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Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focused attention on the changes in GEP accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo patients with DLBCL. COO remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from activated B-cell–like (ABC) to germinal center B-cell–like (GCB). Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC–DLBCLs derived from relapse-associated genes that defined clinically distinct high- and low-risk subgroups in ABC–DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of

DLC-001 Study Design (CONSORT diagram)

Grade 3/4 Treatment-Emergent Adverse Events Reported in {greater than or equal to}5% of Patients (Safety Population)

List of Primer Sequences

Supplementary Table 1 PDF file 55K, Cut-points for protein markers used in different analyses. Cut-points selected for pair-wise comparisons were chosen to reduce the total number of comparisons that would be done. Cut-points for the discovery/confirmation analyses (see Supplementary Methods) were optimized based on enrichment of responders versus non-responders and reasonable population size

Supplementary Figure 1 PDF file 77K, Biomarker sample collection from the LYM-3001 intent-to-treat population

Supplementary Table 4 PDF file 69K, OS, ORR, CR rate, and TTNT in all patients in the cross-validation model (see Supplementary Methods) who were positive or negative for the biomarker pair PSMB1 P11A (G allele) and low CD68 expression (≤50 CD68-positive cells). Among all biomarker-positive patients there was a significantly longer OS with bortezomib-rituximab versus rituximab, a significantly higher ORR, a higher CR rate, and a significantly longer TTNT. No significant differences were seen for biomarker-negative patients

Supplementary Table 3 PDF file 70K, Median PFS for patients in the discovery and confirmation sets, and in all patients, in the cross-validation model (see Supplementary Materials) who were positive or negative for the biomarker pair PSMB1 P11A (G allele) and low CD68 expression (≤50 CD68-positive cells). Presence of the biomarker pair was associated with a significant PFS benefit in patients treated with bortezomib-rituximab versus rituximab in the discovery set, a positive trend in the smaller confirmation sets, and a significant benefit among all patients. No significant differences were seen for biomarker-negative patients

Purpose: Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib–rituximab versus rituximab in the phase III LYM-3001 study.Experimental Design: A total of 676 patients were randomized to five 5-week cycles of bortezomib–rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes.Results: In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib–rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib–rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib–rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets.Conclusions: Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib–rituximab versus rituximab. Clin Cancer Res; 19(9); 2551–61. ©2013 AACR.

Supplementary Figure 2 PDF file 135K, Forest plot for single marker (A) protein and (B) germ-line DNA biomarker analyses

Supplementary Methods PDF file 64K, TaqMan SNP Genoytping Assays and Ligation-based Multiplexed Genotyping Assays

Investigator's Choice (IC) Dosing Regimens

Supplementary Table 2 PDF file 78K, Evaluation of PFS and OS under the G-dominant genetic model for PSMB1 P11A among all patients evaluable for the biomarker pair of PSMB1 P11A genotype and CD68 expression who had low (≤50 CD68-positive cells) CD68 expression

Supplementary Figure 3 PDF file 78K, Kaplan-Meier distributions of A) PFS and B) OS under the G-dominant genetic model for PSMB1 P11A among all patients evaluable for the biomarker pair of PSMB1 P11A genotype and CD68 expression who had low (≤50 CD68-positive cells) CD68 expression

Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550).Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127–37. ©2017 AACR.

We report final analysis outcomes from the phase 3 HELIOS study (NCT01611090). Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma without deletion 17p (n = 578) were randomized 1:1 to 420 mg daily ibrutinib or placebo plus ≤6 cycles of bendamustine plus rituximab (BR), followed by ibrutinib or placebo alone. Median follow-up was 63.7 months. Median investigator-assessed progression-free survival was longer with ibrutinib plus BR (65.1 months) than placebo plus BR (14.3 months; hazard ratio [HR] 0.229 [95% confidence interval (CI) 0.183-0.286]; p

Mantle cell lymphoma is a rare, aggressive, and largely incurable form of non-Hodgkin lymphoma. There are a number of well-characterized prognostic features but nothing that can help guide therapy. Treatment with chemotherapy is generally effective in the short term, but relapse is inevitable and subsequent treatment is challenging. The use of Bruton tyrosine kinase inhibitors, however, has transformed practice. These agents are highly active in relapsed disease and are very well-tolerated drugs. Chemotherapy-free combinations using Bruton tyrosine kinase inhibitors look very exciting and will likely evolve to be part of frontline care in the future.

This is a 5-year real-world study of 65 patients treated with ibrutinib for relapsed/refractory mantle cell lymphoma across the UK and Ireland. Ibrutinib was well tolerated with no fatal adverse events. The median progression-free survival and overall survival (OS) was 12 and 18·5 months, respectively. Overall, 80% of patients discontinued treatment, predominantly for progressive disease. On discontinuation, 20% received alternative immunochemotherapy with a median OS of 24 months. Ibrutinib was used as a bridge to transplant in 8% (median OS not reached). These observations are comparable with trial outcomes with encouraging responses to immunochemotherapy at relapse.

B-cell receptor (BCR) signaling pathway inhibitors (including Bruton’s tyrosine kinase [BTK] inhibitors, and phosphatidylinositol-3 kinase inhibitors [PI3Ki]) have shown clinical efficacy in non-Hodgkin lymphoma (NHL). However, responses to these agents have been limited in depth and duration. This may be due to resistance to PI3Kδ and BTK inhibitors as monotherapy [1,2,3,4,5]. The emergence of resistant clones may be addressed by combining these 2 classes of drugs. Furthermore, tolerability of these drug classes has been a concern. Combination therapy using lower doses of one or more classes of inhibitors may address some limitations.

