + RCHOP arm, respectively. In pts < 65 yrs, 90.4% vs 91.1% of pts received ≥ 6 cycles of RCHOP in the ibr + RCHOP vs pbo + RCHOP arm, respectively. Fewer pts ≥ 65 yrs in the ibr + RCHOP arm (69.0%) received ≥ 6 cycles of RCHOP compared with the pbo + RCHOP arm (90.0%). Ibr pharmacokinetics with RCHOP was similar to other studies in B-cell malignancies where ibr was used as a single agent or in combination. Median follow-up was 34.8 months. Ibr + RCHOP did not improve EFS in pts with non-GCB (by IHC) or ABC (by GEP) DLBCL: The hazard ratio (HR) for EFS was 0.934 (95% confidence interval [CI], 0.726-1.200) for the ITT and 0.949 (95% CI, 0.704-1.279) for the ABC subset. Multivariate analysis showed a significant interaction (based on SAP prespecified 1-sided α level p < 0.1) between tx effect and age as a continuous or categorical variable. Efficacy was a function of age: stable benefit seen in younger pts, with a decline with increasing age, and benefit no longer favorable in pts ≥ 65 yrs. Efficacy outcomes favored ibr + RCHOP-treated pts < 65 years with statistically significant risk reduction in EFS (30%), PFS (33%), and OS (43%; Table, Figure). A similar trend was seen in the ABC subset. Multivariate analyses, adjusting for other baseline covariates, confirmed the tx benefit in younger but not elderly pts. Grade ≥ 3 AE rates were 89.9% and 87.1% in the ibr + RCHOP and pbo + RCHOP arms, respectively. Serious AEs (SAEs) were greater in the ibr + RCHOP vs pbo + RCHOP arm (53.1% vs 34.0%), particularly febrile neutropenia and pneumonia, as were AEs leading to RCHOP discontinuation. In pts ≥ 65 yrs, there were more SAEs (67.4% vs 40.6%) and pts who received < 6 cycles of RCHOP (31.0% vs 10.0%) in the ibr + RCHOP vs pbo + RCHOP arm. In pts < 65 yrs, grade ≥ 3 AEs were similar; SAEs were numerically higher (41.5% vs 29.8%) in the ibr + RCHOP vs pbo + RCHOP arm, but the proportion of pts who received < 6 cycles of RCHOP was similar (9.6% vs 8.9%) between arms. Conclusions While the addition of ibr to RCHOP did not improve efficacy in the ITT population, there was a significant interaction between tx and age. Among pts ≥ 65 yrs, unexpected increased toxicity associated with ibr + RCHOP resulted in reduced RCHOP exposure, which may explain in part the worse clinical benefit/risk profile of pts in the ibr + RCHOP vs pbo + RCHOP arm. However, in pts < 65 yrs, the addition of ibr showed clinically meaningful improvement in EFS, PFS, and OS with an acceptable safety profile. Funding Source Sponsored by Janssen. Writing assistance was provided by Liqing Xiao of PAREXEL and funded by Janssen. Disclosures Younes: J&J: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; Celgene: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; Incyte: Honoraria; Curis: Research Funding; Novartis: Research Funding; Seattle Genetics: Honoraria; Genentech: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Merck: Honoraria. Sehn:Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Johnson:Takeda: Honoraria, Travel, accommodations, expenses; Incyte: Consultancy; Celgene: Honoraria; Novartis: Honoraria; Janssen: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Eisai: Research Funding; Bristol-Myers Squibb: Honoraria; Kite: Consultancy; Boeringher Ingelheim: Consultancy; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Genmab: Consultancy. Zinzani:Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lopez-Hernandez:Servier: Speakers Bureau; Roche: Research Funding; Takeda: Speakers Bureau. Dührsen:Celgene: Honoraria, Research Funding; Amgen: Research Funding; Janssen: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Carey:Janssen Research & Development: Employment. Liu:Janssen Research & Development: Employment, Equity Ownership. Shreeve:Janssen Research & Development: Employment, Equity Ownership. Sun:Janssen Research & Development: Employment, Equity Ownership. Vermeulen:Janssen Research & Development: Employment, Equity Ownership.

