Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

High dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is included in the term HDC when applicable. HDC results in marrow ablation and thus HDC is accompanied by a reinfusion of stem cells in order to repopulate the bone marrow.

Sources of Stem Cells:

Hodgkin Lymphoma

Hodgkin lymphoma (HL) is a relatively uncommon B-cell lymphoma. In 2022, the estimated number of new cases in the United States was approximately 8540, with 920 estimated deaths (NCI, 2022). 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 classification divided HL into 2 main types; these classifications did not change in the 2022 update (Swerdlow, 2008; Alaggio, 2022):

In Western countries, “classical” HL accounts for 95% of cases of HL and, for nodular lymphocyte-predominant HL, only 5% (NCCN, 2022). “Classical” HL is characterized by the presence of neoplastic Reed-Sternberg cells in a background of numerous non-neoplastic inflammatory cells. Nodular lymphocyte-predominant HL lacks Reed-Sternberg cells but is characterized by the presence of lymphocytic and histiocytic cells termed “popcorn cells”.

The Ann Arbor staging system for HL 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 patients with localized HL who can be treated with extended field radiation from those who require systemic chemotherapy.

Each stage is subdivided into A and B categories. “A” indicates no systemic symptoms are present and “B” indicates the presence of systemic symptoms, which include unexplained weight loss of more than 10% of body weight, unexplained fevers >38°C, or drenching night sweats (NCCN, 2022).

Ann Arbor Staging System for Hodgkin Lymphoma

Stage I - Single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)

Stage 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).

Stage 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)

Stage 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

Patients 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) (NCCN, 2022).

Patients with nonbulky stage IA or IIA disease are considered to have the clinically early-stage disease. These patients are candidates for chemotherapy, combined modality therapy, or radiotherapy alone (ACS, 2018). Patients with obvious stage III or IV disease, bulky disease (defined as a 10-cm mass or mediastinal disease with a transverse diameter >33% of the transthoracic diameter), or the presence of B symptoms will require combination chemotherapy with or without additional radiotherapy.

Hodgkin lymphoma is highly responsive to conventional chemotherapy, and up to 80% of newly diagnosed patients can be cured with chemotherapy and/or radiotherapy. Patients who prove refractory or who relapse after first-line therapy have a significantly worse prognosis. Primary refractory 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 the first-line treatment (Brice, 2008).

In patients with relapse, the results of salvage therapy vary depending on a number of prognostic factors, as follows: the length of the initial remission, stage at recurrence, and the severity of anemia at the time of relapse (Schmitz, 2004). 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 hematopoietic cell transplantation (HCT) but not more than 40% with early first relapse (Schmitz, 2007).

Only 25% to 35% of patients 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 1 to 2 years, and once relapse occurs posttransplant, median survival is less than 12 months.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT [allo-HCT]). These cells can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. Human leukocyte antigen refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by the cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease (GVHD), which increases susceptibility to opportunistic infections.

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

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Reduced-intensity conditioning regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term RIC will refer to all conditioning regimens intended to be nonmyeloablative.

Regulatory Status

The FDA 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.

Reimbursement for high dose chemotherapy (HDC) with stem and/or progenitor cell transplant that has been pre-authorized is made as a global fee limited to the lesser of billed charges or the average allowable charge authorized by the Blue Quality Centers for Transplant in the geographic region where the transplant is performed. This global payment includes all related transplant services including institutional, professional, ancillary, and organ procurement. The global period begins one day prior to the date of the transplant and continues for 48 days after the transplant. This covers the inpatient/outpatient stay and provides a per diem outlier payment if necessary. This global fee also includes the cost of complications arising from the original procedure when services are rendered within the global postoperative period for the particular transplant.

Effective December 2020

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

High dose chemotherapy with autologous bone marrow, stem cell, or progenitor cell support for the treatment of Hodgkin's disease meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for patients with:

Tandem autologous stem cell transplant meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

High dose chemotherapy and stem cell rescue for the initial treatment of Hodgkin's disease does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For member with contracts without primary coverage criteria, high dose chemotherapy and stem cell rescue for the initial treatment of Hodgkin's disease is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.

Effective prior to December 2020

High dose chemotherapy with autologous bone marrow, stem cell, or progenitor cell support for the treatment of Hodgkin's disease meets primary coverage criteria for effectiveness and is covered for patients with:

Tandem autologous stem cell transplant meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:

High dose chemotherapy and stem cell rescue, for the initial treatment of Hodgkin's disease, is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For contracts without primary coverage criteria, high dose chemotherapy and stem cell rescue, for the initial treatment of Hodgkin's disease is considered investigational and is not covered. Investigational services are exclusions in the member certificate of coverage.

Effective prior to December 2011

Tandem transplants are not covered based on a specific exclusion in the member benefit contract.

Initially, this policy focused on high-dose therapy plus autologous stem-cell support and high-dose therapy plus allogeneic stem-cell support. Each report concluded that data showed longer survival of patients with relapsed disease after transplants than after standard therapy. Allogeneic stem cells may be preferred over autologous stem cells, if the relapse occurs in the bone marrow.

Literature focused on HDC and allogeneic stem-cell support after a prior failed course of high-dose chemotherapy and autologous stem-cell support, as treatment for various malignancies including Hodgkin’s disease, found that data were inadequate to permit conclusions about outcomes of this treatment strategy.

A review of the literature performed in November 2002 identified 4 randomized trials on patients with Hodgkin’s disease. Only 1 of these studies compared outcomes of conventional dose chemotherapy with outcomes of high-dose chemotherapy plus stem-cell support. Entered into the trial were 166 patients with relapsed Hodgkin’s disease. Patients were randomized at entry to conventional-dose therapy (DEXA-BEAM; dexamethasone, carmustine, etoposide, cytarabine, and melphalan) or HDC with autologous stem-cell support (BEAM-ASCS). After randomization, patients underwent 2 cycles of DEXA-BEAM; responding patients then proceeded to 2 more courses of DEXA BEAM or to BEAM-ASCS. With a median follow-up of 39 months, freedom from treatment failure was significantly better after HDC than after conventional-dose chemotherapy. Subgroup analyses showed improved survival after transplant for patients treated in early first relapse (<12 months), late first relapse (>12 months), and second or subsequent relapse. No difference was reported for overall survival, although such a difference might become apparent with longer follow-up (median survival had not yet been reached in either arm).