Mantle Cell Lymphoma is a rare and generally aggressive form of non Hodgkin lymphoma. Our understanding of the pathophysiology of this disease is improving and whilst risk factors are understood, treatments are not yet tailored towards these. The treatment algorithm in the front line is well established for older and younger patients and observation is the norm for a subset of patients although these are not well characterised as yet. In the relapse setting the role of novel agents, especially the BTK inhibitors is becoming established and combination approaches look promising. Trials are beginning to challenge the role of chemotherapy against the novel agents especially as part of front line therapy. As a consequence it is likely we will see a paradigm shift in the management of this disease in the next few years.

Blastoid mantle cell lymphoma is characterized by highly aggressive features and a dismal clinical course. These blastoid and pleomorphic variants are defined by cytomorphological features, but the criteria are somewhat subjective. The diagnosis may be supported by a high cell proliferation based on the Ki-67 labeling index. Recent analyses have shown that the Ki-67 index overrules the prognostic information derived from the cytology subtypes. Nevertheless, genetic analysis suggests that blastoid and pleomorphic variants are distinct from classical mantle cell lymphoma. In clinical cohorts, the frequency of these subsets varies widely but probably represents ∼10% of all cases. Chemotherapy regimens commonly used in mantle cell lymphoma, such as bendamustine, rarely achieve prolonged remissions when given at the dosage developed for classical variants of the disease. Thus, high-dose cytarabine–containing regimens with high-dose consolidation may be generally recommended based on the more aggressive clinical course in these patients. However, even with these intensified regimens, the long-term outcome seems to be impaired. Thus, especially in this patient subset, allogeneic transplantation may be discussed at an early time point in disease management. Accordingly, targeted approaches are warranted in these patients, but clinical data are scarce. Ibrutinib treatment results in high rates of responses, but the median duration of remission is

M7583 is a potent, highly selective, covalent BTK inhibitor in development. In this phase I, first-in-human, open label, multicenter dose-escalation trial, M7583 was given at 80 mg (threedays)/160 mg (full 28-day cycle), then 300 mg/day, 600 mg/day, 900 mg/day, and 300 mg twice daily to 18 patients (median age 63years) with refractory/resistant, stage III/IV B-cell malignancies who failed prior therapy (NCT02825836). No dose-limiting toxicities were reported. Treatment-emergent adverse events (AEs) occurred in 89% of patients, treatment-related AEs in 78%, and treatment-related grade ≥3 AEs in 17%. Common AEs were diarrhea (33%), fatigue (22%), and vomiting (17%). M7583 was rapidly absorbed and exposure was dose-proportional. BTK occupancy was >95% in the 300 mg twice daily and 900 mg/day cohorts. Objective response rate was 50% and disease control rate 78%, supporting a favorable benefit:risk profile. Fasted doses up to 900 mg once daily and 300 mg twice daily were well tolerated and may be tested in future clinical studies.

Funder: Janssen Pharmaceuticals; Id: http://dx.doi.org/10.13039/100008897, Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom's National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1-22·2) and median overall survival (OS) 23·9 months (95% CI 15·0-32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1-19·8, vs. 3·6 months, 95% CI 2·6-4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.

Bruton tyrosine kinase (BTK) inhibition is an effective therapy for many B-cell malignancies. Acalabrutinib is a next-generation, potent, highly selective, covalent BTK inhibitor. To characterize acalabrutinib tolerability, we pooled safety data from 1040 patients with mature B-cell malignancies treated with acalabrutinib monotherapy in nine clinical studies (treatment-naive: n = 366 [35%], relapsed/refractory: n = 674 [65%]; median [range] age: 67 [32–90] years; median [range] prior treatments: 1 [0–13]; median [range] duration of exposure: 24.6 [0.0–58.5] months). The most common adverse events (AEs) were headache (38%), diarrhea (37%), upper respiratory tract infection (22%), contusion (22%), nausea (22%), fatigue (21%), and cough (21%). Serious AEs (SAEs) occurred in 39% of patients; pneumonia (6%) was the only SAE that occurred in ≥2%. Deaths due to AEs occurred in 52 patients (5%); pneumonia (n = 8) was the only fatal AE to occur in ≥3 patients. AEs led to treatment discontinuation in 9%. Rates for the AEs of interest (all grades) included infections (67%), hemorrhages (46%), neutropenia (16%), anemia (14%), second primary malignancies (12%), thrombocytopenia (9%), hypertension (8%), and atrial fibrillation (4%). This pooled analysis confirmed acalabrutinib’s tolerability and identified no newly emerging late toxicities, supporting acalabrutinib as a long-term treatment for patients with mature B-cell malignancies.

Ibrutinib, obinutuzumab, and venetoclax demonstrate synergy in preclinical models of mantle cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multicenter prospective phase 1/2 trial, aimed to determine the maximum tolerated dose of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide quantitative polymerase chain reaction. Between 14 October 2015 and 29 May 2018, 48 patients were enrolled. No dose-limiting toxicity was reported, and venetoclax at 400 mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events. The complete response rate assessed by positron emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10/14 patients) and 100% of untreated MRD-evaluable patients (n = 12) at the end of 3 cycles. The median follow-up for relapsed patients was 17 months (range, 10-35 months). The 2-year progression-free survival (PFS) was 69.5% (95% confidence interval [CI], 52.9%-91.4%) and 68.6% (95% CI, 49.5%-95.1%) for overall survival. The median follow-up was 14 months (range, 5-19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5%-100%). The combination of obinutuzumab, ibrutinib, and venetoclax is well tolerated and provides high response rates, including at the molecular level, in relapsed and untreated MCL patients. This trial was registered at www.clinicaltrials.gov as #NCT02558816.

