BACKGROUND The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. METHODS We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. RESULTS Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. CONCLUSIONS Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.)

• Three-year follow-up of ibrutinib in CLL demonstrated continued activity with durable responses that improve in quality with extended treatment.• Toxicity diminished over time with respect to grade $3 cytopenias, fatigue, infections, and adverse events leading to discontinuation.Ibrutinib is an orally administered inhibitor of Bruton tyrosine kinase that antagonizes B-cell receptor, chemokine, and integrin-mediated signaling. In early-phase studies, ibrutinib demonstrated high response rates and prolonged progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). The durable responses observed with ibrutinib relate in part to a modest toxicity profile that allows the majority of patients to receive continuous therapy for an extended period. We report on median 3-year follow-up of 132 patients with symptomatic treatment-naïve and relapsed/ refractory CLL or small lymphocytic lymphoma. Longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease. Treatment-related lymphocytosis remains largely asymptomatic even when persisting >1 year and does not appear to alter longer-term PFS and overall survival compared with patients with partial response or better. Collectively, these data provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period; this information can help direct potential treatment options for different subgroups to diminish the long-term risk of relapse. (Blood. 2015;125(16):2497-2506

Summary Background Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. Methods In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. Findings Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65–84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1–2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22·1 months (IQR 18·4–23·2), 22 (71%) of 31 patients achieved an objective response (95% CI 52·0–85·8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. Interpretation The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials. Funding Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.

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• Single-agent ibrutinib induced durable remissions (ORR 48%) with a favorable benefit-risk profile in patients with previously treated MZL.• Inhibition of BCR signaling with ibrutinib provides a treatment option without chemotherapy for an MZL population with high unmet need.Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ‡1 prior therapy with an anti-CD20 antibody-containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ‡1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ‡3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628. (Blood. 2017;129(16):2224-2232

In selected asymptomatic patients with MCL, deferred initial treatment ("watch and wait") is an acceptable management approach.

© F e r r a t a S t o r t i F o u n d a t i o ncomparable, with different timing of the interim PET during the course of treatment and differing PET methodologies. Most studies used stand-alone PET, which has now been replaced by PET-CT. Reporting methods were not consistent making it difficult to judge how these results should be applied in clinical practice.In 2009 an international meeting attended by hematologists and nuclear medicine specialists was held in Deauville, France, with the intention of defining simple and reproducible criteria for interim-PET reporting in lymphoma.11 A five-point scale (5-PS) developed at Guy's and St. Thomas' Hospital in London was adopted 12 as the "Deauville criteria". An international study was launched to compare previous reports on the accuracy of interim PET in predicting treatment outcome in Hodgkin lymphoma with an international cohort of patients scanned using PET-CT after two cycles of ABVD and to evaluate the reproducibility of the 5-PS among reporters. The criteria for enrollment, the breakdown of patients according to stage (early unfavorable and advanced-stage) and the endpoints were the same as in the JID. Methods Retrieval of patients' dataConsecutive patients affected by Hodgkin lymphoma from participating centers worldwide diagnosed between January 2002 and December 2009 were retrospectively enrolled with the following inclusion criteria: (i) stage IIB to stage IVB or stage IIA Hodgkin lymphoma with adverse prognostic factors (at least three nodal sites involved, sub-diaphragmatic presentation, bulky disease, and erythrocyte sedimentation rate > 40 mm/h); (ii) treatment with four to eight cycles of ABVD with or without involved-field radiotherapy or consolidation radiotherapy; (iii) staging with PET/CT at baseline and after two courses of ABVD (PET-0 and PET-2, respectively); (iv) no change to treatment based on interim-PET results; and (v) a minimum follow-up of 1 year after completion of firstline treatment. Patients escalated to salvage treatment during ABVD chemotherapy were eligible only if the treatment change was based on clinical and/or radiological evidence of disease progression/resistance.The study was approved by the ethical committee of the coordinating center in Cuneo (Italy) and conducted according to the Helsinki declaration. Specific informed written consent was not required as all data were retrospectively collected in an anonymized format, in agreement with specific institutional and national requirements. AG, SC and ER analyzed the data and all co-authors had access to the primary data.Clinical data on 400 patients were collected; however only 335 paired scans (baseline and interim) were available for review. Of these, 75 were then excluded because there were no CT data (n=21), no baseline PET (n=25), no interim PET (n=1), missing CT slices (n=3), missing PET slices (n=10), poor quality PET images (n=6) or miscellaneous reasons (n=9). Complete data from 260 patients were available for analysis from 17 international academic institut...

Bruton agammaglobulinemia tyrosine kinase (BTK), a cytoplasmic protein tyrosine kinase, is a component of the B-cell receptor signaling pathway. Ibrutinib, a BTK inhibitor, has demonstrated a significant clinical activity against chronic lymphocytic leukemia (CLL) in early clinical trials. Understanding the molecular mechanisms of action would shed light on CLL pathophysiology and provide additional opportunities for the development of new therapies. In this study, we have chosen an in vivo approach by employing an ongoing phase 1b trial of ibrutinib. We prospectively collected and analyzed serial samples from the CLL patients before and after the initiation of ibrutinib. We found that the blockage of cell proliferation was one of the primary effects of ibrutinib against leukemic CLL cells in vivo. Using a co-culture system that induces CLL proliferation in vitro, analysis of several parameters, including Ki-67 expression and bromodeoxyuridine (BrdU) incorporation, revealed that the proliferation of CLL cells was directly inhibited by ibrutinib. Furthermore, activities of BTK and phospholipase Cγ2 as well as downstream signaling molecules, AKT and ERK, were all coordinately downregulated over time in ibrutinib-treated patients. Our findings suggest that the cell proliferation is one of the essential properties of CLL. Blocking cell proliferation via inhibition of BTK-mediated signaling may contribute to clinical responses in ibrutinib-treated patients.