Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

POLICY NUMBER

A.8.01.26

DESCRIPTION

Acute myeloid leukemia (AML) refers to leukemias that arise from a myeloid precursor in the bone marrow. There is a high incidence of relapse, which has prompted research into various post-remission strategies using either allogeneic (allo-) or autologous hematopoietic cell transplantation (HCT). Hematopoietic cell transplantation refers to a procedure that infuses hematopoietic stem cells to restore bone marrow function in individuals with cancer who receive bone marrow-toxic doses of drugs with or without whole-body radiotherapy.

Acute Myeloid Leukemia Treatment

Complete remission of acute myeloid leukemia can be achieved initially using induction therapy, consisting of conventional doses of combination chemotherapy. A complete response is achieved in 60% to 80% of adults younger than 60 years of age and 40% to 60% in patients older than 60 years of age. However, the high incidence of disease relapse has prompted research into a variety of post-remission (consolidation) strategies, typically using high-dose chemotherapy with autologous HCT or high-dose or reduced-intensity chemotherapy with allogeneic HCT (allo-HCT). The two treatments, autologous HCT and allo- HCT, represent two different strategies. The first, autologous HCT, is a “rescue,” but not a therapeutic procedure; the second, allo-HCT, is a “rescue” plus a therapeutic procedure.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allo-HCT). These cells can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood transplantation is discussed in detail in the Placental and Umbilical Cord Blood as a Source of Stem Cells policy.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allo-HCT, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. Human leukocyte antigen refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation

Conventional Conditioning

The conventional ("classical") practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by the cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus host disease.

Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and nonrelapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Reduced-intensity conditioning regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. For the purposes of this policy, the term “reduced-intensity conditioning” refers to all conditioning regimens intended to be nonmyeloablative.

A 2015 review in the New England Journal of Medicine summarized advances in the classification of acute myeloid leukemia, the genomics of acute myeloid leukemia and prognostic factors, and current and new treatments. The National Comprehensive Cancer Network guidelines provide updated information on genetic markers for risk stratification, and additional recent reviews summarize information on novel therapies for AML.

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, Title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

POLICY

No benefits will be provided for a covered transplant procedure unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.

Allogeneic hematopoietic cell transplantation (HCT) using a myeloablative conditioning regimen may be considered medically necessary to treat:

• poor- to intermediate-risk acute myeloid leukemia (AML) in first complete remission(CR1) (see Policy Guidelines for information on risk stratification); or

• AML that is refractory to standard induction chemotherapy but can be brought into CR with intensified induction chemotherapy; or

• AML that relapses following chemotherapy-induced CR1 but can be brought into CR2 or beyond with intensified induction chemotherapy; or

• AML in individuals who have relapsed following a prior autologous HCT, but can be brought into CR with intensified induction chemotherapy and are medically able to tolerate the procedure.

Allogeneic HCT using a reduced-intensity conditioning regimen may be considered medically necessary as a treatment of AML in individuals who are in complete marrow and extramedullary remission (CR1 or beyond), and who for medical reasons would be unable to tolerate a myeloablative conditioning regimen (see Policy Guidelines).

Autologous HCT may be considered medically necessary to treat AML in CR1 or beyond, or relapsed AML, if responsive to intensified induction chemotherapy in individuals who are not candidates for allogeneic HCT.

Allogeneic and autologous HCT are investigational in individuals not meeting any of the above criteria.

POLICY EXCEPTIONS

For Federal Employee Program (FEP) subscribers, the Service Benefit Plan includes specific conditions in which autologous or allogeneic blood or marrow stem cell transplants would be considered eligible for coverage. 

For State and School Employee subscribers, all bone marrow/stem cell transplants must be certified as medically necessary by the Plan’s Utilization Review Vendor. No benefits will be provided for any transplant procedure unless prior approval for the transplant is obtained.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Primary refractory acute myeloid leukemia (AML) is defined as leukemia that does not achieve a complete remission after conventionally dosed (non-marrow ablative) chemotherapy.