Background As the coronavirus disease 2019 (COVID-19) pandemic grows daily, we remain with no prophylactic and only minimal therapeutic interventions to prevent or ameliorate severe acute respiratory syndrome Corona-virus 2 (SARS-CoV-2). Prior to SARS-CoV-2 emergence, high throughput screens utilizing clinically developed drugs identified compounds with in vitro inhibitory effect on human coronaviruses that may have potential for repurposing as treatment options for COVID-19. However, caution should be applied to repurposing of these drugs when they are taken out of context of human pharmacokinetic parameters associated with normal therapeutic use. Methods Our aim was to provide a tier-based scoring system to interrogate this data set and match each drug with its human pharmacokinetic criteria, such as route of administration, therapeutic plasma levels and half-life, tissue distribution and safety. Results Our analysis excluded most previously identified drugs but identified members of four drug classes (anti-malarial amino-quinolones, selective estrogen receptor modulators [SERMs], low potency tricyclic antipsychotics and tricyclic antidepressants) as potential drug candidates for COVID-19. Two of them, the tricyclic antipsychotics and tricyclic antidepressants were further excluded based on a high adverse event profile. Conclusions In summary, our findings using a new pharmacokinetic-based scoring system supports efficacy testing of only a minority of candidates against SARS-CoV-2 infection.

Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.

IntroductionOutcomes after frontline treatment of Burkitt lymphoma (BL) have improved with the introduction of dose‐intense chemotherapy regimens, such as CODOX‐M/IVAC. While rituximab has increased survival rates for most forms of high‐grade B‐cell lymphoma, there has previously been hesitancy about incorporating it into BL treatment, partly due to concerns about increased toxicity. Prospective data using the standard dose CODOX‐M/IVAC regimen in combination with rituximab are lacking. We conducted a single‐arm phase 2 trial to assess the efficacy and toxicity of R‐CODOX‐M/R‐IVAC.MethodsEligible patients were aged 18–65 years, with newly diagnosed BL with MYC rearrangement as the sole cytogenetic abnormality, and high‐risk disease, defined by an International Prognostic Index (IPI) score of 3‐5. Patients received two cycles of R‐CODOX‐M chemotherapy alternating with two cycles of R‐IVAC, followed by two further cycles of rituximab alone. The primary endpoint was 2‐year progression‐free survival.ResultsThirty‐eight patients were registered but after central pathology review, 27 patients had confirmed BL and commenced study treatment. Median age was 35 years, 14.8% patients had central nervous system involvement and 18.5% were HIV positive. Twenty‐two (81.4%) patients completed four cycles of chemotherapy. There were two treatment‐related deaths (7.4%). Two‐year progression‐free and overall survival rates were 77.2% (90% confidence interval [CI]: 56.0‐89.0) and 80.7% (90% CI: 59.6‐91.5), respectively.ConclusionsThis prospective trial demonstrates excellent survival rates with R‐CODOX‐M/R‐IVAC in a high‐risk BL cohort. It provides reassuring evidence regarding the feasibility of this regimen and also provides a benchmark for future studies.

Mantle cell lymphoma (MCL) is a comparatively rare non-Hodgkin’s lymphoma characterised by overexpression of cyclin D1. Many patients present with or progress to advanced stage disease within 3 years. MCL is considered an incurable disease with median survival between 3 and 4 years. We have investigated the role(s) of CCN1 (CYR61) and cell cycle regulators in progressive MCL. We have used the human MCL cell lines REC1 G519 > JVM2 cells by RQ-PCR, depicting a decrease in CCN1 expression with disease progression. Investigation of CCN1 isoform expression by western blotting showed that whilst expression of full-length CCN1 was barely altered in the cell lines, expression of truncated forms (18–20 and 28–30 kDa) decreased with disease progression. We have then demonstrated that cyclin D1 and cyclin dependent kinase inhibitors (p21(CIP1)and p27(KIP1)) are also involved in disease progression. Cyclin D1 was highly expressed in REC1 cells (OD: 1.0), reduced to one fifth in G519 cells (OD: 0.2) and not detected by western blotting in JVM2 cells. p27(KIP1) followed a similar profile of expression as cyclin D1. Conversely, p21(CIP1) was absent in the REC1 cells and showed increasing expression in G519 and JVM2 cells. Subcellular localization detected p21(CIP1)/ p27(KIP1) primarily within the cytoplasm and absent from the nucleus, consistent with altered roles in treatment resistance. Dysregulation of the CCN1 truncated forms are associated with MCL progression. In conjunction with reduced expression of cyclin D1 and increased expression of p21, this molecular signature may depict aggressive disease and treatment resistance.

We present a long-term follow-up of the UK chlorambucil, mitoxantrone and dexamethasone (CMD) versus fludarabine, mitoxantrone and dexamethasone (FMD) for untreated advanced, symptomatic follicular lymphoma (FL). This trial was the first to prospectively assess molecular response and the impact on outcomes for 400 patients. The median progression-free survival (PFS) and overall survival (OS) for CMD were 3·6 and 14·6 years vs. 3·0 and 15·7 years for FMD, respectively. Estimates for Restricted Mean Survival Time (RMST) suggested no difference in PFS or OS. For the whole cohort there was a highly significant difference in survival by POD24, with a median OS from a risk-defining event of 3·9 years compared to 13·7 years for all others (RMST P < 0·001). Molecular remission was achieved in 25/46 patients (54·3%) in the CMD arm and 20/41 (48·8%) in the FMD arm (P = 0·6). Molecular negativity resulted in median PFS of 5·6 years vs. 2·3 years for molecularly positive (log-rank P < 0·001) and median OS not reached versus 12·5 years (log-rank P < 0·01). No cases of progression occurred in minimal residual disease (MRD) negative patients after six years of follow-up. Although there was no difference in outcomes between arms, this is the first prospective study to report MRD negativity resulting in significantly improved OS.