Although the duration of first remission remains a strong prognostic factor predicting outcome of both conventional and high-dose therapy for relapse, there is consensus across recent authoritative reviews, historical cohort comparisons, and clinical series that patients treated with high dose therapy tend to fare better overall than those managed with conventional dose regimens, regardless of the duration of remission. Therefore, the policy statement is changed and now suggests that HDC may be considered medically necessary for any patient with relapsed Hodgkin’s disease, regardless of the length of remission.

The updated literature search identified few reports on outcomes of HDC with stem-cell support for up front treatment of Hodgkin’s disease, or to consolidate a complete response to initial induction therapy. These were all uncontrolled clinical series and are inadequate to permit conclusions. In addition, the literature was inadequate regarding the role of HDC with allogeneic stem-cell support as a treatment of Hodgkin’s disease relapsing after HDC with autologous stem cell support.

Allotransplants after a failed autotransplant

The literature search found no prospective controlled studies comparing allotransplants to alternative strategies for managing failure (progression or relapse) after an autotransplant for Hodgkin’s disease. Only 3 reports that included patients with Hodgkin’s disease have been published since the 2000 Blue Cross Blue Shield Association Technology Evaluation Center Assessment on this topic. Two series included 1 patient each who relapsed after an autotransplant, while a third series included 6 patients. The scant new data clearly are insufficient to change conclusions of the prior assessment. Note also that highly selected patients with Hodgkin’s disease that has relapsed after an autotransplant reportedly can achieve complete responses and long-term disease-free survival after a second autotransplant.

The paucity of outcomes data for allotransplants after a failed autotransplant is not surprising. Patients usually are considered ineligible for this option either because their relapsed lymphoma progresses too rapidly, poor health status increases the likelihood of adverse outcomes, or they lack a well-matched donor. A few institutions have treated up to 15 or 20 such (Hodgkin’s plus non-Hodgkin’s) lymphoma patients in the last 1 to 2 decades. Thus, it appears highly unlikely that adequately powered randomized trials comparing this therapy to alternatives could ever be conducted, even by a multi-institutional group. Nevertheless, several institutions report that a minority of patients achieved long-term disease-free survival following an allotransplant for Hodgkin’s disease that relapsed after an autotransplant. Factors that apparently increase the likelihood of survival include a chemosensitive relapse, younger age, longer disease-free interval since the prior autotransplant, availability of an HLA-identical sibling donor, and fewer chemotherapy regimens prior to the failed autotransplant. Thus, clinician judgment confirmed by external review can play an important role in selecting patients for this treatment with a reasonable likelihood that potential benefits may exceed harms.

2006-2007 Update

Updated MEDLINE searches identified no clinical trial publications that would alter the above conclusions. Therefore, the policy statement is unchanged. A study published by Federico and colleagues concluded that HDC with autologous stem-cell transplantation offered no benefit in outcomes over conventional chemotherapy in front-line therapy for advanced Hodgkin's lymphoma patients. This supports the above policy statement indicating HDC as initial or upfront therapy is investigational.

The 2006 National Comprehensive Cancer Network (NCCN) guidelines on Hodgkin's disease recommend HDC with autologous stem-cell support for relapsed or refractory disease consistent with this policy.

This update focuses on tandem autologous stem-cell transplants.

Fung and colleagues reported results from a pilot study to evaluate the toxicities and efficacy of tandem autologous HSCT in patients with primary refractory or poor risk recurrent HL (Fung, 2007). The study involved 28 patients with primary progressive and 18 with recurrent HL who were enrolled in the study between April 1998 and March 2000. Patients had at least one of the following poor prognostic factors: first CR less than 12 months, extranodal disease, or B symptoms at relapse. Forty-one patients (89%) received the second transplant. With a median follow-up of 5.3 years (range, 1.6-8.1), the 5-year OS and PFS were 54% (95% CI: 40–69%) and 49% (95% CI: 34–63%), respectively.

Morschhauser and colleagues reported on the results of a multicenter prospective trial that evaluated a risk-adapted salvage treatment with single or tandem autologous HSCT in 245 patients with relapsed/refractory HL (Morschhauser, 2008). Median follow-up time was 51 months (range, 20–110 months). Patients who were categorized as poor risk (n=150) had primary refractory disease (n=77) or 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV disease at the time of relapse, or relapse occurring within previously irradiated sites (n=73). In this study, these poor-risk patients were eligible for tandem autologous transplants. Intermediate-risk patients (n=95), defined as 1 risk factor at relapse, were eligible for a single transplant. Overall, 70% of the poor-risk patients received tandem transplants, and 97% of the intermediate-risk patients received a single transplant.

Overall, 94 poor-risk patients responded to cytoreductive chemotherapy (partial response [PR] or CR), whereas 55 patients had chemotherapy-resistant disease. A total of 137 patients (including the 94 patients with chemotherapy-sensitive disease and 43 of 55 with chemotherapy–resistant disease) received the first autologous HSCT. Among 121 patients who were fully restaged, 64 patients had achieved a CR, 37 a PR, and 4 had stable disease. These 105 patients then underwent the second autologous HSCT after a median of 65 days. Among them, 80 patients achieved a CR, including 17 patients who had achieved PR, and 3 patients with stable disease after the first transplant. Among the 55 patients who had cytoreduction failure, 30 responded to the first transplant (9 with CR), and 17 achieved CR after the second transplant.

Outcome analysis based on the intent-to-treat sample showed 5-year freedom from second failure and OS were 73% and 85% for the intermediate-risk group and 46% and 57% for the poor-risk group, all respectively.

