Clinical Policy: Antithymocyte Globulin (Atgam, Thymoglobulin) Form

# Clinical Policy: Antithymocyte Globulin (Atgam, Thymoglobulin)
Reference Number: CP.PHAR.506  
Effective Date: 12.01.20  
Last Review Date: 11.25  
Line of Business: Commercial, HIM, Medicaid  

[Coding Implications](Coding Implications)  
[Revision Log](Revision Log)  

See [Important Reminder](Important Reminder) at the end of this policy for important regulatory and legal information.  

## Description  
Antithymocyte globulin (Thymoglobulin®, Atgam®) is an immunoglobulin G.  

## FDA Approved Indication(s)  
Atgam is indicated for:  
* The management of allograft rejection in renal transplant patients; when administered with conventional therapy at the time of rejection, Atgam increases the frequency of resolution of the acute rejection episode  
* The treatment of moderate-to-severe aplastic anemia in patients unsuitable for bone marrow transplantation.  

Limitation(s) of use: The usefulness of Atgam has not been demonstrated in patients with aplastic anemia who are suitable candidates for bone marrow transplantation or in patients with aplastic anemia secondary to neoplastic disease, storage disease, myelofibrosis, Fanconi’s syndrome, or in patients known to have been exposed to myelotoxic agents or radiation.  

Thymoglobulin is indicated for the prophylaxis and treatment of acute rejection in adult and pediatric patients receiving a kidney transplant in conjunction with concomitant immunosuppression.  

## Policy/Criteria  
Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.  

It is the policy of health plans affiliated with Centene Corporation® that Atgam and Thymoglobulin are **medically necessary** when the following criteria are met:  

### I. Initial Approval Criteria  
#### A. Kidney Transplant Rejection (must meet all):  
1. Member has received or is scheduled for a kidney transplant;  
2. If request is for prophylaxis of acute rejection, request is for Thymoglobulin;  
3. Prescribed by or in consultation with a nephrologist, transplant specialist, or hematologist/oncologist;  
4. For Atgam: Age ≥ 18 years;  
5. Prescribed in combination with conventional therapy for transplant rejection (see Appendix D);  
6. Dose does not exceed one of the following (a or b):  
   a. For Atgam, all of the following (i, ii, or iii):  
      i. 15 mg/kg per day;  
      ii. 42 days of total treatment duration;  
      iii. 21 doses of Atgam;  
   b. For Thymoglobulin, all of the following (i, ii, and iii):  
      i. 1.5 mg/kg per day;  
      ii. For prophylaxis of acute rejection, both of the following (1 and 2):  
         1) 7 days of total treatment duration;  
         2) 7 doses of Thymoglobulin;  
      iii. For treatment of acute rejection, both of the following (1 and 2):  
         1) 14 days of total treatment duration;  
         2) 14 doses of Thymoglobulin.  

**Approval duration**:  
7 days for Thymoglobulin for prophylaxis of acute rejection (7 doses)  
14 days for Thymoglobulin for treatment of acute rejection (14 doses)  
Up to 42 days for Atgam (21 doses)  

#### B. Aplastic Anemia (must meet all):  
1. Diagnosis of moderate to severe aplastic anemia;  
2. Request is for Atgam;  
3. Prescribed by or in consultation with a hematologist;  
4. Age ≥ 18 years;  
5. Prescribed in combination with cyclosporine;  
6. Dose does not exceed all of the following (a, b, or c):  
   a. 20 mg/kg per day;  
   b. 42 days of total treatment duration;  
   c. 21 doses of Atgam.  

**Approval duration**: Up to 42 days (21 doses)  

#### C. NCCN Recommended Uses (off-label) (must meet all):  
1. One of the following (a, b, or c):  
   a. Immune checkpoint inhibitor-related toxicity that is one of the following (i, ii, or iii; see Appendix E):  
      i. Myocarditis;  
      ii. Hepatobiliary toxicity;  
      iii. Aplastic anemia;  
   b. CAR T-cell-related cytokine release syndrome (CRS) that is Grade 4*;  
      *Grade 4 CRS: fever with hypotension requiring multiple vasopressors, excluding vasopressin, and/or hypoxia requiring positive pressure  
   c. Request is for Atgam, and one of the following indications (i, ii, or iii):  
      i. Acute graft-versus-host disease (GVHD) that is steroid-refractory;  
      ii. Conditioning for hematopoietic stem cell transplant;  
      iii. Myelodysplastic syndrome that is lower-risk (IPSS-R [very low, low, intermediate]);  
2. Prescribed by or in consultation with an oncologist;  
3. Age ≥ 18 years;  
4. For immune checkpoint inhibitor-related hepatobiliary toxicity, one of the following (a, b, c, or d):  
   a. G2 elevated ALT/AST, and liver enzymes suggest worsening or no improvement after 3-7 days of prednisone;  
   b. G3 or G4 elevated ALT/AST, and no improvement after 1-2 days of prednisone/methylprednisolone;  
   c. G2 elevated alkaline phosphatase (predominant), and alkaline phosphatase worsens or does not improve within 3 days after initiating corticosteroids;  
   d. G3 or G4 elevated alkaline phosphatase (predominant), and no improvement after 1-2 days of prednisone/methylprednisolone and ursodiol;  
5. For CAR T-cell-related CRS, member is refractory to high-dose corticosteroids and anti-IL-6 therapy (e.g., Actemra®);  
6. For aplastic anemia, both of the following (a and b):  
   a. Severe or very severe;  
   b. Not responsive to corticosteroids after 7 days;  
7. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).*  
   *Prescribed regimen must be FDA-approved or recommended by NCCN.  

