Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent ...when administered as long-term continuous therapy. Preclinical models predict synergy in combination.
We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood.
The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).
In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).
Both nilotinib, a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukaemia (CML), and ponatinib, a third-generation TKI used in CML and Philadelphia ...positive acute lymphocytic leukaemia, have been associated with an increase in arterial occlusive events, in contrast to other TKIs such as imatinib and dasatinib. We have previously demonstrated evidence of a pro-thrombotic state associated with nilotinib, using microvascular and arterial thrombosis C57BL/6 mouse models. In this study, we examined ponatinib and determined if a calcium channel blocker could ameliorate the pro-thrombotic and pro-inflammatory phenotypes. In vitro treatment of whole human or murine blood with ponatinib and nilotinib increased platelet activation, adhesion and three-dimensional thrombi over time compared with vehicle control or other TKIs. Treatment of wild-type C57BL/6 mice with ponatinib and nilotinib but not imatinib, dasatinib or vehicle control for 4 hours significantly increased thrombus growth following ex vivo perfusion on collagen and FeCl
-induced vascular injury of mesenteric arterioles and carotid artery in vivo and increased plasma levels of soluble P-selectin, tumour necrosis factor-α, interleukin-6, interferon-γ and thromboxane B
(TxB
). Ponatinib-treated CML patients had increased ex vivo thrombus formation and a pro-inflammatory phenotype compared with healthy controls. Pre-treatment of mice with the calcium channel antagonist, diltiazem, prior to ponatinib or nilotinib reversed the pro-thrombotic phenotype and the increase in cytokine levels. These observations suggest that the pro-thrombotic effect of nilotinib and ponatinib is partially related to calcium channel activation and TxA
generation and this should be explored clinically as a mechanism to prevent vascular events.
Abstract Tyrosine kinase inhibitors (TKI) such as imatinib, nilotinib and dasatinib are now established as highly effective frontline therapies for chronic myeloid leukaemia (CML). Disease control is ...achieved in the majority of patients and survival is excellent such that recent focus has been on toxicities of these agents. Cumulative data have reported an excess of serious vascular complications, including arterial thrombosis and peripheral arterial occlusive disease, in patients receiving nilotinib in comparison with other TKIs, with resultant interest in delineating the pathophysiology and implications for rationale cardiovascular risk modification. To address this issue, we studied the effects of imatinib, nilotinib and dasatinib on platelet function and thrombus formation in human and mouse models using in vitro, ex vivo and in vivo approaches. In vitro studies demonstrated that dasatinib and imatinib but not nilotinib inhibited ADP, CRP, and collagen-induced platelet aggregation and moreover, that nilotinib potentiated PAR-1-mediated alpha granule release. Pretreatment of wild-type C57BL/6 mice with nilotinib but not imatinib or dasatinib, significantly increased thrombus growth and stability, on type I collagen under ex vivo arterial flow conditions and increased thrombus growth and stability following FeCl3 -induced vascular injury of mesenteric arterioles and carotid artery injury in vivo . Whole blood from nilotinib-treated CML patients, demonstrated increased platelet adhesion ex vivo under flow, increased plasma soluble P- and E -selectin, sICAM-1, sVCAM-1, TNF-alpha, IL-6 levels and endogenous thrombin potential (ETP) levels in vivo, despite being on daily low-dose aspirin. These results demonstrate that nilotinib can potentiate platelet and endothelial activation and platelet thrombus formation ex vivo and in vivo.
Background
Preoperative absolute and functional iron deficiency anaemia is associated with poor postoperative outcomes in patients undergoing surgery for colorectal cancer. It is biologically ...plausible that “early”, or “nonanaemic” iron deficiency may also be associated with worse postoperative outcomes in similar cohorts, albeit at lesser severity than that seen for anaemia. The evidence supporting this assertion is of low quality.
Methods
We have designed a prospective, observational study to delineate associations between preoperative non‐anaemic iron deficiency and postoperative outcomes after surgery for colorectal cancer. Patients without anaemia, undergoing elective surgery for colorectal cancer will be allocated to an iron replete or an iron deficient group based on preoperative transferrin saturation. The primary outcome is days alive and at home on postoperative day 90. Secondary outcomes include days alive and at home on postoperative day 30, length of hospital stay, readmission to acute care, postoperative complications, health‐related quality of life scores, quality of postoperative recovery, and requirement for allogeneic blood transfusion. The planned sample size is 422 patients, which has 80% power to detect a two‐day difference in the primary outcome. The study commenced in May 2019.
Conclusion
The results of this study will provide patients and clinicians with high‐quality evidence concerning associations between nonanaemic iron deficiency and patient‐centred outcomes after surgery for colorectal cancer. The study will be conducted in multiple urban and rural centres across Australia and New Zealand. The results will be highly generalisable to contemporary surgical practice and should be rapidly translated.
Patients with abscopal regressions of lymphoma after palliative involved-site radiation therapy (ISRT), detected on sequential
F-fluorodeoxyglucose positron emission tomography (FDG-PET), were ...identified by audit. A retrospective analysis was subsequently conducted to estimate the frequency of abscopal regression in follicular lymphoma (FL).
