ASH Clinical News July 2017 V2 - Page 22

Written in Blood to the current diagnostic work-up of unexplained cytopenia .”
The authors included 873 patients with unexplained cytopenias who underwent evaluation ( including peripheral blood and bone marrow examinations ) at the Fondazione IRCCS Policlinico San Matteo and the University of Pavia between 2003 and 2015 . Patients were split into a learning cohort ( those being investigated for unexplained cytopenias ; n = 683 consecutively seen patients ) and a validation cohort ( those referred to the same institution for a second opinion for a suspected myeloid malignancy ; n = 190 ). Mutation analysis was performed on DNA collected at the time of initial evaluation .
After undergoing diagnostic work-up , patients were prospectively followed to establish the diagnosis and to monitor disease .
In the learning cohort , patients were eventually diagnosed with : a myeloid malignancy ( n = 409 ), ICUS ( n = 154 ), or other cytopenias , including those due to iatrogenic , immune-mediated , or secondary cytopenia ( n = 120 ). In the validation cohort , the final diagnosis was a myeloid malignancy in 138 patients , while a myeloid malignancy was ruled out as a cause of cytopenias in 38 patients . ICUS was provisionally adopted as a diagnosis in 14 patients .
Among patients with ICUS after initial diagnostic work-up , those who carried at least one of the mutations had a significantly
BOSULIF ® ( bosutinib ) tablets for oral use
Initial U . S . Approval : 2012
Brief summary of Prescribing Information
INDICATIONS AND USAGE
BOSULIF is indicated for the treatment of adult patients with chronic , accelerated , or blast phase Philadelphia chromosome – positive ( Ph +) chronic myelogenous leukemia ( CML ) with resistance or intolerance to prior therapy .
DOSAGE AND ADMINISTRATION
Recommended Dosing : The recommended dose and schedule of BOSULIF is 500 mg orally once daily with food . Continue treatment with BOSULIF until disease progression or patient intolerance . If a dose is missed beyond 12 hours , the patient should skip the dose and take the usual prescribed dose on the following day . Dose Escalation : Consider dose escalation to 600 mg once daily with food in patients who do not reach complete hematological response ( CHR ) by week 8 or a complete cytogenetic response ( CCyR ) by week 12 , who did not have Grade 3 or higher adverse reactions , and who are currently taking 500 mg daily . Dose Adjustments for Non-Hematologic Adverse Reactions : Elevated liver transaminases : If elevations in liver transaminases greater than 5 x institutional upper limit of normal ( ULN ) occur , withhold BOSULIF until recovery to less than or equal to 2.5 x ULN and resume at 400 mg once daily thereafter . If recovery takes longer than 4 weeks , discontinue BOSULIF . If transaminase elevations greater than or equal to 3 x ULN occur concurrently with bilirubin elevations greater than 2 x ULN and alkaline phosphatase less than 2 x ULN ( Hy ’ s law case definition ), discontinue BOSULIF . Diarrhea : For NCI CTCAE Grade 3-4 diarrhea ( increase of greater than or equal to 7 stools / day over baseline / pretreatment ), withhold BOSULIF until recovery to Grade less than or equal to 1 . BOSULIF may be resumed at 400 mg once daily . For other clinically significant , moderate or severe non-hematological toxicity : Withhold BOSULIF until the toxicity has resolved , then consider resuming BOSULIF at 400 mg once daily . If clinically appropriate , consider re-escalating the dose of BOSULIF to 500 mg once daily . Dose Adjustments for Myelosuppression : Dose reductions for severe or persistent neutropenia and thrombocytopenia are as follows : If absolute neutrophil count ( ANC ) is less than 1000x10 6 / L or platelets are less than 50,000x10 6 / L : Withhold BOSULIF until ANC is greater than or equal to 1000x10 6 / L and platelets are greater than or equal to 50,000x10 6 / L . Resume treatment with BOSULIF at the same dose if recovery occurs within 2 weeks . If blood counts remain low for greater than 2 weeks , upon recovery , reduce dose by 100 mg and resume treatment . If cytopenia recurs , reduce the dose by an additional 100 mg upon recovery and resume treatment . Doses less than 300 mg / day have not been evaluated . Concomitant Use With CYP3A Inhibitors : Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected ( strong CYP3A inhibitors include boceprevir , clarithromycin , conivaptan , indinavir , itraconazole , ketoconazole , lopinavir / ritonavir , mibefradil , nefazodone , nelfinavir , posaconazole , ritonavir , saquinavir , telaprevir , telithromycin , and voriconazole . Moderate CYP3A inhibitors include amprenavir , aprepitant , atazanavir , ciprofloxacin , crizotinib , darunavir / ritonavir , diltiazem , erythromycin , fluconazole , fosamprenavir , grapefruit products , imatinib , and verapamil ). Concomitant Use With CYP3A Inducers : Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected ( strong CYP3A inducers include carbamazepine , phenytoin , rifampin , and St . John ’ s Wort . Moderate CYP3A inducers include bosentan , efavirenz , etravirine , modafinil , and nafcillin ). Hepatic Impairment : In patients with mild ( Child-Pugh A ), moderate ( Child-Pugh B ), or severe ( Child-Pugh C ) hepatic impairment , the recommended dose of BOSULIF is 200 mg daily . Renal Impairment : If creatinine clearance ( CrCL ) is 30 to 50 mL / min , the recommended starting dose of BOSULIF is 400 mg daily . If CrCL is < 30 mL / min , the recommended starting dose of BOSULIF is 300 mg daily .
CONTRAINDICATIONS
History of hypersensitivity to BOSULIF . Reactions have included anaphylaxis . Anaphylactic shock occurred in less than 0.2 % of treated patients in clinical trials .
WARNINGS AND PRECAUTIONS
Gastrointestinal Toxicity : Diarrhea , nausea , vomiting , and abdominal pain occur with BOSULIF treatment . Monitor and manage patients using standards of care , including antidiarrheals , antiemetics , and fluid replacement . In the single-arm Phase 1 / 2 clinical trial , the median time to onset for diarrhea ( all grades ) was 2 days and the median duration per event was 1 day . Among the patients who experienced diarrhea , the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 ( range 1-221 ). To manage gastrointestinal toxicity , withhold , dose reduce , or discontinue BOSULIF as necessary . Myelosuppression : Thrombocytopenia , anemia , and neutropenia occur with BOSULIF treatment . Perform complete blood counts weekly for the first month of therapy and then monthly thereafter , or as clinically indicated . To manage myelosuppression , withhold , dose reduce , or discontinue BOSULIF as necessary . Hepatic Toxicity : One case consistent with drug-induced liver injury ( defined as concurrent elevations in ALT or AST greater than or equal to 3 x ULN with total bilirubin greater than 2 x ULN and alkaline phosphatase less than 2 x ULN ) occurred in a trial of BOSULIF in combination with letrozole . The patient recovered fully following discontinuation of BOSULIF . This case represented 1 out of 1209 patients in BOSULIF clinical trials . In the 546 patients from the safety population , the incidence of ALT elevation was 17 % and AST elevation was 14 %. Twenty percent of the patients experienced an increase in either ALT or AST . Most cases of transaminase elevations occurred early in treatment ; of patients who experienced transaminase elevations of any grade , more than 80 % experienced their first event within the first 3 months . The median time to onset of increased ALT and AST was 30 and 33 days , respectively , and the median duration for each was 21 days . Perform hepatic enzyme tests monthly for the first three months of BOSULIF treatment and as clinically indicated . In patients with transaminase elevations , monitor liver enzymes more frequently . Withhold , dose reduce , or discontinue BOSULIF as necessary . Fluid Retention : Fluid retention occurs with BOSULIF and may manifest as pericardial effusion , pleural effusion , pulmonary edema , and / or peripheral edema . In the single-arm , Phase 1 / 2 clinical trial in 546 patients with CML treated with prior therapy , severe fluid retention was reported in 14 patients ( 3 %). Specifically , 9 patients had a Grade 3 or 4 pleural effusion , 3 patients experienced both Grade 3 or Grade 4 pleural and pericardial effusions , 1 patient experienced Grade 3 peripheral and pulmonary edema , and 1 patient had a Grade 3 edema . Monitor and manage patients using standards of care . Interrupt , dose reduce , or discontinue BOSULIF as necessary . Renal Toxicity : An on-treatment decline in estimated glomerular filtration rate ( eGFR ) has occurred in patients treated with BOSULIF . The table identifies the shift from baseline to lowest observed eGFR during BOSULIF therapy for patients in the global Ph + Leukemia studies . The median duration of therapy with BOSULIF was approximately 17 months ( range , 0.03 to 95 ) for patients in these studies .
Shift from Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies ( n = 818 )*
Baseline
Follow Up
Renal Function Status n Normal Mild
Mild to Moderate n (%) n (%) Moderate to Severe
Severe n (%) n (%) n (%)
Notes : Grading is based on Modification in Diet in Renal Disease method ( MDRD ). KDIGO Classification by eGFR : Normal : greater than or equal to 90 , Mild : 60 to less than 90 , Mild to Moderate : 45 to less than 60 , Moderate to Severe : 30 to less than 45 , Severe : 15 to less than 30 , Kidney Failure : less than 15 mL / min / 1.73 m 2 . * Among the 818 patients , eGFR was missing in 5 patients at baseline or on-therapy . There were no patients with kidney failure at baseline .
Monitor renal function at baseline and during therapy with BOSULIF , with particular attention to those patients who have preexisting renal impairment or risk factors for renal dysfunction . Consider dose adjustment in patients with baseline and treatment emergent renal impairment . Embryofetal Toxicity : There are no adequate and well controlled studies of BOSULIF in pregnant women . BOSULIF can cause fetal harm when administered to a pregnant woman . Bosutinib caused embryofetal toxicities in rabbits at maternal exposures that were greater than the clinical exposure at the recommended bosutinib dose of 500 mg / day . Females of reproductive potential should be advised to avoid pregnancy while being treated with BOSULIF . If this drug is used during pregnancy , or if the patient becomes pregnant while taking this drug , the patient should be apprised of the potential hazard to the fetus .
ADVERSE REACTIONS
Clinical Trials Experience : Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice . Serious adverse reactions reported include anaphylactic shock , myelosuppression , gastrointestinal toxicity ( diarrhea ), fluid retention , hepatotoxicity , and rash . Adverse reactions of any toxicity grade reported for greater than 20 % of patients in the Phase 1 / 2 safety population ( n = 546 ) were diarrhea ( 82 %), nausea ( 46 %), thrombocytopenia ( 41 %), vomiting ( 39 %), abdominal pain ( 37 %), rash ( 35 %), anemia ( 27 %), pyrexia ( 26 %), and fatigue ( 24 %). Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph + Chronic Phase ( CP ), Accelerated Phase ( AP ), and Blast Phase ( BP ) CML : The single-arm , Phase 1 / 2 clinical trial enrolled patients with Ph + chronic , accelerated , or blast phase chronic myelogenous leukemia ( CML ) with resistance or intolerance to prior therapy . The safety population ( received at least 1 dose of BOSULIF ) included 546 CML patients . Within the safety population there were 287 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 24 months and a median dose intensity of 484 mg / day ; 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 475 mg / day ; and 140 patients with advanced phase CML , including 76 patients with AP CML and 64 patients with BP CML . In the patients with AP CML and BP CML , the median duration of BOSULIF treatment was 10 months and 3 months , respectively . The median dose intensity was 483 mg / day and 500 mg / day in the AP CML and BP CML cohorts , respectively .
