Simpson, David

SummaryThe phase I/II AU‐003 study in patients with treatment‐naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow‐up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2‐ and 3‐year progression‐free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow‐up of ~4 years, responses remain clinically meaningful and durable and long‐term tolerability to zanubrutinib therapy continues.

Abstract Background: The oral BTK inhibitor ibrutinib is the only approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). Bing-Neel syndrome (BNS) is a rare complication of WM that results from infiltration of malignant lymphoplasmacytic cells into the central nervous system (CNS) causing neurological deficits. Treatment options in patients with BNS are limited to agents with CNS penetration. Ibrutinib can penetrate into the CNS, but data on its efficacy in BNS is lacking outside case reports. Methods: We performed a multicenter retrospective study evaluating the efficacy of ibrutinib in patients with BNS. The diagnosis of BNS was established in patients with a clinicopathological diagnosis of WM by radiological and/or cytological evidence of CNS involvement by WM, and response was assessed based on recently published criteria. Ibrutinib was given orally at doses of 420-560 mg PO once daily until disease progression or intolerable toxicity. Response was assessed using criteria from the 8th International Workshop for WM (Minnema et al. Haematologica 2017). Events were defined as death from any cause, progression of disease and stopping ibrutinib from any reason. Time to events was estimated using the Kaplan-Meier method. Results: We present data on 24 patients with BNS treated with ibrutinib. The median age at diagnosis of WM was 60 years (range 38-76 years) and 14 patients (58%) were men. The median lines of therapy for WM prior to BNS diagnosis was 1 (range 0-7 lines), and 9 patients (38%) were untreated for WM at the time of BNS diagnosis. Previous WM therapies included anti-CD20 antibodies (n=15), alkylators (n=13), nucleoside analogues (n=8), proteasome inhibitors (n=3), immunomodulators (n=2), and autologous transplant (n=1). The median age at BNS diagnosis was 65 years (range 38-80). The median time from WM to BNS diagnosis was 4 years (range 0-27 years). In 2 patients, the diagnosis of BNS was made concurrently with WM diagnosis. The median number of BNS lines prior to ibrutinib was 1 (range 0-5 lines). Previous BNS therapies included intrathecal chemotherapy (n=9), high-dose methotrexate (n=6), bendamustine (n=3) and radiation therapy (n=3). In 7 patients (29%), ibrutinib was the first line of treatment for BNS. The most common symptoms at BNS presentation were cognitive deficits (n=10), sensory deficits (n=8), ataxia/falls (n=8), motor deficits (n=6), headache (n=5) and seizures (n=5). MRI findings included leptomeningeal enhancement (n=16) and brain masses (n=5). Cerebrospinal fluid (CSF) flow cytometry confirmed the presence of clonal CD19+ in 19 patients (79%). Biopsies were performed in 5 patients (21%) and confirmed presence of WM cells. 4 patients had normal MRI but had abnormal CSF cytology and/or flow cytometry. Tissue was not obtained in 1 patient in whom MRI showed leptomeningeal enhancement. Interestingly, 2 patients were diagnosed with lymphoplasmacytic lymphoma secreting IgG paraprotein. The median serum IgM (n=20) prior to ibrutinib initiation was 1,294 mg/dl (range 125-5,938 mg/dl), and the median hemoglobin level was 11.9 g/dl (7.7-15.2 g/dl). Ten patients (42%) received ibrutinib 560 mg PO once daily, and 14 (58%) received ibrutinib 420 mg PO once daily. At best response, median serum IgM and hemoglobin levels were 340 mg/dl (82-3,330 mg/dl) and 14.6 g/dl (range 9.2-16.0 g/dl). Based on consensus BNS response criteria, complete response was attained in 2 patients (8%), partial response in 14 (58%) and clinical improvement in 3 patients (13%). With a median follow-up time of 13 months (95% CI 8-21 months), 5 patients have stopped ibrutinib, 3 due to BNS progression, 1 due to grade 3 muscle cramps and 1 due to arrhythmia, and 3 patients have died, 2 from infection and 1 from BNS progression. The median event-free survival (EFS) from ibrutinib initiation was not yet reached. The 1-year and 2-year EFS rates were 71% (95% CI 46-86%) and 52% (23-75%), respectively. Conclusion: Ibrutinib is a safe and effective treatment option for patients with BNS. Disclosures Palomba: Pharmacyclics: Consultancy; Celgene: Consultancy. Talaulikar:Amgen: Consultancy, Honoraria; Takeda: Research Funding; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Buske:Janssen: Honoraria, Research Funding; Bayer: Research Funding; Roche: Honoraria, Research Funding. Tedeschi:Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau. Simpson:Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ansell:Affimed: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Pfizer: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding. Treon:Johnson & Johnson: Consultancy; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Castillo:Millennium: Research Funding; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Abstract Introduction: Despite recent advances in available treatments, chronic lymphocytic leukemia (CLL) remains an incurable disease, and the vast majority of patients (pts) will relapse and require additional lines of therapy. Thus, prolonging remission is a key treatment goal in CLL. This