Medical Policy


Subject: Gemtuzumab Ozogamicin (Mylotarg®)
Document #: DRUG.00112 Publish Date:    12/12/2018
Status: Reviewed Last Review Date:    11/08/2018



This document addresses gemtuzumab ozogamicin (Mylotarg) (Pfizer, New York, NY), a humanized anti-CD33 monoclonal antibody for the treatment of acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL). Gemtuzumab ozogamicin acts by binding the CD33 antigen expressed by hematopoietic cells.


Position Statement

Medically Necessary:

Gemtuzumab ozogamicin is considered medically necessary for the treatment of the following indications:

  1. Newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults greater than or equal to 18 years of age; or
  2. Relapsed or refractory CD33-positive AML in adults and in children 2 years and older.

Gemtuzumab ozogamicin is considered medically necessary for the treatment of acute promyelocytic leukemia (APL) in high-risk individuals who are ineligible for treatment with anthracycline.

Investigational and Not Medically Necessary:

Gemtuzumab ozogamicin is considered investigational and not medical necessary when the medically necessary criteria have not been not met, and for all other indications.


Acute Myeloid Leukemia

In May 2000, gemtuzumab ozogamicin was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed CD33 positive AML in individuals over 60 years of age unable to receive other chemotherapy. This approval was based on a response rate of approximately 30% observed in phase II trials (Bross, 2001; Sievers, 2001). Results from the required post-approval study of the addition of gemtuzumab to standard induction therapy (daunorubicin and cytosine arabinoside) as first-line therapy for AML in individuals less than 61 years of age showed significantly greater fatal induction toxicity and no improvement in survival compared to chemotherapy alone (NCT00085709 [SWOG S0106]). Due to safety and efficacy concerns raised by the post-approval study, gemtuzumab ozogamicin was voluntarily withdrawn from the U.S. market on June 21, 2010.

However, clinical trials evaluating the safety and efficacy of the agent continued and the regulatory status of gemtuzumab ozogamicin was re-evaluated in 2017. In January 2017, a Biologics License Application (BLA) for gemtuzumab ozogamicin was accepted for filing by the FDA. This FDA submission was based on additional data from a phase III randomized, open-label study (ALFA-0701) (Castaigne, 2012) and a large meta-analysis (Hills, 2014).

Re-approval for gemtuzumab ozogamicin was granted by the FDA on September 1, 2017. The indications and usage section in the FDA-approved label states treatment of two indications. The first is “newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults”. The second is “treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients 2 years and older”. The label indicates that for newly diagnosed AML, gemtuzumab ozogamicin may be used as either a single agent or in combination with daunorubicin and cytarabine. For relapsed or refractory AML, the label states that it should be used as a single agent.

Castaigne and colleagues (2012) evaluated the addition of gemtuzumab ozogamicin to standard induction chemotherapy using an alternative fractionated dosing schedule. This phase III randomized, open label trial (ALFA-0701) was performed between January, 2008 and November, 2010 at 26 French hematology centers. Subjects aged 50-70 years with normal cardiac function were eligible if they had previously untreated, locally confirmed AML. Exclusion criteria included previous myeloproliferative/myelodysplastic syndrome; previous exposure to chemotherapy or radiotherapy; CNS involvement, severe uncontrolled infection; or liver or kidney dysfunction. A total of 280 individuals were randomly assigned with a 1:1 ratio to a standard treatment (control group, n=140) or a gemtuzumab ozogamicin group (n=140). In each group, 139 of the 140 subjects were analyzed. The primary endpoint was event-free survival (EFS) and secondary endpoints were relapse-free survival (RFS), overall survival (OS), and safety. EFS and RFS at 2 years were significantly higher in the gemtuzumab ozogamicin group than the control group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group. EFS at 2 years was estimated as 17.1% (10.8-27.1) in the control group versus 40.8% (32.8-50.8) in the gemtuzumab ozogamicin group (hazard ratio 0.58, 0.43-0.78; p=0.0003), and RFS 22.7% (14.5-35.7) versus 50.3% (41.0-61.6), respectively (0.52, 0.36-0.75; p=0.0003). However, OS did not differ significantly between groups at 2 years. OS was 41.9% (33.1-53.1) versus 53.2% (44.6-63.5), respectively (0.69, 0.49-0.98; p=0.0368). The analysis for OS, a secondary outcome, may have been underpowered. Hematological toxicity was more frequent in the gemtuzumab ozogamicin group than in the control group although there was not an increase in the risk of death from toxicity.

