Ibrutinib for mantle cell lymphoma Tucker, David L; Rule, Simon A
Future oncology (London, England),
02/2016, Letnik:
12, Številka:
4
Journal Article
Recenzirano
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase which acts by downstream inhibition of the ...B-cell receptor. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile in relapsed/refractory MCL. Although the majority of disease responses are partial, efficacy data are impressive with more than two-thirds of patients demonstrating a durable response. This article focuses on all aspects of ibrutinib in the context of MCL, including a summary of the basic pharmacology and pharmacokinetics; a review of the safety and efficacy data published to date and a discussion of the future implications in MCL.
The observational MCL-004 study evaluated outcomes in patients with relapsed/refractory mantle cell lymphoma who received lenalidomide-based therapy after ibrutinib failure or intolerance.
The ...primary endpoint was investigator-assessed overall response rate based on the 2007 International Working Group criteria.
Of 58 enrolled patients (median age, 71 years; range, 50-89), 13 received lenalidomide monotherapy, 11 lenalidomide plus rituximab, and 34 lenalidomide plus other treatment. Most patients (88%) had received ≥ 3 prior therapies (median 4; range, 1-13). Median time from last dose of ibrutinib to the start of lenalidomide was 1.3 weeks (range, 0.1-21.7); 45% of patients had partial responses or better to prior ibrutinib. Primary reasons for ibrutinib discontinuation were lack of efficacy (88%) and ibrutinib toxicity (9%). After a median of two cycles (range, 0-11) of lenalidomide-based treatment, 17 patients responded (8 complete responses, 9 partial responses), for a 29% overall response rate (95% confidence interval, 18-43%) and a median duration of response of 20 weeks (95% confidence interval, 2.9 to not available). Overall response rate to lenalidomide-based therapy was similar for patients with relapsed/progressive disease after previous response to ibrutinib (i.e., ≥PR) versus ibrutinib-refractory (i.e., ≤SD) patients (30 versus 32%, respectively). The most common all-grade treatment-emergent adverse events after lenalidomide-containing therapy (n = 58) were fatigue (38%) and cough, dizziness, dyspnea, nausea, and peripheral edema (19% each). At data cutoff, 28 patients have died, primarily due to mantle cell lymphoma.
Lenalidomide-based treatment showed clinical activity, with no unexpected toxicities, in patients with relapsed/refractory mantle cell lymphoma who previously failed ibrutinib therapy.
Clinicaltrials.gov identifier NCT02341781 . Date of registration: January 14, 2015.
Bone marrow aspiration and trephine (BMAT) biopsies remain important tests in haematology. However, the procedures can be moderately to severely painful despite standard methods of pain relief. To ...test the efficacy of transcutaneous electrical nerve stimulation (TENS) in alleviating the pain from BMAT in addition to standard analgesia using a numerical pain rating scale (NRS).
70 patients requiring BMAT were randomised (1:1) in a double-blind, placebo-controlled trial. -35 patients received TENS impulses at a strong but comfortable amplitude (intervention group) and 35 patients received TENS impulses just above the sensory threshold (control group) (median pulse amplitude 20 and 7 mA, respectively). Patients and operators were blinded to group allocation. Pain assessments were made using a numerical pain scale completed after the procedure.
No significant difference in NRS pain recalled after the procedure was detected (median pain score 5.7 (95% CI 4.8 to 6.6) in control vs 5.6 (95% CI 4.8 to 6.4) in the intervention group). However, 100% of patients who had previous experience of BMAT and >94% of participants overall felt they benefited from using TENS and would recommend it to others for this procedure. There were no side effects from the TENS device, and it was well tolerated.
TENS is a safe, non-invasive adjunct to analgesia for reducing pain during bone marrow biopsy and provides a subjective benefit to most users; however, no objective difference in pain scores was detected when using TENS in this randomised controlled study.
NCT02005354.
Mantle cell lymphoma is an incurable and generally aggressive lymphoma that is more common in elderly patients. Whilst a number of different chemotherapeutic regimens are active in this disease, ...there is no established gold standard therapy. Rituximab has been used widely to good effect in B-cell malignancies but there is no evidence that it improves outcomes when added to chemotherapy in this disease. We performed a randomized, open-label, multicenter study looking at the addition of rituximab to the standard chemotherapy regimen of fludarabine and cyclophosphamide in patients with newly diagnosed mantle cell lymphoma. A total of 370 patients were randomized. With a median follow up of six years, rituximab improved the median progression-free survival from 14.9 to 29.8 months (P<0.001) and overall survival from 37.0 to 44.5 months (P=0.005). This equates to absolute differences of 9.0% and 22.1% for overall and progression-free survival, respectively, at two years. Overall response rates were similar, but complete response rates were significantly higher in the rituximab arm: 52.7% vs. 39.9% (P=0.014). There was no clinically significant additional toxicity observed with the addition of rituximab. Overall, approximately 18% of patients died of non-lymphomatous causes, most commonly infections. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy significantly improves outcomes in patients with mantle cell lymphoma. However, these regimens have significant late toxicity and should be used with caution. This trial has been registered (ISRCTN81133184 and clinicaltrials.gov:00641095) and is supported by the UK National Cancer Research Network.
Summary Background Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study ...in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. Methods In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2–5, either alone or with bortezomib 1·6 mg/m2 , administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov , number NCT00312845. Findings Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4–39·7), median progression-free survival was 11·0 months (95% CI 9·1–12·0) in the rituximab group and 12·8 months (11·5–15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68–0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1–5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 23% patients in the rituximab group, and 56 17% patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 21% of 339 rituximab-treated patients vs 152 46% of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 11% patients vs 59 18% patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 4% patients in the rituximab group and 37 11% patients in the bortezomib plus rituximab group), infection (15 4% patients and 36 11% patients, respectively), diarrhoea (no patients and 25 7% patients, respectively), herpes zoster (one <1% patient and 12 4% patients, respectively), nausea or vomiting (two <1% patients and 10 3% patients, respectively) and thrombocytopenia (two <1% patients and 10 3% patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients 2%) and pyrexia (six patients 2%) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. Interpretation Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. Funding Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc.
The comparative efficacy of these drugs clearly shows that ibrutinib is the most active drug and has the best side-effect profile.1 In the treatment of lymphoma, when a drug shows activity in B-cell ...non-Hodgkin lymphoma the next trial invariably investigates the addition of rituximab and, in general, this results in an increase in efficacy. ...ibrutinib has been shown to strongly inhibit all cell-mediated mechanisms induced by anti-CD20 antibodies in a variety of in vitro models2 and in a mouse model the concurrent use of ibrutinib and rituximab significantly antagonised the rituximab anti-lymphoma effect.3 Ibrutinib is an oral small molecule that irreversibly binds to the phosphorylation site of Bruton's tyrosine kinase leading to irreversible inactivation of this key component of the B-cell receptor signalling pathway. Interleukin-2 inducible tyrosine kinase is important in the expression of Fc receptor-stimulated natural killer cells and hence antibody-dependant cell-mediated cytotoxicity. ISM/Science Photo Library I declare grants...
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