Hematopoietic Cell Transplantation for Hodgkin Lymphoma

POLICY NUMBER

A.8.01.29

DESCRIPTION

Hodgkin lymphoma results from a clonal expansion of a B-cell lineage, characterized by the presence of Reed-Sternberg cells on pathology. Standard treatment is based on the stage at presentation and may involve chemotherapy with or without radiotherapy. Hematopoietic cell transplantation (HCT) has been used for Hodgkin lymphoma, particularly in the setting of relapse or refractory disease.

Hodgkin Lymphoma

Hodgkin lymphoma is a relatively uncommon B-cell lymphoma. In 2024, the estimated number of new cases in the United States was approximately 8,570, with 910 estimated deaths related to Hodgkin lymphoma. The disease has a bimodal distribution, with most patients diagnosed between the ages of 20 and 39 years, with a second peak in adults aged 65 years and older.

The 2008 World Health Organization (WHO) classification divided Hodgkin lymphoma into 2 main types; these classifications did not change in the 2022 update:

1. “Classical” Hodgkin lymphoma

   • Nodular sclerosis

   • Mixed cellularity

   • Lymphocyte depleted

   • Lymphocyte-rich

2. Nodular lymphocyte-predominant Hodgkin lymphoma.

In Western countries, "classical" Hodgkin Lymphoma accounts for 95% of cases of Hodgkin lymphoma, and for nodular lymphocyte-predominant Hodgkin lymphoma, only 5%. "Classical" Hodgkin lymphoma is characterized by the presence of neoplastic Reed-Sternberg cells in a background of numerous non-neoplastic inflammatory cells. Nodular lymphocyte-predominant Hodgkin lymphoma lacks Reed-Sternberg cells, but is characterized by the presence of lymphocytic and histiocytic cells termed “popcorn cells.”

Staging

The Ann Arbor staging system for Hodgkin lymphoma recognizes that the disease is thought to typically to arise in a single lymph node and spread to contiguous lymph nodes with eventual involvement of extranodal sites. The staging system attempts to distinguish patients with localized Hodgkin lymphoma who can be treated with extended field radiation from those who require systemic chemotherapy.

Each stage is subdivided into A and B categories. “A” indicates no systemic symptoms are present and “B” indicates the presence of systemic symptoms, which include unexplained weight loss of more than 10% of body weight, unexplained fevers >38°C, or drenching night sweats (see Table 1).

Table 1. Ann Arbor Staging System for Hodgkin Lymphoma

Patients with Hodgkin lymphoma are generally classified into 3 groups: early-stage favorable (stage I to II with no B symptoms, large mediastinal lymphadenopathy, or other unfavorable factors), early-stage unfavorable (stage I to II with a large mediastinal mass, multiple involved nodal regions, B symptoms, extranodal involvement, or elevated erythrocyte sedimentation rate ≥50), and advanced-stage disease (stage III to IV).

Treatment

Patients with nonbulky stage IA or IIA disease are considered to have the clinically early-stage disease. These patients are candidates for chemotherapy, combined modality therapy, or radiotherapy alone. Patients with obvious stage III or IV disease, bulky disease (defined as a 10-cm mass or mediastinal disease with a transverse diameter exceeding >33% of the transthoracic diameter), or the presence of B symptoms will require combination chemotherapy with or without additional radiotherapy.

Hodgkin lymphoma is highly responsive to conventional chemotherapy, and up to 80% of newly diagnosed patients can be cured with chemotherapy and/or radiotherapy. Patients who prove refractory or who relapse after first-line therapy have a significantly worse prognosis. Primary refractory Hodgkin lymphoma is defined as disease regression of less than 50% after 4 to 6 cycles of anthracycline-containing chemotherapy, disease progression during induction therapy, or progression within 90 days after the completion of the first-line treatment.

In patients with relapse, the results of salvage therapy vary depending on a number of prognostic factors, as follows: the length of the initial remission, stage at recurrence, and the severity of anemia at the time of relapse. Early and late relapse are defined as less or more than 12 months from the time of remission, respectively. Approximately 70% of patients with late first relapse can be salvaged by autologous HCT, but not more than 40% with early first relapse. 

