CLINICAL NEWS acute myeloid leukemia [ sAML ] = 360 ). They identified 2,322 mutations in 1,383 genes , of which 49 genes were significantly mutated when compared with the background mutation rate ( p < 0.01 ). These driver gene mutations ( those thought to be directly responsible for causing the disease ) were present in 77 percent of patients analyzed by WES .
Univariate comparison between lower- and higher-risk MDS revealed that
OVERDOSAGE There is no specific antidote for VENCLEXTA . For patients who experience overdose , closely monitor and provide appropriate supportive treatment ; during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs and symptoms of TLS along with other toxicities . Based on venetoclax large volume of distribution and extensive protein binding , dialysis is unlikely to result in significant removal of venetoclax . NONCLINICAL TOXICOLOGY Carcinogenesis , Mutagenesis , Impairment of Fertility Carcinogenicity studies have not been conducted with venetoclax . Venetoclax was not mutagenic in an in vitro bacterial mutagenicity ( Ames ) assay , did not induce numerical or structural aberrations in an in vitro chromosome aberration assay using human peripheral blood lymphocytes , and was not clastogenic in an in vivo mouse bone marrow micronucleus assay at doses up to 835 mg / kg . The M27 metabolite was negative for genotoxic activity in in vitro Ames and chromosome aberration assays . Fertility and early embryonic development studies were conducted in male and female mice . These studies evaluate mating , fertilization , and embryonic development through implantation . There were no effects of venetoclax on estrus cycles , mating , fertility , corpora lutea , uterine implants or live embryos per litter at dosages up to 600 mg / kg / day . However , a risk to human male fertility exists based on testicular toxicity ( germ cell loss ) observed in dogs at exposures as low as 0.5 times the human AUC exposure at the recommend dose . Animal Toxicology and / or Pharmacology In dogs , venetoclax caused single-cell necrosis in various tissues , including the gallbladder , exocrine pancreas , and stomach with no evidence of disruption of tissue integrity or organ dysfunction ; these findings were minimal to mild in magnitude . Following a 4-week dosing period and subsequent 4-week recovery period , minimal single-cell necrosis was still present in some tissues and reversibility has not been assessed following longer periods of dosing or recovery . In addition , after approximately 3 months of daily dosing in dogs , venetoclax caused progressive white discoloration of the hair coat , due to loss of melanin pigment . PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ).
• Tumor Lysis Syndrome Advise patients of the potential risk of TLS , particularly at treatment initiation and during ramp-up phase , and to immediately report any signs and symptoms associated with this event ( fever , chills , nausea , vomiting , confusion , shortness of breath , seizure , irregular heartbeat , dark or cloudy urine , unusual tiredness , muscle pain , and / or joint discomfort ) to their doctor for evaluation [ see Warnings and Precautions ]. mutated genes occurred more commonly in higher-risk MDS , with the exception of SF3B1 , which was more frequently mutated in low-risk MDS .
The mean number of mutations was 11.4 per patient ; patients with sAML had a significantly higher mutation rate compared with patients with lower-risk MDS ( p = 0.002 ), and the number of mutations increased significantly over time ( p = 0.032 ). Although most of these driver mutations
Advise patients to be adequately hydrated every day when taking VENCLEXTA to reduce the risk of TLS . The recommended volume is 6 to 8 glasses ( approximately 56 ounces total ) of water each day . Patients should drink water starting 2 days before and on the day of the first dose , and every time the dose is increased . Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests . Advise patients that it may be necessary to take VENCLEXTA in the presence of a doctor to allow monitoring for TLS .
• Neutropenia Advise patients to contact their doctor immediately if they develop a fever or any signs of infection . Advise patients of the need for periodic monitoring of blood counts [ see Warnings and Precautions ].
• Drug Interactions Advise patients to avoid consuming grapefruit products , Seville oranges , or starfruit during treatment with VENCLEXTA . Advise patients that VENCLEXTA may interact with some drugs ; therefore , advise patients to inform their doctor of the use of any prescription medication , over-thecounter drugs , vitamins and herbal products [ see Contraindications and Drug Interactions ].
• Immunizations Advise patients to avoid vaccination with live vaccines because they may not be safe or effective during treatment with VENCLEXTA [ see Warnings and Precautions ].
