CLINICAL NEWS months in the placebo cohort , with 73 percent ( n = 210 ) and 55 percent ( n = 160 ) of patients , respectively , receiving treatment for 12 months or more .
PFS outcomes were also consistent irrespective of whether the patient had received one or more than one previous line of therapy . “ This result suggests that there might be a benefit of treating patients with CLL with ibrutinib in addition to bendamustine plus rituximab earlier in their disease course rather than later ,” according to the authors .
At an interim analysis , after a median follow-up of 17 months ( range = 13.7-20.7 months ), PFS was significantly longer in the ibrutinib cohort compared with the placebo group : not reached versus 13.3 months ( hazard ratio [ HR ] = 0.203 ; 95 % CI 0.15-0.276 ; p < 0.0001 ). At 18 months , PFS was 79 percent in the ibrutinib group and 24 percent in the placebo cohort ( HR = 0.203 ; 95 % CI 0.15-0.276 ; p < 0.0001 ).
However , there was no statistically significant difference in OS between the ibrutinib and placebo groups ( HR = 0.628 ; 95 % CI 0.385-1.024 ; p = 0.0598 ), with median OS not reached in either cohort . When adjusting for crossover , patients in the ibrutinib group had significantly longer OS compared with those in the placebo group ( HR = 0.577 ; 95 % CI 0.348-0.957 ; p = 0.033 ).
“ OS data should be interpreted with some caution because most OS events have not yet occurred ,” the authors noted . “ Long-term follow-up for OS is planned and intended to be reported at a later date .”
ORR was significantly higher in the ibrutinib group ( n = 239 ; 83 %) than the placebo cohort ( n = 196 ; 68 %; risk ratio = 1.22 ; 95 % CI 1.11-1.34 ; p < 0.0001 ). The proportion of patients with MRD-negative status was also higher in the ibrutinib group than in the placebo group : 37 ( 13 %) versus 14 ( 5 %; p = 0.0011 ).
Thirty-one percent ( n = 90 ) of patients originally receiving placebo had crossed over to receive ibrutinib monotherapy , and follow-up is continuing for all patients .
Grade 3 or 4 adverse events ( AEs ) were similar between the treatment groups : 77 percent ( n = 222 ) in the ibrutinib group and 74 percent ( n = 212 ) in the placebo group . The most common grade 3 or 4 AEs were neutropenia and thrombocytopenia , while the most common all-grade AEs were neutropenia and nausea . Diarrhea occurred more frequently in the ibrutinib group , but it was predominantly grade 1 . Bleeding events also occurred more frequently in the ibrutinib group , though the events were mostly grade 1 or 2 , the authors noted .
Dr . Chanan-Khan and co-authors noted a few limitations : the study was not designed to evaluate ibrutinib as a single agent , or ibrutinib plus rituximab compared with ibrutinib , bendamustine , and rituximab . “ While it seems clear that ibrutinib adds to the efficacy of bendamustine plus rituximab , the question remains if bendamustine plus rituximab is necessary to achieve good patient outcomes in this relapsed / refractory population .”
Because PFS had not yet been reached in the ibrutinib cohort , follow-up and more mature data are required to truly interpret the effects of ibrutinib in combination with bendamustine and rituximab , they added .
REFERENCE
Chanan-Khan A , Cramer P , Demirkan F , et al . Ibrutinib combined with bendamustine and rituximab compared with placebo , bendamustine , and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma ( HELIOS ): a randomised , double-blind , phase 3 study . Lancet Oncol . 2016 ; 17:200-11 .
Long-Term Exposure to Low-Molecular-Weight Heparins May Put Patients at Risk for Bone Fractures
In men and non-pregnant women requiring at least three months of anticoagulation therapy , three- to six-months ’ use of lowmolecular-weight heparin ( LMWH ) may not increase the risk of fractures , though longer exposure can adversely affect bone mineral density ( BMD ) in patients with cancer or underlying cardiovascular disease , according to a study published in the Journal of General Internal Medicine .
“ This is the most comprehensive systematic review and meta-analysis in this area to date and highlights the need to study the bone effects of LMWH and other anticoagulation medications ,” Angela M . Cheung , MD , PhD , the senior author of the study , told ASH Clinical News . Most previous research on bone-density loss and risk of fractures associated with LMWH focused on pregnant women , she added .