Adverse Reactions ( 10 % or Greater ) in Patients with CML in Study 1
All Grades (%)
Chronic Phase CML N = 406
Grade 3 / 4 (%)
Advanced Phase CML N = 140
All Grades (%)
Kidney Failure n (%)
Normal
274
53 ( 19 )
174 ( 64 )
30 ( 11 )
14 ( 5 )
1 (< 1 )
1 (< 1 )
Mild
438
10 ( 2 )
170 ( 39 )
177 ( 40 )
63 ( 14 )
14 ( 3 )
2 ( 1 )
Mild to Moderate
79
0
4 ( 5 )
28 ( 35 )
37 ( 47 )
10 ( 13 )
0
Moderate to Severe
24
0
1 ( 4 )
1 ( 4 )
6 ( 25 )
15 ( 63 )
1 ( 4 )
Severe
1
0
0
0
0
0
1 ( 100 )
Total
816
63 ( 8 )
349 ( 43 )
236 ( 29 )
120 ( 15 )
40 ( 5 )
5 ( 1 )
Grade 3 / 4 (%)
Diarrhea
84
9
76
5
Nausea
46
1
47
2
Abdominal Pain a
40
1
29
5
Thrombocytopenia
40
26
42
37
Vomiting
37
3
42
4
Rash b
34
8
35
4
Fatigue c
26
1
20
4
Anemia
23
9
37
26
Pyrexia
22
< 1
36
3
Increased alanine aminotransferase
20
7
10
5
Headache
20
1
18
4
Cough
20
0
21
0
Increased aspartate aminotransferase
16
4
11
3
Neutropenia
16
11
19
18
Edema d
14
< 1
14
1
Arthralgia
14
< 1
13
0
Decreased appetite
13
1
14
0
Respiratory tract infection e
12
< 1
10
0
Nasopharyngitis
12
0
5
0
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Written in Blood to the current diagnostic work-up of unex- plained cytopenia.” The authors included 873 patients with unexplained cytopenias who underwent eval- uation (including peripheral blood and bone marrow examinations) at the Fondazione IRCCS Policlinico San Matteo and the University of Pavia between 2003 and 2015. Patients were split into a learning cohort (those being in- vestigated for unexplained cytopenias; n=683 consecutively seen patients) and a validation cohort (those referred to the same institution for a second opinion for a suspected myeloid malignancy; n=190). Mutation analysis was performed on DNA collected at the time of initial evaluation. After undergoing diagnostic work-up, patients were prospectively followed to estab- lish the diagnosis and to monitor disease. In the learning cohort, patients were eventually diagnosed with: a myeloid malignancy (n=409), ICUS (n=154), or S:6.75” BOSULIF ® (bosutinib) tablets for oral use Initial U.S. Approval: 2012 Brief summary of Prescribing Information INDICATIONS AND USAGE BOSULIF is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. DOSAGE AND ADMINISTRATION Recommended Dosing: The recommended dose and schedule of BOSULIF is 500 mg orally once daily with food. Continue treatment with BOSULIF until disease progression or patient intolerance. If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dose Escalation: Consider dose escalation to 600 mg once daily with food in patients who do not reach complete hematological response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, who did not have Grade 3 or higher adverse reactions, and who are currently taking 500 mg daily. Dose Adjustments for Non-Hematologic Adverse Reactions: Elevated liver transaminases: If elevations in liver transaminases greater than 5 x institutional upper limit of normal (ULN) occur, withhold BOSULIF until recovery to less than or equal to 2.5 x ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue BOSULIF. If transaminase elevations greater than or equal to 3 x ULN occur concurrently with bilirubin elevations greater than 2 x ULN and alkaline phosphatase less than 2 x ULN (Hy’s law case definition), discontinue BOSULIF. Diarrhea: For NCI CTCAE Grade 3-4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold BOSULIF until recovery to Grade less than or equal to 1. BOSULIF may be resumed at 400 mg once daily. For other clinically significant, moderate or severe non-hematological toxicity: Withhold BOSULIF until the toxicity has resolved, then consider resuming BOSULIF at 400 mg once daily. If clinically appropriate, consider re-escalating the dose of BOSULIF to 500 mg once daily. Dose Adjustments for Myelosuppression: Dose reductions for severe or persistent neutropenia and thrombocytopenia are as follows: If absolute neutrophil count (ANC) is less than 1000x10 6 /L or platelets are less than 50,000x10 6 /L: Withhold BOSULIF until ANC is greater than or equal to 1000x10 6 /L and platelets are greater than or equal to 50,000x10 6 /L. Resume treatment with BOSULIF at the same dose if recovery occurs within 2 weeks. If blood counts remain low for greater than 2 weeks, upon recovery, reduce dose by 100 mg and resume treatment. If cytopenia recurs, reduce the dose by an additional 100 mg upon recovery and resume treatment. Doses less than 300 mg/day have not been evaluated. Concomitant Use With CYP3A Inhibitors: Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected (strong CYP3A inhibitors include boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole. Moderate CYP3A inhibitors include amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit products, imatinib, and verapamil). Concomitant Use With CYP3A Inducers: Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected (strong CYP3A inducers include carbamazepine, phenytoin, rifampin, and St. John’s Wort. 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