Latest Review Date: January 2024

Category: Surgery                                                                

POLICY:

Effective for dates of service on or after August 28, 2020:

Autologous hematopoietic cell transplantation (HCT) may be medically necessary for treatment of individuals with primary refractory or relapsed Hodgkin lymphoma (HL).

Allogeneic hematopoietic cell transplantation (HCT) using either myeloablative or reduced-intensity conditioning regimens may be medically necessary for the treatment of individuals with primary refractory or relapsed Hodgkin lymphoma (HL).

Tandem autologous HCT is considered investigational in patients with Hodgkin lymphoma.

A second autologous hematopoietic cell transplantation for relapsed lymphoma after a prior autologous HCT is considered investigational.

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

POLICY GUIDELINES:

Hematopoietic cell transplantation refers to any source of stem cells, i.e., autologous, allogeneic, syngeneic, or umbilical cord blood.

*Primary refractory disease is defined as a tumor that does not achieve a complete remission after initial standard-dose chemotherapy.

**Relapse is defined as tumor recurrence after a prior complete response.

Salvage transplantation is defined as a hematologic cell transplantation (HCT), either autologous, allogeneic, or RIC (Reduced Intensity Conditioning)-allogeneic. This treatment is used as a second-line therapy after failure of primary therapy of any type. Salvage transplantation is sometimes referred to as a “rescue” transplant. It implies that the initial therapy has failed. A salvage second HCT is often an autologous HCT if the prior therapy is chemotherapy. If the prior therapy is a failed autologous transplant a salvage second HCT would more likely be an allogeneic HCT or an RIC-allogeneic HCT. Typically, a salvage transplantation is done after enough time has elapsed to identify that the primary therapy was unsuccessful, so the interval between the two transplants would be longer.

Tandem transplantation is defined as a HCT procedure where the initial intent for therapy involves two sequential HCT. The “tandem” involves a very short pre planned interval between the two transplants, as well as the therapeutic intent to do two transplants from the outset of therapy. These may be autologous followed by a second autologous (auto-auto) transplantation, autologous followed by allogeneic (auto-allo) transplantation, or autologous followed by RIC-allogeneic (auto–RIC-allo) transplantation.

In the Morschhauser et al (2008) study of risk-adapted salvage treatment with single or tandem autologous hematopoietic cell transplantation for first relapse or refractory Hodgkin lymphoma, poor-risk relapsed Hodgkin lymphoma was defined as 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV at relapse, and relapse within previously irradiated sites. The primary refractory disease was defined as disease regression less than 50% after 4 to 6 cycles of doxorubicin-containing chemotherapy or disease progression during induction or within 90 days after the end of first-line treatment.

Some individuals for whom a conventional myeloablative allotransplant could be curative may be considered candidates for reduced-intensity conditioning allogeneic hematopoietic cell transplantation. These include those with malignancies that are effectively treated with myeloablative allogeneic transplantation, but whose age (typically >55 or >60 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score) preclude the use of a standard myeloablative conditioning regimen.

The ideal allogeneic donors are human leukocyte antigen-identical matched siblings. Related donors mismatched at a single locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Program is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the individual, with whom usually there is sharing of only three of the six major histocompatibility antigens. Most individuals will have such a donor; however, the risk of graft-versus-host disease and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.

DESCRIPTION OF PROCEDURE OR SERVICE:

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

Hodgkin lymphoma (HL) is a relatively uncommon B-cell lymphoma. In 2023, the estimated number of new cases in the United States was approximately 8830, with 900 estimated deaths. The disease has a bimodal distribution, with most patients diagnosed between the ages of 20 and 39 years, with a second peak in adults aged 65 years and older.

