ASH Clinical News July 2017 V2 | Page 23

CLINICAL NEWS higher risk of developing a myeloid malignancy compared with those without clonal evidence ( HR = 13.9 ; 95 % CI 5.40-35.91 ; p < 0.001 ). The 5- and 10-year cumulative probabilities of progression were 82 percent versus 9 percent and 95 percent versus 9 percent , respectively ( p < 0.001 ).

A total of 435 patients ( 64 %) in the learning cohort carried at least one of the 40 somatic mutations included in the panel . Patients with ≥1 mutation had a positive predictive value for a myeloid malignancy of 81 percent ( 0.81 ; 95 % CI 0.76-0.84 ), and the positive predictive value appeared to be even stronger in patients with ≥2 mutations , at 88 percent ( 0.88 ; 95 % CI 0.84-0.92 ). Conversely , the absence of any of these mutations had a negative predictive value for myeloid neoplasm ( 0.76 ; 95 % CI 0.70-0.81 ; p value not reported ).

Within the 40-gene panel , spliceosome genes ( SF3B1 , SRSF2 , U2AF1 ), JAK2 , and RUNX1 were associated with the highest predictive value for myeloid malignancies , ranging from 0.88 to 0.97 .

The positive predictive value of mutations in TET2 , DNMT3A , or ASXL1 occurring as single lesions ranged from 29 percent to 57 percent , and co-mutation patterns involving these same genes had positive predictive values for myeloid neoplasm ranging from 86 percent to 100 percent . Together , these mutations and patterns “ accounted for 73 percent of mutated myeloid malignancies ,” the authors wrote .

In multivariate regression analysis , two factors were found to be independent predictors of MDS or another myeloid malignancy :

• the presence of ≥2 mutations ( odds ratio [ OR ] = 4.69 ; p < 0.001 )

Adverse Reactions ( 10 % or Greater ) in Patients with CML in Study 1 ( cont ’ d )

All Grades (%)

Chronic Phase CML N = 406

Grade 3 / 4 (%)

Advanced Phase CML N = 140

All Grades (%)

Grade 3 / 4 (%)

Back pain 12 1 7 1 Asthenia 11 1 10 1 Pruritus 11 1 8 0 Dizziness 10 0 13 1 Dyspnea 10 1 19 6

Advanced phase ( AdvP ) CML includes patients with accelerated phase and blast phase CML

a . Abdominal pain includes the following preferred terms : abdominal pain , upper abdominal pain , lower abdominal pain , abdominal tenderness , gastrointestinal pain , abdominal discomfort

b . Rash includes the following preferred terms : rash , macular rash , pruritic rash , generalized rash , papular rash , maculo-papular rash

c . Fatigue includes the following preferred terms : fatigue , malaise d . Edema includes the following preferred terms : edema , peripheral edema , localized edema , face edema

e . Respiratory tract infection includes the following preferred terms : respiratory tract infection , upper respiratory tract infection , lower respiratory tract infection , viral upper respiratory tract infection , viral respiratory tract infection

In the single-arm , Phase 1 / 2 clinical trial , one patient ( 0.2 %) experienced QTcF interval of greater than 500 ms . Patients with uncontrolled or significant cardiovascular disease , including QT interval prolongation , were excluded by protocol .

Additional Adverse Reactions from Multiple Clinical Trials :

The following adverse reactions were reported in patients in clinical trials with BOSULIF ( less than 10 % of BOSULIF-treated patients ). They represent an evaluation of the adverse reaction data from 870 patients with Ph + leukemia who received at least 1 dose of single-agent BOSULIF . These adverse reactions are presented by system organ class and are ranked by frequency . These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category .

Blood and Lymphatic System Disorders : 1 % and less than 10 % - febrile neutropenia Cardiac Disorders : 1 % and less than 10 % - pericardial effusion ; 0.1 % and less than 1 % - pericarditis Ear and Labyrinth Disorders : 1 % and less than 10 % - tinnitus Gastrointestinal Disorders : 1 % and less than 10 % - gastritis ; 0.1 % and less than 1 % - acute pancreatitis , gastrointestinal hemorrhage a General Disorders and Administrative Site Conditions : 1 % and less than 10 % - chest pain , b pain Hepatobiliary Disorders : 1 % and less than 10 % - hepatotoxicity , c abnormal hepatic function d ; 0.1 % and less than 1 % - liver injury Immune System Disorders : 1 % and less than 10 % - drug hypersensitivity ; 0.1 % and less than 1 % - anaphylactic shock Infections and Infestations : 1 % and less than 10 % - pneumonia , e influenza , bronchitis Investigations : 1 % and less than 10 % - electrocardiogram QT prolonged , increased blood creatine phosphokinase , increased blood creatinine Metabolism and Nutrition Disorder : 1 % and less than 10 % - hyperkalemia , dehydration Musculoskeletal and Connective Tissue Disorder : 1 % and less than 10 % - myalgia Nervous System Disorders : 1 % and less than 10 % - dysgeusia Renal and Urinary Disorders : 1 % and less than 10 % - acute renal failure , renal failure Respiratory , Thoracic , and Mediastinal Disorders : 1 % and less than 10 % - pleural effusion ; 0.1 % and less than 1 % - acute pulmonary edema , respiratory failure , pulmonary hypertension Skin and Subcutaneous Disorders : 1 % and less than 10 % - urticaria , pruritus , acne ; 0.1 % and less than 1 % - erythema multiforme , exfoliative rash , drug eruption