Introduction Chemoimmunotherapy with purine analogues and the anti-CD20 antibody rituximab is the standard of care as initial therapy in younger and physically fit patients with chronic lymphocytic leukemia (CLL). However, most CLL patients are elderly and/or have comorbidities, meaning that fludarabine-containing regimens are often inappropriate, carry greater toxicity, and treatment of these patients remains challenging. Most randomized studies in previously untreated CLL have been conducted in younger or fit patients and results cannot necessarily be extrapolated to older, less fit patients. While chlorambucil (CHL) remains a standard of care for this patient population, more effective but tolerable treatment choices are still needed. Ofatumumab (O) demonstrated superior preclinical activity, compared to rituximab, against cells with low CD20 density like CLL and showed clinical activity as monotherapy, with high overall response rates (ORR) in patients with refractory CLL. Therefore, the addition of O to CHL could provide superior clinical outcomes than CHL alone, while being tolerable, for patients who are elderly and/or have comorbidities and currently have limited treatment options. Methods Patients with CLL who required therapy (2008 NCI-WG guidelines) and were considered inappropriate for fludarabine-based therapy due to advanced age and/or co-morbidities were randomized (1:1) to receive either O+CHL or CHL. CHL was given orally (10mg/m2 at days 1-7 of each 28 day cycle) and O was administered as intravenous infusions (Cycle 1: 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1). O premedication included acetaminophen, antihistamine and glucocorticoid. Treatment duration was a minimum of 3 cycles, until best response up to a maximum of 12 cycles. The primary endpoint was progression-free survival (PFS) assessed by an Independent Review Committee (IRC) and secondary endpoints included overall response rate (ORR), overall survival (OS) and safety. Patients 447 patients from 16 countries were randomized. Baseline demographics and disease characteristics were well balanced between the 2 arms. Median age was 69 years with 82% ≥65 years and/or having ≥2 comorbidities. All modified Rai stages were represented (Low 8%, intermediate 51%, high 40%). 56% of patients had unmutated IgVH, 6% showed 17p deletions and 75% had β-2-microglobulin levels ≥3500μg/L. Results PFS as assessed by an IRC was significantly prolonged in the O+CHL arm (22.4 months) compared to CHL alone (13.1 months, p<0.001). ORR was higher for O+CHL vs CHL (82% vs 69%, p=0.001), with a superior CR rate (12% vs 1%). 37% of O+CHL subjects with an IRC-assessed CR were MRD negative. With a median follow-up of 29 months, median OS was not reached for O+CHL or CHL. Median duration of treatment for both arms was 6 cycles and 82% of patients received 6 or more cycles of O+CHL. Grade ≥3 AEs that occurred from start of treatment until 60 days after the last dose were experienced by 50% of patients receiving O-CHL and 43% of patients on CHL with the most common being neutropenia (O+CHL: 26%, CHL: 14%). Grade ≥3 infusion-related AEs were reported in 10% of patients. No fatal infusion reactions were reported. Grade ≥3 infections were reported in 15% (O+CHL) and 14% (CHL) of patients, with the most common infection being pneumonia (O+CHL: 4%, CHL: 3%). Deaths during treatment occurred in 2% of subjects in both arms. Conclusion Ofatumumab added to chlorambucil (O+CHL) demonstrated clinically important improvements with a manageable side effect profile in patients with CLL who have not received prior therapy and who are considered inappropriate for fludarabine based therapy. Disclosures: Hillmen: Roche Pharmaceuticals: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: The use of ofatumumab in combination with chlorambucil in previously untreated CLL. The reported trial will support the extension of the ofatumumab licence. Robak:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GlaxoSmithKline: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau; Amgen: Speakers Bureau. Mayer:Glaxo: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Panagiotidis:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Kimby:Pharmacyclics: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Teva: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Emergent: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schuh:GSK: Honoraria, Research Funding. Montillo:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. McKeown:GSK: Employment. Carey:GlaxoSmithKline: Employment. Gupta:GSK: Employment. Chang:GSK: Employment. Lisby:Genmab: Employment, hold stock options Other. Offner:Lilly: Membership on an entity’s Board of Directors or advisory committees.