In the poor-risk group, patients who underwent tandem transplant and had a complete response to cytoreduction chemotherapy did not have superior outcomes compared to complete responders receiving a single transplant in previous studies (Ferme, 2002). However, in this study, poor-risk patients who were partial responders who underwent tandem transplants did better when compared to partial responders who received a single transplant in previous studies. In this study, 5-year OS rates for poor-risk patients who completed the tandem transplant were 79% and 73% for complete and partial responders, whereas in a previous trial of single autologous HSCT, 5-year OS rates were 86% and 37% for complete and partial responders, respectively (Ferme. 2002). The authors concluded that a single autologous HSCT is appropriate for intermediate-risk patients and for poor-risk patients who are complete responders to cytoreductive chemotherapy but that tandem autologous HSCT showed a benefit in patients with chemotherapy-resistant disease and in partial responders to cytoreductive conditioning. The authors stated that a trial of random assignment of single versus tandem autologous HSCT was unrealistic, given the low yearly incidence of poor-risk patients, and that the best possible comparisons are with data from previous findings with single transplants.

A search of the MEDLINE database through September 2012 did not reveal any new information that would prompt a change in the coverage statement.

A search of the MEDLINE database was conducted through September 2013. There was no new information that would prompt a change in the coverage statement.

A literature search conducted through November 2014 did not reveal any new information that would prompt a change in the coverage statement.

A literature search was conducted using the MEDLINE database through November 2017. There was no information identified that would prompt a change in the coverage statement.

Practice Guidelines And Position Statements

American Society for Blood and Marrow Transplantation

In 2015, guidelines were published by the American Society for Blood and Marrow Transplantation (ASBMT) on indications for autologous and allogeneic HCT (Majhail, 2015). Recommendations described the current consensus on use of HCT within and outside of the clinical trial setting. Recommendations are graded : Standard of Care (S); Clinical Evidence Available (C); and Not generally recommended (N). ASBMT recommendations on Hodgkin lymphoma are provided below.

ASBMT Recommendations for Treating Hodgkin Lymphoma (Majhail, 2015)

Standard of Care (S)

Autologous HCT for primary refractory, sensitive

Autologous HCT or Allogeneic HCT for first relapse, sensitive

Autologous HCT for second or greater relapse

Clinical Evidence Available (C)

Autologous HCT for first complete response (PET+)

Autologous HCT for primary refractory, sensitive

Autologous HCT for primary refractory resistant

Allogeneic HCT for first relapse, resistant

Allogeneic HCT for second or greater relapse

Allogeneic HCT for relapse after autologous transplant

Not Generally Recommended (N)

Allogeneic & Autologous HCT for First complete response (PET -)

Allogeneic HCT for First complete response (PET +)

Autologous HCT for primary refractory resistant

Autologous HCT for first relapse, resistant

Autologous HCT for relapse after autologous transplant

Standard of Care (S)

Clinical Evidence Available (C)

Allogeneic & Autologous HCT for primary refractory, sensitive

Allogeneic for primary refractory resistant

Allogeneic & Autologous HCT for first relapse, sensitive

Allogeneic HCT for first relapse, resistant

Allogeneic & Autologous HCT for second or greater relapse

Not Generally Recommended (N)

Allogeneic & Autologous HCT for first complete response

Autologous HCT for primary refractory, resistant

Autologous HCT for first relapse, resistant

European Society for Medical Oncology

In 2014, the European Society for Medical Oncology published guidelines on the diagnosis and treatment of Hodgkin lymphoma (Eichenauer, 2014). The guidelines stated: “The standard of care for most patients with disease recurrence after first-line treatment consists of high-dose chemotherapy followed by autologous stem cell transplantation (ACT).”

A literature search was conducted through November 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

American College of Radiology

The American College of Radiology issued an Appropriateness Criteria on recurrent HL (ACR, 2016). The criteria stated that while salvage therapy followed by autologous HCT is standard of care for relapsed HL, alternative therapies may 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 of the original site of disease.

Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

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.

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 reported on the outcomes for 329 individuals with HL with risk factors for post-transplantation relapse or progression (eg, primary refractory HL, relapse <12 months after initial therapy, and/or relapse with extranodal disease) (Moskowitz, 2015). 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) (Moskowitz, 2018). In addition, a recent study by Smith et al 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 (Smith, 2018).

A survival benefit with novel agents has been found in the setting of relapse post-autologous HCT. Bair et al reported a retrospective comparative analysis that evaluated the outcomes of 87 individuals with relapsed/refractory HL who had relapsed post-autologous HCT (Bair, 2017). 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.

No RCTs have compared tandem autologous HCT with other standard of care therapies. One prospective, nonrandomized study has compared tandem to single autologous HCL for HL. Morschhauser et al and Sibon et al reported on the results of a prospective multicenter trial that evaluated a risk-adapted salvage treatment with single or tandem autologous HCT in 245 patients with relapsed or refractory HL (Morschhauser, 2008; Sibon, 2016). Median follow-up time in the initial publication by Morschhauser et al was 51 months (range, 20-110 months). Sibon et al reported on the 10-year follow-up. Patients categorized as poor-risk (n=150) had the primary refractory disease (n=77) or 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV disease at the time of relapse, or relapse in previously irradiated sites (n=73). In this trial, these poor-risk patients were eligible for tandem autologous transplants. Intermediate-risk (n=95) patients, defined as 1 risk factor at relapse, were eligible for a single transplant. Overall, 70% of the poor-risk patients received tandem transplants, and 97% of the intermediate-risk patients received a single transplant.

