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Medical Policy Hematopoietic Cell Transplantation for Non-Hodgkin Lymphomas Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History
• Endnotes
Policy Number: 143 BCBSA Reference Number: 8.01.20 (For Plan internal use only) Related Policies
• Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma, #074 • Hematopoietic Cell Transplantation for Hodgkin Lymphoma, #207 • Hematopoietic Cell Transplantation for Primary Amyloidosis, #181 • Hematopoietic Cell Transplantation for Waldenstrom’s Macroglobulinemia, #322
Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity

Non-Hodgkin’s lymphoma (NHL) For individuals with non-Hodgkin’s lymphoma (NHL), B-cell subtypes considered aggressive (except mantle cell lymphoma), either allogeneic hematopoietic stem cell transplantation (HCT) using a myeloablative conditioning regimen or autologous HCT for the following indications may be considered MEDICALLY NECESSARY: • As salvage therapy for individuals who do not achieve a complete remission (CR) after first-line treatment (induction) with a full course of standard-dose chemotherapy, • To achieve or consolidate a CR for those in a chemosensitive first or subsequent relapse, or • To consolidate a first CR in individuals with diffuse large B-cell lymphoma, with an adjusted International Prognostic Index score that predicts a high- or high-intermediate risk of relapse.

Mantle Cell Lymphoma For individuals with mantle cell lymphoma: • Autologous HCT to consolidate a first remission may be MEDICALLY NECESSARY.
• Allogeneic HCT, myeloablative or reduced-intensity conditioning, as salvage therapy may be MEDICALLY NECESSARY. • Autologous HCT is considered INVESTIGATIONAL as salvage therapy. • Allogeneic HCT is considered INVESTIGATIONAL to consolidate a first remission.

NHL B-cell Subtypes

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For individuals with NHL B-cell subtypes considered indolent, either allogeneic HCT using a myeloablative conditioning regimen or autologous HCT for the following indications may be MEDICALLY NECESSARY: • As salvage therapy for individuals who do not achieve CR after first-line treatment (induction) with a full course of standard-dose chemotherapy, or • To achieve or consolidate CR for those in a first or subsequent chemosensitive relapse, whether or not their lymphoma has undergone transformation to a higher grade.

Either autologous HCT or allogeneic HCT is considered INVESTIGATIONAL:
• as initial therapy (ie, without a full course of standard-dose induction chemotherapy) for any NHL; • to consolidate a first CR for individuals with diffuse large B-cell lymphoma and an International Prognostic Index score that predicts a low- or low-intermediate risk of relapse; • to consolidate a first CR for those with indolent NHL B-cell subtypes.

T-cell or NK-cell (peripheral T-cell) Lymphoma For individuals with mature T-cell or NK-cell (peripheral T-cell) lymphoma for the specified indications: • Autologous HCT may be MEDICALLY NECESSARY to consolidate a first CR in high-risk peripheral T-cell lymphoma.
• Autologous or allogeneic HCT (myeloablative or reduced-intensity conditioning) may be MEDICALLY NECESSARY as salvage therapy. • Allogeneic HCT is considered INVESTIGATIONAL to consolidate a first remission.

Hepatosplenic T-cell Lymphoma For individuals with hepatosplenic T-cell lymphoma: • Allogeneic HCT may be considered MEDICALLY NECESSARY to consolidate a first CR or partial response. • Autologous HCT may be considered MEDICALLY NECESSARY to consolidate a first response if a suitable donor is not available or for individuals who are ineligible for allogeneic HCT. • Autologous or allogeneic HCT as initial therapy (i.e., without a full course of standard-dose induction chemotherapy) is considered INVESTIGATIONAL.

Reduced-intensity conditioning allogeneic HCT as a treatment of NHL may be MEDICALLY NECESSARY in patients who meet criteria for an allogeneic HSCT but who do not qualify for a myeloablative allogeneic HCT.

Tandem transplants are considered INVESTIGATIONAL to treat patients with any stage, grade, or subtype of NHL.

Guidelines for use of bone marrow Stem cells when harvested from the patient’s bone marrow prior to marrow ablative therapy or from a donor’s marrow after verifying the donor and recipient are well matched with respect to human leukocyte antigens (HLA) may be considered MEDICALLY NECESSARY. Verification of well-matched HLA donor and recipient is based on the attending or treating physician’s clinical judgment.

