Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia

POLICY NUMBER

A.8.01.30

DESCRIPTION

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the presence of a chromosomal abnormality called the Philadelphia chromosome, which results from a reciprocal translocation between the long arms of chromosomes 9 and 22. Chronic myeloid leukemia most often presents in a chronic phase from which it progresses to an accelerated and then a blast phase. Allogeneic hematopoietic cell transplantation (allo-HCT) is a treatment option for CML.

Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the presence of a chromosomal abnormality called the Philadelphia chromosome, which results from a reciprocal translocation between the long arms of chromosomes 9 and 22. This cytogenetic change results in constitutive activation of the fusion gene BCR-ABL, a tyrosine kinase that stimulates unregulated cell proliferation, inhibits cell apoptosis, creates genetic instability, and upsets interactions between CML cells and the bone marrow stroma only in malignant cells. The disease accounts for about 15% of newly diagnosed cases of leukemia in adults and occurs in 1 to 2 cases per 100,000 adults.

The natural history of the disease consists of an initial (indolent) chronic phase, lasting a median of 3 years, which typically transforms into an accelerated phase, followed by a "blast crisis," which is usually the terminal event. Most patients present in chronic phase, often with nonspecific symptoms secondary to anemia and splenomegaly. A diagnosis is based on the presence of the Philadelphia chromosome abnormality by routine cytogenetics, or by detection of abnormal BCR-ABL products by fluorescence in situ hybridization or molecular studies, in the setting of persistent unexplained leukocytosis. Conventional dose chemotherapy regimens used for chronic phase disease can induce multiple remissions and delay the onset of blast crisis to a median of 4 to 6 years. However, successive remissions are invariably shorter and more difficult to achieve than their predecessors.

TreatmentHistorically, the only curative therapy for CML in blast phase has been allogeneic hematopoietic transplantation (allo-HCT), which was used more widely earlier in the disease process given the lack of other therapies for chronic phase CML. Drug therapies for chronic phase CML were limited to nonspecific agents including busulfan, hydroxyurea, and interferon-α.

Imatinib mesylate (Gleevec®), a selective inhibitor of the abnormal BCR-ABL tyrosine kinase protein, is considered the treatment of choice for newly diagnosed CML. While imatinib can be highly effective in suppressing CML, it is not curative and is ineffective in 20% to 30% of patients, initially or due to development of BCR-ABL variants that cause resistance to the drug. Even so, the overall survival of patients who present in the chronic phase is greater than 95% at 2 years and 80% to 90% at 5 years.

For CML, two other tyrosine kinase inhibitors (TKIs; dasatinib, nilotinib) have received marketing approval from the U.S. Food and Drug Administration (FDA) as first-line therapies or following failure or patient intolerance of imatinib. Three additional TKIs (bosutinib, ponatinib, asciminib) have been approved for use in patients resistant or intolerant to prior therapy.

For patients on imatinib who have disease progression, the therapeutic options include increasing the imatinib dose, changing to another TKI, or allo-HCT. Detection of BCR-ABL variants may be important in determining an alternative TKI; the presence of the T315I variant is associated with resistance to all TKIs and should indicate the need for allo-HCT or experimental therapy. Tyrosine kinase inhibitors have been associated with long-term remissions; however, if disease progression occurs on TKI therapy, allo-HCT is generally indicated and offers the potential for cure.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) 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). They 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 (GVM) effect mediated by non-self-immunologic effector cells. While the slower GVM 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 cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and GVHD, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy, with or without radiotherapy to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow 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 GVHD.

Reduced-Intensity Conditioning 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 non-relapse 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 GVM 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 this policy, the term "reduced-intensity conditioning" will refer to all conditioning regimens intended to be nonmyeloablative.

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 as a treatment of chronic myeloid leukemia.

Allogeneic hematopoietic cell transplantation using a reduced-intensity conditioning regimen may be considered medically necessary as a treatment of chronic myeloid leukemia in individuals who meet clinical criteria for an allogeneic HCT, but who are not considered candidates for a myeloablative conditioning allogeneic HCT.

Autologous HCT is investigational as a treatment of chronic myeloid leukemia.

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.

Some individuals for whom a conventional myeloablative allotransplant could be curative may be considered candidates for reduced-intensity conditioning allogeneic hematopoietic cell transplantation. They include those individuals whose age (typically older than 60 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score) preclude use of a standard myeloablative conditioning regimen.

For individuals who qualify for a myeloablative allogeneic hematopoietic cell transplantation on the basis of clinical status, either a myeloablative or a reduced-intensity conditioning regimen may be considered medically necessary.