a . Gastrointestinal hemorrhage includes the following preferred terms : gastrointestinal hemorrhage , gastric hemorrhage , upper gastrointestinal hemorrhage b . Chest pain includes the following preferred terms : chest pain , chest discomfort c . Hepatotoxicity includes the following preferred terms : hepatotoxicity , toxic hepatitis , cytolytic hepatitis d . Abnormal hepatic function includes the following preferred terms : abnormal hepatic function , liver disorder e . Pneumonia includes the following preferred terms : pneumonia , bronchopneumonia , lobar pneumonia , primary atypical pneumonia

DRUG INTERACTIONS

Drugs That May Increase Bosutinib Plasma Concentrations : CYP3A inhibitors : Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected . In a dedicated cross-over drug-interaction trial in healthy volunteers ( N = 24 ), concomitant ketoconazole ( strong CYP3A inhibitor ) increased bosutinib C max 5.2-fold and AUC 8.6-fold compared to BOSULIF alone . Drugs That May Decrease Bosutinib Plasma Concentrations : CYP3A Inducers : Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected . In a dedicated cross-over drug-interaction trial in healthy volunteers ( N = 24 ), concomitant rifampin ( strong CYP3A inducer ) decreased bosutinib C max by 86 % and AUC by 94 % compared to BOSULIF alone . Proton Pump Inhibitors : In a dedicated cross-over drug-interaction trial in healthy volunteers ( N = 24 ), concomitant lansoprazole ( PPI ) decreased bosutinib C max by 46 % and AUC by 26 % compared to BOSULIF alone . Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in bosutinib exposure . Separate antacid or H2 blocker dosing and BOSULIF dosing by more than 2 hours .

USE IN SPECIFIC POPULATIONS

Pregnancy Category D : Based on its mechanism of action and findings in animals , BOSULIF can cause fetal harm when administered to a pregnant woman . Studies in animals showed reproductive toxicities . If BOSULIF is used during pregnancy , or if the patient becomes pregnant while taking BOSULIF , the patient should be apprised of the potential hazard to the fetus . Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats . Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1 , 3 , and 10 mg / kg / day . This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes . In a study conducted in rabbits , bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3 , 10 , and 30 mg / kg / day . At the maternally-toxic dose of 30 mg / kg / day of bosutinib , there were fetal anomalies ( fused sternebrae , and two fetuses had various visceral observations ), and an approximate 6 % decrease in fetal body weight . The dose of 30 mg / kg / day resulted in exposures ( AUC ) approximately 4 times those in humans at the 500 mg / day dose of bosutinib . Nursing Mothers : It is not known whether bosutinib is excreted in human milk . Bosutinib and / or its metabolites were excreted in the milk of lactating rats . Radioactivity was present in the plasma of suckling offspring 24 to 48 hours after lactating rats received a single oral dose of radioactive bosutinib . Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BOSULIF , a decision should be made whether to discontinue nursing or to discontinue the drug , taking into account the importance of the drug to the mother . Pediatric Use : The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established . Geriatric Use : In the Phase 1 / 2 clinical trial of BOSULIF in patients with Ph + CML , 20 % were age 65 and over , and 4 % were 75 and over . No overall differences in safety or effectiveness were observed between these patients and younger patients , and other reported clinical experience has not identified differences in responses between the elderly and younger patients , but greater sensitivity of some older individuals cannot be ruled out . Hepatic Impairment : Treat with a dose of 200 mg daily in patients with any baseline hepatic impairment . In a dedicated hepatic impairment trial , the exposure to bosutinib increased ( C max increased 1.5- to 2.3-fold and the AUC increased 1.9- to 2.4-fold ) in patients with hepatic impairment ( Child-Pugh classes A , B , and C ; N = 18 ) compared to matched healthy volunteers ( N = 9 ). Renal Impairment : Reduce the BOSULIF starting dose in patients with severe ( CrCL < 30 mL / min ) or moderate ( CrCL 30-50 mL / min ) renal impairment at baseline . For patients who have declining renal function while on BOSULIF who cannot tolerate a 500-mg dose , follow dose adjustment recommendations for toxicity . In a dedicated renal impairment trial , compared to subjects with normal renal function , the exposure ( AUC ) of bosutinib increased by 60 % and 35 % in subjects with CrCL < 30 mL / min and CrCL 30-50 mL / min , respectively , compared to subjects with normal renal function . BOSULIF has not been studied in patients undergoing hemodialysis .