Ninety-four poor-risk patients responded to cytoreductive chemotherapy (partial or CR), whereas 55 patients had the chemotherapy-resistant disease. A total of 137 patients (including the 94 patients with chemotherapy-sensitive disease and 43 of 55 with the chemotherapy-resistant disease) received the first autologous HCT. Among 121 patients who were fully restaged, 64 patients had achieved a complete response, 37 a partial response, and 4 had stable disease. These 105 patients then underwent a second autologous HCT after a median of 65 days. Among them, 80 patients achieved a complete response, including 17 patients who had achieved partial response and 3 patients with stable disease after the first transplant. Among the 55 patients who had cytoreduction failure, 30 responded to the first transplant (9 with complete response), and 17 achieved a complete response after the second transplant. Outcome analysis based on the intention-to-treat sample revealed the 5-year freedom from the second failure and OS estimates were 73% and 85% for the intermediate-risk group and 46% and 57% for the poor-risk group, all respectively. At the 10-year follow-up reported by Sibon et al, freedom from second failure and OS rates were 64% (95% CI, 54% to 74%) and 70% (95% CI, 61% to 80%) for the intermediate-risk group, and 41% (95% CI, 33% to 49%) and 47% (95% CI, 39% to 55%) for the poor-risk group (Sibon, 2016).

In the poor-risk group, patients who underwent tandem transplant and had a CR to cytoreduction chemotherapy did not have superior outcomes compared with complete responders receiving a single transplant in previous studies by the same group (Ferme, 2002). However, in this 2002 study, poor-risk patients who were partial responders and underwent tandem transplants did better compared with partial responders who received a single transplant in previous studies. In this study, 5-year OS rates for poor-risk patients who completed the tandem transplant were 79% and 73% for complete and partial responders, whereas, in a previous trial of single autologous HCT, 5-year OS rates were 86% and 37% for complete and partial responders, all respectively (Ferme, 2002). The findings suggested that a single autologous HCT would be appropriate for intermediate-risk patients and for poor-risk patients who are complete responders to cytoreductive chemotherapy but that tandem autologous HCT showed a benefit in patients with chemotherapy-resistant disease and in partial responders to cytoreductive conditioning. The authors concluded that a trial, randomizing patients to single vs tandem autologous HCT was unrealistic, given the low yearly incidence of poor-risk patients; in their estimation, the best possible comparisons would be with data from previous findings with single transplants.

Tandem autologous HCL for HL has also been evaluated in single-arm studies. Fung et al reported results from a pilot study on HL that evaluated the toxicities and efficacy of tandem autologous HCT in patients with primary refractory or poor-risk recurrent HL (Fung, 2007). The study involved patients with primary progressive and 18 with recurrent HL who were enrolled in the study between 1998 and 2000. Patients had at least one of the following poor prognostic factors: first CR less than 12 months, extranodal disease, or B symptoms (presence of systemic symptoms) at relapse. Forty-one (89%) patients received the second transplant. With a median follow-up of 5.3 years (range, 1.6-8.1 years), the 5-year OS and PFS rates were 54% (95% CI, 40% to 69%) and 49% (95% CI, 34% to 63%), respectively. Additionally, Smith et al reported results from a more recent Phase II trial of 89 patients with primary progressive or recurrent HL conducted by the Southwest Oncology Group (SWOG) Clinical Trials Network (Smith, 2018). This single-arm trial was conducted at 10 centers and enrolled patients between 2006 and 2009. Key patient characteristics included that 53% had induction failure, 18% had initial response of ≤ 12 months, 83% were stage III or IV at the time of trial enrollment, and 48% previously irradiated patients relapsed in an irradiated site. Eighty-two patients (92%) received the second transplant. With a median follow-up of 6.2 years, the 5-year PFS and OS rates were 55% (95% CI: 44%–64%) and 84% (95% CI: 74%–90%).

Current National Comprehensive Cancer Network guidelines for Hodgkin lymphoma (HL; v.2.2020) include a recommendation for autologous or allogeneic 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 (NCCN, 2020). 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.

Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

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 (Majhail, 2015). These guidelines were updated in 2020 (Kanate, 2020). Recommendations described the current consensus on the use of HCT in and out of the clinical trial setting.

2020 Recommendations for use of Autologous HCT to Treat Hodgkin Lymphoma:

Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

A retrospective observational cohort study by Merryman et al evaluated autologous HCT after anti-programmed death-1 (PD-1) therapy for patients with relapsed or refractory HL (Merryman, 2021). Seventy-eight patients were identified who underwent autologous HCT as a third-line (or later) treatment; 74% of patients underwent autologous HCT after anti-PD-1 treatment and 26% of patients received anti-PD-1 treatment along with additional therapy prior to autologous HCT. The 18-month PFS and OS after autologous HCT were 81% (95% CI, 69 to 89) and 96% (95% CI, 87 to 99), respectively. Favorable outcomes were reported for patients who had received greater than 4 systemic therapies before autologous HCT (18-month PFS, 73%), who were refractory to 2 consecutive therapies immediately prior to anti-PD-1 treatment (18-month PFS, 78%), and who had positive pre-HCT positron emission tomography (PET) (18-month PFS, 75%); patients who were non-responders to anti-PD-1 treatment had inferior outcomes (18-month PFS, 51%).

Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement.