Umbilical cord stem cell support as an acceptable cell source for transplants that are otherwise covered for either high-dose chemo with stem cell support, or for bone marrow transplant may be considered MEDICALLY NECESSARY when ALL the following are met:

1. Recipient is a child or adult, AND
2. There is no other available stem-cell donor with the same or better matching characteristics, AND

3. Donors may be related or unrelated.

   Collection and storage of cord blood from neonate when an allogeneic transplant is “imminent” in an identified recipient with a diagnosis that is consistent with the possible need for allogeneic transplant may be considered MEDICALLY NECESSARY.

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Exclusions:

1. Facility providing umbilical cord blood that is not in compliance with any existing FDA regulations governing umbilical cord transplants. FDA regulations are currently under development.
2. There is a suitable stem cell donor of equal or superior HLA match, and

3. Storage for future use, in case of a future need for transplant (prophylactic collection and storage).

   Prior Authorization Information
   Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
   Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

   Outpatient Commercial Managed Care (HMO and POS) Prior authorization is required. Commercial PPO and Indemnity Prior authorization is required.

   Requesting Prior Authorization Using Authorization Manager Providers will need to use Authorization Manager to submit initial authorization requests for services. Authorization Manager, available 24/7, is the quickest way to review authorization requirements, request authorizations, submit clinical documentation, check existing case status, and view/print the decision letter. For commercial members, the requests must meet medical policy guidelines.
   To ensure the service request is processed accurately and quickly: • Enter the facility’s NPI or provider ID for where services are being performed. • Enter the appropriate surgeon’s NPI or provider ID as the servicing provider, not the billing group.

   Authorization Manager Resources Refer to our Authorization Manager page for tips, guides, and video demonstrations.

   CPT Codes / HCPCS Codes / ICD Codes
   Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

   Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

   The following codes are included below for informational purposes only; this is not an all-inclusive list.

   The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity:
   CPT Codes CPT codes: Code Description 38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor 38241 Hematopoietic progenitor cell (HPC); autologous transplantation HCPCS Codes HCPCS codes: Code Description S2142 Cord blood derived stem-cell transplantation, allogeneic

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S2150 Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services)

Description Treatment for Non-Hodgkin Lymphoma

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 (allogeneic HCT [allo- HCT]). These cells can be harvested from bone marrow, peripheral blood, or the umbilical cord blood shortly after delivery of neonates. Cord blood transplantation is discussed in detail in policy #285.

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 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 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 cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease (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 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 graft-versus-malignancy effect of allogeneic transplantation develops. 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

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chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term reduced- intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative.

Summary Description Hematopoietic cell transplantation (HCT) refers to a procedure by which hematopoietic stem cells are 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]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although umbilical cord blood is an allogeneic source, the stem cells in it are antigenically “naive” and thus are associated with a lower incidence of rejection or graft-versus-host disease. Umbilical cord blood is discussed in greater detail in policy #285.

Summary of Evidence For individuals who have indolent B-cell non-Hodgkin lymphoma (NHL) who receive autologous hematopoietic cell transplant (HCT) as first-line therapy, the evidence includes observational studies, randomized controlled trials (RCTs), and systematic reviews. Relevant outcomes are overall survival (OS), disease-specific survival (DSS), change in disease status, morbid events, and treatment- related mortality and morbidity. The RCTs have not shown a survival advantage with HCT as first-line therapy for indolent B-cell lymphomas; however, RCTs have shown a survival benefit for relapsed disease. Observational studies have shown similar results. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have aggressive B-cell NHL, excluding mantle cell lymphoma (MCL), who receive autologous HCT as consolidation therapy after first complete remission (CR), the evidence includes RCTs and a systematic review. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. While the data from the RCTs offer conflicting results, some data have revealed an OS benefit in patients with aggressive B-cell lymphomas (at high- or high-intermediate risk of relapse) who receive HCT to consolidate a first CR. The RCTs of HCT for relapsed aggressive B-cell lymphomas have also shown an OS benefit with the previously described approach. Results of a retrospective study comparing autologous and allo-HCT for relapsed or refractory B-cell NHL showed more positive outcomes for autologous HCTs. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have NHL, excluding MCL, who receive tandem autologous and allo-HCT, the evidence includes several nonrandomized trials. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. No RCTs have been conducted on the use of tandem HCT for the treatment of NHL, and the published evidence comprises of a limited number of patients. Presently, conclusions on the use of tandem transplants cannot be made about autologous and allo-HCT. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have MCL who receive autologous, allogeneic, or tandem HCT, the evidence includes case series and RCTs. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Case series and RCTs have shown long-term disease control of this aggressive lymphoma with autologous HCT (with rituximab) to consolidate a first remission; however, the use of autologous HCT in the relapsed setting has not shown improved outcomes. Allo-HCT has shown prolonged disease control in the relapsed or refractory setting. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have peripheral T-cell lymphoma (PTCL) who receive autologous or allo-HCT, the evidence mainly includes prospective trials and case reports/series. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. The role of HCT

