Dosing & TLS prophylaxis
(tumour lysis syndrome)
Prescribing information can be accessed by the Prescribing Information button on the left
UK-VNCAML-220172 | November 2022.
VENCLYXTO in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.1
Adverse events should be reported.
Reporting forms and information can be found at https://yellowcard.mhra.gov.uk or via the MHRA Yellow Card app, available in the Google Play or Apple App Stores.
Adverse events should also be reported to AbbVie on [email protected]
WHAT IS THE GUIDANCE ON TLS PROPHYLAXIS FOR AML PATIENTS WITH RISK FACTORS FOR TLS??
Consider additional measures, including increasing laboratory monitoring and reducing VENCLYXTO starting dose for patients with risk factors for TLS, e.g. circulating blasts, high burden of leukaemia involvement in bone marrow, elevated pre-treatment LDH levels, reduced renal function.1
| PRIOR TO INITIATION1 |
WBC count <25 x 109/L Cytoreduction may be required Assess blood chemistries and correct pre-existing abnormalities
Administer prophylaxis All patients should be adequately hydrated and receiving anti-hyperuricaemic agents prior to initiation of VENCLYXTO and throughout the dose titration period |
Monitor blood chemistries for TLS at pre-dose, 6-8 hours after each new dose, and 24 hours after reaching final dose
More guidance is available in Dose initiation & TLS prophylaxis
AML=Acute Myeloid Leukaemia; AZA=azacitidine; LDH=lactate dehydrogenase; TLS=tumour lysis syndrome; VEN=VENCLYXTO; WBC=white blood cell.
WHAT WAS THE LEVEL AND DURATION OF CYP3A INHIBITOR USE IN VIALE-A?
Anti-infective prophylaxis was required for patients with ANC<500/μL2
CYP3A INHIBITOR USE IN THE FIRST 2 CYCLES IN VIALE A2
MEDIAN DURATION OF PROPHYLACTIC CYP3A INHIBITOR USE2
Examples of moderate anti-infective CYP3A inhibitors include fluconazole, erythromycin and ciprofloxacin. Examples of strong anti-infective CYP3A inhibitors include itraconazole, posaconazole and voriconazole1
More guidance on managing drug-drug interactions is available in DDI management
Please refer to the SmPC for full prescribing information
*For any end date that was not available, the end date was the date of study cut.
ANC=absolute neutrophil count; AZA=azacitidine; CYP3A=cytochrome P450 3A; CYP3Ai=CYP3A inhibitor; VEN=VENCLYXTO.
WHAT IS THE DOSE ADJUSTMENT OF VENCLYXTO IN THE PRESENCE OF CYP3A INHIBITORS?
Concomitant use of VENCLYXTO with strong or moderate CYP3A inhibitors increases VENCLYXTO exposure and may increase the risk for TLS at initiation and during the dose titration phase and for other toxicities. Consider alternative medications1
The SmPC recommends VENCLYXTO dose reductions when co-administered with moderate or strong CYP3A inhibitors. Patients should be monitored closely for signs of toxicities and the dose may need to be further adjusted1
MAXIMUM DOSE OF VENCLYXTO WHEN USED IN COMBINATION WITH STRONG CYP3A INHIBITORS1
Reduce to 100 mg or less (or by at least 75% if already modified for other reasons)
MAXIMUM DOSE OF VENCLYXTO WHEN USED IN COMBINATION WITH MODERATE CYP3A INHIBITORS1
Reduce VENCLYXTO dose by at least 50%
More guidance on managing drug-drug interactions is available in DDI management
Please refer to the SmPC for full prescribing information
CYP3A=cytochrome P450 3A; P-gp=permeability glycoprotein.
DOES USE OF ANTIMICROBIAL PROPHYLAXIS IMPACT PATIENT OUTCOMES WITH VENCLYXTO?
Antimicrobial prophylaxis with CYP3A inhibitors was used in neutropenic patients in the VIALE-A study, with overall similar composite remission rates with VENCLYXTO dose reductions2*
OVERALL SURVIVAL
Median OS in patients receiving VEN+AZA was not statistically different regardless of use of moderate or strong CYP3A inhibitor2
ADVERSE EVENTS
Rates of discontinuation from infections were similar across all patients treated with VEN+AZA regardless of CYP3Ai use2
RESPONSES
Rates of CR+CRi as best response in the VEN+AZA arm of VIALE-A were similar with concomitant use of CYP3Ai vs. no use2
More guidance on managing drug-drug interactions is available in DDI management
Graphs adapted from Jonas BA et al.