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 # 8.01.30 per approval by Medical Policy Advisory Committee (MPAC).

6/25/2004: Code Reference section completed.

11/18/2004: Reviewed by MPAC; no changes.

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

3/16/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy.

5/21/2007: Policy reviewed, no changes.

12/19/2007: Coding updated per 2008 CPT/HCPCS revisions.

7/22/2008: Policy updated; terminology modified but materially unchanged. High dose chemotherapy terminology removed from title and policy statement and replaced with stem cell transplantation (SCT). Policy statement added; reduced-intensity conditioning (RIC) allogeneic SCT is considered investigational as treatment of chronic myelogenous leukemia in those who do not qualify for a myeloablative allogeneic SCT.

9/12/2008: Code reference section updated per the annual ICD-9 updates effective 10-1-2008.

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

04/26/2010:  Policy description updated regarding conventional and RIC allogeneic SCT. Policy statement revised to indicate that SCT using a RIC regimen may be considered medically necessary in patients who meet clinical criteria for an allogeneic SCT but who are not considered candidates for a myeloablative conditioning allogeneic SCT. The policy guidelines were updated based on the revised statement. FEP and State and School Employee verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826 and HCPCS S2140 and S2150. Deleted HCPCS G0265, G0266, and G0267 from the code section as these codes were deleted on 12/31/2007. 

02/23/2011: Policy reviewed; no changes.

01/19/2012: Policy reviewed; no changes.

04/03/2013: Policy reviewed; no changes.

03/10/2014: Policy reviewed; no changes.

01/28/2015: Policy description updated regarding CML and RIC for allogeneic HSCT. First policy statement updated to state that allogeneic hematopoietic stem cell transplantation (HSCT)using a myeloablative conditioning regimen may be considered medically necessary as a treatment of chronic myelogenous leukemia. Second policy statement revised to state: Allogeneic hematopoietic stem cell transplantation using a reduced-intensity conditioning regimen may be considered medically necessary as a treatment of chronic myelogenous leukemia in patients who meet clinical criteria for an allogeneic HSCT but who are not considered candidates for a myeloablative conditioning allogeneic HSCT. Policy guidelines updated to add the following: For patients who qualify for a myeloablative allogeneic HSCT on the basis of clinical status, either a myeloablative or reduced-intensity conditioning regimen may be considered medically necessary.

08/26/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240, 38241, and 38242; removed deleted HCPCS code G0363, and removed deleted code CPT 96445 and replaced with CPT code 96446.

03/29/2016: Policy description updated regarding HSCT and FDA regulations. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigative definitions.

05/26/2016: Policy number A.8.01.30 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.

01/31/2017: Policy title and statements updated to change "hematopoietic stem cell transplantation" to "hematopoietic cell transplantation" and "myelogenous" changed to "myeloid." Policy description updated.

12/21/2017: Code Reference section updated to add new 2018 CPT code 38222. Revised descriptions for CPT codes 38220 and 38221 effective 01/01/2018. Removed deleted ICD-10 procedure codes 30230G1, 30233G1, 30240G1, 30243G1, 30230Y1, 30233Y1, 30240Y1, 30243Y1 and ICD-9 procedure codes 41.02, 41.03, 41.05, and 41.08.

03/08/2018: Policy description updated. Policy statements unchanged.

03/14/2019: Policy reviewed; no changes. Code Reference section updated to remove deleted CPT code 86822 and HCPCS code G0364.

09/26/2019: Code Reference section updated to add new ICD-10 procedure codes 30230U2, 30233U2, 30240U2, 30243U2, 30230U3, 30233U3, 30240U3, 30243U3, 30230U4, 30233U4, 30240U4, and 30243U4, effective 10/01/2019.

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

03/22/2021: Policy description updated. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

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

02/18/2022: Policy description updated regarding FDA approved tyrosine kinase inhibitors. Policy statements unchanged.

11/29/2022: Code Reference section updated to remove deleted ICD-10 procedure codes 30230G2, 30240G2, 30230G3, 30240G3, 30230G4, 30240G4, 30230U2, 30240U2, 30230U3, 30240U3, 30230U4, 30240U4, 30230Y2, 30240Y2, 30230Y3, 30240Y3, 30230Y4, 30240Y4, 30230G0, 30240G0, 30230Y0, and 30240Y0.

03/01/2023: Policy reviewed. Policy statement 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.

02/27/2024: Policy reviewed; no changes.

04/07/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 8.01.30

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

Investigational Codes

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