Medical Policy


Subject: Inotuzumab ozogamicin (Besponsa®)
Document #: DRUG.00110 Publish Date:    12/12/2018
Status: Reviewed Last Review Date:    11/08/2018


This document addresses uses of inotuzumab ozogamicin (Besponsa, Pfizer Inc., Philadelphia, PA). Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) consisting of a monoclonal antibody targeting CD22, a protein found on the surface of mature B-cells in most cases of acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin also contains a cytotoxic agent of calicheamicin. This cytotoxic agent is released into the B-cells when inotuzumab ozogamicin attaches to the CD22 protein on the surface of mature B-cells.

Note: Please see the following related document for additional information:

Position Statement

Medically Necessary:

Inotuzumab ozogamicin is considered medically necessary for the treatment of individuals 18 years and older with acute lymphocytic leukemia when all of the following criteria are met:

  1. Relapsed or refractory disease; and
  2. CD22+ B-cell ALL; and
  3. Current Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

Investigational and Not Medically Necessary:

Inotuzumab ozogamicin is considered investigational and not medically necessary in individuals when the criteria above are not met, and for all other indications, including, but not limited to:

  1. Use as first-line of therapy for ALL.
  2. Use in combination with other chemotherapy agents.

On August 17, 2017, the U.S. Food and Drug Administration (FDA) approved inotuzumab ozogamicin for the treatment of adults with relapsed or refractory B-cell precursor ALL. The FDA approval was based upon a randomized trial of 326 individuals with relapsed or refractory B-cell ALL who had previously undergone one or two previous treatments.  

Kantarjian and colleagues (2016) compared the outcomes of individuals with relapsed or refractory ALL treated with inotuzumab ozogamicin versus those treated with standard chemotherapy. In the open-label, two-group, randomized phase III trial (INO-VATE ALL), 218 adults (18 years of age or older) with relapsed or refractory, CD22-positive, Philadelphia chromosome (Ph)-positive or Ph-negative ALL were assigned to one of two groups (n=109 inotuzumab ozogamicin, n=109 standard therapy). In the standard therapy group, 13 subjects refused to start treatment and they were not included in the as-treated remission analysis population (n=109 inotuzumab ozogamicin, n=96 standard therapy). The rate of complete remission or complete remission with incomplete hematologic recovery was higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval (CI), 72.1 to 87.7] vs. 33.3% [95% CI, 24.0 to 43.7], p<0.001). Within the group of subjects who reached complete remission or complete remission with incomplete hematologic recovery, the inotuzumab group had the higher percentage of bone marrow blast results below the threshold for minimal residual disease than the standard therapy group (78.4% [95% CI, 68.4 to 86.5] vs. 28.1% [95% CI, 13.7 to 46.7], p<0.001). More subjects in the inotuzumab ozogamicin group continued to stem cell transplantation right after treatment than in the standard therapy group (41% [45 of 109 subjects] vs. 11% [12 of 109 subjects], p<0.001). The intention-to-treat survival analysis included 164 subjects in the inotuzumab ozogamicin group and 162 subjects in the standard-therapy group. This analysis showed the progression-free survival was longer in the inotuzumab ozogamicin group than in the standard-therapy group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio for disease progression, starting new induction therapy or stem cell transplantation without achieving complete remission, or death, 0.45 [97.5% CI, 0.34 to 0.61]; p<0.001). The potential of inotuzumab ozogamicin to increase the number of individuals capable to continue to stem cell transplantation after salvage therapy is encouraging.

In 2018(b), Kantarjian and associates reported on the INO-VATE ALL participant’s self- reported quality of life (QoL) during treatment. Individuals in both the inotuzumab ozogamicin group and the standard chemotherapy group completed questionnaires at baseline, on the first day of each cycle, and at the end of treatment. The inotuzumab ozogamicin group reported overall better QoL, functioning, and symptom scores with significant differences in physical, role, social functioning and appetite areas.

Adverse Events

From the clinical trials data, the known adverse events with the use of inotuzumab ozogamicin were thrombocytopenia, grade 3 or higher febrile neutropenia, nausea, headache, pyrexia, and veno-occlusive disease. Kantarjian and colleagues (2016) reported adverse events pertaining to the liver were more common in the inotuzumab ozogamicin group than in the standard-therapy group. Subjects in the inotuzumab ozogamicin group received the trial drug at a starting dose of 1.8 mg/m2. Veno-occlusive disease was noted more often in the inotuzumab ozogamicin group than in the standard therapy group (11% [15 individuals] vs. 1% [1 individual]). In the inotuzumab ozogamicin group, veno-occlusive disease occurred while the treatment was being given or shortly after in 5 individuals. After the trial, stem cell transplantation was performed in 48 subjects in the inotuzumab ozogamicin group, 10 of those subjects developed veno-occlusive disease post transplantation.

A weekly versus single-dose study reported that weekly inotuzumab ozogamicin is less toxic and as effective as single-dose inotuzumab ozogamicin (Kantarjian, 2013). This study included 90 subjects with refractory or relapsed ALL. The individuals were separated into two schedule groups, weekly (n=41) and single-dose (n=49). The study showed 58% of participants reached bone marrow complete response and no change in response rate whether treatments were provided weekly or single dose. Liver function abnormalities and veno-occlusive disease were less common with the weekly schedule of inotuzumab ozogamicin.