Only 25% to 35% of patients with primary progressive or poor-risk recurrent Hodgkin lymphoma achieve durable remission after autologous HCT, with most failures being due to disease progression after transplant. Most relapses after transplant occur within 1 to 2 years, and once relapse occurs post-transplant, median survival is less than 12 months.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow 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 (allogeneic HCT [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 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. 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 and 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 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 graft-versus-host disease.

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 (NRM) 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 will refer to all conditioning regimens intended to be non-myeloablative.

Targeted Chemotherapy and Autologous Hematopoietic Cell Transplantation for the Treatment of Hodgkin Lymphoma

A recent important development in the Hodgkin lymphoma treatment landscape is the emergence of several novel agents that are now being used as alternatives to stem cell transplantation in patients at high-risk for relapse after chemotherapy or relapse following autologous HCT. These agents include brentuximab vedotin, a CD30-directed antibody-drug conjugate, and nivolumab and pembrolizumab which are 2 programmed death receptor-1 (PD-1) blocking antibodies. The U.S. Food and Drug Administration (FDA) regulatory status of these agents for the treatment of HL is summarized in Table 2.

Brentuximab vedotin was evaluated in a large, phase 3, multinational, double-blind randomized controlled trial known as the AETHERA trial (abbreviation definition unknown). Moskowitz and colleagues reported on the outcomes for 329 individuals with HL with risk factors for post-transplantation relapse or progression (eg, primary refractory HL, relapse <12 months after initial therapy, and/or relapse with extranodal disease). Results showed that early consolidation with brentuximab vedotin after autologous HCT significantly improved 2-year progression-free survival (PFS) versus placebo (63% versus 51%, hazard ratio [HR] 0.57; 95% confidence interval [CI], 0.40 to 0.81). At 5-year follow-up, the significant PFS benefit for brentuximab vedotin persisted (59% versus 41%; HR 0.52; 95% CI, 0.38 to 0.72). In addition, a study by Smith and colleagues of tandem autologous HCT observed that the 2-year PFS of 63% for brentuximab vedotin demonstrated in the AETHERA RCT "matches" the 2-year PFS rates for tandem autologous HCT.

A survival benefit with novel agents has been found in the setting of relapse post-autologous HCT. Bair and colleagues reported a retrospective comparative analysis that evaluated the outcomes of 87 individuals with relapsed/refractory HL who had relapsed post-autologous HCT. Compared to individuals who did not receive any novel agents, those that received novel agents, including brentuximab vedotin or nivolumab, experienced a significant improvement in median overall survival (85.6 versus 17.1 months; P<.001). The availability of safe and effective targeted systemic therapy represents an alternative to the use of a second autologous transplant or planned tandem autologous HCT for HL consolidation treatment or relapse/refractory disease treatment.

The 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.

Table 2 describes several novel agents that have been approved by the FDA for use as alternatives to tandem autologous HCT or a second autologous HCT in individuals at high-risk for, or with, respectively, refractory or relapsed HL following autologous HCT.

Table 2. Novel Agents Approved by the U.S. Food and Drug Administration

BLA: Biologic License Application; FDA: U.S. Food and Drug Administration; HL: Hodgkin Lymphoma; HCT: Hematopoietic Cell TransplantationªIn the pivotal trial, a multicenter, nonrandomized, open-label study, prior lines of therapy included prior autologous HCT (61%) and brentuximab (83%)

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.

Autologous hematopoietic cell transplantation (HCT) may be considered medically necessary in individuals with primary refractory or relapsed Hodgkin lymphoma.

Allogeneic HCT, using either myeloablative or reduced-intensity conditioning regimens, may be considered medically necessary in individuals with primary refractory or relapsed Hodgkin lymphoma.

Second autologous HCT for relapsed lymphoma after a prior autologous HCT is considered investigational.

Tandem autologous HCT is considered investigational in individuals with Hodgkin Lymphoma.

Other uses of HCT in individuals with Hodgkin lymphoma are considered investigational, including, but not limited to, initial therapy for newly diagnosed disease to consolidate a first complete remission.

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 from the Plan’s Utilization Review Vendor.

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.