**Approval duration**: 1 month  

#### D. Other diagnoses/indications (must meet 1 or 2):  
1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b):  
   a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or  
   b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or  
2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.  

## II. Continued Therapy  
#### A. Kidney Transplant Rejection and Aplastic Anemia (must meet all):  
1. Member meets one of the following (a, b, or c):  
   a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria;  
   b. Documentation supports that member is currently receiving Atgam or Thymoglobulin for kidney transplant rejection and has received this medication for at least 30 days;  
   c. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);  
2. Member is responding positively to therapy;  
3. For Thymoglobulin for prophylaxis of acute rejection, member has not received more than both of the following (a and b):  
   a. 7 days of total treatment duration;  
   b. 7 doses of Thymoglobulin;  
4. For Thymoglobulin for treatment of acute rejection, member has not received more than both of the following (a and b):  
   a. 14 days of total treatment duration;  
   b. 14 doses of Thymoglobulin;  
5. For Atgam, member has not received more than both of the following (a and b):  
   a. 42 days of total treatment duration;  
   b. 21 doses of Atgam;  
6. If request is for a dose increase, new dose does not exceed (a or b):  
   a. For Atgam (i or ii):  
      i. For treatment of acute rejection: 15 mg/kg per day;  
      ii. For aplastic anemia: 20 mg/kg per day;  
   b. For Thymoglobulin for treatment or prophylaxis of acute rejection: 1.5 mg/kg per day.  

**Approval duration**: Up to a total treatment duration of:  
7 days for Thymoglobulin for prophylaxis of acute rejection (7 doses)  
14 days for Thymoglobulin for treatment of acute rejection (14 doses)  
42 days for Atgam (21 doses)  

#### B. NCCN Recommended Uses (off-label)  
1. Member meets one of the following (a or b):  
   a. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Atgam or Thymoglobulin for a covered indication that has received this medication for at least 30 days;  
   b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);  
2. Member is responding positively to therapy;  
3. If request is for a dose increase, new dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).*  
   *Prescribed regimen must be FDA-approved or recommended by NCCN  

**Approval duration**: 1 month  

#### C. Other diagnoses/indications (must meet 1 or 2):  
1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b):  
   a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or  
   b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or  
2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.  

## III.Diagnoses/Indications for which coverage is NOT authorized:  
#### A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents.  

## IV.Appendices/General Information  
Appendix A: Abbreviation/Acronym Key  
ALT: alanine aminotransferase  
AST: aspartate aminotransferase  
CRS: cytokine release syndrome  
FDA: Food and Drug Administration  
GVHD: graft-versus-host disease  
IPSS-R: Revised International Prognostic Scoring System  
ULN: upper limit of normal  

Appendix B: Therapeutic Alternatives  
This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.  

| Drug Name | Dosing Regimen | Dose Limit/ Maximum Dose |  
|-----------|---------------|------------------------|  
| cyclosporine | Aplastic Anemia <br> Adults: 12 mg/kg PO QD <br> Children: 15 mg/kg PO QD | See dosing regimen |  

Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic.  

## Appendix C: Contraindications/Boxed Warnings  
* Contraindication(s):  
  * Atgam: anaphylactic reaction during prior administration of Atgam or any other equine gamma globulin preparation  
  * Thymoglobulin:  
    * Patients with history of allergy or anaphylactic reaction to rabbit proteins or to any product excipients  
    * Patients who have active acute or chronic infections that contraindicate any additional immunosuppression  
* Boxed warning(s):  
  * Atgam: anaphylaxis  
  * Thymoglobulin: immunosuppression  

Appendix D: General Information  
* The current standard first-line treatment for aplastic anemia is equine antithymocyte globulin (Atgam) combined with cyclosporine (off-label use).  
* Conventional therapy for transplant rejection include: calcineurin inhibitors (tacrolimus, cyclosporine), antimetabolite (mycophenolate, azathioprine, corticosteroid (prednisone)  
* Myelodysplastic syndrome prognostic scoring system online calculator for IPSS-R: https://qxmd.com/calculate/calculator_109/mds-revised-international-prognostic-scoringsystem-ipss-r  