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in PTCL is not well-defined. Few studies have been conducted, and most were performed retrospectively with a limited number of patients; moreover, the patient populations were heterogeneous and included good- and poor-risk patients in the same study. Patient population and characteristics of the studies can be explained partially by the rarity and heterogeneity of the particular group of lymphomas addressed. Additionally, studies of this nature often mix 3 types of patients: 1 type of patient has PTCL not otherwise specified, which has a poorer prognosis; another type has anaplastic lymphoma kinase-positive anaplastic large-cell lymphomas, which has a better prognosis-even with conventional chemotherapy regimens; and a third type has anaplastic lymphoma kinase-negative anaplastic large-cell lymphomas, whifch has a worse prognosis than anaplastic lymphoma kinase-positive anaplastic large-cell lymphomas (but better than patients with PTCL not otherwise specified). For first-line therapy, autologous and allo- HCT were compared in a phase 3 trial, and there were comparable OS and PFS rates between the two groups. Results from recent phase 2 studies with autologous HCT as consolidation offers the best survival outcomes for patients with high-risk features; RCTs to confirm this have not been performed. A single retrospective registry study showed a potential survival benefit among patients treated with allo- HCT in the front-line setting; however, prospective studies are not available. Similarly, high-dose chemothearpy plus consolidation with autologous HCT as the first-line therapy for adults with nodal PTCL demonstrated improved OS and progression-free (PFS) in 2 systematic reviews. Patients with relapsed or refractory PTCL are generally considered incurable with chemotherapy alone. In the salvage setting, data have shown that the use of HCT may improve survival outcomes similar to the results seen in corresponding aggressive B-cell lymphomas in the same treatment setting. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have hepatosplenic T-cell lymphoma (HSTCL) who receive autologous or allo-HCT as consolidation therapy after first response (complete or partial), the evidence includes observational studies and systematic reviews. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Two meta-analyses using patient-level data found that consolidation therapy with HCT improves survival in patients with HSTCL. Two small, retrospective studies have shown similar results. A third small, retrospective study showed no significant differences in OS or PFS between allo-HCT and auto-HCT, but the achievement of CR at the time of HCT was associated with improved OS in auto-HCT recipients. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Policy History Date Action 2/2026 Annual policy review. References updated. Minor editorial refinements made to policy statements; intent unchanged. 10/2025 Clarified coding information 3/2025 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 3/2024 Annual policy review. References updated. Policy statements unchanged. 9/2023 Policy clarified to include prior authorization requests using Authorization Manager.
7/2023 Annual policy review. Medically necessary policy statement added for hepatosplenic T-cell lymphoma. Effective 7/1/2023.
1/2023 Medicare information removed. See MP #132 Medicare Advantage Management for local coverage determination and national coverage determination reference. 2/2022 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 3/2021 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 10/2020 Clarified coding information 4/2020 Bone marrow harvesting codes were removed. Outpatient prior authorization is not required.
3/2020 Annual policy review. Description, summary, and references updated. Policy statements unchanged.

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3/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2019 Outpatient prior authorization is required for all commercial products including Medicare Advantage. Effective 1/1/2019. 8/2018 Clinical trials for cancer information removed. For information on clinical trials for cancer, see subscriber certificate. 8/13/2018 2/2018 Annual policy review. New references added. 2/2018 Clarified coding information. 11/2017 Annual policy review. “Stem” removed from title and policy. HSCT changed to HCT in Policy statements otherwise unchanged. 11/1/2017 3/2016 Annual policy review. New references added 3/2015 Annual policy review. New references added 1/2015 Clarified coding information. 5/2014 Updated Coding section with ICD10 procedure and diagnosis codes, effective 10/2015. 4/2013 New references from Annual policy review. 2/2013 Annual policy review. No change in medical policy statement. Effective 2/4/2013. 11/2011-4/2012 Medical policy ICD 10 remediation: Formatting, editing and coding updates. No changes to policy statements.
11/1/2011 Annual policy review. Changes to policy statements. 7/2011 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements. 7/2009 New policy, effective 7/2009, describing covered and non-covered indications. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

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