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Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee-assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples. Results Between March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to ≥ 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 ( P = .02), and Th1-promoting (antitumor) cytokines interferon-γ and interleukin-12 increased ( P ≤ .035). Conclusion With an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.

Background and objectives: In clinical practice, physicians often use once-weekly (QW) and biweekly (Q2W) dosing of epoetin alfa to treat anemia in patients with chronic kidney disease (CKD). Although the literature supports this practice, previous studies were limited by short treatment duration, lack of randomization, or absence of the approved three times per week (TIW) dosing arm. This randomized trial evaluated extended dosing regimens of epoetin alfa, comparing QW and Q2W to TIW dosing in anemic CKD subjects. The primary objective was to show that treatment with epoetin alfa at QW and Q2W intervals was not inferior to TIW dosing.Design, setting, participants, & measurements: 375 subjects with stage 3 to 4 CKD were randomized equally to the three groups and treated for 44 wk; to explore the impact of changing from TIW to QW administration on hemoglobin (Hb) control and adverse events, subjects on TIW switched to QW after 22 wk. The Hb was measured weekly, and the dose of epoetin alfa was adjusted to achieve and maintain an Hb level of 11.0 to 11.9 g/dl.Results: Both the QW and Q2W regimens met the primary efficacy endpoint. More subjects in the TIW group than in the QW and Q2W groups exceeded the Hb ceiling. Adverse events were similar across treatment groups and consistent with the morbidities of CKD patients.Conclusions: Administration of epoetin alfa at QW and Q2W intervals are potential alternatives to TIW dosing for the treatment of anemia in stage 3 to 4 CKD subjects.

Interleukin-6 (IL-6) may play an important role in the pathophysiology of anemia of inflammation associated with myelodysplastic syndrome (MDS). This double-blind, placebo-controlled, phase 2 study assessed the efficacy and safety of siltuximab, a chimeric anti-IL-6 monoclonal antibody, in patients with low-and intermediate-1-risk MDS who require transfusions for MDS anemia. Patients were randomized in a 2:1 ratio to siltuximab 15 mg kg 21 every 4 weeks 1 best supportive care (BSC) or placebo 1 BSC for 12 weeks. The primary endpoint was reduction in red blood cell (RBC) transfusions to treat MDS anemia, defined as 50% relative decrease and 2-unit absolute decrease in RBC transfusions. Fifty and 26 patients were randomized to the siltuximab and placebo groups, respectively. The study did not meet its prespecified hypothesis, with six (12%) patients in the siltuximab group and one (3.8%) in the placebo group having reductions in RBC transfusions (P 5 0.271). At the time of the planned futility analysis, the prespecified cutoff criteria were not met, and the study was terminated early due to lack of efficacy. No unexpected safety findings were observed. In conclusion, compared to placebo, treatment with siltuximab did not reduce RBC transfusions in transfusion-dependent patients with low-and intermediate-1-risk MDS. Future studies might explore siltuximab in patients with less iron overload and with elevated IL-6 levels and/or using higher doses for MDS.

Cefaclor, a new oral cephalosporin, was administered to 18 normal human volunteers in either single or multiple doses of 250 and 500 mg. Mean serum concentrations of 6.09 and 12.8 microgram/ml were achieved 1 hour after single oral doses of 250 and 500 mg, respectively. The serum concentrations declined rapidly and no drug was detected at 4 hours. Very high concentrations of cefaclor were found in urine during the first 8 hours after ingestion of the drug. Forty-three per cent of the total dose was excreted in urine during the first 8 hours. There was no accumulation of drug in serum during the multiple-dose studies.

