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Hematopoietic Cell Transplantation for Non-Hodgkin Lymphomas

Policy Number: MP-387

Latest Review Date: January 2024

Category: Surgery

POLICY:

Effective for dates of service on or after April 15, 2023:

Non-Hodgkin Lymphoma (NHL) B-cell Subtypes (Aggressive)

For individuals with non-Hodgkin 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 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 age-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 may be considered medically necessary to consolidate a first remission.

  • Allogeneic HCT, myeloablative or reduced-intensity conditioning, may be considered medically necessary as salvage therapy.

  • Autologous HCT is considered investigational as salvage therapy.

  • Allogeneic HCT is considered investigational to consolidate a first remission.

NHL B-Cell Subtypes (Indolent)

For individuals with NHL B-cell subtypes considered indolent, either allogeneic HCT using a myeloablative conditioning regimen or autologous HCT may be considered 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 transformed* to a higher grade.

T-cell or Natural Killer (NK) cell (peripheral T-cell) neoplasms

For individuals with mature *T-cell or NK-cell (peripheral T-cell) neoplasms:

  • Autologous HCT may be considered medically necessary to consolidate a first complete remission in high-risk subtypes (see Policy Guidelines section).

  • Autologous or allogeneic HCT (myeloablative or reduced-intensity conditioning) may be considered medically necessary as salvage therapy.

  • Allogeneic HCT is considered investigational to consolidate a first remission.

Waldenström Macroglobulinemia

For individuals with Waldenström Macroglobulinemia:

  • Autologous hematopoietic cell transplantation may be considered medically necessary as salvage therapy of chemosensitive Waldenström Macroglobulinemia.

  • Allogeneic hematopoietic cell transplantation is considered investigational to treat Waldenström Macroglobulinemia.

Hepatosplenic T-cell Lymphoma

For individuals with Hepatosplenic T-cell Lymphoma:

  • Allogenic HCT may be considered medically necessary to consolidate a first complete remission 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

Either autologous HCT or allogeneic HCT are considered investigational

  • As initial therapy (i.e., 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.

Tandem transplants

Are considered investigational to treat individuals with any stage, grade, or subtype of NHL.

Reduced-intensity conditioning (RIC) allogeneic HCT

 May be considered medically necessary as a treatment of NHL in individuals who meet criteria for an allogeneic HCT but who do not qualify for a myeloablative allogeneic HCT (see Policy Guidelines section)

POLICY GUIDELINES:

Chemosensitive relapse: This is defined as relapsed non-Hodgkin lymphoma (NHL) that does not progress during or immediately after standard-dose induction chemotherapy (i.e., achieves stable disease or a partial response).

Myeloablative allogeneic hematopoietic HCT: This is considered in individuals who qualify for a myeloablative allogeneic hematopoietic HCT based on overall health and disease status, allogeneic HCT using either myeloablative or RIC may be considered. However, a myeloablative conditioning regimen with allogeneic HCT may benefit younger individuals with good performance status and minimal comorbidities more than allogeneic HCT with RIC.

 Reduced-intensity conditioning (RIC):

  • This refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments.
  • This would be considered an option in individuals who meet criteria for an allogeneic hematopoietic stem-cell transplant (HCT) but whose age (typically older than 55 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, and prior intensive chemotherapy) preclude use of a standard conditioning regimen.

*Salvage Therapy: The term salvage therapy describes therapy given to individuals who have either:

  • Failed to achieve complete remission after initial treatment for newly diagnosed lymphoma, or
  • Relapsed after an initial complete remission.

Tandem Transplants: This is usually defined as the planned administration of two successive cycles of high-dose myeloablative chemotherapy, each followed by infusion of autologous hematopoietic stem cells, whether or not there is evidence of persistent disease following the first treatment cycle. Sometimes, the second cycle may use non-myeloablative immunosuppressive conditioning followed by infusion of allogeneic stem cells.

*High-risk (aggressive) T-cell and natural killer cell neoplasms: These are a clinically heterogeneous group of rare disorders, most of which have an aggressive clinical course and poor prognosis. The exception includes the following subtypes, which typically have a relatively indolent and protracted course: T-cell large granulocyte leukemia, chronic lymphoproliferative disorder of natural killer cells, early-stage mycosis fungoides, primary cutaneous anaplastic large-cell lymphoma, and anaplastic lymphoma kinase-anaplastic large-cell lymphomas.

*Transformation: This describes a lymphoma whose histologic pattern has evolved to a higher grade lymphoma. Transformed lymphomas typically evolve from a nodular pattern to a diffuse pattern.

Effective for dates of service on or after April 19, 2020 and prior to April 15, 2023:

For individuals with non-Hodgkin 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 may be considered medically necessary:

  • As salvage therapy for patients 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 patients with diffuse large B-cell lymphoma, with an age-adjusted International Prognostic Index score that predicts a high- or high-intermediate risk of relapse.

For patients with mantle cell lymphoma:

  • Autologous HCT may be considered medically necessary to consolidate a first remission.
  • Allogeneic HCT, myeloablative or reduced-intensity conditioning, may be considered medically necessary as salvage therapy.
  • Autologous HCT is considered investigational as salvage therapy.
  • Allogeneic HCT is considered investigational to consolidate a first remission.

For patients with NHL B-cell subtypes considered indolent, either allogeneic HCT using a myeloablative conditioning regimen or autologous HCT may be considered medically necessary:

  • As salvage therapy for patients 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.

*Transformation describes a lymphoma whose histologic pattern has evolved to a higher-grade lymphoma. Transformed lymphomas typically evolve from a nodular pattern to a diffuse pattern.

Reduced-intensity conditioning (RIC) allogeneic HCT may be considered medically necessary as a treatment of NHL in patients who meet criteria for an allogeneic HCT but who do not qualify for a myeloablative allogeneic HCT.

Either autologous HCT or allogeneic HCT are considered investigational:

  • As initial therapy (i.e., without a full course of standard-dose induction chemotherapy) for any NHL;
  • To consolidate a first CR for patients 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.

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

For patients with mature *T-cell or NK-cell (peripheral T-cell) neoplasms:

  • Autologous HCT may be considered medically necessary to consolidate a first complete remission in high-risk peripheral T-cell lymphoma.
  • Autologous or allogeneic HCT (myeloablative or reduced-intensity conditioning) may be considered medically necessary as salvage therapy.
  • Allogeneic HCT is considered investigational to consolidate a first remission.