	HDC & Autologous Stem &/or Progenitor Cell Support-Hodgkin's Disease

Description:	High dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is included in the term HDC when applicable. HDC results in marrow ablation and thus HDC is accompanied by a reinfusion of stem cells in order to repopulate the bone marrow. Sources of Stem Cells: Autologous stem cells may be harvested from the patient's bone marrow or peripheral blood. Peripheral cells are harvested via one or more pheresis procedures. Pretreatment with chemotherapy and/or hemapoietic growth factors can increase the number of circulating stem cells. Syngeneic stem cells refer to genetically identical bone marrow or peripheral stem cells harvested from an identical twin. Hodgkin Lymphoma Hodgkin lymphoma (HL) is a relatively uncommon B-cell lymphoma. In 2022, the estimated number of new cases in the United States was approximately 8540, with 920 estimated deaths (NCI, 2022). 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 classification divided HL into 2 main types; these classifications did not change in the 2022 update (Swerdlow, 2008; Alaggio, 2022): "Classical" HL Nodular sclerosis Mixed cellularity Lymphocyte depleted Lymphocyte-rich Nodular lymphocyte-predominant HL. In Western countries, “classical” HL accounts for 95% of cases of HL and, for nodular lymphocyte-predominant HL, only 5% (NCCN, 2022). “Classical” HL is characterized by the presence of neoplastic Reed-Sternberg cells in a background of numerous non-neoplastic inflammatory cells. Nodular lymphocyte-predominant HL 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 HL 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 patients with localized HL who can be treated with extended field radiation from those who require systemic chemotherapy. Each stage is subdivided into A and B categories. “A” indicates no systemic symptoms are present and “B” indicates the presence of systemic symptoms, which include unexplained weight loss of more than 10% of body weight, unexplained fevers >38°C, or drenching night sweats (NCCN, 2022). Ann Arbor Staging System for Hodgkin Lymphoma Stage I - Single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE) Stage 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). Stage 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) Stage 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 Patients 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) (NCCN, 2022). Treatment Patients with nonbulky stage IA or IIA disease are considered to have the clinically early-stage disease. These patients are candidates for chemotherapy, combined modality therapy, or radiotherapy alone (ACS, 2018). Patients with obvious stage III or IV disease, bulky disease (defined as a 10-cm mass or mediastinal disease with a transverse diameter >33% of the transthoracic diameter), or the presence of B symptoms will require combination chemotherapy with or without additional radiotherapy. Hodgkin lymphoma is highly responsive to conventional chemotherapy, and up to 80% of newly diagnosed patients can be cured with chemotherapy and/or radiotherapy. Patients who prove refractory or who relapse after first-line therapy have a significantly worse prognosis. Primary refractory 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 the first-line treatment (Brice, 2008). In patients with relapse, the results of salvage therapy vary depending on a number of prognostic factors, as follows: the length of the initial remission, stage at recurrence, and the severity of anemia at the time of relapse (Schmitz, 2004). 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 hematopoietic cell transplantation (HCT) but not more than 40% with early first relapse (Schmitz, 2007). Only 25% to 35% of patients 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 1 to 2 years, and once relapse occurs posttransplant, median survival is less than 12 months. Hematopoietic Cell Transplantation Hematopoietic cell transplantation is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT [allo-HCT]). These cells can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. Human leukocyte antigen refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci. Conditioning for Hematopoietic Cell Transplantation Conventional Conditioning The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by the cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease (GVHD), which increases susceptibility to opportunistic infections. The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVHD. Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Reduced-intensity conditioning regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term RIC will refer to all conditioning regimens intended to be nonmyeloablative. Regulatory Status The FDA 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. Reimbursement for high dose chemotherapy (HDC) with stem and/or progenitor cell transplant that has been pre-authorized is made as a global fee limited to the lesser of billed charges or the average allowable charge authorized by the Blue Quality Centers for Transplant in the geographic region where the transplant is performed. This global payment includes all related transplant services including institutional, professional, ancillary, and organ procurement. The global period begins one day prior to the date of the transplant and continues for 48 days after the transplant. This covers the inpatient/outpatient stay and provides a per diem outlier payment if necessary. This global fee also includes the cost of complications arising from the original procedure when services are rendered within the global postoperative period for the particular transplant.

Policy/ Coverage:	Effective December 2020 Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria High dose chemotherapy with autologous bone marrow, stem cell, or progenitor cell support for the treatment of Hodgkin's disease meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for patients with: Primary refractory disease; or Relapsed disease. Tandem autologous stem cell transplant meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes: In patients with primary refractory HL or In patients with relapsed disease with poor risk features who do not attain a complete remission to cytoreductive chemotherapy prior to transplantation. Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria High dose chemotherapy and stem cell rescue for the initial treatment of Hodgkin's disease does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For member with contracts without primary coverage criteria, high dose chemotherapy and stem cell rescue for the initial treatment of Hodgkin's disease is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage. Effective prior to December 2020 High dose chemotherapy with autologous bone marrow, stem cell, or progenitor cell support for the treatment of Hodgkin's disease meets primary coverage criteria for effectiveness and is covered for patients with: Primary refractory disease; or Relapsed disease. Tandem autologous stem cell transplant meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes: In patients with primary refractory HL or In patients with relapsed disease with poor risk features who do not attain a complete remission to cytoreductive chemotherapy prior to transplantation. High dose chemotherapy and stem cell rescue, for the initial treatment of Hodgkin's disease, is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, high dose chemotherapy and stem cell rescue, for the initial treatment of Hodgkin's disease is considered investigational and is not covered. Investigational services are exclusions in the member certificate of coverage. Effective prior to December 2011 High dose chemotherapy with autologous bone marrow, stem cell, or progenitor cell support for the treatment of Hodgkin's disease meets primary coverage criteria for effectiveness and is covered for patients with: Primary refractory disease; or Relapsed disease. High dose chemotherapy and stem cell rescue, for the initial treatment of Hodgkin's disease, is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, high dose chemotherapy and stem cell rescue, for the initial treatment of Hodgkin's disease is considered investigational and is not covered. Investigational services are exclusions in the member certificate of coverage. Tandem transplants are not covered based on a specific exclusion in the member benefit contract.