Background: While first line therapy for FL with chemotherapy or chemoimmunotherapy produces durable responses, most patients (pts) with FL eventually relapse. Those who become resistant to chemoimmunotherapy have limited treatment options. Ibrutinib, an inhibitor of BTK (Bruton's tyrosine kinase) and ITK (interleukin-2-inducible T-cell kinase), has demonstrated robust clinical activity in various B-cell non-Hodgkin lymphomas. Previous Phase 1 and 2 studies have shown promising results with single-agent ibrutinib in pts with relapsed or refractory FL (Bartlett NL. Blood. 2014; 800 & Fowler N. Blood. 2015; 2706). The aim of the DAWN study was to provide additional efficacy and safety data with single-agent ibrutinib in a chemoimmunotherapy-refractory FL pt population. Methods: The DAWN study (FLR2002) was an open-label, multicenter, single-arm, Phase 2 study of ibrutinib in pts with chemoimmunotherapy-refractory FL (NCT01779791). Eligible pts had ≥ 2 prior lines of therapy with documented progressive disease (PD) within 12 months after last dose of chemotherapy in a chemoimmunotherapy regimen comprising an anti-CD20 monoclonal antibody. All pts received 560 mg oral ibrutinib once daily until disease progression or unacceptable toxicity. A protocol amendment allowed clinically stable patients with radiographic PD to remain on ibrutinib to allow for the possibility of tumor flare and delayed responses. The primary objective was Independent Review Committee (IRC)-assessed objective response rate (ORR; complete response [CR] + partial response [PR]). Secondary/ exploratory objectives included duration of response (DoR), time to next treatment (TTNT), progression-free survival (PFS), overall survival (OS), resolution of lymphoma-related symptoms, and safety. Results: The final analysis included 110 pts enrolled at 45 centers in 10 countries. The median age was 61.5 years, median number of prior therapies was 3; 40.9% of pts had refractory disease (defined as failure to achieve at least PR to the last prior regimen). Median follow-up is 27.7 months and median (range) ibrutinib exposure was 7.0 (1-37) months. The mean (SD) ibrutinib exposure was 11.2 (9.9) months. The ORR by IRC was 20.9% (23/110) and CR rate was 10.9% (12/110) with a median duration of response of 19.4 months; of the 23 pts who responded, 5 had refractory disease. ORR was 24.7% in pts with non-bulky disease (longest diameter ≤6 cm). The disease control rate (CR + PR + stable disease [SD for ≥ 6 months]) was 56.3% (62/110). 30 pts were allowed to remain on ibrutinib after initial radiographic PD (termed pseudo-progression); 7 pts had IRC-confirmed response when allowed to remain on therapy. Median TTNT on ibrutinib was 16 months compared with 10 months on the last line of treatment prior to enrollment. Median PFS was 4.6 months. The median OS has not been reached; the 24-month OS was 63% (95% CI, 0.53-0.72). Of 39 pts who had lymphoma-related symptoms at baseline, resolution of symptoms was seen in 26 pts (66.7%), including 10 whose best response was SD and 8 pts who had PD. The median duration of symptom resolution was 10.4 months. The most common adverse events (AEs) were diarrhea (50.9%; 51/56 pts had grade 1/2), fatigue (40.0%; 38/44 pts had grade 1/2), and cough (35.5%; all were grade 1/2). Serious AEs were reported in 48.2% of pts. Major hemorrhage and atrial fibrillation were consistent with previous reports at 3.6% and 9.1%, respectively. Seven pts (6.4%) discontinued ibrutinib because of an AE (none due to AF); 1 pt required a dose reduction due to AE. Biomarker analyses identifying classifiers for response or progression are ongoing. Conclusion: Treatment with single-agent ibrutinib in pts with chemoimmunotherapy-refractory FL achieved durable responses of 20.9%. The clinical benefit for these pts is also supported by disease control rate, resolution of symptoms, TTNT and OS. Safety results in this study were consistent with the current known profile of ibrutinib; the majority of events reported were grade 1/2. In pts with chemoimmunotherapy-refractory FL who have limited treatment options, treatment with ibrutinib resulted in a clinical benefit with acceptable safety and good tolerability. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Gopal: Paid Consultancy- Gilead, Janssen, Seattle Genetics, Spectrum, Research funding- Gilead, Janssen, Pfizer, BMS, Merck, Teva, Takeda, Spectrum, Seattle Genetics: Consultancy, Honoraria, Research Funding. Schuster:Celgene: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Research & Development: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Honoraria; Hoffman-LaRoche: Research Funding; Merck: Research Funding. Fowler:Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy; Infinity: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding. Hess:Roche: Honoraria; Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Martin:Novartis: Consultancy; Teva: Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Acerta: Consultancy; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses. Vitolo:Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jurczak:Morphosys: Consultancy; Acerta, Novartis, Pfizer, Celgene, Gillead, Janssen, Celtrion, Bayer, Morphosys, Takeda, Servier, Teva, and Roche: Research Funding; Sandoz - Novartis, Morphosys, Roche: Speakers Bureau. Osmanov:Seattle Genetics Inc.: Research Funding. Gartenberg:Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment. Balasubramanian:Janssen Research & Development: Employment. Wang:Janssen Research & Development: Employment. Deshpande:Janssen Research & Development: Employment. Salles:Celgene: Consultancy, Honoraria; Mundipharma: Honoraria; Gilead: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding.

Background and objectives: Extended-interval dosing of epoetin alfa (EPO) is commonly used to treat anemia in patients with chronic kidney disease (CKD).This study aimed to demonstrate that EPO dosed every 2 weeks (Q2W) and every 4 weeks (Q4W) was noninferior to once-weekly (QW) dosing.Design, setting, participants, & measurements: 430 anemic subjects with stage 3 to 4 CKD receiving a stable QW dose of EPO were randomized 1:1:2 to QW, Q2W, and Q4W dosing for 36 weeks. Hemoglobin (Hb) was measured weekly, and the dose of EPO was adjusted to maintain an Hb level of 11.0 to 11.9 g/dl. The primary endpoint was change in Hb from baseline to the average of the last 12 weeks of treatment.Results: Both the Q2W and Q4W dosing groups were noninferior to the QW group. The estimated difference of the mean change in Hb between Q2W and QW was ؊0.03 g/dl; and between Q4W and QW was ؊0.09 g/dl. From weeks 13 to 37, the mean percentage of weeks per subject with Hb 10.0 to 11.9 g/dl, inclusive, was 81% for QW, 81% for Q2W, and 75% for Q4W. Death occurred, respectively, in 4%, 3%, and 4%; thromboembolic vascular events occurred in 3%, 5%, and 3%; and serious adverse events occurred in 22%, 26%, and 26% of subjects.Conclusions: Q2W and Q4W EPO dosing maintained Hb levels in subjects with stage 3 to 4 CKD. Deaths, thromboembolic vascular events, and serious adverse events were comparable across the dosing groups.

Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), has demonstrated robust clinical activity in various B-cell malignancies, whose mechanism of action, beside BTK signaling inhibition in B-cells may also depend partially on immune modulation as it also an inhibitor of ITK (interleukin-2-inducible T-cell kinase), a key regulator of T-cell activity. Immune-modulatory cancer therapy, such as check-point inhibitors, may result in different response patterns than traditional cytotoxic therapy, eg, resembling "tumor flare." In a recent study of single-agent ibrutinib for treatment of refractory follicular lymphoma (FL), 7 patients (pts) had documented tumor responses after initial radiological progressive disease (PD), a phenomenon termed "pseudo-progression." We describe these cases that led to a study protocol amendment. Methods: The FLR2002 (DAWN) study was an open-label, multicenter, single-arm, phase 2 study of ibrutinib in pts with chemoimmunotherapy-refractory (ie, ≥ 2 prior lines of therapy & PD within 12 months after last dose of chemotherapy in a chemoimmunotherapy regimen) FL (NCT01779791). All pts received ibrutinib (560 mg QD) until PD or unacceptable toxicity. A protocol amendment was made to address the novel situation of delayed responses that were observed after PD to allow for continuation of ibrutinib in pts with radiological evidence of PD (any new lesion or increase by ≥ 50% of previously involved sites from nadir), but who were clinically stable/improving/exhibiting signs of tumor flare without documented PD by other methods. The primary end point was Independent Review Committee (IRC)-assessed overall response rate (ORR; complete response [CR] + partial response [PR]). T-cell subsets in peripheral blood were monitored by flow cytometry at various timepoints. Results: The sentinel case was a pt diagnosed with grade 1 FL in 2008 and subsequently treated with 3 lines of therapy including autologous stem cell transplant. At time of enrollment, pt had stage III disease, an ECOG score: 0 and FLIPI (Follicular Lymphoma International Prognostic Index) score: 1. At Week 12, the pt was assessed as having PD. Ibrutinib was discontinued, and no other anti-cancer treatment was instituted. However, PET & CT scans performed 4 months later showed CR. Thereafter, 2 other investigators reported similar phenomena, prompting the aforementioned protocol amendment. Investigator assessment of the pt in the sentinel case was confirmed by IRC and ibrutinib treatment was resumed. The pt remains on treatment in CR for 30 months at the time of this report. On the basis of the protocol amendment, approximately 30 pts were approved to continue ibrutinib treatment after radiographic PD. Of these, an additional 6 pts were identified (7 in total) with IRC-confirmed "pseudo-progression" (confirmed by imaging) at a median of 22.0 (range: 11.6-59.6) weeks after starting Ibrutinib. Three of these pts (2 CR, 1 PR) maintained their response for > 1 year and 2 continue to respond. Two pts (1 CR, 1 PR) maintained responses for > 8 months, but eventually progressed. One pt maintained a PR > 1 year, but discontinued ibrutinib therapy due to an adverse event (grade 3 diarrhea). Sufficient sample was available in 2 of these 7 pts and examination of the T-cell profiles showed a strong downregulation of regulatory Tcells (Tregs) at early timepoints after initiation of therapy in both, an effect that was significant also in other responders (CR+ PR, mean decrease 17 to 12.9% CD4, p=0.02) but not in non-responders (SD+PD, 11.5 to 10.4% CD4, ns). Conclusion: Experience from the DAWN study suggests that pts with relapsed or refractory FL treated with ibrutinib may experience initial pseudo-progression followed by robust and durable responses when continued on ibrutinib. This effect may be related to the immune-modulatory effects of ibrutinib as seen by the decrease in Tregs after start of therapy. Biomarker studies are continuing to further understand this phenomenon. Nevertheless, these and other observations have prompted a revision in response criteria that recognize specific response patterns such as these in pts treated with immune modulating agents. Therefore current and future clinical trials should consider the observed phenomenon and physicians should be aware of this pattern of response when utilizing immune-related or targeted therapies to avoid premature discontinuation of therapy. Disclosures Salles: Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria. Cheson:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schuster:Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen Research & Development: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding. Radford:GSK: Equity Ownership; Astra-Zeneca: Equity Ownership; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Schaffer:Janssen Research & Development: Employment. Damle:Janssen Research & Development: Employment. Gartenberg:Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment. Balasubramanian:Janssen Research & Development: Employment. Deshpande:Janssen Research & Development: Employment.