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

1. “Classical” HL (CHL)
   1. Nodular sclerosis
   2. Mixed cellularity
   3. Lymphocyte depleted
   4. Lymphocyte rich
2. Nodular lymphocyte-predominant HL (NLPHL)

In Western countries, CHL accounts for 95% of cases of HL and NLPHL only 5%.  Classic HL is characterized by the presence of neoplastic Reed-Sternberg cells in a background of numerous non-neoplastic inflammatory cells. NLPHL lacks Reed-Sternberg cells, but is characterized by the presence of lymphocytic and histiocytic cells termed “popcorn cells”.

Staging

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

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

Table 1: Ann Arbor Staging System for Hodgkin Lymphoma

Stage	Area of Concern
I	Single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)
II	2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph node(s) with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of lymph node regions involved should be indicated by a subscript (e.g., II2).
III	Involvement of lymph node regions or structures on both sides of the diaphragm, which may involve an extralymphatic organ or site(IIIE), spleen (IIIS), or both (IIIE+S)
IV	Disseminated (multifocal) involvement of 1 or more extralymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement

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

Treatment

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

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

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

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

Hematopoietic Cell Transplantation

Hematopoietic stem-cell transplantation (HCT) refers to a procedure in 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 from a donor (allogeneic HCT). They can be harvested from bone marrow, peripheral blood, or 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. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the Class I and Class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for HCT

Conventional Conditioning

The conventional (“classical”) practice of allogeneic HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect mediated by non-self immunologic effector cells that develop after engraftment of allogeneic stem cells within the individual's bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to individuals who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HSCT, immunosuppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.

The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient prior to undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the individual’s disease is in complete remission. Individuals who undergo autologous HCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.

Reduced-Intensity Conditioning for Allogeneic HCT

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.

Targeted Chemotherapy and Autologous HCT for the Treatment of Hodgkin Lymphoma

A recent important development in the HL treatment landscape is the emergence of several novel agents that are now being used as alternatives to stem cell transplantation in patients at high-risk for relapse after chemotherapy or relapse following autologous HCT. These agents include brentuximab vedotin, a CD30-directed antibody-drug conjugate, and nivolumab and pembrolizumab, which are two programmed death receptor-1 (PD-1) blocking antibodies. The U.S. Food and Drug Administration regulatory status of these agents for the treatment of Hodgkin Lymphoma is summarized in Table 5.

Brentuximab vedotin was evaluated in a large, phase 3, multinational; double blind randomized controlled trial known as the AETHERA trial (abbreviation definition unknown). Moskowitz et al (2015), reported on the outcomes for 329 individuals with HL with risk factors for post-transplantation relapse or progression (e.g., primary refractory HL, relapse <12 months after initial therapy, and/or relapse with extranodal disease). Results showed that early consolidation with brentuximab vedotin after autologous HCT significantly improved 2-year progression-free survival (PFS) versus placebo (63% versus 51%, hazard ratio [HR] 0.57; 95% confidence interval [CI], 0.40-0.81). At 5-year follow-up, the significant PFS benefit for brentuximab vedotin persisted (59% versus 41%; HR 0.52; 95% CI, 0.38 to 0.72). In addition, a study by Smith et al (2018) of tandem autologous HCT observed that the 2-year PFS of 63% for brentuximab vedotin demonstrated in the AETHERA RCT "matches" the 2-year PFS rates for tandem autologous HCT.

A survival benefit with novel agents has been found in the setting of relapse post-autologous HCT. Bair et al (2017) reported a retrospective comparative analysis that evaluated the outcomes of 87 individuals with relapsed/refractory HL who had relapsed post-autologous HCT. Compared to individuals who did not receive any novel agents, those that received novel agents, including brentuximab vedotin or nivolumab, experienced a significant improvement in median overall survival (85.6 versus 17.1 months; P<.001). The availability of safe and effective targeted systemic therapy represents an alternative to the use of a second autologous transplant or planned tandem autologous HCT for HL consolidation treatment or relapse/refractory disease treatment.

KEY POINTS:

The most recent literature review was performed through November 28, 2023.

