Byrd J.C.,Ohio State University |
Brown J.R.,Dana-Farber Cancer Institute |
O'Brien S.,University of Texas M. D. Anderson Cancer Center |
Kay N.E.,Mayo Medical School |
And 29 more authors.
New England Journal of Medicine | Year: 2014
BACKGROUND: In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome. METHODS: In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. RESULTS: At a median follow-up of 9.4 months, ibrutinib significantly improved progressionfree survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P = 0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group. CONCLUSIONS: Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. Copyright © 2014 Massachusetts Medical Society. All rights reserved. Source
Dreger P.,University of Heidelberg |
Schetelig J.,TU Dresden |
Andersen N.,Rigshospitalet |
Corradini P.,Istituto Nazionale dei Tumori |
And 7 more authors.
Blood | Year: 2014
Allogeneic hematopoietic stem cell transplantation (HSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (HR-CLL; ie, refractory to purine analogs, short response [<24 months] to chemoimmunotherapy, and/or presence of del[17p]/TP53 mutations). Currently, treatment algorithms for HR-CLL are being challenged by the introduction of novel classes of drugs. Among them, BCR signal inhibitors (BCRi) and B-cell lymphoma 2 antagonists (BCL2a) appear particularly promising. As a result of the growing body of favorable outcome data reported for BCRi/BCL2a, uncertainty is emerging on how to advise patients with HR-CLL about indication for and timing of HSCT. This article provides an overview of currently available evidence and theoretical considerations to guide this difficult decision process. Until the risks and benefits of different treatment strategies are settled, all patients with HR-CLL should be considered for treatment with BCRi/BCL2a. For patients who respond to these agents, there are 2 treatment possibilities: (1) performingan HSCT or (2) continuing treatment with the novel drug. Individual disease-specific and transplant-related risk factors, along with patient's preferences, should be taken into account when recommending one of these treatments over the other. © 2014 by The American Society of Hematology. Source
Feeney E.R.,HIV Molecular Research Group |
Van Vonderen M.G.A.,Medical Center Leeuwarden |
Danner S.A.,VU University Amsterdam |
Van Agtmael M.A.,VU University Amsterdam |
And 5 more authors.
AIDS | Year: 2012
OBJECTIVE: No randomized study has prospectively followed subcutaneous adipose tissue mitochondrial DNA (mtDNA) changes when starting thymidine nucleoside reverse transcriptase inhibitors (tNRTIs). DESIGN: The Metabolic Effects of DIfferent CLasses of AntiretroviralS study randomized HIV-positive, treatment-naive male participants to start lopinavir/ritonavir (LPVr) with either zidovudine/lamivudine (ZDV/3TC) or nevirapine (NVP). METHODS: Regional body fat was assessed by dual energy x-ray absorptiometry and abdominal computed tomography at months 0, 3, 12, 24 and 36. In a molecular substudy, subcutaneous adipose tissue (SAT) biopsies were taken, with mtDNA quantified by quantitative PCR. Data were analyzed using repeated measures linear regression analyses. RESULTS: Of 50 participants recruited (23 to LPVr/ZDV/3TC), 48 started therapy, and 37 participants (19 on LPVr/ZDV/3TC) enrolled in the substudy. At 36 months, the LPVr/ZDV/3TC group had significantly lower limb fat [6.4kg (0.26) versus 7.3kg (0.31), P=0.017] and a trend toward lower abdominal SAT compared to the LPVr/NVP group [131cm (6.86) versus 146cm (6.33), P=0.097]. Over 36 months, mtDNA declined in the LPVr/ZDV/3TC group [mtDNA region 1: -190 (95)copies/cell, P=0.053, region 2: -269 (106)copies/cell, P=0.016] but not within the LPVr/NVP group [region 1: +28 (99)copies/cell, P=0.78, region 2: +51 (111)copies/cell, P=0.65, between-group difference P<0.01 for both measurements]. mtDNA was significantly lower in the LPVr/ZDV/3TC group at 36 months. CONCLUSION: This is the first randomized study to prospectively demonstrate reductions in SAT mtDNA in patients initiating ZDV/3TC-containing antiretroviral therapy (ART) but not in those initiating nucleoside reverse transcriptase inhibitor-sparing ART containing NVP and protease inhibitor. That reductions in SAT mtDNA were also accompanied by lower limb fat suggests that use of ART not containing ZDV/3TC may help prevent development of peripheral lipoatrophy. © 2012 Wolters Kluwer Health / Lippincott Williams & Wilkins. Source