Mantle cell lymphoma (MCL) is a rare but often aggressive B-cell non-Hodgkin lymphoma (NHL). Initial therapy can achieve high response rates but invariably patients relapse and die from their disease. Incorporating a maintenance phase into the treatment strategy may prolong remission duration and ultimately prolong survival. Areas covered: The current literature incorporating a maintenance phase into treatment strategies for newly diagnosed and pre-treated MCL patients has been summarized. A literature search was performed using search terms 'mantle cell lymphoma', 'indolent NHL', 'maintenance', 'interferon', 'rituximab', 'lenalidomide', 'bortezomib' and 'ibrutinib'. Relevant conference proceedings and on-going clinical trial databases were also searched. Expert commentary: There have been few significant trials evaluating the use of maintenance therapy in the context of MCL. Of those performed only rituximab has a significant body of evidence to support it's use and it's benefit is confined to use after certain specific therapies. Of the newer drugs ibrutinib is the most active of the single agents being used in this condition and it is given as continuous therapy to patients who respond to it. How it will be used precisely in a maintenance approach needs to be better defined and is the subject of on-going clinical trials.

Rituximab (MabThera®/Rituxan®), a chimeric murine/human monoclonal antibody that binds specifically to the transmembrane antigen CD20, was the first therapeutic antibody to enter clinical practice for the treatment of cancer. As monotherapy and in combination with chemotherapy, rituximab has been shown to prolong progression-free survival and, in some indications overall survival, in patients with various B-cell malignancies, while having a well-established and manageable safety profile and a wide therapeutic window. As a result, rituximab is considered to have revolutionized treatment practices for patients with B-cell malignancies. A subcutaneous (SC) formulation of rituximab has been developed, comprising the same monoclonal antibody as the originally marketed formulation [rituximab concentrate for solution for intravenous (IV) infusion], and has undergone a detailed, sequential clinical development program. This program demonstrated that, at fixed doses, rituximab SC achieves non-inferior serum trough concentrations in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia, with comparable efficacy and safety relative to the IV formulation. The added benefit of rituximab SC was demonstrated in dedicated studies showing that rituximab SC allows for simplified and shortened drug preparation and administration times resulting in a reduced treatment burden for patients as well as improved resource utilization (efficiency) at the treatment facility. The improved efficiency of delivering rituximab’s benefit to patients may broaden patient access to rituximab therapy in areas with low levels of healthcare resources, including IV-chair capacity constraints. This article is a companion paper to G. Salles, et al., which is also published in this issue. Funding F. Hoffmann-La Roche Ltd.

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were 18.6, 12.8 and 25.0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non-blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0–1, non-bulky disease and non-blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.

Background: Mantle cell lymphoma (MCL) accounts for approximately 5-7% of non-Hodgkin lymphomas (NHL). Bruton's tyrosine kinase (BTK) inhibitors, eg ibrutinib, are indicated for treatment of adults with MCL who have received ≥1 prior therapy. Primary and acquired resistance to ibrutinib is common and linked with poor outcomes, and remains an unmet medical need. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor, demonstrated clinical activity in patients (pts) with relapsed or refractory (R/R) NHL. We report preliminary results for parsaclisib monotherapy in a cohort of pts with R/R MCL who were previously treated with ibrutinib in the open-label, phase 2 study CITADEL-205 (NCT03235544). Methods: Pts must be ≥18 years of age with pathologically confirmed MCL, R/R disease to the most recent treatment, documented cyclin D1 overexpression or t(11;14) translocation, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and received 1 to 3 prior systemic treatments (including ibrutinib). Prior treatment with PI3Ki was prohibited. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From October 2017 to January 17, 2020 (data cut-off), 47 pts were treated (WG, n = 12; DG, n = 35). Enrollment is ongoing. At cut-off, 70% of pts had discontinued treatment, most commonly due to progressive disease (62%). Median exposure (range) was 2.2 (0.1-18.0) months. Median age was 70 years and 79% of pts were men. Median time since initial diagnosis was 4.7 years. Most pts (85%) had ECOG PS ≤1 and 51% had high-risk MCL International Prognostic Index. The median number of prior systemic therapies was 3; 38% of pts had prior hematopoietic stem cell transplant, and 38% were refractory to most recent systemic therapy. At data cut-off, 46 pts were evaluable for efficacy, including 12 in WG and 34 in DG (Table). Median follow-up (range) for this population was 10.2 months (1.5-25.9) overall and 7.6 months (1.5-25.9) for DG. ORR (95% confidence interval [CI]) and CRR were 28.3% (16.0-43.5) and 2.2%, respectively in all evaluable pts, and 35.3% (19.7-53.5) and 2.9%, respectively in DG. Median time to complete or partial response was 7.6 weeks. Median DOR (95% CI) was 7.3 months (0.2-not estimable) among all responders and 3.7 months (0.2-7.3) for DG. Median PFS (95% CI) was 3.65 months (1.9-3.9) overall and 3.65 months (1.9-5.5) for DG. Among 47 safety-evaluable pts, most common treatment-emergent adverse events (TEAEs) occurring in >10% of pts were anemia (19.1%), diarrhea (19.1%), neutropenia (14.9%), asthenia and cough (12.8% each), decreased appetite, dyspnea, fatigue, pyrexia and rash (10.6% each). Most common grade ≥3 TEAEs reported in ≥5% of pts included anemia (12.8%), neutropenia (10.6%), thrombocytopenia and rash (6.4% each). TEAEs leading to dose interruption or reduction occurred in 31.9% and 2.1% of pts, respectively. TEAEs leading to treatment discontinuation occurred in 2 (4.3%) pts (diarrhea and colitis). Serious TEAEs reported in ≥2 pts were diarrhea, dyspnea, peripheral swelling and pneumonia (4.3% each). Two pts experienced fatal TEAEs (one pt had general physical health deterioration and respiratory tract infection, deemed not related to treatment; one pt had pneumonia, neutropenia, and septic shock, deemed related to treatment and disease progression). New or worsening grade ≥3 laboratory test values of clinical interest occurring in ≥5% of pts included decreased neutrophils (14.9%), platelets (10.6%), and hemoglobin (8.5%); there were no grade ≥3 increases in alanine/aspartate aminotransferase. Conclusion: Preliminary efficacy data indicate that parsaclisib monotherapy is clinically active in this difficult-to-treat patient population. Treatment with parsaclisib had an acceptable safety profile and was generally well tolerated. Updated study results will be presented. Disclosures Zinzani: EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, 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, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eusapharma: Consultancy, Speakers Bureau. Delwail:Amgen: Consultancy. Paneesha:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Rule:AstraZeneca: Consultancy; Celgene: Consultancy; Celltrion: Consultancy; Janssen Oncology: Consultancy, Research Funding, Speakers Bureau; Roche Pharma AG: Consultancy, Research Funding. Martin Garcia-Sancho:Roche, Celgene, Janssen, Servier, Gilead: Honoraria; Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy. Salles:Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Servier: Consultancy, Honoraria; Acerta Pharma: Consultancy; Kite Pharma: Consultancy; Merck: Consultancy, Research Funding; Novimmune: Consultancy; Pfizer: Consultancy; Sanofi: Other. Sancho:Sandoz: Consultancy; Celltrion: Consultancy; Roche: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria; Kern-Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Mehta:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gelgene/BMS: Research Funding; Affimed: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding; Juno Parmaceuticals/BMS: Research Funding; Innate Pharmaceuticals: Research Funding; Oncotartis: Research Funding; Roche-Genentech: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; fortyseven Inc/Gilead: Research Funding; Takeda: Research Funding.