Summary of Evidence

Autologous Hematopoietic Cell Transplantation

For individuals who have Hodgkin lymphoma who receive autologous hematopoietic cell transplantation (HCT) as initial therapy, the evidence includes randomized controlled trials (RCTs). Relevant outcomes are overall survival (OS), disease-specific survival (DSS), change in disease status, morbid events, and treatment-related mortality and morbidity. RCTs of autologous HCT as first-line treatment have reported that this therapy does not provide additional benefit compared to conventional chemotherapy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have relapsed or refractory Hodgkin lymphoma who receive autologous HCT, the evidence includes RCTs, nonrandomized studies, and case series. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. Two RCTs in patients with relapsed or refractory disease have reported a benefit in progression-free survival and a trend toward a benefit in overall survival. The evidence is sufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have relapsed Hodgkin lymphoma after an autologous HCT who receive a second autologous HCT, the evidence includes case series. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. No RCTs or nonrandomized comparative studies were identified. In one case series, treatment-related mortality at 100 days was 11%; at a median follow-up of 72 months, the mortality rate was 73%. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Allogeneic Hematopoietic Cell Transplantation

For individuals who have Hodgkin lymphoma who receive allo-HCT as initial therapy, the evidence includes no published studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. No studies specifically addressing allo-HCT as first-line treatment for Hodgkin lymphoma were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have relapsed or refractory Hodgkin lymphoma who receive allo-HCT, the evidence includes a number of case series and a meta-analysis. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. A 2016 meta-analysis identified 38 case series evaluating allo-HCT for relapsed or refractory Hodgkin lymphoma. Pooled analysis found a 6-month overall survival rate of 83% and a 3-year overall survival rate of 50%. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsed Hodgkin lymphoma after autologous HCT who receive allo-HCT, the evidence includes case series and a meta-analysis. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. A 2016 meta-analysis of 38 case series found that a previous autologous HCT was significantly associated with higher 1- and 2-year overall survival rates and significantly higher recurrence-free survival rates at 1 year compared with no previous autologous HCT. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsed or refractory Hodgkin lymphoma who receive reduced-intensity conditioning (RIC) with allo-HCT, the evidence includes case series, cohort studies, and a systematic review. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. A 2015 systematic review cited a number of studies, including some with comparison groups, showing acceptable outcomes after RIC allo-HCT in patients with relapsed or refractory Hodgkin lymphoma. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Tandem Autologous Hematopoietic Cell Transplantation

For individuals who have Hodgkin lymphoma who receive tandem autologous HCT, the evidence includes nonrandomized comparative studies and case series. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. One prospective, nonrandomized study reported that, in patients with poor prognostic markers, response to tandem autologous HCT may be higher than that for single autologous HCT. This study is not definitive due to potential selection bias, and RCTs are needed to determine the impact of tandem autologous HCT on health outcomes in this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Practice Guidelines and Position Statements

American College of Radiology

In 2016, the American College of Radiology issued Appropriateness Criteria on recurrent HL. The criteria stated that while salvage therapy followed by autologous HCT is standard of care for relapsed HL, alternative therapies might be considered in select patients. For example, there is evidence that in patients with small isolated relapses occurring more than 3 years after initial presentation, a course of radiotherapy or combined modality therapy without autologous HCT may be considered. Also, radiotherapy may be considered as part of combined modality therapy for patients with local relapse after treatment with chemotherapy alone or for relapses outside the original site of disease.

American Society for Transplantation and Cellular Therapy

In 2015, guidelines were published by the American Society for Blood and Marrow Transplantation (now referred to as the American Society for Transplantation and Cellular Therapy) on indications for autologous and allogeneic HCT. These guidelines were updated in 2020. Recommendations described the current consensus on the use of HCT in and out of the clinical trial setting. The 2015 and 2020 Society recommendations on HL are provided in Table 2.