Rationale:	Initially, this policy focused on high-dose therapy plus autologous stem-cell support and high-dose therapy plus allogeneic stem-cell support. Each report concluded that data showed longer survival of patients with relapsed disease after transplants than after standard therapy. Allogeneic stem cells may be preferred over autologous stem cells, if the relapse occurs in the bone marrow. Literature focused on HDC and allogeneic stem-cell support after a prior failed course of high-dose chemotherapy and autologous stem-cell support, as treatment for various malignancies including Hodgkin’s disease, found that data were inadequate to permit conclusions about outcomes of this treatment strategy. 2003 Update A review of the literature performed in November 2002 identified 4 randomized trials on patients with Hodgkin’s disease. Only 1 of these studies compared outcomes of conventional dose chemotherapy with outcomes of high-dose chemotherapy plus stem-cell support. Entered into the trial were 166 patients with relapsed Hodgkin’s disease. Patients were randomized at entry to conventional-dose therapy (DEXA-BEAM; dexamethasone, carmustine, etoposide, cytarabine, and melphalan) or HDC with autologous stem-cell support (BEAM-ASCS). After randomization, patients underwent 2 cycles of DEXA-BEAM; responding patients then proceeded to 2 more courses of DEXA BEAM or to BEAM-ASCS. With a median follow-up of 39 months, freedom from treatment failure was significantly better after HDC than after conventional-dose chemotherapy. Subgroup analyses showed improved survival after transplant for patients treated in early first relapse (<12 months), late first relapse (>12 months), and second or subsequent relapse. No difference was reported for overall survival, although such a difference might become apparent with longer follow-up (median survival had not yet been reached in either arm). Although the duration of first remission remains a strong prognostic factor predicting outcome of both conventional and high-dose therapy for relapse, there is consensus across recent authoritative reviews, historical cohort comparisons, and clinical series that patients treated with high dose therapy tend to fare better overall than those managed with conventional dose regimens, regardless of the duration of remission. Therefore, the policy statement is changed and now suggests that HDC may be considered medically necessary for any patient with relapsed Hodgkin’s disease, regardless of the length of remission. The updated literature search identified few reports on outcomes of HDC with stem-cell support for up front treatment of Hodgkin’s disease, or to consolidate a complete response to initial induction therapy. These were all uncontrolled clinical series and are inadequate to permit conclusions. In addition, the literature was inadequate regarding the role of HDC with allogeneic stem-cell support as a treatment of Hodgkin’s disease relapsing after HDC with autologous stem cell support. Allotransplants after a failed autotransplant The literature search found no prospective controlled studies comparing allotransplants to alternative strategies for managing failure (progression or relapse) after an autotransplant for Hodgkin’s disease. Only 3 reports that included patients with Hodgkin’s disease have been published since the 2000 Blue Cross Blue Shield Association Technology Evaluation Center Assessment on this topic. Two series included 1 patient each who relapsed after an autotransplant, while a third series included 6 patients. The scant new data clearly are insufficient to change conclusions of the prior assessment. Note also that highly selected patients with Hodgkin’s disease that has relapsed after an autotransplant reportedly can achieve complete responses and long-term disease-free survival after a second autotransplant. The paucity of outcomes data for allotransplants after a failed autotransplant is not surprising. Patients usually are considered ineligible for this option either because their relapsed lymphoma progresses too rapidly, poor health status increases the likelihood of adverse outcomes, or they lack a well-matched donor. A few institutions have treated up to 15 or 20 such (Hodgkin’s plus non-Hodgkin’s) lymphoma patients in the last 1 to 2 decades. Thus, it appears highly unlikely that adequately powered randomized trials comparing this therapy to alternatives could ever be conducted, even by a multi-institutional group. Nevertheless, several institutions report that a minority of patients achieved long-term disease-free survival following an allotransplant for Hodgkin’s disease that relapsed after an autotransplant. Factors that apparently increase the likelihood of survival include a chemosensitive relapse, younger age, longer disease-free interval since the prior autotransplant, availability of an HLA-identical sibling donor, and fewer chemotherapy regimens prior to the failed autotransplant. Thus, clinician judgment confirmed by external review can play an important role in selecting patients for this treatment with a reasonable likelihood that potential benefits may exceed harms. 2006-2007 Update Updated MEDLINE searches identified no clinical trial publications that would alter the above conclusions. Therefore, the policy statement is unchanged. A study published by Federico and colleagues concluded that HDC with autologous stem-cell transplantation offered no benefit in outcomes over conventional chemotherapy in front-line therapy for advanced Hodgkin's lymphoma patients. This supports the above policy statement indicating HDC as initial or upfront therapy is investigational. The 2006 National Comprehensive Cancer Network (NCCN) guidelines on Hodgkin's disease recommend HDC with autologous stem-cell support for relapsed or refractory disease consistent with this policy. 2011 Update This update focuses on tandem autologous stem-cell transplants. Fung and colleagues reported results from a pilot study to evaluate the toxicities and efficacy of tandem autologous HSCT in patients with primary refractory or poor risk recurrent HL (Fung, 2007). The study involved 28 patients with primary progressive and 18 with recurrent HL who were enrolled in the study between April 1998 and March 2000. Patients had at least one of the following poor prognostic factors: first CR less than 12 months, extranodal disease, or B symptoms at relapse. Forty-one patients (89%) received the second transplant. With a median follow-up of 5.3 years (range, 1.6-8.1), the 5-year OS and PFS were 54% (95% CI: 40–69%) and 49% (95% CI: 34–63%), respectively. Morschhauser and colleagues reported on the results of a multicenter prospective trial that evaluated a risk-adapted salvage treatment with single or tandem autologous HSCT in 245 patients with relapsed/refractory HL (Morschhauser, 2008). Median follow-up time was 51 months (range, 20–110 months). Patients who were categorized as poor risk (n=150) had primary refractory disease (n=77) or 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV disease at the time of relapse, or relapse occurring within previously irradiated sites (n=73). In this study, these poor-risk patients were eligible for tandem autologous transplants. Intermediate-risk patients (n=95), defined as 1 risk factor at relapse, were eligible for a single transplant. Overall, 70% of the poor-risk patients received tandem transplants, and 97% of the intermediate-risk patients received a single transplant. Overall, 94 poor-risk patients