Written in Blood
Investigating a Venetoclax-Based Triplet Therapy for Patients With Relapsed / Refractory Myeloma
In a phase Ib trial of patients with relapsed / refractory multiple myeloma , targeting BCL2 and MCL1 with a triplet combination of the BCL2 inhibitor venetoclax plus bortezomib and dexamethasone led to high response rates with a “ manageable safety profile ,” according to a study published in Blood .
In the open-label , single arm , multicenter M12-901 study , Philippe Moreau , MD , head of the hematology department at the University Hospital Hôtel-Dieu in Nantes , France , and co-authors enrolled 66 patients ( median age = 64 years ; range = 38-79 years ) from eight sites between November 2012 and May 2016 . Patients were excluded if they received prior treatment with bortezomib within 30 days of the first dose of venetoclax ; experienced grade 3 / 4 peripheral neuropathy ; or had systemic infection , fever , or neutropenia within one week of the first venetoclax dose . All patients had received prior myeloma treatment ( median prior lines of therapy = 3 ; range = 1-13 therapies ), and 39 patients ( 59 %) had undergone hematopoietic cell transplantation .
Most patients ( n = 53 ; 80 %) had previously received bortezomib ( 26 [ 39 %] of whom were refractory ), and 48 patients ( 73 %) had received lenalidomide ( 35 [ 53 %] of whom were refractory ). Patients had the following cytogenetic abnormalities : t ( 11 ; 14 ) ( n = 9 ; 14 %), t ( 4 ; 14 ) ( n = 5 ; 8 %), del ( 17p ( n = 15 ; 23 %), del ( 13q ) ( n = 30 ; 45 %), and hyperdiploidy ( n = 30 ; 45 %). Patients received :
• bortezomib 1.3 mg / m 2 administered via subcutaneous injection on days 1 , 4 , 8 , and 11 during cycles 1-8 and on days 1 , 8 , 15 , and 22 during cycles 9-11
• dexamethasone 20 mg administered orally on days 1 , 2 , 4 , 5 , 8 , 9 , 11 , and 12 during cycles 1-8 and on days 1 , 8 , 15 , and 22 during cycles 9-11
• venetoclax 50 mg administered alone during a 1-week leadin period , followed by doses ranging from 100 to 1,200 mg
After 11 cycles , patients could remain on venetoclax monotherapy .
At data cutoff ( August 19 , 2016 ), the median time on study was 5.9 months ( range = 0.3-29 months ) for all
26 ASH Clinical News patients . Those who were refractory to prior bortezomib appeared to have a shorter time on study than those who were not refractory to prior bortezomib ( 2.8 months and 9.1 months , respectively ).
Forty-six patients ( 70 %) discontinued the study because of disease progression
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( n = 36 ), adverse events ( AEs ; n = 5 ), or withdrawal of consent ( n = 2 ; the other three were not specified ). AEs that led to treatment discontinuation were respiratory and cardiac failure ( n = 2 ), lung adenocarcinoma ( n = 1 ), Guillain-Barré syndrome ( n = 1 ), and sepsis ( n = 1 ); none was deemed related to venetoclax , the authors noted .
Six patients ( 9 %) receiving venetoclax required dose reductions related to AEs , and 27 patients ( 41 %) temporarily interrupted treatment because of AEs . Five deaths were reported : four related to disease progression and one related to respiratory syncytial virus infection .
The most common all-grade AEs were diarrhea ( 46 %), constipation ( 41 %),
The first dual-drug liposomal encapsulation of daunorubicin and cytarabine shown to ...
Deliver superior overall survival vs 7 + 3 a to adults with newly-diagnosed t-AML or AML-MRC 1
VYXEOS improved overall survival compared to 7 + 3 in a Phase 3 trial 1
• Median survival of 9.6 months for VYXEOS vs 5.9 months for 7 + 3 ( P = 0.005 ), HR = 0.69 ( 0.52 , 0.90 )
Study Design 1 The Phase 3 study was a randomized , multicenter , open-label , active-controlled superiority study of VYXEOS versus cytarabine and daunorubicin ( 7 + 3 ) in patients 60 to 75 years of age with newly-diagnosed t-AML or AML-MRC . There were 153 patients randomized to VYXEOS and 156 patients randomized to the 7 + 3 arm . 20 % of patients had t-AML , 54 % had AML with an antecedent hematological disorder , and 25 % had de novo AML with MDS-related cytogenetic abnormalities . Eff icacy was established on the basis of overall survival from the date of randomization to death from any cause .
VYXEOS 44 mg / 100 mg per m 2 ( daunorubicin / cytarabine ) was given intravenously on Days 1 , 3 , and 5 for first induction and on Days 1 and 3 for those needing a second induction . For consolidation , the VYXEOS dose was 29 mg / 65 mg per m 2 ( daunorubicin / cytarabine ) on Days 1 and 3 . In the 7 + 3 arm , first induction was cytarabine 100 mg / m 2 / day on Days 1-7 by continuous infusion + daunorubicin 60 mg / m 2 / day on Days 1-3 . For second induction and consolidation , cytarabine was dosed on Days 1-5 and daunorubicin on Days 1 and 2 .
INDICATION
VYXEOS ( daunorubicin and cytarabine ) liposome for injection 44 mg / 100 mg is indicated for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia ( t-AML ) or AML with myelodysplasia-related changes ( AML-MRC ).
IMPORTANT SAFETY INFORMATION
WARNING : DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND / OR CYTARABINE-CONTAINING PRODUCTS
VYXEOS has different dosage recommendations than daunorubicin hydrochloride injection , cytarabine injection , daunorubicin citrate liposome injection , and cytarabine liposome injection . Verify drug name and dose prior to preparation and administration to avoid dosing errors .
Contraindications
VYXEOS is contraindicated in patients with a history of serious hypersensitivity reactions to cytarabine , daunorubicin , or any component of the formulation .
Warnings and Precautions
Hemorrhage Serious or fatal hemorrhage events , including fatal CNS hemorrhages , associated with prolonged thrombocytopenia , have occurred with VYXEOS . The overall incidence ( grade 1-5 ) of hemorrhagic events was 74 % in the VYXEOS arm and 56 % in the control arm . The most frequently reported hemorrhagic event was epistaxis ( 36 % in VYXEOS arm and 18 % in control arm ). Grade 3 or greater events occurred in 12 % of VYXEOS-treated patients and in 8 % of patients in the control arm . Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2 % of patients in the VYXEOS arm and in 0.7 % of patients in the control arm . Monitor blood counts regularly and administer platelet transfusion support as required .
Cardiotoxicity VYXEOS contains daunorubicin , which has a known risk of cardiotoxicity . This risk may be increased in patients with prior anthracycline therapy , preexisting cardiac disease , previous radiotherapy to the mediastinum , or concomitant use of cardiotoxic drugs . Assess cardiac function prior to VYXEOS treatment and repeat prior to consolidation and as clinically required . VYXEOS is not recommended in patients with impaired cardiac function unless the benefit of treatment outweighs the risk .
Total cumulative doses of non-liposomal daunorubicin greater than 550 mg / m 2 have been associated with an increased incidence of drug-induced congestive heart failure . The tolerable limit appears lower ( 400 mg / m 2 ) in patients who received radiation therapy to the mediastinum . Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS . VYXEOS is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit .