The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis.

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September 1, 2017

On September 1, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (Mylotarg, Pfizer Inc.) for the treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults and for treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients 2 years and older. Gemtuzumab ozogamicin may be used in combination with daunorubicin and cytarabine for adults with newly-diagnosed AML, or as a stand-alone treatment for certain adult and pediatric patients.

Approval of gemtuzumab ozogamicin in combination with chemotherapy for adults was based on ALFA-0701 (NCT00927498), a multicenter, randomized, open-label phase 3 study of 271 patients with newly-diagnosed, de novo AML aged 50 to 70 years. Patients were randomized (1:1) to receive induction therapy consisting of daunorubicin (60 mg/m2 on days 1 to 3) and cytarabine (200 mg/m2 on days 1 to 7) with (n=135) or without (n=136) gemtuzumab ozogamicin 3 mg/m2 (up to maximum of one vial) on days 1, 4, and 7. Using the per protocol definition of event-free survival (EFS), estimated median EFS was 17.3 months for patients receiving gemtuzumab ozogamicin vs. 9.5 months for those receiving chemotherapy alone, with hazard ratio of 0.56 (95% CI: 0.42, 0.76).

Gemtuzumab ozogamicin was evaluated in two clinical trials for use as a single agent. The first trial, AML-19, was a multicenter, randomized (1:1), open-label phase 3 study in 237 patients comparing gemtuzumab ozogamicin monotherapy to best supportive care (BSC). Eligible patients had newly-diagnosed AML and were 1) greater than 75 years of age or 2) 61 to 75 years of age with a WHO performance status greater than 2 or were unwilling to receive intensive chemotherapy. During induction, gemtuzumab ozogamicin 6 mg/m2 was given on day 1 and gemtuzumab ozogamicin 3 mg/m2 was given on day 8. Patients with no evidence of disease progression or significant toxicities after induction received continuation therapy as outpatients with up to 8 courses of treatment including gemtuzumab ozogamicin 2 mg/m2 on day 1, every 4 weeks. BSC included standard supportive care measures and hydroxyurea or other anti-metabolites for palliative purposes. Estimated median overall survival (OS) was 4.9 months for patients receiving gemtuzumab ozogamicin vs. 3.6 months for those receiving BSC, with hazard ratio of 0.69 (95% CI: 0.53, 0.90).

The second trial, MyloFrance-1, a phase 2, single-arm, open-label study, included 57 patients with CD33-positive AML in first relapse. Patients received a single course of gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7. Consolidation therapy consisted of cytarabine intravenously every 12 hours for 3 days. Fifteen (26%; 95% CI: 16% - 40%) patients achieved complete response (CR) following a single course of gemtuzumab ozogamicin. Median relapse-free survival, measured from the first documentation of CR to the date of relapse or death, was 11.6 months.

The label contains a box warning for hepatotoxicity. The most common adverse reactions (>15%) were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, and mucositis. Serious adverse reactions associated with gemtuzumab ozogamicin are hepatotoxicity (including veno-occlusive disease), infusion-related reactions (including anaphylaxis), and hemorrhage.

This approval includes a lower recommended dose and schedule of gemtuzumab ozogamicin than what FDA approved previously in 2000, as well as a different patient population. Gemtuzumab ozogamicin was voluntarily withdrawn in 2010 after trials failed to confirm benefit and demonstrated safety concerns, including early mortality and VOD.

Full prescribing information for tisagenlecleucel is available at:

FDA previously granted orphan drug designation to gemtuzumab ozogamicin. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Gemtuzumab Ozogamicin for the Treatment of Newly Diagnosed CD33-Positive Acute Myeloid Leukemia in Adults and Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia in Adults and Children 2 Years and Older

Author: Heather Moore, PharmD
PGY-2 Oncology Pharmacy Resident
VCU Health
Richmond, VA

What is the potential role for gemtuzumab ozogamicin (GO) in the management of newly diagnosed CD33-Positive Acute Myeloid Leukemia (AML) and relapsed or refractory (R/R) CD33-positive AML?1-5