Introduction: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is physiologically expressed during embryogenesis, largely disappears by birth, but can be reexpressed pathologically in transformed tissues of many hematological and solid cancers. VLS-101 is an antibody-drug conjugate (ADC) comprising a rapidly internalizing, humanized monoclonal antibody (UC-961) that recognizes extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin, monomethyl auristatin E (MMAE). Methods: This first-in-human, Phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and efficacy of VLS-101 in patients unselected for tumor ROR1 expression who had previously treated chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Richter transformation lymphoma (RTL). VLS-101 was infused over 30 min every 3 wk until cancer progression or intolerable toxicity. After accrual of 1 patient at the first dose level, cohorts were enrolled by 3+3 dose escalation with additional patients accrued and intrapatient dose escalation permitted to refine estimates of maximum tolerated dose and recommended dosing regimen (RDR). Results: 32 patients were enrolled, including 19 males and 13 females with median (range) ages of 70 (54-84) ys; ECOG performance status (n) of 0 (18), 1 (10), or 2 (4); and tumor types (n) of MCL (15), CLL (7), DLBCL (5), FL (3), MZL (1), and RTL (1). Patients had received a median (range) of 4 (1-24) prior systemic therapies including hematopoietic stem cell transplantation (5) and/or chimeric antigen receptor (CAR)-T or -natural killer (NK) cells (6). Among patients with MCL, 15/15 (100%) had received a Bruton tyrosine kinase inhibitor (BTKi), 13/15 (87%) discontinued the BTKi due to progressive disease, and 2/15 (13%) discontinued for atrial fibrillation after 15.6 or 68.5 months of BTKi therapy. Patients (n) by VLS-101 starting dose were 0.5 (1), 1.0 (3), 1.5 (3), 2.25 (11), and 2.5 (14) mg/kg. With intrapatient dose escalation, many patients (n) received a maximum of 2.25 mg/kg (12) or 2.5 mg/kg (17) during VLS-101 therapy (range: 1 to 13 cycles). Cycle 1 DLTs (n/N) by mg/kg dose level were 0.5 (0/1), 1.0 (0/3), 1.5 (0/3), 2.25 (1/11 [9%] Gr 4 neutropenia), and 2.5 (2/14 [14%]; one Gr 4 neutropenia; one Gr 3 diarrhea of uncertain cause). Gr 4 neutropenia occurred in 9/32 (28%) patients; 1/32 (3%) had neutropenic fever. Granulocyte colony-stimulating factor successfully ameliorated neutropenia. Baseline Gr 1 neuropathy was present in 10/32 (31%) patients. On-study reversible Gr 3 neuropathy occurred in 3/32 (9%) patients; no Gr 4 neuropathy occurred. Except for Gr ≤2 alopecia in 3/32 (9%) patients, other adverse events were not obviously drug-related. Considering all 175 infusions administered, drug-related infusion reactions, vomiting, tumor lysis syndrome, rash, hepatic or renal abnormalities, or QT prolongation were not observed. PK showed changes in ADC and MMAE exposures proportional with VLS-101 dose and a mean ADC half-life of ~2.5 d. PD indicated exposure-dependent ROR1 occupancy on circulating CLL cells. No neutralizing anti-drug antibodies were detected. Objective tumor responses were not seen in patients with other tumor types but were observed in 7/15 (47%) of patients with MCL (4 partial; 3 complete) and in 4/5 (80%) of patients with DLBCL (2 partial; 2 complete). From start of therapy, 6/7 patients with responding MCL have responses ongoing at 35, 38, 45, 47, 50, and 58 wk and 2/4 patients with responding DLBCL have responses ongoing at 23 and 47 wk of follow-up. Conclusions: In heavily pretreated patients, VLS-101 infusions were well tolerated and demonstrated a predictable safety profile consistent with an MMAE-containing ADC. Tumor selectivity was confirmed, with no evidence of ROR1-mediated toxicities or non-MMAE toxicities that would suggest normal tissue binding. Considering all data, the VLS-101 RDR was 2.5 mg/kg every 3 wk. Efficacy results provide clinical proof of concept for targeting ROR1 with VLS-101 and demonstrate durable objective responses in patients with advanced MCL or DLBCL, including those with prior BTKi or cellular therapies. Phase 1-2 studies of VLS-101 monotherapy and combination therapy in patients with hematological cancers and solid tumors are planned. Figure Disclosures Wang: Nobel Insights: Consultancy; Lu Daopei Medical Group: Honoraria; Oncternal: Consultancy, Research Funding; MoreHealth: Consultancy; Juno: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; OncLive: Honoraria; Guidepoint Global: Consultancy; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Targeted Oncology: Honoraria. Barrientos:Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Oncternal Therapeutics: Research Funding; Sandoz: Consultancy; Janssen: Honoraria; AstraZeneca: Consultancy. Furman:Verastem: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Genentech: Consultancy. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Barr:AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy; Morphosys: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Choi:Genentech: Consultancy; Pharmacyclics/Abbvie: Research Funding. de Vos:Bayer: Consultancy; Verastem: Consultancy. Patel:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Rule:Janssen: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy. Flanders:VelosBio: Current Employment, Current equity holder in private company. Jessen:VelosBio: Current Employment, Current equity holder in private company; eFFECTOR: Current equity holder in private company. Riebling:VelosBio: Current Employment, Current equity holder in private company. Graham:Ce3: Current Employment. King:Ce3: Current Employment; VelosBio: Consultancy; AI Therapeutics: Consultancy. Schmidt:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Lannutti:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Johnson:Zentalis: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Current equity holder in publicly-traded company; Neoleukin: Current equity holder in publicly-traded company; Oncternal: Divested equity in a private or publicly-traded company in the past 24 months; Appelis: Divested equity in a private or publicly-traded company in the past 24 months; Acerta: Patents & Royalties; VelosBio: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Miller:Cleveland BioLabs: Consultancy, Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company; Cancer Genetics: Current equity holder in publicly-traded company; Incuron: Consultancy; Zentalis: Consultancy, Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; EpiThany: Current equity holder in private company; AstraZeneca: Current equity holder in publicly-traded company; VelosBio: Consultancy, Current Employment, Current equity holder in private company; AI Therapeutics: Consultancy, Current equity holder in private company; Catalys Pacific: Consultancy. Spurgeon:Cardinal Health: Honoraria; VelosBio: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; Beigene: Research Funding; Verastem: Research Funding.