multicenter, randomized, double-blinded phase 3 trial (NCT00774345) was designed to evaluate the efficacy and safety of lenalidomide (LEN) vs placebo (PBO) as maintenance therapy in previously treated CLL pts. Methods: Eligible CLL pts must have had at least a partial response (PR) to second-line therapy. Pts were randomized 1:1 to receive either LEN 2.5 mg once daily on days 1-28 of the first 28-day cycle, or matching PBO. If LEN was well tolerated, escalation to 5 mg/day was permitted from cycle 2, and further escalation to 10 mg/day at cycle 7 and thereafter. Pts were stratified by their response at the end of second-line therapy (PR, nodular PR, complete response [CR], or CR with incomplete bone marrow recovery; vs minimal residual disease [MRD]-negative CR by flow cytometry); age (≤ 70 vs > 70 years); and presence of at least one of the following poor prognostic factors: del(11q), del(17p), unmutated IGHV, or b2M > 0.4 mg/L (Yes vs No vs Unknown). Co-primary endpoints were progression-free survival (PFS; IRAC assessed) and overall survival (OS). Secondary endpoints included: safety, tumor response, duration of response, second PFS (PFS2, time from randomization to second disease progression or death), and health-related quality of life (HRQoL). Results: Overall, 314 pts were enrolled (LEN, n = 160; PBO, n = 154). Baseline characteristics were balanced between the treatment arms: median age was 63 years (range 37-82) and 63 years (range 37-84), 71.9% and 72.1% were male, 9.4% and 11.7% had MRD-negative CR to second-line treatment, and 47.5% and 47.4% had at least one poor prognostic factor, in the LEN and PBO arms, respectively. On review of the primary analysis, 30 Sept 2015 data cutoff, the required number of progression events to complete the co-primary analysis had occurred, and the data monitoring committee recommended that the study be unblinded. Median follow-up time was 31.5 months, and the median PFS was significantly longer for LEN vs PBO: 33.9 vs 9.2 months, respectively (HR 0.40 [95% CI 0.29, 0.55]; P < 0.001). At the time of the analysis there were 86 deaths and there was no significant difference in the OS (HR 0.96 [95% CI 0.63, 1.48]; P = 0.856). Subsequent CLL therapy was received by 35.7% of pts in the LEN arm and 58.4% of pts in the PBO arm, of these pts 16% in the LEN arm and 20% in the PBO arm were treated with a BTK or PI3K inhibitor. Median PFS2 was significantly longer for LEN vs PBO: 57.5 vs 32.7 months, respectively (HR 0.46 [95% CI 0.29, 0.70]; P <0.001). Median number of treatment cycles received was 18 vs 9 cycles, for LEN vs PBO, respectively; a higher proportion of pts in the LEN arm started ≥25 cycles vs the PBO arm (38.9% vs 24.0%, respectively). Median dose intensity in the LEN arm was 4.2 mg/day. The most common adverse events (AEs) of all grades were neutropenia (66.2% vs 30.5%) and diarrhea (40.8% vs 16.2%) in the LEN vs PBO arm, respectively. Febrile neutropenia occurred in 1.9% vs 0%, deep vein thrombosis in 1.9% vs 0%, and pulmonary embolism in 2.5% vs 0.6% of pts in the LEN vs PBO arm, respectively. Most common grade 3/4 AEs were neutropenia (59.9% vs 22.7%), thrombocytopenia (16.6% vs 6.5%), and diarrhea (8.3% vs 0.6%) in the LEN vs PBO arm, respectively; all other grade 3/4 AEs occurred in <5% of pts in either arm. While there was a significant difference in the incidence of neutropenia, the rate of grade 3/4 infections was 16.6% for LEN vs 10.4% for PBO-treated pts. There were 13 (8.3%) vs 14 (9.1%) pts with at least one invasive second primary malignancy (SPM) in the LEN vs PBO arm, respectively. Hematologic invasive SPMs occurred in 7 vs 2 pts, and solid tumor invasive SPMs occurred in 7 vs 12 pts, in the LEN vs PBO arm, respectively. Overall, 44 pts in the LEN arm and 41 pts in the PBO arm died; 1 pt died on treatment in the LEN arm, and 2 pts in the PBO arm. There was no clinically meaningful difference in HRQoL for LEN vs PBO, as measured by FACT-Leu and EQ-5D, during maintenance treatment. Conclusions: LEN maintenance therapy significantly improved PFS from 9.2 to 33.9 months following second-line treatment in pts with CLL. The incidence of invasive SPMs was similar in both arms, and LEN maintenance treatment had an expected and acceptable safety profile. Disclosures Foà: Roche: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Gilead,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Pfizer, Ariad: Speakers Bureau; Genentech, Janssen, BMS: Consultancy. Schuh:Gilead: Consultancy, Honoraria, Research Funding; Roche, Janssen, Novartis, Celgene, Abbvie: Consultancy, Honoraria. Zaritskey:Novartis: Consultancy; Janssen: Consultancy. Semochkin:Celgene, Sandoz, Novartis, Astellas, Janssen Pharmaceuticals, Bristol-Myers Squibb: Speakers Bureau; Celgene, Bayer Healthcare, Astellas Pharma Inc.: Research Funding; City Clinical Hospital 52, Moscow, Russia: Consultancy. Simpson:Amgen Pharmaceuticals: Research Funding; Celgene, Roche, Janssen: Honoraria. Vokurka:Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Zhang:Celgene Corporation: Employment, Equity Ownership. Purse:Celgene Corporation: Employment, Equity Ownership.

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was &gt;95% at all doses. Sustained complete (&gt;95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in &gt;2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Abstract The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.

Abstract Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.