Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

POLICY NUMBER

A.8.01.32

DESCRIPTION

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with different genetic variations resulting in distinct biologic subtypes. Patients are stratified to risk-adapted therapy according to certain clinical and genetic risk factors that predict an outcome. Therapy may include hematopoietic cell transplantation (HCT).

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with different genetic variations resulting in distinct biologic subtypes. Patients are stratified by certain clinical and genetic risk factors that predict an outcome, with risk-adapted therapy tailoring treatment based on the predicted risk of relapse. Two of the most important factors predictive of risk are patient age and white blood cell count at diagnosis. Certain genetic characteristics of the leukemic cells strongly influence prognosis. Clinical and biologic factors predicting clinical outcomes and relapse risk are summarized in the Policy Guidelines section.

ChildhoodAcute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children; it represents nearly 25% of cancer diagnoses in children younger than 15 years. Remission of disease is now typically achieved with pediatric chemotherapy regimens in 98% of children with ALL, with long-term survival rates of up to 85%. Survival rates have improved with the identification of effective drugs and combination chemotherapy through large randomized trials, integration of presymptomatic central nervous system prophylaxis, and intensification and risk-based stratification of treatment. The prognosis after the first relapse is related to the length of the original remission. For example, leukemia-free survival is 40% to 50% for children whose first remission was longer than 3 years compared with 10% to 15% for those who relapse less than 3 years after treatment. Thus, hematopoietic cell transplantation (HCT) may be a strong consideration in those with short remissions. At present, comparative outcomes with autologous or allogeneic HCT (allo-HCT) are unknown.

AdultAcute Lymphoblastic Leukemia

In adults, ALL accounts for 20% of acute leukemias. Between 60% and 80% of adults with ALL can be expected to achieve a complete response after induction chemotherapy; however, patients who experience a relapse after remission usually die within 1 year. Differences in the frequency of genetic abnormalities that characterize adult ALL versus childhood ALL help, in part, to explain differences in outcomes between the two groups. For example, the “good prognosis” genetic abnormalities, such as hyperdiploidy and translocation of chromosomes 12 and 21, are seen much less commonly in adult ALL, whereas they are some of the most common in childhood ALL. Conversely, “poor prognosis” genetic abnormalities such as the Philadelphia chromosome (translocation of chromosomes 9 and 22) are seen in 25% to 30% of adult ALL but infrequently in childhood ALL. Other adverse prognostic factors in adult ALL include age greater than 35 years, poor performance status, male sex, and leukocytosis at presentation of greater than 30,000/µL (B-cell lineage) or greater than 100,000/µL (T-cell lineage).

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). 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 medical policy.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, 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. HLA 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 existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients whose health status is sufficient to tolerate the procedure of 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 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 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 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 Allogeneic Hematopoietic Cell Transplantation

Reduced-intensity conditioning (RIC) allogeneic HCT 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. These RIC 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” 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 the Code of Federal Regulation, Title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Note: The use of killer cells in the treatment of malignancies is addressed in a separate policy, Adoptive Immunotherapy .

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. 

Childhood Acute Lymphoblastic Leukemia (ALL)

Autologous or allogeneic hematopoietic cell transplantation (HCT) may be considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in first complete remission but at high-risk of relapse. (For definition of high-risk factors, see Policy Guidelines).

Autologous or allogeneic HCT may be considered medically necessary to treat childhood ALL in second or greater remission or refractory ALL.

Allogeneic HCT is consideredmedically necessaryto treat relapsing ALL after a prior autologous HCT in children. 

Adult ALL

Autologous HCT may be considered medically necessary to treat adult ALL in first complete remission but at high-risk of relapse (For definition of high-risk factors, see Policy Guidelines).

Allogeneic HCT may be considered medically necessary to treat adult ALL in first complete remission for any risk level (For definition of risk factors, see Policy Guidelines)

Allogeneic HCT may be considered medically necessary to treat adult ALL in second or greater remission, or in adults with relapsed or refractory ALL.

Reduced-intensity conditioning allogeneic HCT may be considered medically necessary as a treatment of ALL in individuals who are in complete marrow and extramedullary first or second remission, and who, for medical reasons (see Policy Guidelines), would be unable to tolerate a standard myeloablative conditioning regimen.

Autologous HCT is investigational to treat adult ALL in second or greater remission or those with refractory disease.

Allogeneic HCT is medically necessary to treat relapsing adult ALL after a prior autologous HCT.

NOTE: The use of donor leukocyte infusions to treat relapse after allogeneic HCT for either children or adults is considered separately in the  Donor Lymphocyte Infusion for Malignancies Treated with an Allogeneic Hematopoietic Stem-Cell Transplant policy.

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.

Relapse Risk Prognostic Factors

Childhood Acute Lymphoblastic Leukemia

Adverse prognostic factors in children include the following: age younger than 1 year or older than 9 years, male sex, white blood cell count at presentation above 50,000/µL, hypodiploidy (<45 chromosomes), translocation involving chromosomes 9 and 22 (t[9;22]) or BCR/ABL fusion, translocation involving chromosomes 4 and 11 (t[4;11]) or MLL-AF4 fusion, and ProB or T-lineage immunophenotype. Several risk-stratification schema exist, but, in general, the following findings help define children at high-risk of relapse: 1) poor response to initial therapy including poor response to prednisone prophase defined as an absolute blast count of 1,000/µL or greater, or poor treatment response to induction therapy at 6 weeks with high-risk having 1% or higher minimal residual disease measured by flow cytometry; 2) all children with T-cell phenotype; and 3) individuals with either the t(9;22) or t(4;11) regardless of early response measures.