responded to cytoreductive chemotherapy (partial response [PR] or CR), whereas 55 patients had chemotherapy-resistant disease. A total of 137 patients (including the 94 patients with chemotherapy-sensitive disease and 43 of 55 with chemotherapy–resistant disease) received the first autologous HSCT. Among 121 patients who were fully restaged, 64 patients had achieved a CR, 37 a PR, and 4 had stable disease. These 105 patients then underwent the second autologous HSCT after a median of 65 days. Among them, 80 patients achieved a CR, including 17 patients who had achieved PR, and 3 patients with stable disease after the first transplant. Among the 55 patients who had cytoreduction failure, 30 responded to the first transplant (9 with CR), and 17 achieved CR after the second transplant. Outcome analysis based on the intent-to-treat sample showed 5-year freedom from second failure and OS were 73% and 85% for the intermediate-risk group and 46% and 57% for the poor-risk group, all respectively. In the poor-risk group, patients who underwent tandem transplant and had a complete response to cytoreduction chemotherapy did not have superior outcomes compared to complete responders receiving a single transplant in previous studies (Ferme, 2002). However, in this study, poor-risk patients who were partial responders who underwent tandem transplants did better when compared to partial responders who received a single transplant in previous studies. In this study, 5-year OS rates for poor-risk patients who completed the tandem transplant were 79% and 73% for complete and partial responders, whereas in a previous trial of single autologous HSCT, 5-year OS rates were 86% and 37% for complete and partial responders, respectively (Ferme. 2002). The authors concluded that a single autologous HSCT is appropriate for intermediate-risk patients and for poor-risk patients who are complete responders to cytoreductive chemotherapy but that tandem autologous HSCT showed a benefit in patients with chemotherapy-resistant disease and in partial responders to cytoreductive conditioning. The authors stated that a trial of random assignment of single versus tandem autologous HSCT was unrealistic, given the low yearly incidence of poor-risk patients, and that the best possible comparisons are with data from previous findings with single transplants. 2012 Update A search of the MEDLINE database through September 2012 did not reveal any new information that would prompt a change in the coverage statement. 2013 Update A search of the MEDLINE database was conducted through September 2013. There was no new information that would prompt a change in the coverage statement. 2014 Update A literature search conducted through November 2014 did not reveal any new information that would prompt a change in the coverage statement. 2017 Update 2017 Update A literature search was conducted using the MEDLINE database through November 2017. There was no information identified that would prompt a change in the coverage statement. Practice Guidelines And Position Statements American Society for Blood and Marrow Transplantation In 2015, guidelines were published by the American Society for Blood and Marrow Transplantation (ASBMT) on indications for autologous and allogeneic HCT (Majhail, 2015). Recommendations described the current consensus on use of HCT within and outside of the clinical trial setting. Recommendations are graded : Standard of Care (S); Clinical Evidence Available (C); and Not generally recommended (N). ASBMT recommendations on Hodgkin lymphoma are provided below. ASBMT Recommendations for Treating Hodgkin Lymphoma (Majhail, 2015) ADULT Standard of Care (S) Autologous HCT for primary refractory, sensitive Autologous HCT or Allogeneic HCT for first relapse, sensitive Autologous HCT for second or greater relapse Clinical Evidence Available (C) Autologous HCT for first complete response (PET+) Autologous HCT for primary refractory, sensitive Autologous HCT for primary refractory resistant Allogeneic HCT for first relapse, resistant Allogeneic HCT for second or greater relapse Allogeneic HCT for relapse after autologous transplant Not Generally Recommended (N) Allogeneic & Autologous HCT for First complete response (PET -) Allogeneic HCT for First complete response (PET +) Autologous HCT for primary refractory resistant Autologous HCT for first relapse, resistant Autologous HCT for relapse after autologous transplant PEDIATRIC Standard of Care (S) No recommendations Clinical Evidence Available (C) Allogeneic & Autologous HCT for primary refractory, sensitive Allogeneic for primary refractory resistant Allogeneic & Autologous HCT for first relapse, sensitive Allogeneic HCT for first relapse, resistant Allogeneic & Autologous HCT for second or greater relapse Not Generally Recommended (N) Allogeneic & Autologous HCT for first complete response Autologous HCT for primary refractory, resistant Autologous HCT for first relapse, resistant European Society for Medical Oncology In 2014, the European Society for Medical Oncology published guidelines on the diagnosis and treatment of Hodgkin lymphoma (Eichenauer, 2014). The guidelines stated: “The standard of care for most patients with disease recurrence after first-line treatment consists of high-dose chemotherapy followed by autologous stem cell transplantation (ACT).” 2018 Update A literature search was conducted through November 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below. American College of Radiology The American College of Radiology issued an Appropriateness Criteria on recurrent HL (ACR, 2016). The criteria stated that while salvage therapy followed by autologous HCT is standard of care for relapsed HL, alternative therapies may 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 of the original site of disease. 2019 Update Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement. 2020 Update Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below. 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. 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 reported on the outcomes for 329 individuals with HL with risk factors for post-transplantation relapse or progression (eg, primary refractory HL, relapse <12 months after initial therapy, and/or relapse with extranodal disease) (Moskowitz, 2015). 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) (Moskowitz, 2018). In addition, a recent study by Smith et al 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 (Smith, 2018). A survival benefit with novel agents has been found in the setting of relapse post-autologous HCT. Bair et al reported a retrospective comparative analysis that evaluated the outcomes of 87 individuals with relapsed/refractory HL who had relapsed post-autologous HCT (Bair, 2017). 