  • GO was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in May 2000 as monotherapy for patients 60 years of age or older with relapsed CD33-positive AML. The drug was subsequently withdrawn in 2010 because of safety concerns, including increased mortality, and the failure to verify its clinical benefit.
  • The FDA reapproved GO in September 2017 and expanded its indication to include newly diagnosed CD33-positive AML in adults as well as R/R CD33-positive AML in both adults and children 2 years and older.
    • Combination therapy was approved on the basis of data from a randomized open-label phase 3 trial (ALFA-0701) of newly diagnosed de novo AML patients (N = 271).  Patients who received GO exhibited improved event-free survival (EFS) of 17.3 months versus 9.5 months with standard-of-care (SOC) chemotherapy (hazard ratio [HR] .56, confidence interval [CI] .42–.76; p = .001). SOC chemotherapy consisted of daunorubicin and cytarabine for both induction (7+3) and consolidation. Patients who required a second induction received only daunorubicin and cytarabine.
    • The AML-19 and MyloFrance-1 studies provided data for GO’s approval as monotherapy in the R/R setting and in newly diagnosed, intensive chemotherapy-ineligible AML patients. Study AML-19 (N = 237) was a randomized open-label phase 3 study that compared GO to best supportive care (BSC) in newly diagnosed AML patients ineligible for intensive chemotherapy (greater than 75 years of age or 61–75 years of age with a performance status of 2 or higher). GO showed an overall survival benefit of 4.9 months compared to 3.6 months with BSC (HR .69, CI .53–.9; p = .005), providing a 14.6% survival advantage (24.3% vs. 9.7%). There were no episodes of gemtuzumab-related veno-occlusive disease (VOD) reported; however, grade 3 and 4 hepatic adverse effects were slightly higher in the gemtuzumab arm (7.2% vs. 6.1%). MyloFrance-1 (N = 57), a phase-2 single-arm study in AML patients in first relapse, showed a complete remission (CR) rate of 26% (CI 16%–40%) and median relapse-free survival of 11.6 months. No grade 3 or 4 hepatotoxicity or VOD was observed.
  • GO’s prior approval in 2000 was at a dose of 9 mg/m2 and was associated with hematologic and hepatic toxicity as well as reports of VOD.  The current approval incorporates lower, fractionated dosing of 3 mg/m2 (capped at 1 vial of 4.5 mg) on days 1, 4, and 7 (3-3-3) in combination therapy or R/R monotherapy. Newly diagnosed patients ineligible for intensive chemotherapy receive 6 mg/m2 on day 1 and 3 mg/m2 on day 8 of induction and 2 mg/m2 on day 1 every 28 days for eight cycles for continuation. Lower, fractionated dosing has exhibited reduced toxicity while maintaining drug efficacy.
  • The National Comprehensive Cancer Network (NCCN) guidelines have not yet been updated to reflect the recent FDA approval of GO; thus there are no current recommendations for its use in AML.
  • Based on current literature, GO is best considered for patients with high CD33-expressing leukemic cells and intermediate or favorable cytogenetics.
    • CD33 expression was greater than 80% in patients in the ALFA-0701 study. The benefit of GO was less pronounced in patients with CD33 expression less than 80% in the AML-19 trial.
    • GO’s benefit was more pronounced in patients with favorable or intermediate cytogenetics in the ALFA-0701, AML-19, and MyloFrance-1 trials. The overall response rate was 35% in patients with intermediate cytogenetic risk, compared to 25% in patients with poor cytogenetic risk in MyloFrance-1. In the AML-19 study, patients with favorable or intermediate cytogenetic risk had a complete response rate of 35.7% versus 6.7% in those with adverse cytogenetic risk.
  • Gemtuzumab is currently the only anti-CD33 agent approved for use in AML for newly diagnosed patients as well as patients in the R/R setting. 