* The T-cell and NK-cell neoplasm are a clinically heterogeneous group of rare disorders, most of which have an aggressive clinical course and poor prognosis. The exception would include the following subtypes which typically have a relatively indolent and protracted course: T-cell large granulocyte leukemia (T-LGL), chronic lymphoproliferative disorder of NK cells, early stage mycosis fungoides, primary cutaneous ALCL, and ALK+ ALCL.

For patients with Waldenström Macroglobulinemia:

  • Autologous hematopoietic cell transplantation may be considered medically necessary as salvage therapy of chemosensitive Waldenström Macroglobulinemia.
  • Allogeneic hematopoietic cell transplantation is considered investigational to treat Waldenström Macroglobulinemia.

POLICY GUIDELINES:

Note: The term salvage therapy describes therapy given to patients who have either:

  1. Failed to achieve complete remission after initial treatment for newly diagnosed lymphoma, or
  2. Relapsed after an initial complete remission.

A chemosensitive relapse is defined as relapsed non-Hodgkin lymphoma (NHL) that does not progress during or immediately after standard-dose induction chemotherapy (i.e., achieves stable disease or a partial response).

Note: Reduced-intensity conditioning (RIC) would be considered an option in patients who meet criteria for an allogeneic hematopoietic stem-cell transplant (HCT) but whose age (typically older than 55 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, and prior intensive chemotherapy) preclude use of a standard conditioning regimen.

In patients who qualify for a myeloablative allogeneic hematopoietic HCT based on overall health and disease status, allogeneic HCT using either myeloablative or RIC may be considered. However, a myeloablative conditioning regimen with allogeneic HCT may benefit younger patients with good performance status and minimal comorbidities more than allogeneic HCT with RIC.

Tandem transplants usually are defined as the planned administration of two successive cycles of high-dose myeloablative chemotherapy, each followed by infusion of autologous hematopoietic stem cells, whether or not there is evidence of persistent disease following the first treatment cycle. Sometimes, the second cycle may use non-myeloablative immunosuppressive conditioning followed by infusion of allogeneic stem cells.

DESCRIPTION OF PROCEDURE OR SERVICE:

In the United States, B-cell lymphomas represent approximately 85% of cases of NHL, and T-cell lymphomas represent approximately 15%. Natural killer lymphomas are relatively rare.

The International Lymphoma Classification Project identified the most common NHL subtypes as follows: diffuse large B-cell lymphoma (DLBCL) 31%, follicular lymphoma 22%, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) 6%, mantle cell lymphoma (MCL) 6%, peripheral T-cell lymphoma (PTCL) 6%, and marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue lymphoma 5%. All other subtypes each represent fewer than 2% of cases of NHL.

Staging

The Ann Arbor staging classification is commonly used to stage lymphomas. Originally developed for Hodgkin disease, the classification was later expanded to include NHL (see Table 1).

Table 1. Ann Arbor Classification

Stage

Involvement

I

Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE)

II

Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE)

III

Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS) or both (IIISE)

IV

Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement

Non-Hodgkin Lymphoma

A heterogeneous group of lymphoproliferative malignancies, non-Hodgkin lymphoma (NHL) usually originates in lymphoid tissue. Historically, the uniform treatment of individuals with NHL was hampered by the lack of a uniform classification system. In 1982, the Working Formulation was developed to unify different classification systems into one. The Working Formulation divided NHL into low-, intermediate-, and high-grade, with subgroups based on histologic cell type. Because our understanding of NHL has improved, the diagnosis has become more sophisticated and includes the incorporation of new immunophenotyping and genetic techniques. As a result, the Working Formulation has become outdated.

European and American pathologists proposed a new classification, the Revised European-American Lymphoma (REAL) Classification and an updated version of the REAL system, the new World Health Organization classification. The WHO/REAL classification recognized three major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer cell neoplasms, and Hodgkin lymphoma. The most recent lymphoma classification is the 2022 WHO classification (see Table 2).

Table 2. Updated World Health Organization Classification (2022)

Classification of Neoplasms

Tumor-like lesions with B-cell predominance

Reactive B-cell-rich lymphoid proliferations that can mimic lymphomaa

IgG4-related diseasea

Idiopathic multicentric Castleman diseasea

KSHV/HHV8-associated multicentric Castleman diseasea

Precursor B-cell neoplasms

B-cell lymphoblastic leukemias/lymphomas

B-lymphoblastic leukaemia/lymphoma, NOS

B-lymphoblastic leukaemia/lymphoma with high hyperdiploidya

B-lymphoblastic leukaemia/lymphoma with hypodiploidy

B-lymphoblastic leukaemia/lymphoma with iAMP21

B-lymphoblastic leukaemia/lymphoma with BCR::ABL1 fusiona

B-lymphoblastic leukaemia/lymphoma with BCR::ABL1-like featuresa

B-lymphoblastic leukaemia/lymphoma with KMT2A rearrangementa

B-lymphoblastic leukaemia/lymphoma with ETV6::RUNX1 fusiona

B-lymphoblastic leukaemia/lymphoma with ETV6::RUNX1-like featuresa

B-lymphoblastic leukaemia/lymphoma with TCF3::PBX1 fusiona

B-lymphoblastic leukaemia/lymphoma with IGH::IL3 fusiona

B-lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion

B-lymphoblastic leukaemia/lymphoma with other defined genetic abnormalities

Mature B-cell neoplasms

Pre-neoplastic and neoplastic small lymphocytic proliferations

Monoclonal B-cell lymphocytosis

Chronic lymphocytic leukaemia/small lymphocytic lymphoma

Splenic B-cell lymphomas and leukemias

Hairy cell leukaemia

Splenic marginal zone lymphoma

Splenic diffuse red pulp small B-cell lymphoma

Splenic B-cell lymphoma/leukaemia with prominent nucleolia

Lymphoplasmacytic lymphoma

Lymphoplasmacytic lymphoma

Marginal zone lymphoma

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

Primary cutaneous marginal zone lymphomaa

Nodal marginal zone lymphoma

Paediatric marginal zone lymphoma

Follicular lymphoma

In situ follicular B-cell neoplasma

Paediatric-type follicular lymphoma

Duodenal-type follicular lymphoma

Cutaneous follicle centre lymphoma

Primary cutaneous follicle centre lymphoma

Mantle cell lymphoma

In situ mantle cell neoplasma

Leukemic non-nodal mantle cell lymphoma

Transformations of indolent B-cell lymphomas

Transformations of indolent B-cell lymphomasa

Large B-cell lymphomas

Diffuse large B-cell lymphoma, NOS

T-cell/histiocyte-rich large B-cell lymphoma

Diffuse large B-cell lymphoma/ high grade B-cell lymphoma with MYC and BCL2 rearrangementsa