Background: Acalabrutinib (acala) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. The efficacy and safety of acala in relapsed/refractory (R/R) MCL pts was demonstrated in a single-arm phase 2 study (ACE-LY-004; NCT02213926) after a median follow-up of 26 mo (Wang M, et al. Leukemia. 2019;33:2762-6). Here, we present results after an additional year of follow-up. Methods: Adults with MCL and ECOG PS ≤2 who had relapsed or were refractory to 1-5 prior therapies, had no prior BTK/BCL-2 inhibitor exposure, and did not require warfarin/vitamin K antagonists, received oral acala 100 mg twice daily until progressive disease (PD) or toxicity. Overall response rate (ORR; investigator-assessed partial response [PR] or better per Lugano classification), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Minimal residual disease (MRD) was analyzed in formalin-fixed, paraffin-embedded samples and peripheral blood by next-generation sequencing (5x10-6) in pts with available paired samples. Results: 124 pts were included (median age, 68 [range: 42-90] y; ECOG PS ≤1, 93%; bulky lymph nodes ≥10 cm, 8%; extranodal involvement, 72%; intermediate-/high-risk simplified MCL International Prognostic Index score, 44%/17%; median number of prior therapies, 2 [range: 1-5]; refractory disease, 24%). After a median follow-up of 38.1 mo (range: 0.3-59.5), 24 (19%) pts remain on treatment and an additional 31 pts (55 total; 44%) remain in follow-up for survival. Of the 31 pts in post-acala follow-up, 6 remain PD-free (4 received post-acala treatment: anticancer treatment combinations and allogeneic stem cell transplant [n=3]; radiotherapy [n=1]). ORR was 81% (95% CI: 74, 88); 48% (95% CI: 39, 57) achieved complete response (CR). Median DOR was 28.6 mo (95% CI: 17.5, 39.1) and the estimated 36-mo DOR rate was 41.9% (95% CI: 31.7, 51.8). Median PFS was 22.0 mo (95% CI: 16.6, 33.3; Figure); estimated 36-mo PFS rate was 37.2% (95% CI: 28.2, 46.1). ORR and PFS were not significantly different between subgroups divided by Ki-67 index (≤50%, >50%); PFS also did not differ significantly by prior treatment regimen (bendamustine/rituximab [BR]-based, non-BR) or prior therapy line (1, 2, ≥3). Median OS was not reached; estimated 36-mo OS rate was 60.5% (95% CI: 51.1, 68.7). Of 30 MRD-evaluable pts, 6 (20%) achieved CR and undetectable MRD (uMRD) and maintained uMRD at last assessment. The adverse event (AE) profile was largely unchanged with an additional year of follow-up. The most frequent AEs (≥20%) of headache (39%), diarrhea (37%), fatigue (30%), cough (23%), myalgia (22%), and nausea (22%) were primarily grade 1/2. Grade 3/4 AEs (≥5%) were neutropenia (11%), anemia (10%), and pneumonia (6%). Overall, 16 pts (13%) had cardiac AEs (11 with prior cardiac risk factors); 3 of the 16 pts had cardiac AEs in the last year of follow-up (grade 3/4: n=2). Overall, 6 pts (5%) had grade 3/4 cardiac AEs (acute coronary syndrome, acute myocardial infarction, complete atrioventricular block, cardiac failure, cardiorespiratory arrest, coronary artery disease, sinus arrest; n=1 each). One pt had grade 3/4 hypertension in the last year (total any grade, n=5 [4%]; total grade 3/4, n=2 [2%]). Five pts had bleeding AEs in the last year (n=46 [37%] total) including 2 with grade 3/4 AEs of gastrointestinal hemorrhage (n=2 total) and 1 with grade 3/4 subdural hematoma (n=1 total). Three pts had grade 3/4 infections in the last year (n=21 [17%] total). Treatment discontinuation was primarily due to PD (n=74; 60%) and AEs (n=14; 11%). Seventeen AEs led to discontinuation in 14 pts; each AE occurred in only 1 pt. There were 57 deaths (46%), most commonly due to PD (n=38; 31%) or AEs (n=6; 5%); 14 deaths (11%) occurred in the last year of follow-up (PD, n=9; other, n=1; unknown, n=4). There were 6 deaths due to AEs (bilateral pulmonary embolism, critical aortic stenosis, myelodysplastic syndrome, pneumonia, suicide, non-small cell lung cancer); none were related to acala. Conclusion: Extended follow-up demonstrates no emerging safety concerns for acala in R/R MCL pts. After a median of 38.1 mo, 19% of pts remain on acala. Overall, an estimated one-third of pts remain progression free at 36 mo, with median OS not yet reached. These data support long-term use of acala in R/R MCL pts. Disclosures Wang: Dava Oncology: Honoraria; Verastem: Research Funding; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; OncLive: Honoraria; Molecular Templates: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; BioInvent: Research Funding; Acerta Pharma: Research Funding; VelosBio: Research Funding; Targeted Oncology: Honoraria; Lu Daopei Medical Group: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; MoreHealth: Consultancy; Juno: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding. Rule:Celgene: Consultancy; Celltrion: Consultancy; Roche Pharma AG: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, 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, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Goy:Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; MD Anderson: Research Funding; Celgene: Honoraria, Research Funding; CALBG: Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Karyopharm: Research Funding; Xcenda: Consultancy; Regional Cancer Care Associates/OMI: Current Employment; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; RCCA/OMI: Current Employment; PracticeUpdate Oncology: Consultancy; Infinity Verastem: Research Funding; AbbVie: Research Funding; Morphosys: Research Funding; Genentech/Roche: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Bayer: Research Funding; Infinity: Research Funding; Constellation: Research Funding. Casasnovas:Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Smith:Ignyta: Research Funding; Genentech: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Merck: Research Funding; De Novo Biopharma: Research Funding; Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Pharmacyclics: Research Funding; Millenium/Takeda: Consultancy; Acerta Pharma BV: Research Funding; Incyte: Research Funding; Karyopharm: Consultancy; Seattle Genetics: Research Funding; AstraZeneca: Consultancy; Portola: Research Funding; Beigene: Consultancy. Doorduijn:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Morschhauser:Celgene: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Epizyme: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Panizo:Bristol-Myers Squibb, Kyowa Kirin: Speakers Bureau; Clínica Universidad de Navarra: Current Employment; Janssen, Roche: Membership on an entity's Board of Directors or advisory committees. Shah:Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria; NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Jazz, Incyte: Research Funding; Moffitt Cancer Center: Current Employment; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Davies:Celegene, Roche, Kite Pharma, Celegene: Honoraria; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding. Dupuis:Henri Mondor University Hospital Creteil France: Current Employment. Jacobsen:Merck, Pharmacyclics, F. Hoffmann-LaRoche, Novartis: Research Funding; Takeda: Honoraria; Acerta, AstraZeneca, Merck: Consultancy. Kater:Roche: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Janssen: Research Funding. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy. Oberic:Roche, Janssen: Consultancy; Roche: Honoraria; Roche, Janssen: Other: Travel, Accommodations, Expenses. Robak:Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UCB: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Acerta: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Medical University of Lodz: Current Employment; GSK: Research Funding; Novartis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; UTX-TGR: Research Funding; Takeda: Consultancy; Morphosys: Research Funding; BioGene: Honoraria, Research Funding; Bristol Meyers Squibb: Research Funding; Pfizer: Research Funding; Momenta: Consultancy. Brock:Jazz Pharmaceuticals Inc: Current Employment; Acerta Pharmaceuticals: Ended employment in the past 24 months; Astra Zeneca: Current equity holder in publicly-traded company. Patel:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Tao:Clindata Insight inc: Ended employment in the past 24 months; Acerta Pharma, LLC: Current Employment.