Additional Considerations

The National Comprehensive Cancer Network® Clinical Practice Guidelines in OncologyTM (NCCN CPG) for acute lymphoblastic leukemia (V1.2018) recommends inotuzumab ozogamicin therapy for relapsed/refractory Ph-negative (category 1) and Ph-positive (category 2A) ALL.

Other Proposed Uses

While the use of inotuzumab ozogamicin has been shown to improve complete remission rates, progression-free survival and overall survival in adults with relapsed or refractory ALL when compared to standard therapy, the 5-year overall survival rate after relapse is 7% (Yurkiewicz, 2018). Studies are underway to evaluate the efficacy and safety of using inotuzumab ozogamicin during different phases of ALL (Kantarjian, 2018a; Yurkiewicz, 2018). In addition, use in the pediatric population is also in the early stages of evaluation (NCT02981628).

Preliminary clinical trials are evaluating the use of inotuzumab ozogamicin to treat other conditions, such as Non-Hodgkin lymphoma (Dang, 2017). At this time, there is a lack of evidence to support the use of inotuzumab ozogamicin to treat other conditions.


The American Cancer Society estimates about 5960 new cases of ALL and 1470 deaths in the United States for 2018. For adults with newly diagnosed B-cell ALL, current therapies are related to 60% to 90% complete remission rates. Many of these individuals will relapse and only about 30% to 50% will have disease-free survival lasting 3 or more years. Allogeneic stem cell transplantation is the main objective after salvage therapy, and complete remission is a requirement for subsequent transplantation. Few adults with relapsed or refractory B-cell ALL continue to transplantation because of the low rates of complete remission linked to current chemotherapy treatments (Kantarjian, 2016).

Adverse Events and Warnings 

Black box warnings from the FDA PI Label (2018) include the following information and recommendations:

Additional Warnings from the FDA PI Label (2018) include:


Acute lymphocytic leukaemia (ALL): A cancer which originates in the bone marrow and affects white blood cell production; also called acute lymphoblastic leukemia.

Chemotherapy: Medical treatment of a disease, particularly cancer, with drugs or other chemicals.

Complete response/remission (CR): The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured.

Cytotoxic: Destructive to cells.

Line of therapy:

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Refractory disease: Illness or disease that does not respond to treatment.

Relapse: After a period of improvement, the return of signs and symptoms of illness or disease.


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 or Reconstructive when criteria are met:




Injection, inotuzumab ozogamicin, 0.1 mg [Besponsa] [Note: code will be deleted 12/31/2018]


Injection, inotuzumab ozogamicin, 0.1 mg [Besponsa] [Note; code effective 01/01/2019; NOC codes J3590 or J9999 until 12/31/2018]




ICD-10 Diagnosis




Acute lymphoblastic leukemia (ALL)


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. Dang NH, Ogura M, Castaigne S, et al. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2017. doi: 10.1111/bjh.14820.
  2. Kantarjian HM, DeAngelo DJ, Advani AS, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol. 2017; 4 (8):e387-e398.
  3. Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018a; 19(2):240-248.
  4. Kantarjian HM, Su Y, Jabbour EJ, et al. Patient-reported outcomes from a phase 3 randomized controlled trial of inotuzumab ozogamicin versus standard therapy for relapsed/refractory acute lymphoblastic leukemia. Cancer. 2018b; 124(10):2151-2160.
  5. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016; 375(8):740-753.
  6. Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012; 13(4):403-411.
  7. Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013; 119(15):2728-2736.
  8. Reichert JM. Antibodies to watch in 2017. MAbs. 2017; 9(2):167-181.
  9. Yurkiewicz IR, Muffly L, Liedtke M. Inotuzumab ozogamicin: a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Drug Des Devel Ther. 2018; 12:2293-2300.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Besponsa [Product Information Label]. Philadelphia, PA. Pfizer Inc. March 2018. Available at: Accessed on September 25, 2018.
  2. 1.2. Children’s Oncology Group; National Cancer Institute (NCI). Inotuzumab Ozogamicin in Treating Younger Patients With Relapsed or Refractory CD22 Positive B Acute Lymphoblastic Leukemia. NLM Identifier: NCT02981628. Last updated on December 26, 2017. Available at: Accessed on September 25, 2018.
  3. National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in OncologyTM. For additional information visit the NCCN website: Accessed on October 10, 2018.
    • Acute Lymphoblastic Leukemia (V1.2018). Revised March 12, 2018.
Websites for Additional Information
  1. American Cancer Society (ACS).
  2. National Cancer Institute (NCI). Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version. Available at: Updated on June 1, 2018. Accessed on September 25, 2018.

Acute Lymphocytic Leukemia
Inotuzumab 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 Rationale, Background, References, Definitions and Websites for Additional Information sections. Updated Coding section with 01/01/2019 HCPCS changes; added J9229, C9028 deleted 12/31/2018.



MPTAC review.



Hematology/Oncology Subcommittee review. Updated Rationale, Background and References sections.



The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 HCPCS changes; added C9028.



MPTAC review.