• Pregnancy and Lactation Advise women of the potential risk to the fetus and to avoid pregnancy during treatment with VENCLEXTA . Advise female patients of reproductive potential to use effective contraception during therapy and for at least 30 days after completing of therapy . Advise females to contact their doctor if they become pregnant , or if pregnancy is suspected , during treatment with VENCLEXTA . Also advise patients not to breastfeed while taking VENCLEXTA [ see Warnings and Precautions and Use in Specific Populations ].
• Male Infertility Advise patients of the possibility of infertility and possible use of sperm banking for males of reproductive potential [ see Use in Specific Populations ].
Instructions for Taking VENCLEXTA Advise patients to take VENCLEXTA exactly as prescribed and not to change their dose or to stop taking VENCLEXTA unless they are told to do so by their doctor . Advise patients to take VENCLEXTA orally once daily , at approximately the same time each day , according to their doctor ’ s instructions and that the tablets should be swallowed whole with a meal and water without being chewed , crushed , or broken . Advise patients to keep VENCLEXTA in the original packaging during the first 4 weeks of treatment , and not to transfer the tablets to a different container . had been reported previously , the authors identified several possible new drivers , including C1QTNF3 , IRF2 , NEURL1 , GNL2 , PCDHA1 , and PDGFRB .
“ The driver genes can be classified into molecular subtypes differentially associated with lower-risk MDS , higher-risk MDS , or sAML ,” the authors wrote . Multivariate analyses identified seven genes ( FLT3 , PTPN11 , WT1 , IDH1 , NPM1 , IDH2 , and NRAS ) that could be designated as “ type-1 ” mutations ,
Advise patients that if a dose of VENCLEXTA is missed by less than 8 hours , to take the missed dose right away and take the next dose as usual . If a dose of VENCLEXTA is missed by more than 8 hours , advise patients to wait and take the next dose at the usual time . Advise patients not to take any additional dose that day if they vomit after taking VENCLEXTA , and to take the next dose at the usual time the following day .
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750-1839967 which were significantly enriched in sAML compared with higher-risk MDS . They also identified 10 “ type-2 ” mutations , which were significantly enriched in higher-risk MDS : GATA2 , NRAS , KRAS , IDH2 , TP53 , RUNX1 , STAG2 , ASXL1 , ZRSR2 , and TET2 . “ This new categorization provides insights into clonal dynamics and allows for the use of sub-clonal events as MDS progression biomarkers ,” they explained . The researchers also conducted a separate analysis to characterize the chronologic behavior of type-1 and type-2 mutations in the 122 patients who were followed longitudinally – 90 of whom progressed to sAML . Most of those patients ( n = 109 ; 82 %) had one of the 401 mutations in known driver genes detected at one or more timepoints . In most cases ( n = 70 ), the number of mutations was higher at the second timepoint ( average = 2.7 mutations ) than at diagnosis ( average = 1.9 mutations ).
“ Overall , driver mutations tended to increase their clone sizes and were more likely to be newly acquired than lost between two timepoints ,” Dr . Makishima and co-authors reported .
Type-1 mutations in sAML were more likely to be newly acquired than present before progression , compared with type-2 and other mutations ( p = 0.0001 ), whereas type-2 mutations were more frequently persistent than newly acquired ( p = 0.002 ).
The time from the acquisition of type-1 mutations to sAML progression was , on average , shorter than the time from the acquisition of other mutations to sAML ( hazard ratio [ HR ] = 1.82 ; 95 % CI 1.08-3.05 ; p = 0.025 ). Overall survival ( OS ) also was significantly shorter for patients with type-1 mutations ( HR = 1.50 ; 95 % CI 1.20-1.86 ; p = 0.001 ). “ When present in MDS , [ type-1 ] mutations were associated with a higher risk of progression to sAML and shorter OS , compared with other mutations ,” the authors concluded . “ Close monitoring of the emergence of type-1 mutations might allow for early diagnosis of progression to sAML .”
The study ’ s findings are limited by the potential shortcomings of the previously published data that were included in the current trial . The role of SF3B1 mutations ( which was strongly enriched in lower-risk MDS but not higher-risk MDS ) also confounded the results . “ The two novel sets of gene mutations might be simply associated with sAML evolution from MDS , because the examined cohort included only MDS cases , even though sAML is sometimes derived from other types of myeloid neoplasms , including MDS / myeloproliferative neoplasms ,” the authors noted . ●
REFERENCE
Makishima H , Yoshizato T , Yoshida K , et al . Dynamics of clonal evolution in myelodysplastic syndromes . Nat Genet . 2016 December 19 . [ Epub ahead of print ]
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