ALK-positive large B-cell lymphoma

Large B-cell lymphoma with IRF4 rearrangement

High-grade B-cell lymphoma with 11q aberrationsa

Lymphomatoid granulomatosis

EBV-positive diffuse large B-cell lymphomaa

Diffuse large B-cell lymphoma associated with chronic inflammation

Fibrin-associated large B-cell lymphomaa

Fluid overload-associated large B-cell lymphomaa

Plasmablastic lymphoma

Primary large B-cell lymphoma of immune-privileged sitesa

Primary cutaneous diffuse large B-cell lymphoma, leg type

Intravascular large B-cell lymphoma

Primary mediastinal large B-cell lymphoma

Mediastinal grey zone lymphomaa

High-grade B-cell lymphoma, NOS

Burkitt lymphoma

Burkitt lymphoma

KSHV/HHV8-associated B-cell lymphoid proliferations and lymphomas

Primary effusion lymphoma

KSHV/HHV8-positive diffuse large B-cell lymphomaa

KSHV/HHV8-positive germinotropic lymphoproliferative disordera

Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation

Hyperplasias arising in immune deficiency/dysregulationa

Polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulationa

EBV-positive mucocutaneous ulcer

Lymphomas arising in immune deficiency / dysregulationa

Inborn error of immunity-associated lymphoid proliferations and lymphomasa

Hodgkin lymphoma

Classic Hodgkin lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma

Plasma cell neoplasms and other diseases with paraproteins

Monoclonal gammopathies

Cold agglutinin diseasea

IgM monoclonal gammopathy of undetermined significance

Non-IgM monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of renal significancea

Diseases with monoclonal immunoglobulin deposition

Immunoglobulin-related (AL) amyloidosisa

Monoclonal immunoglobulin deposition diseasea

Heavy chain diseases

Mu heavy chain disease

Gamma heavy chain disease

Alpha heavy chain disease

Plasma cell neoplasms

Plasmacytoma

Plasma cell myeloma

Plasma cell neoplasms with associated paraneoplastic syndromea

POEMS syndrome

TEMPI syndrome

AESOP syndrome

aChanges from 2016 WHO classification.

AESOP: adenopathy and extensive skin patch overlying a plasmacytoma; ALK: anaplastic lymphoma kinase; EBV: Epstein-Barr virus; HHV: human herpes virus; KSHV: Kaposi's sarcoma-associated herpesvirus; NOS: not otherwise specified; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes; TEMPI: telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting.

Risk Assessment for aggressive NHL

Oncologists developed a clinical tool to aid in predicting the prognosis of individuals with aggressive NHL (specifically DLBCL), referred to as the International Prognostic Index (IPI). Before its development in 1993, the prognosis was predominantly based on the disease stage.

Based on the following 5 risk factors prognostic of overall survival (OS) and adjusted for patient age, the IPI defines 4 risk groups: low, low-intermediate, high-intermediate, and high-risk:

  1. Age older than 60 years
  1. Elevated serum lactate dehydrogenase (LDH) level
  1. Ann Arbor stage III or IV disease
  1. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2, 3, or 4
  1. Involvement of more than 1 extranodal site.

Risk groups are stratified by a number of adverse factors as follows: 0 or 1 is low-risk, 2 is low-intermediate, 3 is high-intermediate, and 4 or 5 are high-risk.

Individuals with 2 or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. Age-adjusted IPI and stage-adjusted modifications of this IPI are used for younger individuals with localized disease.

Adverse risk factors for age-adjusted IPI include stage III or IV disease, elevated LDH, and ECOG Performance Status of 2 or greater and can be calculated as follows: 0 is low-risk, 1 is low-intermediate, 2 is high-intermediate, and 3 is high-risk. 

With the success of the IPI, a separate prognostic index was developed for Follicual Lymphoma, which has multiple independent risk factors for relapse after first complete remission (CR). The proposed and validated Follicular Lymphoma International Prognostic Index contains 5 adverse prognostic factors:

  1. Age older than 60 years
  1. Ann Arbor stage III or IV disease
  1. Hemoglobin level less than 12.0 g/dL
  1. More than 4 lymph node areas involved
  1. Elevated serum LDH level.

These 5 factors are used to stratify individuals into 3 categories of risk: low (0 to 1 risk factor), intermediate (2 risk factors), or poor (3 or more risk factors).

Risk Assessment for Mantle Cell Lymphoma

A prognostic index has recently been established for individuals with Mantle Cell Lymphoma (MCL). Application of the IPI or FLIPI system to individuals with MCL has shown limitations, which included no separation of some important risk groups. In addition, some of the individual IPI and FLIPI risk factors, including number of extranodal sites and number of involved nodal areas showed no prognostic relevance, and hemoglobin showed no independent prognostic relevance in individuals with MCL. Therefore, a new prognostic index for individuals with MCL was developed and is useful in comparing clinical trial results for MCL.

The MCL International Prognostic Index (MIPI) is based on the following risk factors prognostic for OS.

  1. Age
  2. ECOG performance status
  3. Serum LDH (calculated as a ratio of LDH to a laboratory’s upper limit of normal)
  4. White blood cell (WBC) count
  • 0 points each are assigned for age younger than 50 years, ECOG Performance Status score of 0-1, LDH ratio of less than 0.67 U/L, WBC of less than 6700m/L
  • 1 point each for age 50 to 59 years, LDH ratio of 0.67-0.99 U/L, WBC 6700-9999m/L  
  • 2 points each for age 60 to 69 years, ECOG Performance Status score of 2-4, LDH ratio of 1.00-1.49 U/L, WBC of 10,000-14,999m/L:
  • 3 points each for age 70 years or older, LDH ratio of 1.5 U/L or greater, WBC of 15,000m/L or more.