OVERDOSAGE

Experience with BOSULIF overdose in clinical studies was limited to isolated cases . There were no reports of any serious adverse events associated with the overdoses . Patients who take an overdose of BOSULIF should be observed and given appropriate supportive treatment .

PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling . Dosing and Administration : Instruct patients to take BOSULIF exactly as prescribed , not to change their dose or to stop taking BOSULIF unless they are told to do so by their doctor . If patients miss a dose beyond 12 hours , they should be advised to take the next scheduled dose at its regular time . A double dose should not be taken to make up for any missed dose . Advise patients to take BOSULIF with food . Patients should be advised : “ Do not crush or cut tablet . Do not touch or handle crushed or broken tablets .” Gastrointestinal Problems : Advise patients that they may experience diarrhea , nausea , vomiting , abdominal pain , or blood in their stools with BOSULIF and to seek medical attention promptly for these symptoms . Low Blood Cell Counts : Advise patients of the possibility of developing low blood cell counts and to immediately report fever , any suggestion of infection , or signs or symptoms suggestive of bleeding or easy bruising . Liver Problems : Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice . Fluid Retention : Advise patients of the possibility of developing fluid retention ( swelling , weight gain , or shortness of breath ) and to seek medical attention promptly if these symptoms arise . Renal Problems : Advise patients of the possibility of developing renal problems and to immediately report frequent urination , polyuria , or oliguria . Other Adverse Reactions : Advise patients that they may experience other adverse reactions such as respiratory tract infections , rash , fatigue , loss of appetite , headache , dizziness , back pain , arthralgia , or pruritus with BOSULIF and to seek medical attention if symptoms are significant . There is a possibility of anaphylactic shock . Pregnancy and Breast-feeding : Advise patients that BOSULIF can cause fetal harm when administered to a pregnant woman . Advise women of the potential hazard to the fetus and to avoid becoming pregnant . If BOSULIF is used during pregnancy , or if the patient becomes pregnant while taking BOSULIF , the patient should be apprised of the potential hazard to the fetus . Because a potential risk to the nursing infant cannot be excluded , women that are taking BOSULIF should not breast-feed or provide breast milk to infants . Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during and for at least 30 days after completing treatment with BOSULIF . Instruct patients to contact their physicians immediately if they become pregnant during treatment . Advise patients not to take BOSULIF treatment while pregnant or breast-feeding . If a patient wishes to restart breast-feeding after treatment , advise her to discuss the appropriate timing with her physician . Drug Interactions : Advise patients that BOSULIF and certain other medicines , including over-the-counter medications or herbal supplements ( such as St . John ’ s wort ), can interact with each other and may alter the effects of BOSULIF .

Rx only This brief summary is based on BOSULIF Prescribing Information LAB-0443-6.0 , revised April 2016 .

© 2016 Pfizer Inc . All rights reserved . May 2016

• the presence of an SF3B1 mutation ( OR = 4.83 ; p = 0.003 ) Print-only content

Factors independently associated with diagnoses other than myeloid malignancies included isolated DNMT3A ( OR = 0.21 ; p = 0.001 ) or TET2 ( OR = 0.43 ; p = 0.023 ) mutations . “ The results of this study suggest that mutation analysis of peripheral blood cells may significantly improve the current diagnostic approach to [ patients ] with unexplained cytopenias ,” the authors concluded . “ More effective , non-invasive diagnostic procedures are in turn expected to improve compliance to diagnostic tests .”

“ We also identified mutation patterns showing a high specificity for myeloid malignancies with dysplasia ,” Dr . Malcovati added . “ Notably , patients with ICUS carrying these highly specific mutation patterns have a clinical course not significantly different from that of patients with a myelodysplastic syndrome . This indicates that cases with inconclusive dysplasia but highly specific mutation patterns might be classified as bona fide myelodysplastic syndromes .”

The study is limited by its lack of sequential mutation analysis – the authors were unable to exclude changes in mutation pattern or variant allele frequency as factors potentially contributing to the risks for myeloid malignancies . ●

REFERENCE

Malcovati L , Gallì A , Travaglino E , et al . Clinical significance of somatic mutation in unexplained blood cytopenia . Blood . 2017 April 19 . [ Epub ahead of print ]

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