Safety Profile

mylotarg2-cobb-safety-profile

HEPATOTOXICITY/VOD

Hepatotoxicity, including VOD, in the Phase 3, open-label study1,2
Hepatotoxicity, including life-threatening and sometimes fatal VOD, has been reported in patients with newly diagnosed AML who received MYLOTARG combination therapy. Review the Phase 3, open-label study design.
  • 2 cases of VOD were also observed in the control arm in patients who received MYLOTARG as therapy for relapsed AML
  • The median time from the last MYLOTARG dose to onset of VOD was 9 days (range, 2-298 days)
  • Patients who experienced remission were also eligible for allogeneic transplantation 
  • 32/135 (24%) patients in the MYLOTARG arm received a transplant
  • 53/136 (39%) patients in the control arm received a transplant
  • Although no relationship was found between VOD and time of HSCT relative to higher MYLOTARG monotherapy doses, the Phase 3 open-label study recommended an interval of 2 months between the last dose of MYLOTARG and HSCT
Factors associated with increased risk of VOD1,2
Based on an analysis across trials using MYLOTARG as a single agent for R/R AML, primarily at a 9 mg/m2 dose, the following factors were associated with an increased risk of VOD:
  • Higher doses of MYLOTARG as monotherapy in adult patients
  • HSCT before or following treatment with MYLOTARG
  • Moderate/severe hepatic impairment prior to treatment with MYLOTARG
Strategies to manage hepatotoxicity, including VOD1
Prior to each dose of MYLOTARG
  • Assess ALT, AST, total bilirubin, and alkaline phosphatase
After treatment with MYLOTARG
  • Monitor frequently for signs and symptoms of VOD, such as:
    Elevations in ALT or AST
    Elevations in total bilirubin
    Rapid weight gain
    Ascites
    Hepatomegaly (which may be painful)
  • Monitoring only total bilirubin may not identify all patients at risk of VOD
  • For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended
  • Manage signs or symptoms of hepatic toxicity by dose interruption or discontinuation of MYLOTARG. In patients who experience VOD, discontinue MYLOTARG and treat according to standard medical practice
Patients proceeding to HSCT
  • Although no relationship was found between VOD and time of HSCT relative to higher MYLOTARG monotherapy doses, the Phase 3 open-label study recommended an interval of 2 months between the last dose of MYLOTARG and HSCT
  • Monitor liver tests frequently during the post-HSCT period, as appropriate
ALT=alanine aminotransferase; AML=acute myeloid leukemia; AST=aspartate aminotransferase; chemo=daunorubicin + cytarabine; HSCT=hematopoietic stem cell transplant; R/R=relapsed or refractory; VOD=veno-occlusive liver disease.
REFERENCES
1. MYLOTARG Prescribing Information. New York, NY: Pfizer Inc.
2. Data on file. Pfizer Inc, New York, NY.

SELECTED ADVERSE REACTIONS

Fractionated MYLOTARG allowed for optimized drug delivery with a positive benefit-risk profile1,2
The safety data are limited by the retrospective collection of AEs and include AEs considered most important for understanding the safety profile of MYLOTARG, as well as all AEs that led to permanent discontinuation.
  • Discontinuation due to any AE occurred in 31% of patients in the MYLOTARG arm vs 7% in the chemotherapy arm
  • The most frequent (≥1%) AEs in patients treated with MYLOTARG that led to permanent discontinuation were thrombocytopenia (15%), VOD (3%), and septic shock (2%)
Fatal events
  • Fatal adverse reactions occurred in 8 patients (6%) in the MYLOTARG arm vs 3 patients (2%) in the chemotherapy arm
    In the MYLOTARG arm, 3 patients died of VOD, 4 patients died of hemorrhage-related events (CNS hemorrhage, hemorrhagic shock), and 1 patient died of suspected cardiac cause
    In the chemotherapy arm, 3 patients died of sepsis
AE= adverse event; chemo=daunorubicin + cytarabine; CNS=central nervous system; VOD=veno-occlusive liver disease.
Chemo=daunorubicin + cytarabine.
*Platelets <50,000/mm3 or neutrophils <500/mm3 lasting past cycle Day 42 in the absence of active leukemia.
Chemo=daunorubicin + cytarabine.
See full Prescribing Information for complete BOXED WARNING.
Hepatotoxicity, including severe or fatal hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), has been reported in association with the use of MYLOTARG.
REFERENCES
1. MYLOTARG Prescribing Information. New York, NY: Pfizer Inc.
2. Castaigne S, Pautas C, Terré C, et al; for the Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508-1516.

HEMORRHAGE

Hemorrhage in the Phase 3, open-label study1,2
*Including cerebral hematoma, intracranial hematoma, and subdural hematoma.
  • MYLOTARG is myelosuppressive and can cause fatal or life-threatening hemorrhage due to prolonged thrombocytopenia
  • The proportion of patients with persistent thrombocytopenia increased with progressive treatment phases and was higher in patients treated with MYLOTARG plus chemotherapy than with chemotherapy alone
  • Assess blood counts prior to each dose of MYLOTARG, and monitor blood counts frequently after treatment with MYLOTARG until resolution of cytopenias
  • Monitor patients for signs and symptoms of bleeding during treatment with MYLOTARG
  • Manage severe bleeding, hemorrhage, or persistent thrombocytopenia using dose delay or permanent discontinuation of MYLOTARG, and provide supportive care per standard practice 
Chemo=daunorubicin + cytarabine.
REFERENCES
1. MYLOTARG Prescribing Information. New York, NY: Pfizer Inc.
2. Data on file. Pfizer Inc, New York, NY.