 MCL IPI allows separation of 3 groups with significantly different prognoses:

  • 0-3 points denotes low risk, which affects 44% of individuals, who have a 5-year OS rate of 60% (median OS, not reached)
  • 4-5 points denotes intermediate risk, which affects 35% of individuals, who have a median OS of 51 months
  • 6-11 points denotes high risk, which affects 21% of individuals, who have a median OS of 29 months.

Waldenström Macroglobulinemia

Waldenström Macroglobulinemia (WM) is a clonal disorder of B-lymphocytes that accounts for 1% to 2% of hematologic malignancies, with an estimated 1500 new cases annually in the United States. Symptoms include weakness, headaches, stroke-like symptoms (confusion, loss of coordination), vision problems, excessive bleeding, unexplained weight loss, and frequent infections. The median age of WM individuals does 63 to 68 years, with men comprise 55% to 70% of cases. Median survival of WM ranges from five to 10 years, with age, hemoglobin concentration, serum albumin level, and ß2-microglobulin level as predictors of outcome.

The Revised European American Lymphoma and World Health Organization classification and a consensus group formed at the Second International Workshop on Waldenström’ s Macroglobulinemia recognize WM primarily as a lymphoplasmacytic lymphoma with an associated immunoglobulin M (IgM) monoclonal gammopathy. The definition also requires the presence of a characteristic pattern of bone marrow infiltration with small lymphocytes demonstrating plasmacytic differentiation with variable cell surface antigen expression. The Second International Workshop indicated no minimum serum concentration of IgM is necessary for a diagnosis of WM.

Treatment

The goal of therapy for individuals with WM is to achieve symptomatic relief and reduce organ damage without compromising quality of life. Treatment of WM is indicated only in symptomatic individuals and should not be initiated solely based on serum IgM concentration. Clinical and laboratory findings that indicate the need for therapy of diagnosed WM include a hemoglobin concentration less than 10 g/dL; platelet count less than 100,000/ųL; significant adenopathy or organomegaly; symptomatic Ig-related hyperviscosity (>50 g/L); severe neuropathy; amyloidosis; cryoglobulinemia; cold-agglutinin disease; or evidence of disease transformation.

Primary chemotherapeutic options in individuals that may undergo autologous hematopoietic cell transplantation (HCT) often combine rituximab with other agents (e.g., dexamethasone, cyclophosphamide, bortezomib, bendamustine), but other agents may also be used including purine analogues (cladribine, fludarabine). Plasma exchange is indicated for acute treatment of symptomatic hyperviscosity.

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 individuals 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. The use of cord blood is discussed in Medical Policy #439: Placental/Umbilical Cord Blood as a Source of Stem Cells.

 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 individual 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 individual 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 individuals 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 inidividual’s disease is in complete remission. Individuals 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 individual condition. Individuals who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed 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.

KEY POINTS:

The most recent literature update was performed through November 15, 2023.

Summary of Evidence

For individuals who have indolent B-cell non-Hodgkin lymphomas 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, disease-specific survival, 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 the effects of the technology on health outcomes.

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 comprises of 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 individuals 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 demonstrated 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 Non-Hodgkin lymphomas, excluding MCL, who receive tandem autologous and allogeneic HCT, the evidence includes several nonrandomized trials. Relevant outcomes are overall survival, disease-specific survival, 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 non-Hodgkin lymphoma, and the published evidence comprises a limited number of individuals. Presently, conclusions on the use of tandem transplants cannot be made about autologous and allogeneic HCT. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have mantle cell lymphoma who receive autologous, allogeneic, or tandem HCT, the evidence includes case series and RCTs. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. Case series 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. Allogeneic HCT has shown prolonged disease control in the relapsed or refractory setting. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have peripheral T-cell lymphoma (PTCL) PTCL who undergo autologous or allo-HCT, the evidence mainly comprises of 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 in PTCL is not well-defined. Few studies have been conducted, and most were performed retrospectively with a limited number of individuals; moreover, the individual populations were heterogeneous and included good- and poor-risk individuals in the same study. Individual 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 individuals: 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, which has a worse prognosis than anaplastic lymphoma kinase-positive anaplastic large-cell lymphomas (but better than individuals with PTCL not otherwise specified). For first-line therapy, autologous and allo-HCT were compared in a phase 3 trial, and there were similar 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 individuals with high-risk features; RCTs to confirm this have not been performed. A single retrospective registry study showed a potential survival benefit among individuals treated with allo-HCT in the front-line setting; however, prospective studies are not available and therefore considered investigational. Similarly, high-dose chemotherapy plus consolidation with autologous HCT as the first-line therapy for adults with nodal PTCL demonstrated improved OS and progression-free (PFS) in a systematic review. Individuals 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 utilizing individual-level data found that consolidation therapy with HCT improves survival in individuals with HSTCL. Two small, retrospective studies have shown similar results. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have WM who receive HCT, the evidence includes case series. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related mortality and morbidity. Several retrospective series have evaluated HCT for WM. Analyses of registry data have found 5-year overall survival rates of 52% after allogeneic HCT and 68.5% after autologous HCT. The total number of individuals studied is small and there is a lack of published controlled studies. There is minimal experience with high dose chemotherapy followed by autologous HCT in WM.  Treatment related mortality appears to be less than 10 % and autologous HCT may be able to produce long-term responses even in heavily pretreated individuals.  On the other hand, allogeneic HCT, which carries a much higher risk of non-relapse mortality, should not be considered outside the context of a clinical trial. Therefore, autologous HCT is considered medically necessary as salvage therapy for chemosensitive WM. The evidence for allogeneic HCT is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

Current National Comprehensive Cancer Network guidelines on B-cell lymphomas (v6.2023) include the following recommendations:

  • For follicular lymphoma, marginal zone lymphomas, and mantle cell lymphoma, recommend allogeneic HCT as second-line consolidation therapy, in select cases, which include mobilization failures and persistent bone marrow involvement. NCCN does note that with recent approval of CAR T-cell therapy for relapsed/refractory MCL, allogeneic HCT has been deferred to disease relapse following multiple prior therapies in many NCCN member institutions.
  • For DLBCL, “[a]llogeneic HCT should be considered in selected patients with mobilization failures and persistent bone marrow involvement or lack of adequate response to second-line therapy, though patients should be in CR or near CR at the time of transplant.”
  • For Burkitt lymphoma, allogeneic HCT is an option for selected patients who achieve a complete or partial response to second-line therapy.