In the Morschhauser study of risk-adapted salvage treatment with single or tandem autologous hematopoietic cell transplantation for first relapse or refractory Hodgkin lymphoma, poor-risk relapsed Hodgkin lymphoma was defined as 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV at relapse, and relapse within previously irradiated sites. The primary refractory disease was defined as disease regression less than 50% after 4 to 6 cycles of doxorubicin-containing chemotherapy or disease progression during induction or within 90 days after the end of first-line treatment.

Some individuals for whom a conventional myeloablative allotransplant could be curative may be considered candidates for reduced-intensity conditioning allogeneic hematopoietic cell transplantation. These include those with malignancies that are effectively treated with myeloablative allogeneic transplantation, but whose age (typically >55 or >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.

The ideal allogeneic donors are human leukocyte antigen-identical matched siblings. Related donors mismatched at a single locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Program is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the individual, with whom usually there 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 # 8.01.29 per approval by Medical Policy Advisory Committee (MPAC).

7/14/2004: Code Reference section completed.

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

7/14/2005: Code Reference section updated, CPT code 38230 added covered codes, HCPCS G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added covered codes, HCPCS J9000-J9999 statement added to HCPCS and all separately listed codes deleted.

10/26/2005: Code Reference section updated, ICD-9 procedure codes 41.01, 41.02, 41.03, 41.09 added.

3/14/2006: 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).

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

04/26/2010: Policy description updated regarding conventional and reduced-intensity conditioning. Policy statement changed to indicate that tandem autologous SCT and reduced-intensity conditioning allogeneic SCT may be considered medically necessary in specific situations. Policy statement also updated to indicate that a second autologous stem-cell transplantation for relapsed lymphoma after a prior autologous hematopoietic stem-cell transplant is considered investigational. Supporting explanations added to the policy guidelines. FEP and State and School Employee verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826. Deleted HCPCS G0265, G0266, and G0267 from the code section as these codes were deleted on 12/31/2007.

12/28/2010: Added policy statement regarding when tandem autologous HSCT may be considered medically necessary.

01/17/2012: Policy reviewed; no changes.

03/13/2013: Policy reviewed; no changes.

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

01/29/2015: Policy description updated regarding the estimated number of cases for Hodgkin Lymphoma and to change "radiation therapy" to "radiotherapy." Investigational policy statements updated to change "stem-cell transplantation" to "hematopoietic stem-cell transplantation."

08/27/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38241; removed deleted HCPCS code G0363, and removed deleted code CPT 96445 and replaced with CPT code 96446.

03/23/2016: Policy description updated regarding FDA regulations. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigative definitions.

05/26/2016: Policy number A.8.01.29 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 updated to change "hematopoietic stem-cell transplantation" to "hematopoietic cell transplantation" throughout policy. Policy description updated. First medically necessary statement divided into two statements, one for autologous HCT and one for allogeneic HCT. Policy statement for allogeneic HCT updated to state that either myeloablative or reduced-intensity conditioning regimens may be considered medically necessary in patients with primary refractory or relapsed Hodgkin lymphoma. Removed medically necessary statement regarding reduced-intensity allogeneic HCT.

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.

03/08/2018: Policy description updated regarding estimated Hodgkin lymphoma cases in 2017. Policy statements unchanged.

03/14/2019: Policy description updated regarding the World Health Organization classifications. Policy statements unchanged. 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.

04/13/2021: Policy description updated regarding 2020 data for Hodgkin Lymphoma. Added information regarding the Ann Arbor Staging System for Hodgkin Lymphoma, targeted chemotherapy and autologous HCT for the treatment of Hodgkin Lymphoma, and novel agents approved by the FDA. Policy statement regarding tandem autologous HCT changed from medically necessary to investigational. 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 new data for Hodgkin lymphoma in the United States. Policy statements unchanged.

11/17/2022: 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 regarding new 2022 data for Hodgkin lymphoma. 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 regarding new data for Hodgkin lymphoma. Policy statements unchanged.

04/07/2025: Policy description updated regarding new data for Hodgkin lymphoma. Policy statements unchanged.

SOURCE(S)

Blue Cross Blue Shield Association Policy # 8.01.29

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.