Adult Acute Lymphoblastic Leukemia

Risk factors for relapse are less well-defined in adults, but an individual with any of the following may be considered at high-risk for relapse: age older than 35 years, leukocytosis at presentation of greater than 30,000/µL (B-cell lineage) or greater than 100,000/µL (T-cell lineage), “poor prognosis” genetic abnormalities like the Philadelphia chromosome (t(9;22)), extramedullary disease, and time to attain complete remission longer than 4 weeks.

Reduced-Intensity Conditioning

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

The ideal allogeneic donors are human leukocyte antigen (HLA)-identical siblings, matched at the HLA-A, -B, and DR (antigen-D related) locion each arm of chromosome 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, where usually there is sharing of only 3 of the 6 major histocompatibility antigens. Most individuals will have such a donor. The risk of morbidity (eg, graft-versus-host-disease) may be higher than with HLA-matched donors; however, as medical treatments improve, the risks of GVHD with haploidentical donors are approaching those similar to HLA-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 # 8.01.32 per approval by Medical Policy Advisory Committee (MPAC)

6/25/2004: Code Reference section completed

11/18/2004: Reviewed by MPAC, the following changed from investigational to medically necessary; "High-dose chemotherapy and allogeneic stem cell support may be medically necessary to treat relapsing ALL after a prior course of high-dose chemotherapy and autologous stem cell support."

10/21/2005: Code reference section updated, codes 38230, g0355 - G0364 added, J9000 - J9999 deleted, ICD9 procedure codes 41.01, 41.02, 41.03, 41.09 added, statement under HCPCS title added, description revised for ICD9 procedure code 99.79, policy revised

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

5/21/2007: Policy reviewed, no changes

9/18/2007: Policy reviewed, no changes

12/20/2007: 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 ALL in those who do not qualify for a myeloablative allogeneic SCT.

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

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

9/30/2009: Code reference section updated. New ICD9 procedure code 17.70 added to covered table. HCPC codes G0265, G0266 and G0267 deleted from covered table due to codes were deleted as of 12-31-2007.

04/27/2010: The term “Lymphocytic” was changed to “Lymphoblastic” in the policy title and throughout the policy. Policy description and guidelines updated regarding prevalence of disease and treatment approaches. Policy statement updated to indicate when RIC allogeneic hematopoietic SCT would be considered medically necessary as a treatment of ALL in adults. Policy statement regarding treatment of adult ALL in first complete remission but at high risk of relapse split to address allogeneic and autologous transplant separately. FEP and State and School Employees verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826 and HCPCS code S2140 and S2142.

04/19/2011: Policy reviewed; no changes.

03/02/2012: Policy reviewed; no changes.

10/17/2013: Added the following policy statement under the Children coverage criteria:  Reduced-intensity conditioning allogeneic HSCT may be considered medically necessary as a treatment of ALL in patients who are in complete marrow and extramedullary first or second remission, and who, for medical reasons (see Policy Guidelines), would be unable to tolerate a standard* myeloablative conditioning regimen.

07/15/2014: Policy reviewed; description updated regarding childhood ALL. Policy statement revised to change "Children" and "Adults" to "Childhood ALL" and "Adult ALL." Policy statements on allogeneic HSCT to treat relapsing ALL after a prior autologous SCT changed from "investigational" to "medically necessary." Policy statement revised to remove the statement on reduced-intensity conditioning from the Childhood ALL section. Policy guidelines updated to add "Relapse Risk Prognostic Factors" as a heading. Added "including autologous or allogeneic HSCT" to the paragraph on reduced-intensity conditioning in the policy guidelines.

08/21/2015: Code Reference section update to add ICD-10 codes. Revise the descriptions for CPT codes 38240 and 38242; removed deleted HCPCS code G0363; remove deleted code CPT 96445 and replaced with CPT code 96446.

10/01/2015: Policy description updated to remove table regarding prognostic factors for childhood ALL; information in Policy Guidelines. Policy statements unchanged. Policy Guidelines updated to add medically necessary and investigative definitions.

04/20/2016: "Hematopoietic stem cell transplantation (HSCT)" changed to "hematopoietic cell transplantation (HCT)" in the policy title and throughout the policy. Policy description updated regarding FDA regulations. Policy statements unchanged. Policy guidelines updated regarding ideal allogeneic donors.

05/26/2016: Policy number A.8.01.32 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.

02/20/2017: Policy description updated. Policy statement regarding allogeneic HCT for Adult ALL updated to replace "patients" with "adults."

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, and 30243Y1.

02/13/2018: 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.

02/25/2020: Policy description updated regarding conditioning for hematopoietic cell transplantation. Policy statements unchanged.

03/22/2021: Policy description updated regarding hematopoietic cell transplantation. 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 conventional conditioning. Policy statements unchanged.

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

03/01/2023: Policy description updated. Policy statements updated with minor wording changes; intent unchanged. 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 # 8.01.32

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

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