National Comprehensive Cancer Network guidelines on T-cell lymphomas (v1.2023) include the following recommendations:

For peripheral T-cell lymphoma: “Second-line systematic therapy followed by consolidation with HDT [high-dose therapy]/ASCR [autologous stem cell rescue] or allogeneic HCT for those with a CR [complete response] or PR [partial response] is recommended for patients who are candidates for transplant.”

For adult T-cell leukemia/lymphoma:

  • "Allogeneic HCT should be considered for patients with acute or lymphoma [ATLL] subtype, if donor is available."
  • "In patients with acute or lymphoma subtypes who achieve a response to second-therapy, allogeneic HSCT should be considered if a donor is available."

For T-cell Prolymphocytic Leukemia: “In patients [with T-PLL] who achieve a CR or PR following initial therapy, consolidation with allogeneic HCT should be considered. Autologous HCT may be considered, if a donor is not available and if the patient is not physically fit enough to undergo allogeneic HCT.”

For Hepatosplenic T-Cell Lymphoma (HSTCL):

  • "Consolidation therapy with allogeneic HCT is recommended for eligible patients with complete response or partial response after initial induction therapy or second-line therapy. Consolidation therapy with autologous HCT can be considered if a suitable donor is not available or for patients who are ineligible for allogeneic HCT."
  • "Long-term remission is primarily or exclusively seen in those who have undergone consolidative HCT."
  • "Few studies have reported improved survival outcomes with autologous or allogeneic HCT as consolidation therapy for patients with disease in first or second remission. Some studies have also reported that graft-versus-lymphoma effect associated with allogeneic HCT may result in long-term survival in a significant proportion of patients with HSTCL and active disease at the time of transplant was not necessarily associated with poor outcomes."
  • "The goal of initial therapy is to induce complete or near complete response to allow successful bridging to HCT, preferably an allogeneic HCT."

The American Society of Transplantation and Cellular Therapy

In 2021, the American Society of Transplantation and Cellular Therapy (ASTCT), Center of International Blood and Marrow Transplant Research (CIBMTR), and the European Society for Blood and Marrow Transplantation (EBMT) formulated consensus recommendations regarding autologous HCT, allogeneic HCT, and chimeric antigen receptor (CAR) T-cell therapy for individuals with MCL. The panel of experts, consisting of physicians and investigators, recommended the use of autologous HCT as consolidation therapy in newly diagnosed MCL inidividuals (without TP53 mutation or bi-allelic deletion) who are in complete or partial remission after first-line therapies.

The ASTCT Committee on Practice Guidelines published guidance on transplantation and cellular therapies in Diffuse Large B Cell Lymphoma (DLBCL) in 2023. The committee made the following recommendations:

  • "The panel does not recommend autologous HCT in DLBCL (regardless of IPI score) as consolidation in complete remission after first-line (R-CHOP or similar) therapy." Grading: A
  • "Autologous HCT may be considered for eligible patients with DLBCL with secondary CNS involvement at diagnosis achieving complete remission and with undetectable CNS disease after first-line therapy." Grading: C
  • "The panel recommends consolidation with autologous HCT for eligible primary CNS lymphoma patients in CR1." Grading: A
  • "In DLBCL patients with early relapse who achieve a complete remission with salvage therapy, the panel considers autologous HCT an acceptable consolidation therapy in eligible patients." Grading: B
  • "In DLBCL patients with early relapse who achieve a partial remission with salvage therapy, the panel considers autologous HCT an acceptable consolidation therapy in eligible patients." Grading: B
  • "In DLBCL patients with late relapse, the panel recommends autologous HCT consolidation therapy in eligible patients who have achieved a complete or partial remission after second-line therapies." Grading: A
  • "The panel recommends allogeneic HCT in eligible DLBCL patients relapsing/progressing after CAR-T therapy if they achieve a complete or partial remission with subsequent antilymphoma therapies." Grading: C
  • "The panel recommends allogeneic HCT in eligible relapsed or refractory DLBCL patients after autologous HCT failure in regions without access to CAR-T therapy, and in those with CAR T cell manufacturing failure, ideally after achieving a complete or partial remission with subsequent antilymphoma therapies." Grading: C

Grading of recommendations:

A, There is good research-based evidence to support the recommendation;

B, There is fair research-based evidence to support the recommendation;

C, The recommendation is based on expert opinion and panel consensus;

X, There is evidence of harm from this intervention.

U.S Preventive Services Task Force Recommendations

Not Applicable.

KEY WORDS:

High-Dose Chemotherapy, Non-Hodgkin’s Lymphoma, Lymphoma, Stem-Cell Transplant, Diffuse Large B-Cell Lymphoma, DLBCL, Mantle Cell Lymphoma, MCL, Peripheral T-Cell Lymphoma, PTCL, Follicular Lymphoma, Hematopoietic Cell Transplantation, HCT, Anaplastic Large-Cell Lymphoma, and ALCL, Histiocytic Sarcoma, HS, Waldenström Macroglobulinemia, Burkitt Lymphoma, Hepatosplenic T-Cell Lymphoma, HSTCL, Marginal Zone Lymphoma, TEMPI Syndrome, AESOP Syndrome

APPROVED BY GOVERNING BODIES:

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.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group- specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply.  Refer to member’s benefit plan.

CURRENT CODING:

CPT Codes:

38204

Management of recipient hematopoietic cell donor search and cell acquisition 

38205

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic 

38206

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous 

38208

Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing; per donor

38209

; thawing of previously frozen harvest with washing; per donor

38210

; specific cell depletion with harvest, T cell depletion

38211

; tumor cell depletion

38212

; red blood cell removal 

38213

; platelet depletion

38214

; plasma (volume) depletion

38215

; cell concentration in plasma, mononuclear, or buffy coat layer

38220

Diagnostic bone marrow; aspiration(s)

38221

Diagnostic bone marrow; biopsy (ies),

38222

Diagnostic bone marrow; biopsy (ies) and aspiration(s)

38230

Bone marrow harvesting for transplantation; allogeneic

38232

; autologous

38240

Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic 

38241

Bone marrow or blood-derived peripheral stem-cell transplantation; autologous

                             

HCPCS:

S2140

Cord blood harvesting for transplantation, allogeneic

S2142

Cord blood-derived stem-cell transplantation, allogeneic

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)

                       

REFERENCES:

  1. Al Khabori M, de Almeida JR, Guyatt GH et al. Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst. Jan 04 2012; 104(1):18-28.
  2. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. Jul 2022; 36(7): 1720-1748.
  3. American Cancer Society. Non-Hodgkin Lymphoma (Adults). www.cancer.org/cancer/non-hodgkinlymphoma/about.html 
  4. Ansell M, Stephen. Treatment and prognosis of Waldenstrom macroglobulinemia. In: Connor F, Rebecca, ed. UpToDate. Waltham, Mass: UpToDate, 2024. www.uptodate.com/contents/treatment-and-prognosis-of-waldenstrom-macroglobulinemia?
  5. Baldissera RC, Nucci M, Vigorito AC, et al. Frontline therapy with early intensification and autologous stem cell transplantation versus conventional chemotherapy in unselected high-risk, aggressive non-Hodgkin's lymphoma patients: A prospective randomized GEMOH report. Acta Haematol 2006; 115(1-2):15-21.
  6. Banks PM, Chan J, Cleary ML, et al. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol.Jul 1992; 16(7):637-640.
  7. Betticher DC, Martinelli G, Radford JA, et al. Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: Results of the international randomized phase III trial (MISTRAL). Ann Oncol. Oct 2006; 17(10):1546-1552.
  8. Bozkaya Y, Uncu D, Dagdas S, et al. Evaluation of lymphoma patients receiving high-dose therapy and autologous stem cell transplantation: experience of a single center. Indian J Hematol Blood Transfus. Sep 2017; 33(3):361-369.
  9. Casasnovas RO, Ysebaert L, Thieblemont C, et al. FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study. Blood. Sep 14 2017; 130(11):1315-1326.
  10. Cornell RF, Bachanova V, D'Souza A, et al. Allogeneic Transplantation for Relapsed Waldenstrom Macroglobulinemia and Lymphoplasmacytic Lymphoma. Biol Blood Marrow Transplant. Jan 2017; 23(1): 60-66.
  11. Corradini P, Tarella C, Zallio F et al. Long-term follow-up of patients with peripheral T-cell lymphoma treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia. Sep 2006; 20(9):1533-1538.
  12. Deconinck E, Foussard C, Milpied N, et al.  High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS.  Blood. May 5 2005; 105(10):3817-3823.
  13. Dreyling M, Lenz G, Hoster E, et al.  Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression free survival in mantle-cell lymphoma: Results of a prospective randomized trial of the European MCL network. Blood. Apr 01 2005; 105(7):2677-2684.
  14. Du J, Yu D, Han X, et al. Comparison of Allogeneic Stem Cell Transplant and Autologous Stem Cell Transplant in Refractory or Relapsed Peripheral T-Cell Lymphoma: A Systematic Review and Meta-analysis. JAMA Netw Open. May 03 2021; 4(5): e219807. 
  15. Epperla N, Kumar A, Abutalib SA, et al. ASTCT Clinical Practice Recommendations for Transplantation and CellularTherapies in Diffuse Large B Cell Lymphoma. Transplant Cell Ther. Sep 2023; 29(9): 548-555.
  16. Fisher RI.  Autologous bone marrow transplantation for aggressive non-Hodgkin’s lymphoma: Lessons learned and challenges remaining.  J Natl Cancer Inst. Jan 03 2001; 93(1):4-5.
  17. Fisher RI.  Autologous stem-cell transplantation as a component of initial treatment for poor-risk patients with aggressive non-Hodgkin's lymphoma: Resolved issues versus remaining opportunity.  J Clin Oncol. Nov 15 2002; 20(22):4411-4412.
  18. Fujita N, Kobayashi R, Atsuta Y, et al. Hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory B-cell non-Hodgkin lymphoma. Int J Hematol. Apr 2019; 109(4): 483-490.
  19. Garcia-Noblejas A, Cannata-Ortiz J, Conde E, et al. Autologous stem cell transplantation (ASCT) in patients with mantle cell lymphoma: a retrospective study of the Spanish lymphoma group (GELTAMO). Ann Hematol. Aug 2017; 96(8):1323-1330.
  20. Geisler C. Mantle cell lymphoma: are current therapies changing the course of disease?. Curr Oncol Rep. Sep 2009; 11(5): 371-7.
  21. Greb A, Bohlius J, Schiefer D, et al.  High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive non-Hodgkin lymphoma (NHL) in adults.  Cochrane Database Syst Review 2008 Jan 23; (1):CD004024.
  22. Hahn T, Wolff SN, Czuczman M, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin's lymphoma: an evidence-based review. Biol Blood Marrow Transplant 2001; 7(6):308-331.
  23. Haioun C, Lepage E, Gisselbrecht C, et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. J Clin Oncol. Mar 1997; 15(3):1131-1137.
  24. Haioun C, Lepage E, Gisselbrecht C, et al. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a Groupe d'Etude des Lymphomes de l'Adulte study. J Clin Oncol. Aug 2000; 18(16):3025-3030.
  25. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol. Dec 1999; 10(12):1419-1432.
  26. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: A proposal from the international lymphoma study group. Blood. Sept 1994; 84(5):1361-1392.
  27. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood Jan 15 2008; 111:558-565.
  28. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
  29. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009:523-531.
  30. Jimenez-Ubieto A, Grande C, Caballero D, et al. Autologous stem cell transplantation may be curative for patients with follicular lymphoma with early therapy failure who reach complete response after rescue treatment. Hematol Oncol. Dec 2018; 36(5). 
  31. Kaiser U, Uebelacker I, Abel U, et al.  Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma.  J Clin Oncol. Nov 15 2002; 20(22):4413-4419.
  32. Kapoor P, Ansell SM, Fonseca R, et al. Diagnosis and Management of Waldenstrom Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016. JAMA Oncol. Sep 01 2017; 3(9): 1257-1265.
  33. Khouri IF, Lee MS, Saliba RM, et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol. Dec 2003; 21:4407-4412.
  34. Kimby E, Brandt L, Nygren P, et al. A systematic overview of chemotherapy effects in aggressive non-Hodgkin's lymphoma. Acta Oncol 2001; 40(2-3):198-212.
  35. Klebaner D, Koura D, Tzachanis D, et al. Intensive Induction Therapy Compared With CHOP for Hepatosplenic T-cell Lymphoma. Clin Lymphoma Myeloma Leuk. Jul 2020; 20(7): 431-437.e2
  36. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: Randomized phase III EORTC study. J Natl Cancer Inst Jan 03 2001; 93(1):22-30.
  37. Kruger WH, Hirt C, Basara N, et al. Allogeneic stem cell transplantation for mantle cell lymphoma-update of the prospective trials of the East German Study Group Hematology/Oncology (OSHO#60 and #74). Ann Hematol. Jun 2021; 100(6): 1569-1577.
  38. Kyriakou C, Canals C, Finke J et al. Allogeneic stem cell transplantation is able to induce long-term remissions in angioimmunoblastic T-cell lymphoma: a retrospective study from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. Aug 20 2009; 27(24):3951-3958.
  39. Ladetto M, De Marco F, Benedetti F, et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: The superior disease control of R-HDS does not translate into an overall survival advantage. Blood. Apr 15 2008; 111(8):4004-4013.
  40. Laport GG. The role of hematopoietic cell transplantation for follicular non-Hodgkin’s lymphoma. Biol Blood Marrow Transplant. Jan 2006; 12:59-65.
  41. Lenz G, Dreyling M, Schiegnitz E, et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low Grade Lymphoma Study Group. Blood. Nov 1 2004; 104(9):2667-2674.
  42. Mamez AC, Dupont A, Blaise D, et al. Allogeneic stem cell transplantation for peripheral T cell lymphomas: a retrospective study in 285patients from the Societe Francophone de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC). J Hematol Oncol. May 19 2020; 13(1): 56.
  43. Maris MB, Sandmaier BM, Storer BE, et al. Allogeneic hematopoietic cell transplantation after fludarabine and two Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood. Dec 01 2004; 104:3535-3542.
  44. Mercadal S, Briones J, Xicoy B et al. Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol 2008; 19(5):958-963. 
  45. Metzner B, Müller TH, Casper J, et al. Long-term outcome in patients with mantle cell lymphoma following high-dosetherapy and autologous stem cell transplantation. Eur J Haematol. Aug 2023; 111(2): 220-228.
  46. Munshi PN, Hamadani M, Kumar A, et al. ASTCT, CIBMTR, and EBMT clinical practice recommendations for transplant and cellular therapies in mantle cell lymphoma. Bone Marrow Transplant. Dec 2021; 56(12): 2911-2921.