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. No RCTs have compared tandem autologous HCT with other standard of care therapies. One prospective, nonrandomized study has compared tandem to single autologous HCL for HL. Morschhauser et al and Sibon et al reported on the results of a prospective multicenter trial that evaluated a risk-adapted salvage treatment with single or tandem autologous HCT in 245 patients with relapsed or refractory HL (Morschhauser, 2008; Sibon, 2016). Median follow-up time in the initial publication by Morschhauser et al was 51 months (range, 20-110 months). Sibon et al reported on the 10-year follow-up. Patients categorized as poor-risk (n=150) had the primary refractory disease (n=77) or 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV disease at the time of relapse, or relapse in previously irradiated sites (n=73). In this trial, these poor-risk patients were eligible for tandem autologous transplants. Intermediate-risk (n=95) patients, defined as 1 risk factor at relapse, were eligible for a single transplant. Overall, 70% of the poor-risk patients received tandem transplants, and 97% of the intermediate-risk patients received a single transplant. Ninety-four poor-risk patients responded to cytoreductive chemotherapy (partial or CR), whereas 55 patients had the chemotherapy-resistant disease. A total of 137 patients (including the 94 patients with chemotherapy-sensitive disease and 43 of 55 with the chemotherapy-resistant disease) received the first autologous HCT. Among 121 patients who were fully restaged, 64 patients had achieved a complete response, 37 a partial response, and 4 had stable disease. These 105 patients then underwent a second autologous HCT after a median of 65 days. Among them, 80 patients achieved a complete response, including 17 patients who had achieved partial response and 3 patients with stable disease after the first transplant. Among the 55 patients who had cytoreduction failure, 30 responded to the first transplant (9 with complete response), and 17 achieved a complete response after the second transplant. Outcome analysis based on the intention-to-treat sample revealed the 5-year freedom from the second failure and OS estimates were 73% and 85% for the intermediate-risk group and 46% and 57% for the poor-risk group, all respectively. At the 10-year follow-up reported by Sibon et al, freedom from second failure and OS rates were 64% (95% CI, 54% to 74%) and 70% (95% CI, 61% to 80%) for the intermediate-risk group, and 41% (95% CI, 33% to 49%) and 47% (95% CI, 39% to 55%) for the poor-risk group (Sibon, 2016). In the poor-risk group, patients who underwent tandem transplant and had a CR to cytoreduction chemotherapy did not have superior outcomes compared with complete responders receiving a single transplant in previous studies by the same group (Ferme, 2002). However, in this 2002 study, poor-risk patients who were partial responders and underwent tandem transplants did better compared with partial responders who received a single transplant in previous studies. In this study, 5-year OS rates for poor-risk patients who completed the tandem transplant were 79% and 73% for complete and partial responders, whereas, in a previous trial of single autologous HCT, 5-year OS rates were 86% and 37% for complete and partial responders, all respectively (Ferme, 2002). The findings suggested that a single autologous HCT would be appropriate for intermediate-risk patients and for poor-risk patients who are complete responders to cytoreductive chemotherapy but that tandem autologous HCT showed a benefit in patients with chemotherapy-resistant disease and in partial responders to cytoreductive conditioning. The authors concluded that a trial, randomizing patients to single vs tandem autologous HCT was unrealistic, given the low yearly incidence of poor-risk patients; in their estimation, the best possible comparisons would be with data from previous findings with single transplants. Tandem autologous HCL for HL has also been evaluated in single-arm studies. Fung et al reported results from a pilot study on HL that evaluated the toxicities and efficacy of tandem autologous HCT in patients with primary refractory or poor-risk recurrent HL (Fung, 2007). The study involved patients with primary progressive and 18 with recurrent HL who were enrolled in the study between 1998 and 2000. Patients had at least one of the following poor prognostic factors: first CR less than 12 months, extranodal disease, or B symptoms (presence of systemic symptoms) at relapse. Forty-one (89%) patients received the second transplant. With a median follow-up of 5.3 years (range, 1.6-8.1 years), the 5-year OS and PFS rates were 54% (95% CI, 40% to 69%) and 49% (95% CI, 34% to 63%), respectively. Additionally, Smith et al reported results from a more recent Phase II trial of 89 patients with primary progressive or recurrent HL conducted by the Southwest Oncology Group (SWOG) Clinical Trials Network (Smith, 2018). This single-arm trial was conducted at 10 centers and enrolled patients between 2006 and 2009. Key patient characteristics included that 53% had induction failure, 18% had initial response of ≤ 12 months, 83% were stage III or IV at the time of trial enrollment, and 48% previously irradiated patients relapsed in an irradiated site. Eighty-two patients (92%) received the second transplant. With a median follow-up of 6.2 years, the 5-year PFS and OS rates were 55% (95% CI: 44%–64%) and 84% (95% CI: 74%–90%). Current National Comprehensive Cancer Network guidelines for Hodgkin lymphoma (HL; v.2.2020) include a recommendation for autologous or allogeneic 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 (NCCN, 2020). 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. 2021 Update Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement. 2022 Update Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below. 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 (Majhail, 2015). These guidelines were updated in 2020 (Kanate, 2020). Recommendations described the current consensus on the use of HCT in and out of the clinical trial setting. 2020 Recommendations for use of Autologous HCT to Treat Hodgkin Lymphoma: Adult First complete response (PET negative) - Not generally recommended First complete response (PET positive) - Subsection removed Primary refractory, sensitive - Standard of care Primary refractory, resistant - Not generally recommended First relapse, sensitive - Standard of care First relapse, resistant - Not generally recommended Second or greater relapse - Standard of care Relapse after autologous transplant - Not generally recommended Pediatric First complete response - Not generally recommended Primary refractory, sensitive - Standard of care, clinical evidence available Primary refractory, resistant - Not generally recommended First relapse, sensitive - Standard of care First relapse, resistant - Not generally recommended Second or greater relapse - Standard of care, clinical evidence available 2023 Update Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below. A retrospective observational cohort study by Merryman et al evaluated autologous HCT after anti-programmed death-1 (PD-1) therapy for patients with relapsed or refractory HL (Merryman, 2021). Seventy-eight patients were identified who underwent autologous HCT as a third-line (or later) treatment; 74% of patients underwent autologous HCT after anti-PD-1 treatment and 26% of patients received anti-PD-1 treatment along with additional therapy prior to autologous HCT. The 18-month PFS and OS after autologous HCT were 81% (95% CI, 69 to 89) and 96% (95% CI, 87 to 99), respectively. Favorable outcomes were reported for patients who had received greater than 4 systemic therapies before autologous HCT (18-month PFS, 73%), who were refractory to 2 consecutive therapies immediately prior to anti-PD-1 treatment (18-month PFS, 78%), and who had positive pre-HCT positron emission tomography (PET) (18-month PFS, 75%); patients who were non-responders to anti-PD-1 treatment had inferior outcomes (18-month PFS, 51%). 2024 Update Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement.

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