Context: Few first-line chemotherapy-free treatment options are available for patients with follicular lymphoma (FL) who are elderly or have comorbid conditions. Single-agent rituximab has been used to treat previously untreated elderly, frail patients or those with low tumor burden. Ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor, is approved in the US and EU for the treatment of various B-cell malignancies. The combination of once-daily ibrutinib with 4 weekly doses of intravenous rituximab was evaluated in a phase 2 study as a first-line treatment option for patients with FL. At a median follow-up of 34 months, an overall response rate of 85% and complete response of 40% were reported. At 30 months, the progression-free survival (PFS) and overall survival rates were 67% and 97%, respectively (Fowler, BJH. 2020). Based on these promising results, the phase 3 PERSPECTIVE study was designed to further evaluate ibrutinib-rituximab combination therapy in previously untreated patients with FL. Objective: To compare PFS outcomes between: (1) ibrutinib-rituximab and placebo-rituximab, and (2) continuous versus fixed-duration ibrutinib treatment. Design: Phase 3, multicenter, randomized, double-blind, placebo-controlled study (PCYC-1141-CA, NCT02947347 ). Patients or other participants: Eligible patients are enrolled if they meet ≥1 Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion, and are aged ≥70 years or 60–69 years with ≥1 comorbidities (creatinine clearance 30–59 mL/min or ECOG performance status of 2). Patients who received any prior treatment for FL or showed evidence of CNS involvement or transformed lymphoma are excluded. Enrollment of approximately 440 patients is planned. Interventions: In Part 1, patients will be randomized to receive either: (1) once-daily oral ibrutinib-rituximab, or (2) once-daily oral placebo-rituximab. Patients in both arms will receive rituximab in 4 weekly doses, followed by rituximab maintenance therapy. In Part 2, patients receiving ibrutinib-rituximab and remaining on ibrutinib treatment for ≥2 years will be randomized again to either receive once-daily oral ibrutinib or switch to once-daily oral placebo. Main outcome measures: The primary endpoint is PFS for both parts. Conclusions: The study is currently enrolling patients at participating sites in the US, EU, and Asia Pacific. Funding: Pharmacyclics LLC, an AbbVie Company.