Final results of ALFA-0701 were reported by Lambert and colleagues in 2018. A total of 271 of 280 (97%) randomized participants were included in the modified intention-to-treat analysis. After a median follow-up of 47.6 months in the treatment arm and 41 months in the control arm, median OS did not differ significantly in the treatment arm (27.5 months) versus the control arm (21.8 months), p=0.16. The primary endpoint, median EFS, remained significantly longer in the treatment arm compared with the control arm (17.3 months and 9.5 months, respectively, p=0.0002). Median RFS also remained significantly longer in the treatment arm than the control arm (28.0 months versus 11.4 months, p-value not reported). A high rate of individuals in both groups experienced severe (grade 3 or higher) infections.

Hills and colleagues (2014) performed a meta-analysis of 3325 subjects (median age 58) from five randomized phase III trials (including ALFA-0701) of gemtuzumab ozogamicin added to intensive induction chemotherapy for AML (excluding acute promyelocytic leukemia [APL]) in adults. All trials with data available as of May 1, 2013 were included. Overall results demonstrated that adding gemtuzumab ozogamicin to intensive induction chemotherapy did not increase the remission rates, with or without complete peripheral count recovery. However, the addition of gemtuzumab ozogamicin significantly reduced the risk of relapse, and improved OS at 5 years. The absolute survival benefit was particularly noted in subjects at 6 years with favorable cytogenetics, but was also seen in those with intermediate characteristics. Doses of 3 mg/m2 and 6 mg/m2 had equal efficacy; however, doses of 3 mg/m2 were associated with fewer early deaths. Subjects with adverse karyotypes treated with gemtuzumab ozogamicin did not benefit within any trial, or overall.

Other published RCTs include a study published in 2013 by Amadori and colleagues who reported the results of a phase III RCT evaluating sequential gemtuzumab ozogamicin and standard chemotherapy use in 472 individuals aged 61-75 years with newly diagnosed AML. Induction chemotherapy consisted of mitoxantrone, cytarabine, and etoposide preceded, or not preceded, by a course of gemtuzumab ozogamicin (6 mg/m2 on days 1 and 15). In remission, individuals received two consolidation courses with or without gemtuzumab ozogamicin (3 mg/m2 on day 0). The primary endpoint was OS. At a median follow-up of 5.2 years, median OS was 7.1 months in the gemtuzumab ozogamicin arm and 10 months in the no-gemtuzumab ozogamicin arm (hazard ratio, 1.20; 95% confidence interval [CI], 0.99 to 1.45; p=0.07). Other survival endpoints were similar in both arms. No benefit was seen in any gemtuzumab ozogamicin prognostic subgroup except possibly in individuals 70 years of age or younger with secondary AML. Grade 3 to 4 liver and hematological toxicities were greater in those that received gemtuzumab ozogamicin.