Appendix E: Immune Checkpoint Inhibitor-Related Toxicity  
* Immune checkpoint inhibitors comprise a class of agents that target immune cell checkpoints, such as programmed cell death-1 (PD-1; e.g., Opdivo®, Keytruda®) and PD-1 ligand (PD-L1; e.g., Tecentriq®, Bavencio®, Imfinzi®), as well as cytotoxic T-lymphocyte–associated antigen 4 (e.g., Yervoy®, Imjudo®).  
* NCCN grading of hepatobiliary toxicity by elevated alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)  
  * G1: ALT/AST elevation of < 3x upper limit of normal (ULN)  
  * G2: ALT/AST elevation of 3-5x ULN  
  * G3: ALT/AST elevation of > 5 to 20x ULN  
  * G4: ALT/AST elevation of > 20x ULN  
* NCCN grading of hepatobiliary toxicity by elevated alkaline phosphatase (predominant) with or without ALT/AST elevation  
  * G1: alkaline phosphatase elevation of < 2.5x ULN (or baseline)  
  * G2: alkaline phosphatase elevation of 2.5-5x ULN (or baseline)  
  * G3: alkaline phosphatase elevation of > 5 to 20x ULN (or baseline)  
  * G4: alkaline phosphatase elevation of > 20x ULN (or baseline)  

## V. Dosage and Administration  
| Drug Name | Indication | Dosing Regimen | Maximum Dose |  
|-----------|------------|---------------|--------------|  
| Antithymocyte globulin (Atgam) | Aplastic anemia | 10 to 20 mg/kg IV QD for 8 to 14 days. Additional alternate-day therapy up to | 20 mg/kg/dose |  
|  | Treatment of acute renal transplant rejection | 10 to 15 mg/kg IV QD for 14 days. Additional alternate-day therapy up to a total of 21 doses may be given | 15 mg/kg/dose |  
| Antithymocyte globulin (Thymoglobulin) | Prophylaxis of acute renal transplant rejection | 1.5 mg/kg IV QD for 4 to 7 days | 1.5 mg/kg/dose |  
|  | Treatment of acute renal transplant rejection | 1.5 mg/kg IV QD for 7 to 14 days | 1.5 mg/kg/dose |  

## VI. Product Availability  
| Drug Name | Availability |  
|-----------|--------------|  
| Antithymocyte globulin (Thymoglobulin) | Vial, powder for solution: 25 mg |  
| Antithymocyte globulin (Atgam) | Ampule: 250 mg/5 mL |  

  

## Coding Implications  
Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services.  

| HCPCS Codes | Description |  
|-------------|-------------|  
| J7504 | Lymphocyte immune globulin, antithymocyte globulin, equine, parenteral, 250 mg |  
| J7511 | Lymphocyte immune globulin, antithymocyte globulin, rabbit, parenteral, 25 mg |  

## Reviews, Revisions, and Approvals  
| Date | P&T Approval Date |  
|------|------------------|  
| 4Q 2021 annual review: no significant changes; revised HIM.PHAR.21 to HIM.PA.154; references reviewed and updated. | 08.19.21 | 11.21 |  
| 4Q 2022 annual review: no significant changes; references reviewed and updated. Template changes applied to other diagnoses/indications in continued therapy section. | 08.26.22 | 11.22 |  
| 4Q 2023 annual review: for transplant rejection added criterion prescribed in combination with conventional therapy per PI with examples added in Appendix D; continuation of care applied to transplant-related indications in continued therapy section; clarified total duration and doses of Thymoglobulin and Atgam therapy in continued therapy section (7days/doses for Thymoglobulin for prophylaxis of acute rejection, 14 days/doses for Thymoglobulin for treatment of acute treatment, and 42 days/21 doses for Atgam); references reviewed and updated. | 07.06.23 | 11.23 |  
| 4Q 2024 annual review: added NCCN supported recommended uses (off-label) section to include immunotherapy-related cardiovascular toxicity, CAR T-cell-related toxicity; GVHD, and myelodysplastic syndrome; references reviewed and updated. | 07.16.24 | 11.24 |  
| 4Q 2025 annual review: no significant changes; references reviewed and updated. | 07.16.25 | 11.25 |  
| RT4: updated Thymoglobulin indication to include pediatric and adult patients; per NCCN; updated “immunotherapy-related” to “immune checkpoint inhibitor-related” toxicity, specified cardiovascular toxicity as myocarditis, added indications of | 02.16.26 |  |  
| immune checkpoint inhibitor-related hepatobiliary toxicity and aplastic anemia, specified that myelodysplastic syndrome and acute GVHD are specific to Atgam requests, specified that acute GVHD is steroid-refractory, specified that myelodysplastic syndrome is lower-risk, added conditioning regimen as an option for Atgam use, and clarified that CAR T-cell-related toxicity is specific to grade 4 CRS. |  |  |  

## Important Reminder  
This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. “Health Plan” means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.  

The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions, and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures.  

This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time.  

This clinical policy does not constitute medical advice, medical treatment, or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions.  

Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan.  

This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members, and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services.  

**Note**:  
For Medicaid members, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.  

©2018 Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene® and Centene Corporation® are registered trademarks exclusively owned by Centene Corporation.  

Page 10 of 10