  47. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: T-Cell Lymphomas. Version 1.2023. www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf. 
  48. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 6.2023. www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. 
  49. National Cancer Institute. Adult Non-Hodgkin Lymphoma Treatment (PDQ)Health Professional Version. 2022; www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/healthprofessional. 
  50. Olivieri A, Santini G, Patti C, et al. Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: Long-term results by the NHLCSG. Ann Oncol. Dec 2005; 16(12):1941-1948.
  51. Papadopoulos KP, Noguera-Irizarry W, Wiebe L, et al. Pilot study of tandem high-dose chemotherapy and autologous stem cell transplantation with a novel combination of regimens in patients with poor risk lymphoma. Bone Marrow Transplant Sep 2005; 36(6):491-497.
  52. Philip T and Biron P. High-dose chemotherapy and autologous bone marrow transplantation in diffuse intermediate- and high-grade non-Hodgkin lymphoma. Crit Rev Oncol Hematol. Feb 2002; 41(2):213-223.
  53. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. Dec 07 1995; 333(23):1540-1545.
  54. Qualls D, Sullivan A, Li S, et al. High-dose thiotepa, busulfan, cyclophosphamide, and autologous stem cell transplantation as upfront consolidation for systemic non-Hodgkin lymphoma with synchronous central nervous system involvement. Clin Lymphoma Myeloma Leuk. Dec 2017; 17(12):884-888.
  55. Rashidi A, Cashen AF. Outcomes of allogeneic stem cell transplantation in Hepatosplenic T-cell lymphoma. Blood Cancer J. Jun 05 2015; 5(6): e318.
  56. Reimer P. Impact of autologous and allogeneic stem cell transplantation in peripheral T-cell lymphomas. Adv Hematol. 2010:320624.
  57. Rodriguez J, Conde E, Gutierrez A et al. The adjusted International Prognostic Index and beta-2-microglobulin predict the outcome after autologous stem cell transplantation in relapsing/refractory peripheral T-cell lymphoma. Haematologica. Aug 2007; 92(8):1067-1074.
  58. Rodriguez J, Conde E, Gutierrez A, et al. Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: A prospective study from The Gel-Tamo Study Group. Eur J Haematol. Jul 2007; 79(1):32-38.
  59. Satwani P, Jin Z, Martin PL, et al. Sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children, adolescents and young adults with poor-risk refractory or recurrent Hodgkin and non-Hodgkin lymphoma. Leukemia. Feb 2015; 29(2): 448-55.
  60. Schaaf M, Reiser M, Borchmann P et al. High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev. Jan 18 2012; 1:CD007678.
  61. Schmitz N, Truemper L, Bouabdallah K, et al. A randomized phase 3 trial of autologous vs allogeneic transplantation as part of first-line therapy in poor-risk peripheral T-NHL. Blood. May 13 2021; 137(19): 2646-2656.
  62. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized European CUP trial. J Clin Oncol. Nov 01 2003; 21:3918-3927.
  63. Sebban C, Mounier N, Brousse N, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: The GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. Oct 15 2006; 108:2540-2544.
  64. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. Sep 01 2004; 104(5):1258-1265.
  65. Song KW, Mollee P, Keating A et al. Autologous stem cell transplant for relapsed and refractory peripheral T-cell lymphoma: variable outcome according to pathological subtype. Br J Haematol. Mar  2003; 120(6):978-985.
  66. Stiff PJ, Unger JM, Cook JR et al. Autologous transplantation as consolidation for aggressive non- Hodgkin's lymphoma. N Engl J Med. Oct 31 2013; 369(18):1681-1690.
  67. Strubmann T, Fritsch K, Baumgarten A, et al. Favourable outcomes of poor prognosis diffuse large B-cell lymphoma patients treated with dose-dense rituximab, high-dose methotrexate and six cycles of CHOP-14 compared to first-line autologous transplantation. Br J Haematol. Sep 2017; 178(6):927-935.
  68. Sweetenham JW, Santini G, Qian W, et al. High-dose therapy and autologous stem-cell transplantation versus conventional-dose consolidation/maintenance therapy as postremission therapy for adult patients with lymphoblastic lymphoma: Results of a randomized trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group.  J Clin Oncol. Jun 01 2001; 19(11):2927-2936.
  69. Tam CS, Bassett R, Ledesma C et al. Mature results of the MD Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood. Apr 30 2009; 113(18):4144-4152.
  70. Tanase A, Schmitz N, Stein H, et al. Allogeneic and autologous stem cell transplantation for Hepatosplenic T-cell lymphoma: a retrospective study of the EBMT Lymphoma Working Party. Leukemia. Mar 2015; 29(3): 686-8.
  71. Tarella C, Zanni M, Di Nicola M, et al. Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: A multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi).  Leukemia. Aug 2007; 21(8):1802-1811.
  72. Till BG, Gooley TA, Crawford N, et al. Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma. Leuk Lymphoma. Jun 2008; 49(6):1062-1073.
  73. Villanueva ML and Vose JM. The role of hematopoietic stem cell transplantation in non-Hodgkin lymphoma. Clin Adv Hematol Oncol. Jun 2006; 4(7):521-530.
  74. Voss MH, Lunning MA, Maragulia JC, et al. Intensive induction chemotherapy followed by early high-dose therapy and hematopoietic stem cell transplantation results in improved outcome for patients with Hepatosplenic T-cell lymphoma: a single institution experience. Clin Lymphoma Myeloma Leuk. Feb 2013; 13(1): 8-14.
  75. Wang J, Wei L, Ye J, et al. Autologous hematopoietic stem cell transplantation may improve long-term outcomes in patients with newly diagnosed extranodal natural killer/T-cell lymphoma, nasal type: a retrospective controlled study in a single center. Int J Hematol. Jan 2018; 107(1):98-104. 
  76. Wu M, Wang F, Zhao S, et al. Autologous hematopoietic stem cell transplantation improves survival outcomes inperipheral T-cell lymphomas: a multicenter retrospective real-world study. Ann Hematol. Nov 2023; 102(11): 3185-3193.
  77. Zhai Y, Wang J, Jiang Y, et al. The efficiency of autologous stem cell transplantation as the first-line treatment for nodal peripheral T-cell lymphoma: results of a systematic review and meta-analysis. Expert Rev Hematol. Mar 2022; 15(3): 265-272.
  78. Zoellner AK, Unterhalt M, Stilgenbauer S, et al. Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. Sep 2021; 8(9): e648-e657.