The GAUDI study assessed safety and preliminary efficacy of induction therapy with obinutuzumab plus chemotherapy, followed by maintenance therapy with obinutuzumab alone, in previously untreated patients with follicular lymphoma. Assignment to chemotherapy was decided on a per-center basis before the patients’ enrollment. Patients (n=81) received four to six cycles of obinutuzumab plus bendamustine every 4 weeks or six to eight cycles of obinutuzumab plus CHOP every 3 weeks. Patients with an end-of-treatment response were eligible for obinutuzumab maintenance therapy every 3 months for 2 years or until disease progression. Induction treatment was completed by 90% of patients in the obinutuzumab plus bendamustine group and 95% in the obinutuzumab plus CHOP group, while maintenance was completed by 81% and 72% of patients, respectively. All patients experienced at least one adverse event during induction, most commonly infusion-related reactions (58%), the majority of which were grade 1/2. The most common hematologic adverse event was grade 3/4 neutropenia (36% during induction and 7% during maintenance). One treatment-related death occurred during the maintenance phase. At the end of induction, 94% of patients had achieved an overall response, with complete response based on computed tomography in 36%. The progression-free survival rate at 36 months was 90% in the obinutuzumab plus bendamustine group and 84% in the obinutuzumab plus CHOP group. These results demonstrate that induction therapy with obinutuzumab plus bendamustine or obinutuzumab plus CHOP, followed by obinutuzumab maintenance, is associated with tolerable safety and promising efficacy. This study is registered at ClinicalTrials.gov as NCT00825149.

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. It is predominantly a disease of older individuals, with a median age at presentation of ∼70 years. For the majority of patients, the management revolves around immuno-chemotherapy often followed by maintenance rituximab, and at relapse, a range of options are available. For the younger patient, it is possible to be more intensive with therapy, consolidate responses with high-dose procedures, and in a few there might be the prospect of a cure. The incorporation of high-dose cytarabine into the treatment algorithm has had a major impact on outcomes, with approximately half of the patients alive at 10 years whether an autologous stem cell transplant is adopted or not. Allogeneic transplantation produces some very durable responses in the relapsed setting and has a potential role up front in the highest-risk patients. However, with the advent of Bruton tyrosine kinase inhibitor and other highly effective nontraditional chemotherapeutic approaches, there is the potential for the management of this disease to change fundamentally over the next few years.

Purpose: Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL. Patients and Methods: Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20–150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day). Results: Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study. Conclusions: Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).

The PI3K inhibitor copanlisib has efficacy and manageable safety in patients with indolent lymphoma and solid tumors. Pharmacodynamic effects relative to copanlisib dose and plasma exposure were evaluated. Patients with lymphoma or solid tumors received copanlisib 0.4 or 0.8 mg/kg on days 1, 8, and 15 of a 28-day cycle. Primary variables were maximum changes in phosphorylated AKT (pAKT) levels in platelet-rich plasma (PRP) and plasma glucose. Other evaluations included PI3K signaling markers and T-lymphocytes in paired tumor biopsies, the relationship between estimated plasma exposure and pharmacodynamic markers, response, and safety. Sixty-three patients received copanlisib. PRP pAKT levels showed sustained reductions from baseline following copanlisib [median inhibition: 0.4 mg/kg, 73.8% (range −94.9 to 144.0); 0.8 mg/kg, 79.6% (range −96.0 to 408.0)]. Tumor pAKT was reduced versus baseline with copanlisib 0.8 mg/kg in paired biopsy samples (P < 0.05). Dose-related transient plasma glucose elevations were observed. Estimated copanlisib plasma exposure significantly correlated with changes in plasma pAKT and glucose metabolism markers. There were two complete responses and six partial responses; seven of eight responders received copanlisib 0.8 mg/kg. Adverse events (all grade) included hyperglycemia (52.4%), fatigue (46.0%), and hypertension (41.3%). Copanlisib demonstrated dose-dependent pharmacodynamic evidence of target engagement and PI3K pathway modulation/inhibition in tumor and immune cells. Results support the use of copanlisib 0.8 mg/kg (or flat-dose equivalent of 60 mg) in solid tumors and lymphoma, and provide a biomarker hypothesis for studies of copanlisib combined with immune checkpoint inhibitors (NCT03711058).