In the French-American-British criteria, the classification of AML is solely based on morphology as determined by the degree of differentiation along different cell lines and the extent of cell maturation.

Clinical features that predict poor outcomes of AML therapy include, but are not limited to, the following:

• Treatment-related AML (secondary to prior chemotherapy and/or radiotherapy for another malignancy)

• AML with antecedent hematologic disease (e.g., myelodysplasia)

• Presence of circulating blasts at the time of diagnosis

• Difficulty in obtaining first complete remission with standard chemotherapy

• Leukemias with monocytoid differentiation (French-American-British classification M4 or M5).

The newer, currently preferred, World Health Organization classification of AML incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers. It attempts to construct a classification that is universally applicable and prognostically valid. The World Health Organization system was adapted by the National Comprehensive Cancer Network to estimate individual prognosis to guide management, as shown in the following table:

Risk Status of AML Based on Genetic Factors

AML: acute myeloid leukemia; ITD: internal tandem duplication

The relative importance of cytogenetic and molecular abnormalities in determining prognosis and guiding therapy is under investigation.

The ideal allogeneic donors are human leukocyte antigen identical siblings, matched at the human leukocyte antigen-A, -B, and -DR loci (6 of 6). Related donors mismatched at one locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Registry is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the individual, for which there usually is sharing of only 3 of the 6 major histocompatibility antigens. Most individuals will have such a donor; however, the risk of graft-versus-host disease and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

3/25/2004: See policy "High-Dose Chemotherapy with Hematopoietic Stem Cell Support for Malignancies" prior to 3/25/2004, separate policy developed and aligned with BCBSA policy # 8.01.26 per approval by Medical Policy Advisory Committee (MPAC).

7/13/2004: Code Reference section completed.

7/1/2004: Reviewed by MPAC; The following changed from investigational to medically necessary: "High-dose chemotherapy with allogeneic stem cell support is may be medically necessary to treat AML relapsing after prior therapy with high-dose chemotherapy and autologous stem cell support."

10/27/2005: Code Reference section updated; CPT-4 code 38230 added; ICD-9 Procedure 41.01, 41.02, 41.03, 41.09 added; HCPCS G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added, J9000-J9999 deleted

3/22/2006: Coding updated. CPT4/HCPCS revisions added to policy

5/18/2007: Policy reviewed, no changes

12/20/2007: Coding updated per 2008 CPT/HCPCS revisions.

7/14/2008: Policy updated; terminology modified but materially unchanged. High dose chemotherapy terminology removed from title and policy statement and replaced with stem cell transplantation (SCT). High dose chemotherapy will allogeneic stem cell support changed to investigational for treatment of AML relapsing after prior therapy with HDC and autologous stem cell support

9/11/2008: Annual ICD-9 updates effective 10-1-2008 applied

1/6/2009: Policy reviewed, "prior authorization before evaluation" deleted

8/07/2009: Policy Description Section updated with definitions and descriptions for Conventional Preparative Conditioning for HSCT, Reduced-Intensity Conditioning for Allogeneic HSCT, and AML as well as WHO information and molecular studies information specific to AML, Policy Statement Section revised to add specific medically necessary criteria to the treatment of AML with Allogeneic HSCT using a myeloablative conditioning regimen, Allogeneic HSCT using a reduced-intensity conditioning regimen, and Autologous HSCT, Policy Guidelines updated to add AML with antecedent hematologic disease as a clinical feature that predicts poor outcomes of AML therapy, WHO classification of AML Risk Status table, candidate information, and donor information, Coding Section updated with a Note added to the CPT-4 Covered Codes Table, ICD-9 Procedure Code 41.00 added to Covered Table, HCPCS codes S2140 and S2142 added to covered table, removed deleted HCPCS codes G0265, G0266, G0267, and G0363 from Covered Table

04/26/2010: FEP and State and School Employee verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826. 