What role can the pharmacist play in the management of patients on gemtuzumab?6

  • GO’s dosing can be highly variable, depending on its indication. Pharmacists should ensure appropriate usage and dosing for each patient during order verification and product preparation.
    • Combination daunorubicin and cytarabine: one induction and two consolidation cycles
      • Induction: 3 mg/m2 (max = 4.5 mg) on days 1, 4, and 7 (3-3-3). GO should not be administered if a second induction cycle is required.
      • Consolidation: 3 mg/m2 on day 1 (max = 4.5 mg) of 28-day cycle for two cycles
    • Monotherapy for first-line AML:  one induction and eight continuation cycles
      • Induction: 6 mg/m2 on day 1 and 3 mg/m2 on day 8
      • Consolidation: 2 mg/m2 on day 1 every 28 days for eight cycles
    • Monotherapy for R/R: 3 mg/m2 (max = 4.5 mg) on days 1, 4, and 7
  • Patients should be premedicated with acetaminophen, diphenhydramine, and methylprednisolone prior to gemtuzumab infusion. Additional doses may be administered as needed based on signs and symptoms of an infusion reaction.
  • Cytoreduction is recommended for leukocyte counts greater than or equal to 30,000 cells/mm3.
  • Grade 3 and higher adverse reactions in the ALFA-0701 trial included infection (47%–55%), hemorrhage (18%), and VOD (2%). Prolonged thrombocytopenia was seen in up to 35% of GO patients, compared with up to 24% in the 7+3 comparative group. Additionally, 8%–14% experienced grade 3 or higher liver function test abnormalities. The most common adverse reactions of any grade in AML-19 included hepatotoxicity (51%), fatigue (46%), infection (44%), cardiac abnormalities (28%), and bleeding (25%).
  • Financial assistance options are available for commercially insured, government-insured, and uninsured patients. Additional information can be found by calling 1.877.744.5675 or visiting

Clinical Pearls1-4,6,7

  • GO is composed of an IgG4 kappa antibody gemtuzumab that is linked to a cytotoxic calicheamicin derivative. QT interval prolongation has been seen in other calicheamicin-containing drugs. Monitor electrolytes and obtain an echocardiogram before starting treatment with gemtuzumab in patients with a history of or predisposition for QTc prolongation or electrolyte disturbances and in patients who are taking other QTc-prolonging medications.
  • Patients with hepatic dysfunction were excluded from the ALFA-0701, AML-19, and MYLOFRANCE-1 trials. Hepatic dysfunction was defined as serum aminotransferase concentrations greater than 2.5 times the upper limit of normal (ULN) or serum bilirubin greater than 2 times the ULN in ALFA-0701, bilirubin greater than 1.5 times the ULN in AML-19, and aspartate aminotransferase and alanine aminotransferase levels greater than 2 times the ULN in MYLOFRANCE-1.
  • When gemtuzumab is given in combination with chemotherapy, if platelet count does not recover to greater than 100,000/mm3 or neutrophil count does not recover to greater than 500/mm3 within 14 days following the anticipated consolidation cycle start date, gemtuzumab should be discontinued and not administered during consolidation.
  • Despite a more pronounced benefit in patients with favorable or intermediate cytogenetics, patients positive for FLT3-ITD responded better than those who were FLT3-ITD negative because of higher CD33 expression. Given the more robust data with recently approved midostaurin in the FLT3-ITD population, it would be more favorably recommended because GO FLT3-ITD patient data is provided as a subgroup analysis within the AML-19 trial.


  1. Gemtuzumab. U.S. Food and Drug Administration: Approved September 1, 2017. Available at Accessed October 7, 2017.
  2. Castaigne S, Pautas C, Terre C, et al. 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;379:1508-1516.
  3. Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34:972-979.
  4. Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the ALFA group. Leukemia. 2007;21:66-71.
  5. Acute Myeloid Leukemia. Version 3.2017. National Comprehensive Cancer Network. Available at Accessed October 8, 2017.
  6. Mylotarg (gemtuzumab ozogamicin) [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; September 2017.
  7. Khan N, Hills RK, Virgo P, et al. Expression of CD33 is a predictive factor for effect of gemtuzumab ozogamicin at different doses in adult acute myeloid leukemia. Leukemia. 2017; 31:1059-1068.