Olga Gajic-Veljanoski , MD , PhD , of the Osteoporosis Program at the University Health Network / Toronto Rehabilitation Institute / Mount Sinai Hospital in Toronto , Canada , and colleagues analyzed 16 articles from electronic databases ( MEDLINE , EM- BASE , the Cochrane Library , and Cochrane Controlled Clinical Trials Register ), conferences , and bibliographies through 2015 .
Dr . Gajic-Veljanoski and co-authors identified clinical trials and observational studies ( retrospective and prospective cohort and case-controlled studies ) of nonpregnant adults that assessed the effects of long-term LMWH treatment ( ≥3 months ) on fractures or BMD . The following were excluded from the study :
• Reviews , letters , and commentaries without original data
• Descriptive ( case series / reports ) or cross-sectional observational studies
• Studies that did not report on bone outcomes
• Studies that reported short-term exposure to LMWH or long-term exposure to unfractionated heparin ( UFH ) only
Sixteen articles were identified , and 14 studies were included in the systematic review : 10 clinical trials that included 4,865 patients ( one was a crossover trial , while the others were parallel-group , randomized , controlled trials ) and four observational cohort studies that included 251 patients , three of which were prospective ( n = 221 ) and one that was retrospective ( n = 30 ). BMD and fractures were primary outcomes in the majority of the observational studies and secondary endpoints in the majority of trials .
The majority of patients in the clinical trials were older than 60 years , male , and had a prior venous thromboembolism
( VTE ) resulting from underlying cardiovascular , renal , or malignant disease ; in the cohort studies , most patients were younger and more heterogeneous in age ( range = 30-67 years ).
Among these studies , long-term LMWH was compared with :
• Long-term UFH in 3 trials and 1 cohort study
• Vitamin K antagonists ( VKA ) in 3 trials and 2 cohort studies
• Short-term LMWH in 1 cohort study
• Compression therapy in 1 trial
• Placebo in 3 trials
• No treatment in 1 cohort study
Most of the studies analyzed LMWH use for a duration of three to six months , up to 24 months , though one cohort study compared long- and short-term LMWH treatment ( 6-48 months vs . < 4 months ). Eight articles reported findings on fractures : seven describing six trials that included 4,320 patients and one describing a prospective , cohort study of 80 patients . Dr . Gajic-Veljanoski and co-authors found that , in the 2,280 patients with VTE and underlying cardiovascular disease or cancer , short-term use of LMWH ( 3-6 months ) did not increase the relative risk of fractures at a six- to 12-month follow-up compared with UFH , oral VKA , or placebo ( pooled risk ratio [ RR ] = 0.58 ; 95 % CI 0.23-1.34 ). In addition , they did not observe a statistically significant increase in the risk of fractures at six to 12 months in cancer patients ( RR = 1.08 ; 95 % CI 0.31-3.75 ).
BMD was assessed in five clinical trials that included 545 patients and in all four cohort studies ( n = 251 ). Based on observational data , use of LMWH for three to 24 months decreased mean BMD by 2.8 percent to 4.8 percent ( depending on the BMD site ); oral VKA treatment , however , decreased mean BMD by 1.2 percent to 2.5 percent . “ Based on the current literature , LMWH does not seem to have a strong detrimental effect on bone ,” the authors observed . Though LMWH is not recognized as a major modifying factor for fracture in standardized fracture-risk assessment tools , “ the potential for a greater than three percent decrease in BMD may be clinically important in some adult populations on LMWH .”
“ We recommend that clinicians be aware of the data and take preventive measures ( such as ensuring adequate calcium and vitamin D intake ) and consider monitoring BMD in patients on long-term LMWH who are at increased risk for bone loss or fractures ,” said Dr . Cheung . “ Since patients on this therapy often have other comorbidities ( older age , cancer , and certain other medications ) that predispose them to increased bone loss or fractures , our study highlights the need to pay close attention to this population in terms of bone health .”
Limitations of the study include the potential for selection bias , small number of available studies , detection bias with fractures ( as they were not collected as primary outcome , only as adverse events or secondary outcomes ) and the variability of outcomes assessment among the studies , thus “ the effect of LMWH on BMD can be distorted in either direction ,” the authors wrote .
“ The lack of solid evidence on the long-term effects of LMWH on bone in non-pregnant adults suggests a need for future prospective studies ,” concluded Dr . Gajic-Veljanoski and colleagues . ●
REFERENCE
Gajic-Veljanoski O , Phua CW , Shah PS , Cheung AM . Effects of long-term low-molecular-weight heparin on factures and bone density in nonpregnant adults : a systemic review with meta-analysis . J Gen Intern Med . 2016 February 19 . [ Epub ahead of print ]
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