POLICY HISTORY:

Medical Policy Group, September 2009 (3)

Medical Policy Administration Committee, September 2009

Available for comment September 18-November 2, 2009

Medical Policy Panel, February 2011

Medical Policy Group, June 2011 (2): Policy, Key Points, References updated

Medical Policy Administration Committee, July 2011

Available for comment, July 6 through August 22, 2011

Medical Policy Group, December 2011(3): 2012 Code Updates- updated 38208, 38209 and 38230 & added 38232

Medical Policy Group, February 2012 (3): 2012 Updates – Policy, Key Points, References

Medical Policy Panel, February 2013

Medical Policy Group, February 2013 (2):  2013 Updates – Description, Key Points and References; no change in policy statement

Medical Policy Panel, February 2014

Medical Policy Group, February 2014 (3):  2014 Updates to Description, Key Points & References; no change in policy statement

Medical Policy Panel, February 2015

Medical Policy Group, February (2): 2015 Updates to Key Points and Coding; no change to policy statement.

Medical Policy Panel, September 2017

Medical Policy Group, October 2017 (7): 2017 Updates to Description, Key Points, Approved by Governing Bodies, and References. Policy Statement- removed policy info from 2011. No change in intent.

Medical Policy Group, December 2017. Annual Coding Update 2018. Added new CPT code 38222 effective 1/1/18 to the Current Coding section.  Updated verbiage for revised CPT codes 38220 and 38221.

Medical Policy Panel, January 2018

Medical Policy Group, January 2018 (7): 2018 Updates to Key Points and References. No change to Policy Statement.

Medical Policy Panel, January 2019

Medical Policy Group, February 2019 (3): 2019 Updates to Key Points, Practice Guidelines and Position Statements, References and Key Words: added: Diffuse Large B-Cell Lymphoma, DLBCL, Mantle Cell Lymphoma, MCL, Peripheral T-Cell Lymphoma, PTCL, Follicular Lymphoma, Hematopoietic Cell Transplantation, HCT, anaplastic large-cell lymphoma, and ALCL. No changes to policy statement or intent. Removed effective for dates of service language from 2012 in the coding section.

Medical Policy Panel, January 2020

Medical Policy Group, March 2020 (3): 2020 Updates to Description, Key Points, Practice Guidelines and Position Statements, References and Key Words: added: Histiocytic Sarcoma, HS. Added Histiocytic Sarcoma to covered diagnoses table. Added Policy Guidelines section. Available for comment March 5, 2020 through April 18, 2020. No changes to policy statement or intent.

Medical Policy Panel, January 2021

Medical Policy Group, February 2021 (3): 2021 Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. Policy statement added to include criteria for patients with Waldenström Macroglobulinemia for both autologous and allogeneic stem cell transplants. Policy statement updated to remove “not medically necessary, “no other changes to policy statement or intent. Key Words added: Waldenström Macroglobulinemia.

Medical Policy Panel, January 2022

Medical Policy Group, January 2022 (3): 2022 Updates to Key Points, Practice Guidelines and Position Statements, and References. No other changes to policy statement or intent.

Medical Policy Panel, February 2023

Medical Policy Group, February 2023 (3): 2023 Updates to Description, Key Points, Practice Guidelines and Position Statements, Benefit Applications, References and Key Words: added: Burkitt Lymphoma, Hepatosplenic T-Cell Lymphoma, HSTCL, Marginal Zone Lymphoma, TEMPI Syndrome, and AESOP Syndrome. Policy statement added to include coverage criteria for patients with Hepatosplenic T-Cell Lymphoma for both autologous and allogeneic stem cell transplants. No other changes to policy statement or intent.

Medical Policy Administration Committee, March 2023

Available for comment March 1, 2023 through April 14, 2023

Medical Policy Panel, January 2024

Medical Policy Group, January 2024 (3): 2023 Updates to Description, Key Points, and References. Policy Guidelines updated clarified information. No change to the policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.