09/28/2011: Policy reviewed; no changes.

09/27/2012: Policy reviewed; no changes.

11/15/2013: Policy reviewed; no changes.

10/10/2014: Policy reviewed; description updated. Policy statement unchanged. Policy guidelines updated to add nonmyeloablative conditioning allogeneic HSCT as a conditioning regimen for some patients for whom a conventional myeloablative allotransplant could be curative.

08/26/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38242; removed deleted code CPT 96445 and replaced with CPT code 96446.

11/18/2015: Policy description updated regarding complete remissions. Policy statements updated to add complete remission information for clarification. Table in policy guidelines section updated to change the following risk status from "Better" to "Favorable."

03/21/2016: Policy description updated regarding FDA regulations. Policy statements unchanged.

05/25/2016: Policy number A.8.01.26 added.

09/30/2016: Code Reference section updated to add the following new ICD-10 procedure codes: 30230G2, 30233G2, 30240G2, 30243G2, 30230G3, 30233G3, 30240G3, 30243G3, 30230G4, 30233G4, 30240G4, 30243G4, 30230Y2, 30233Y2, 30240Y2, 30243Y2, 30230Y3, 30233Y3, 30240Y3, 30243Y3, 30230Y4, 30233Y4, 30240Y4, and 30243Y4.

08/11/2017: Policy title, description, and statements updated to change "Hematopoietic stem cell transplantation" to "Hematopoietic cell transplantation." Policy description updated regarding conventional conditioning for HCT and treatment. Policy Guidelines updated to change "mutation" to "variant."

12/21/2017: Code Reference section updated to add new 2018 CPT code 38222. Revised descriptions for CPT codes 38220 and 38221. Removed deleted ICD-10 procedure codes 30230G1, 30233G1, 30240G1, 30243G1, 30230Y1, 30233Y1, 30240Y1, and 30243Y1.

02/12/2018: Policy description updated. Policy statements unchanged.

05/16/2019: Policy description updated. Medically necessary statement regarding autologous HCT updated to clarify that it applies to patients who are not candidates for allogeneic HCT. Added statement that allogeneic and autologous HCT are investigational in patients not meeting the medically necessary criteria. Removed deleted CPT code 86822 and HCPCS code G0364.

09/24/2019: Code Reference section updated to add new ICD-10 procedure codes 30230U2, 30230U3, 30230U4, 30233U2, 30233U3, 30233U4, 30240U2, 30240U3, 30240U4, 30243U2, 30243U3, and 30243U4, effective 10/01/2019.

02/24/2020: Policy description revised and updated regarding hematopoietic cell transplantation and conditioning for hematopoietic cell transplantation. Policy statements unchanged.

03/05/2021: Policy description updated regarding guidelines provided by the National Comprehensive Cancer Network. Policy statements unchanged. Policy Guidelines updated regarding the risk categories of AML based on genetic factors.

12/22/2021: Code Reference section updated to make note of deleted ICD-10 procedure codes.

02/17/2022: Policy description updated. Policy statements unchanged.

11/22/2022: Code Reference section updated to remove deleted ICD-10 procedure codes 30230G0, 30240G0, 30230Y0, 30240Y0, 30230G2, 30240G2, 30230G3, 30240G3, 30230G4, 30240G4, 30230U2, 30240U2, 30230U3, 30240U3, 30230U4, 30240U4, 30230Y2, 30240Y2, 30230Y3, 30240Y3, 30230Y4, and 30240Y4.

03/01/2023: Policy description updated. Policy statements and Policy Guidelines updated to change "patients" to "individuals."

12/21/2023: Code Reference section updated to revise the code description for CPT code 96446, effective 01/01/2024.

02/26/2024: Policy description updated with minor changes. Policy statements unchanged.

04/07/2025: Policy description updated. Policy statements unchanged.

SOURCE(S)

Blue Cross Blue Shield Association Policy # 8.01.26

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document. 

Covered Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.