Potential cases were identified at multidisciplinary lymphoma meetings and fulfilled these criteria: (1) palliative ISRT given for histologically confirmed lymphoma, (2) >2 lesions visualized on FDG-PET, (3) >1 unirradiated lesion(s) outside ISRT volume, (4) no systemic therapy delivered <2 months before radiation therapy or between radiation therapy and response assessment, (5) complete metabolic response (CMR) in ≥1 unirradiated lesions detected on serial FDG-PET/CT. All ISRT patients with FL treated in 2016 to 2018 were systematically reviewed.
Seven cases of abscopal regression were identified, including 4 patients with FL. In all cases, a CMR was apparent both within the ISRT volume and in ≥1 unirradiated lesions. One patient each was identified with mantle cell lymphoma (4 Gy in 2 fractions), Hodgkin lymphoma (20 Gy in 3 fractions, then 30 Gy in 15 fractions to the same volume), and Richter transformation of chronic lymphatic leukemia (30 Gy in 10 fractions). The 4 patients with FL received either 4 Gy in 2 fractions (n = 3) or 4 Gy followed 8 months later by 30 Gy in 15 fractions (n = 1). From 2016 to 2018, 29 courses of ISRT were prescribed for multifocal FL, after which 4 of 29 (13.8%) abscopal responses were detected, including in 4 of 9 (44.4%) patients with serial PET scans. Two patients, with relapsed disease after initial abscopal responses, experienced durable CMRs with immunotherapies.
In 4 of 7 cases, PET-detected abscopal regression of lymphoma occurred after 4 Gy, in 2 of 7 cases after repeated ISRT to the same volume, and in 2 of 7 was associated with subsequent complete response to immunotherapy, consistent with an immune basis for the abscopal effect. Abscopal regressions in FL appear to be more common than previously suspected.
Abstract Introduction This review aimed to identify candidate biomarkers for the prediction of thromboembolism (TE) in lung cancer. Materials and
m
ethods Systematic review of publications indexed in ...PubMed or EMBASE databases in the past 5 years (01/05/2011
–
01/05/2016) which evaluated baseline and/or longitudinal biomarker measurements as a predictor of subsequent TE (venous and arterial) in lung cancer patients. Results Of 1105 studies identified, 18 fulfilled predefined inclusion criteria: 6 prospective and 12 retrospective.
The 18 studies included 11
,
262 patients and 36 unique biomarkers.
The combined TE rate was 7% (741/10
,
854), increasing to 11% (294/2612) within prospective studies.
All biomarker measurements were baseline only, with no longitudinal assessment reported.
The most frequently investigated biomarkers were tumour-related driver mutations, D-dimer, haemoglobin, white cell, and platelet count; as well as biomarker combinations previously used in risk prediction models, such as Khorana risk score.
Biomarker thresholds rather than continuous variable analyses were generally applied, however thresholds were not consistent across studies.
D-dimer and epidermal growth factor receptor mutation were the strongest and most reproducible predictors of TE. Conclusion An important limitation is the lack of prospective data across specific subpopulations of cancer, with correlative, and preferably longitudinal, biomarker assessments.
This would provide insight into the pathophysiology, allow patient profiling, and the development of personalised decision-making tools that can be used real-time and throughout the course of the patients
'
journey, for targeted, risk-adaptive preventative strategies.
Iron deficiency is common in colorectal cancer. Despite perioperative guidelines advocating for the correction of nonanaemic iron deficiency prior to major surgery, the impact of this pathology on ...postoperative outcome is unclear. We conducted a single-centre, historical cohort study of 141 elective resections for colorectal cancer.We stratified nonanaemic patients into iron deficient and iron replete groups, and collected data on baseline characteristics, preoperative laboratory results, intraoperative events and postoperative outcomes. As this study was an exploratory work for future research, a P-value of 0.25 was considered relevant. Patients in the deficient group demonstrated lower baseline ferritin (median (interquartile range, IQR) 76 (41-141) mg/L versus 207 (140-334) mg/L, P<0.001) and transferrin saturation (mean (standard deviation, SD) 18% (8%) versus 32% (12%), P<0.001) than those in the replete group, and lower starting haemoglobin (mean (SD) 138 (10) g/L versus 144 (12) g/L, P1/40.01). The deficient group had increased readmission (25% (24%) versus 4% (11%), P1/40.15) and all-cause infection (25% (24%) versus 5% (14%), P1/40.24). A decrease of two days in days alive and out of hospital at postoperative day 90 was seen in the deficient group on univariate analysis (median (IQR) 81 (75-84) versus 83 (78-84), P1/40.25). This reduced to 1.24 days in multivariate adjusted quantile regression analysis (P1/40.22). Days alive and out of hospital at day 90, postoperative re-admission and postoperative infection may be meaningful outcome measures for future prospective observational work examining nonanaemic iron deficiency in patients undergoing major surgery for colorectal cancer.
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