More recently, Amadori and colleagues (2016) published an RCT that compared gemtuzumab ozogamicin with best supportive care (BSC) as first-line therapy in subjects at least 61 years of age with AML unsuitable for treatment with intensive chemotherapy. Individuals over the age of 75 years were also included in this trial. A total of 237 subjects were randomized 1:1 to receive BSC with or without an induction course of gemtuzumab ozogamicin (6 mg/m2 on day 1 and 3 mg/m2 on day 8). BSC was given to all subjects and included blood product transfusions, antimicrobials and other symptomatic therapies. Hydroxyurea to control the WBC was permitted in the BSC alone group. The primary endpoint was OS by intention-to-treat analysis. The median OS was 4.9 months (95% CI, 4.2 to 6.8 months) in the gemtuzumab ozogamicin group and 3.6 months (95% CI, 2.6 to 4.2 months) in the BSC group (hazard ratio, 0.69; 95% CI, 0.53 to 0.90; p=0.005). The 1-year OS rate was 24.3% in the gemtuzumab ozogamicin group and 9.7% in the BSC group. The OS benefit of gemtuzumab ozogamicin was consistent across most subgroups, and was especially observed in subjects with high CD33 expression status, in subjects with favorable/intermediate cytogenetic risk profile, and in women. Pancytopenia was commonly seen during gemtuzumab ozogamicin induction. However, the rates of serious adverse events were similar among the two groups, and no excess mortality from adverse events was observed with gemtuzumab ozogamicin.

Although the published literature is largely focused on the use of gemtuzumab ozogamicin in the treatment of adult AML, it is also being studied in the treatment of AML in younger persons (Gamis, 2014; Niktoreh, 2018; Petersdorf, 2013).

The National Comprehensive Cancer Network (NCCN) AML Clinical Practice Guideline (V2.2018) recommended gemtuzumab ozogamicin in individuals with CD33-positive AML for treatment induction, post-remission therapy and relapsed-refractory disease.

Acute Promyelocytic Leukemia

The NCCN AML Clinical Practice Guideline (V2.2018) recommended gemtuzumab ozogamicin in certain situations for individuals with acute promyelocytic leukemia (APL) (an aggressive subtype of AML) and cardiac issues. In 2018, the NCCN changed the category “not able to tolerate anthracyclines” to ‘cardiac issues”. In addition, gemtuzumab ozogamicin was recommended, in combination with  all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), for treatment induction and consolidation therapy in high-risk individuals with APL (whole blood cell count >10,000/mcL) who have no cardiac issues.

In a retrospective uncontrolled study published in 2017, Abaza and colleagues described the use of ATRA and ATO alone or in conjunction with gemtuzumab ozogamicin in 187 subjects from three separate studies. All subjects received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily). Subjects were stratified as either high risk (n=53) or low risk (n=133). The high-risk subjects and low-risk subjects with leukocytosis during induction of ATRA/ATO had gemtuzumab ozogamicin (9 mg/m2 on day 1) added to their regimens (n=45 high risk and n=51 low risk). Another 7 high-risk subjects and 9 low-risk subjects received idarubicin instead of gemtuzumab ozogamicin. Once complete remission was achieved another 4 cycles of ATRA/ATO were administered. Median duration of follow-up was 47.6 months. The authors reported that the 5-year OS was similar among high risk subjects who received gemtuzumab ozogamicin and those who received idarubicin. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk subjects). Among low-risk subjects, 60 (45%) required either gemtuzumab ozogamicin or idarubicin for leukocytosis.



AML, sometimes called acute non-lymphocytic leukemia (ANLL), is a malignancy arising from a myeloid precursor in the bone marrow. It is the most common form of leukemia among older persons. AML incidence rates increase dramatically among people who are over the age of 40. It is most prevalent in the sixth, seventh and eighth decades of life. The American Cancer Society estimates that in 2018 there will be about 19,520 new cases of AML and 10,670 deaths from AML. APL is a subtype of AML and usually occurs in middle-aged adults.

Effective treatment of AML requires the control of bone marrow and systemic disease and specific treatment of CNS disease, if present. There are currently four types of standard therapy generally used to treat adults with AML: chemotherapy, radiation therapy, stem cell transplant and other drug therapy. Typically, there are two treatment stages for adult AML: remission induction therapy (to attain remission) and post-remission therapy (to maintain remission). Chemotherapeutic agents for the treatment of AML (including gemtuzumab ozogamicin) are currently under investigation in clinical trials.