VIALE-A was a phase 3, randomised (2:1), placebo-controlled, trial evaluating the efficacy and safety of VEN+AZA vs. PBO+AZA in first-line adult AML patients ineligible for intensive chemotherapy. VEN+AZA acheived its primary endpoints, achieving statistically significant increases in overall survival and CR/CRi rates vs AZA alone (p<0.001 for both).
*Neutropenic patients were defined as having an ANC <500/µL.2
ANC=absolute neutrophil count; CI=confidence interval; CR=complete remission; CRi=CR with incomplete count recovery; CYP3Ai=cytochrome P450 3A inhibitor;
OS=overall survival; VEN=VENCLYXTO.
IN VIALE-A, WHAT WAS THE INCIDENCE OF DOSE INTERRUPTIONS AND CYCLE DELAYS?
Cycle delays and reduction in dosing duration and/or cycle delay ≥7 days related to Grade 4 cytopenia were more frequent in the VEN+AZA arm.
CYCLE DELAY RELATED TO GRADE 4 CYTOPENIA AFTER BLAST CLEARANCE AMONG PATIENTS WHO ACHIEVED CR/CRh4
REDUCTION IN DOSING DURATION AND/OR CYCLE DELAY ≥7 DAYS RELATED TO GRADE 4 CYTOPENIA AMONG PATIENTS WHO ACHIEVED CR/ CRh4
CYCLE DELAY RELATED TO GRADE 4 CYTOPENIA AFTER BLAST CLEARANCE AMONG PATIENTS WHO ACHIEVED CR/CRh4
REDUCTION IN DOSING DURATION AND/OR CYCLE DELAY ≥7 DAYS RELATED TO GRADE 4 CYTOPENIA AMONG PATIENTS WHO ACHIEVED CR/ CRh4
MEDIAN (RANGE) DURATION OF CYCLE DELAY AMONG PATIENTS WHO ACHEIVED CR/CRh4
MEDIAN NUMBER OF CYCLES FROM REMISSION TO FIRST TREATMENT BREAK OF ≥ 7 DAYS AMONG PATIENTS WHO ACHIEVED CR/CRh4
MEDIAN (RANGE) DURATION OF CYCLE DELAY AMONG PATIENTS WHO ACHEIVED CR/CRh4
MEDIAN NUMBER OF CYCLES FROM REMISSION TO FIRST TREATMENT BREAK OF ≥ 7 DAYS AMONG PATIENTS WHO ACHIEVED CR/CRh4
More guidance on managing cytopenia is available in Cytopenia & AE management
AZA=azacitidine; CR=complete remission; CRh=CR with partial haematologic recovery; VEN=VENCLYXTO.
HOW MANY PATIENTS RECEIVED A GRANULOCYTE-COLONY STIMULATING FACTOR (G-CSF) IN THE VIALE-A STUDIES?
In VIALE‑A, 190/286 patients (66%) treated with VEN+AZA achieved CR/CRi. Of those, 49% (93/190) received G‑CSF after achieving remission5
Post-remission G-CSF use was not associated with inferior duration of CR/CRi or inferior OS among patients treated with VENCLYXTO in VIALE-A5
More guidance on managing cytopenia is available in Cytopenia & AE management
AZA=azacitidine; CR=complete remission; CRi=CR with incomplete count recovery; remission; G-CSF=granulocyte-colony stimulating factor; NR=not reached; OS=overall survival; VEN=VENCLYXTO.
OVERALL SURVIVAL
Median OS in patients receiving VEN+AZA was not statistically different regardless of use of moderate or strong CYP3A inhibitor2*
Adapted from Jonas BA et al.
*As noted by overlapping confidence intervals.
ADVERSE EVENTS
Rates of discontinuation from infections were similar across all patients treated with Ven+AZA regardless of CYP3Ai use2*
Graph adapted from Jonas BA et al.
*Reported AEs that began within the the first 2 cycles of treatment with CYP3Ai were reported as being given for prophylaxis.
RESPONSES
Rates of CR+CRi as best response in the VEN+AZA arm of VIALE-A were similar with concomitant use of CYP3Ai vs. no use2*
Graph adapted from Jonas BA et al.
*CR=absolute ANC ≥1,000/μl, platelets ≥100,000/μl, red blood cell transfusion independence, bone marrow with <5% blasts; absence of circulating blasts and blasts with Auer rods, and absence of extramedullary disease.
CRi=ANC <1,000/μl or platelets <100,000/μl1,4