Table 2. Recommendations for Use of HCT to Treat Hodgkin Lymphoma

Indication	Allogeneic HCT (2015 recommendation)	Allogeneic HCT (2020 recommendation)	Autologous HCT (2015 recommendation)	Autologous HCT (2020 recommendation)
Adult
First complete response (PET negative)	Not generally recommended	Not generally recommended	Not generally recommended	Not generally recommended
First complete response (PET positive)	Not generally recommended	Subsection removeda	Standard of care, clinical evidence available	Subsection removeda
Primary refractory, sensitive	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Standard of care	Standard of care
Primary refractory, resistant	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Not generally recommended	Not generally recommended
First relapse, sensitive	Standard of care	Standard of care	Standard of care	Standard of care
First relapse, resistant	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Not generally recommended	Not generally recommended
Second or greater relapse	Standard of care, clinical evidence available	Standard of care	Standard of care	Standard of care
Relapse after autologous transplant	Standard of care, clinical evidence available	Standard of care	Not generally recommended	Not generally recommended
Pediatric
First complete response	Not generally recommended	Not generally recommended	Not generally recommended	Not generally recommended
Primary refractory, sensitive	Standard of care, clinical evidence available	Not generally recommended	Standard of care, clinical evidence available	Standard of care, clinical evidence available
Primary refractory, resistant	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Not generally recommended	Not generally recommended
First relapse, sensitive	Standard of care, clinical evidence available	Not generally recommended	Standard of care, clinical evidence available	Standard of care
First relapse, resistant	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Not generally recommended	Not generally recommended
Second or greater relapse	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Standard of care, clinical evidence available

HCT: hematopoietic cell transplantation; PET: positron emission tomography.

aSubsection on positron emission tomography positive complete remission was removed because updated response criteria for these lymphoma essentially require normalization of [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography to be assessed as a first complete remission.

In 2015, ASBMT published guidelines on the role of cytotoxic therapy with HCT in individuals with Hodgkin Lymphoma. Select recommendations are shown in Table 3.

Table 3: ASBMT Recommendations on Cytotoxic Therapy With HCT for Hodgkin Lymphoma

Recommendation	Grade	Highest LOE
Autologous HCT
ASCT should not be offered as first-line therapy for advanced disease	A	1+
ASCT should be offered as first-line therapy for patients who fail to achieve CR	B	2++
ASCT should be offered as salvage therapy over non-transplantation (except localized disease or in patients with low-stage disease)	A	1+
ASCT should be offered to pediatric patients with primary refractory disease or high-risk relapse who respond to salvage therapy	B	2++
Tandem ASCT is not routinely recommended in standard-risk patients	C	2+
Allogeneic HCT
Allo-HCT should be used for relapse after ASCT instead of conventional therapy	B	2++
RIC is the recommended regimen intensity	B	2++
All donor sources can be considered	A	1+
There are limited data for tandem ASCT/Allo-HCT	D	4
Allo-HCT is preferred over ASCT as second HCT (except in late relapse)	C	2+

allo: allogeneic; ASCT: autologous stem cell transplant; CR: Complete response; HCT: hematopoietic cell transplantation; LOE: level of evidence; RIC: reduced-intensity conditioning.

National Comprehensive Cancer Network (NCCN) Guidelines

Current National Comprehensive Cancer Network guidelines for Hodgkin lymphoma HL (v.1.2024) include a recommendation for autologous or allogeneic hematopoietic cell transplantation (HCT) in patients with biopsy-proven refractory disease who have undergone second-line systemic therapy and are Deauville stage 5 according to restaging based on findings from positron emission tomography or computed tomography. Additionally, in patients with biopsy-proven refractory disease who have undergone second-line systemic therapy and are Deauville stage 1-3 according to restaging based on findings from positron emission tomography or computed tomography, high-dose therapy and autologous stem cell rescue plus either observation or brentuximab vendotin for 1 year is recommended for patients with high-risk of relapse.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Hematopoietic Stem-Cell Transplantation, Hodgkin Lymphoma, High-Dose Chemotherapy, Hodgkin’s Disease, Stem-Cell Transplant; Nodular lymphocyte-predominant HL (NLPHL), HCT

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.