Acute promyelocytic leukemia (APL), high-risk: A sub-group of individuals with APL at high risk of not going into remission with standard therapies. The currently accepted measure used to identify this population is a white blood count (WBC) greater than 10,000/mcL (cells per microliter) (NCCN, 2017).

Monoclonal antibody: A type of protein made in the laboratory that can bind to substances in the body, including cancer cells. There are many kinds of monoclonal antibodies. A monoclonal antibody is made so that it binds to only one substance. Monoclonal antibodies are being used to treat some types of cancer. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells (NCI, 2017).


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:




Injection, gemtuzumab ozogamicin, 0.1 mg [Mylotarg]



ICD-10 Diagnosis




Acute myeloblastic leukemia



Acute promyelocytic leukemia



Acute myelomonocytic leukemia



Acute myeloid leukemia with 11q23-abnormality



Acute myeloid leukemia with multilineage dysplasia



Acute monoblastic/monocytic leukemia



Acute erythroid leukemia



Acute megakaryoblastic leukemia


When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.


Peer Reviewed Publications:

  1. Abaza Y, Kantarjian H, Garcia-Manero G, et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017; 129(10):1275-1283.
  2. 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(9):972-979.
  3. Amadori S, Suciu S, Stasi R, et al. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol. 2013; 31(35):4424-4430.
  4. Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001; 7(6):1490-1496.
  5. Castaigne S, Pautas C, Terré C, et al; 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.
  6. Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014; 32(27):3021-3032.
  7. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014; 15(9):986-996.
  8. Lambert J, Pautas C, Terré C et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase 3 ALFA-0701 trial. Haematologica. 2018 Aug 3; Epub ahead of print.
  9. Niktoreh N, Lerius B, Zimmermann M et al. Gemtuzumab Ozogamicin in children with relapsed or refractory acute myeloid leukemia: a report of Berlin-Frankfurt-Münster study group. Haematologica. 2018 Aug 9; Epub ahead of print.
  10. Petersdorf SH, Kopecky KJ, Slovak M, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013; 121(24):4854-4860.
  11. Sievers EL, Larson RA, Stadtmauer EA, et al; Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001; 19(13):3244-3354.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. National Cancer Institute (NCI). Available at: Accessed on October 1, 2018.
    • Adult Acute Myeloid Leukemia Treatment (PDQ®)–Health Professional Version. Modified January 20, 2017.
  2. Mylotarg [Product Information], Philadelphia, PA. Wyeth Pharmaceuticals Inc. Updated in April, 2018. Available at: Accessed on September 16, 2018.
  3. NCCN Clinical Practice Guidelines in Oncology© 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: Accessed on September 16, 2018.
    • Acute Myeloid Leukemia (V2.2018). Revised August 1, 2018.
  4. Southwest Oncology Group. A phase III study of the addition of gemtuzumab ozogamicin (Mylotarg®) during induction therapy versus standard induction with daunomycin and cytosine arabinoside followed by consolidation and subsequent randomization to post-consolidation therapy with gemtuzumab ozogamicin (Mylotarg®) or no additional therapy for patients under age 61 with previously untreated de novo acute myeloid leukemia (AML). NLM Identifier: NCT00085709; SWOG Identifier S0106. Last updated on September 25, 2015. Available at: Accessed on  October 1, 2018.
Websites for Additional Information
  1. American Cancer Society (ACS). Acute Myeloid Leukemia. Available at: Accessed on October 1, 2018.

Gemtuzumab ozogamicin

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History






Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee review. Updated Discussion/General Information, Coding and References sections.



MPTAC review.



Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Initial review. Coding section updated to include HCPCS code J9203 effective 01/01/2018.

Preliminary Discussion


MPTAC review. Pre-FDA approval review.

Preliminary Discussion


Hematology/Oncology Subcommittee review. Pre-FDA approval review.