Table 4  describes several novel agents that have been approved by the U.S. FDA for use as alternatives to tandem autologous HCT or a second autologous HCT in individuals at high-risk for, or with, respectively, refractory or relapsed HL following autologous HCT.

Table 4. Novel agents Approved by the U.S. Food and Drug Administration (FDA)

Drug	BLA	Type of Agent	Manufacturer	FDA-Approved Indications for Post-Autologous HCT Use	Date FDA Approved
Brentuximab vedotin	125388	CD30-directed antibody-drug conjugate	Seattle Genetics	Classical HL at high risk of relapse or progression as post-autologous HCT consolidation Classical HL after failure of autologous hematopoietic stem cell transplantation	Aug 2015
Nivolumab	125554	Programmed death receptor-1 (PD-1) blocking antibody	Bristol Myers Squibb	Classical HL that has relapsed or progressed after autologous HCT and post transplantation brentuximab vedotin	May 2016
Pembrolizumab	125514	Programmed death receptor-1 (PD-1) blocking antibody	Merck Sharp Dohme	Adult and pediatric patients with refractory classical HL, or who have relapsed after 3 or more prior lines of therapy	Mar 2017

BLA: Biologic License Application; FDA: U.S. Food and Drug Administration; HL: Hodgkin Lymphoma; HCT: Hematopoietic Cell Transplantation

aIn the pivotal trial, a multicenter, nonrandomized, open-label study, prior lines of therapy included prior autologous HCT (61%) and brentuximab (83%)

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 within 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	Bone marrow harvesting for transplantation; autologous
38240	Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic
38241	; autologous
86812-86821	Histocompatibility studies code range (e.g., for allogeneic transplant)

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)

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20. Perales MA, Ceberio I, Armand P, et al. Role of cytotoxic therapy with hematopoietic cell transplantation in the treatment of Hodgkin lymphoma: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Jun 2015; 21(6):971-983
21. Rancea M, von Tresckow B, Monsef I et al. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed or refractory Hodgkin lymphoma: a systematic review with a meta-analysis. Crit Rev Oncol Hematol. Oct 2014; 92(1):1-10.
22. Rashidi A, Ebadi M, Cashen AF. Allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma: a systematic review and meta-analysis. Bone Marrow Transplant. Apr 2016; 51(4):521-528.
23. Schmitz N, Dreger P, Glass B, et al. Allogeneic transplantation in lymphoma: current status. Haematologica. Nov 2007; 92(11): 1533-1548.
24. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous hemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: A randomized trial.  Lancet. Jun 15 2002; 359(9323): 2065-2071.
25. Schmitz N, Sureda A and Robinson S. Allogeneic transplantation of hematopoietic stem cells after nonmyeloablative conditioning for Hodgkin’s disease: Indications and results. Semin Oncol. Feb 2004; 31(1): 27-32.
26. Seftel M and Rubinger M. The role of hematopoietic stem cell transplantation in advanced Hodgkin lymphoma. Transfus Apher Sci. Aug 2007; 37(1): 49-56.
27. Sibon D, Morschhauser F, Resche-Rigon M, et al. Single or tandem autologous stem-cell transplantation for first-relapsed or refractory Hodgkin lymphoma: 10-year follow-up of the prospective H96 trial by the LYSA/SFGM-TC study group. Haematologica. Apr 2016; 101(4): 474-81.
28. Smith EP, Li H, Friedberg JW, et al. Tandem Autologous Hematopoietic Cell Transplantation for Patients with Primary Progressive or Recurrent Hodgkin Lymphoma: A SWOG and Blood and Marrow Transplant Clinical Trials Network Phase II Trial (SWOG S0410/BMT CTN 0703). Biol Blood Marrow Transplant. Apr 2018; 24(4): 700-707.
29. Smith SM, van Besien K, Carreras J, et al. Second autologous stem cell transplantation for relapsed lymphoma after a prior autologous transplant. Biol Blood Marrow Transplant. Aug 2008; 14(8): 904-912.
30. Sureda A, Canals C, Arranz R et al. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma. Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Espanol de Linfomas/Trasplante de Medula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. Feb 2012; 97(2):310-317.
31. Sureda A, Robinson S, Canals C, et al. Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. Jan 20 2008; 26(3): 455-462.
32. Swerdlow S, Campo E, Harris N et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4 ed. Lyon France: IARC; 2008.
33. Todisco E, Castagna L, Sarina B, et al. Reduced-intensity allogeneic transplantation in patients with refractory or progressive Hodgkin’s disease after high-dose chemotherapy and autologous stem cell infusion. Eur J Haematol. Apr 2007; 78(4): 322-329.
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POLICY HISTORY:

Medical Policy Group, January 2010 (2)

Medical Policy Administration Committee, January 2010

Available for comment January 26-March 11, 2010

Medical Policy Group, November 2010 (1) Key Points updated and references, no policy changes

Medical Policy Group, December 2011 (3): 2012 Code Updates: Verbiage change to codes 38208, 38209 & 38230 & added code 38323

Medical Policy Panel, November 2012.

Medical Policy Group, January 2013 (3): Update to Key Points and References

Medical Policy Panel, December 2013

Medical Policy Group, January 2014 (3):  2013 Updates to Key Points and Reference; no change in policy statement

Medical Policy Panel, December 2014

Medical Policy Group, January 2014 (3): Updates to Key Points; no change in policy statement

Medical Policy Panel, January 2016

Medical Policy Group, February 2016 (2): Updates to Key Points and References. Created previous coding section and added G0265-G0267 to this section. No change to policy statement.

Medical Policy Panel, January 2017

Medical Policy Group, March 2017 (7): 2017 Updates to Title, Key Points and References. Policy statement reworded for clarification. No change in intent.  Previous Coding section deleted.

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. Created Previous Coding section and moved deleted CPT code 86822 to this section.

Medical Policy Panel, February 2018

Medical Policy Group, March 2018 (7): 2018 Removed “Stem” from Title. Updates to Description, Key Points and References. No change in Policy Statement.

Medical Policy Panel, January 2019

Medical Policy Group, February 2019 (3): 2019 Updates to Description, Key Points, Practice Guidelines and Position Statements, References, and Key Words: added: Nodular lymphocyte-predominant HL (NLPHL) and HCT. No change to policy statement or intent.

Medical Policy Panel, January 2020

Medical Policy Group, March 2020 (3): 2020 Updates to Key Points, Practice Guidelines and Position Statements, and References. Added Policy Guidelines section. No changes to policy statement or intent.

Medical Policy Panel, June 2020

Medical Policy Group, July 2020 (3): 2020 Updates to Description, Key Points, Practice Guidelines and Position Statements, Approved by Governing Bodies, and References. Policy statement changed to Investigational for tandem autologous HCT in patients with Hodgkin lymphoma. Placed on DRAFT July 14, 2020 through August 27, 2020.

Medical Policy Panel, January 2021

Medical Policy Group, February 2021 (3): Updates to Description and Key Points.

Medical Policy Panel, January 2022

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

Medical Policy Panel, January 2023

Medical Policy Group, January 2023 (3): 2023 Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. No changes to policy statement or intent.

Medical Policy Panel, January 2024

Medical Policy Group, January 2024 (3): Updates to Description, Key Points, Benefit Application, References, Policy statement and Policy Guidelines verbiage updated -change patients to individuals. Policy statements effective for dates of service March 11, 2010- August 28, 2020 were removed. No changes to 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.