Hodgkin Lymphoma

HL is a relatively uncommon B-cell lymphoma. In 2017, the estimated number of new cases in the United States was approximately 8260 and 1070 estimated deaths.^1, The disease has a bimodal distribution, with most patients diagnosed between the ages of 15 and 30 years, with a second peak in adults aged 55 years and older.

The 2008 World Health Organization classification divided HL into 2 main types^2,; these classifications did not change in the 2016 update:^3,

1.     “Classical” HL

·         Nodular sclerosis

·         Mixed cellularity

·         Lymphocyte depleted

·         Lymphocyte-rich

In Western countries, “Classical” HL accounts for 95% of cases of HL and, for nodular lymphocyte-predominant HL, only 5%.^4, “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, or drenching night sweats (see Table 1).^4,

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 (eg, II2).
III	Involvement of lymph node regions or structures on both sides of the diaphragm. These patients are further subdivided as follows: ·  III-1: disease limited to spleen or upper abdomen ·  III-2: periaortic or pelvic node involvement
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 three groups: early-stage favorable (stage I-II with no B symptoms or large mediastinal lymphadenopathy), early-stage unfavorable (stage I-II with a large mediastinal mass, with or without B symptoms; stage IB-IIB with the bulky disease), and advanced-stage disease (stage III-IV).^4,

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.^5, 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.^5,

HL 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.^6,

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.^7, 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.^8,

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

HCT is a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of 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 [allo-HCT]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naive” and thus are associated with a lower incidence of rejection or graft-versus-host disease. Umbilical cord blood is addressed in a separate policy on 'Placental and Umbilical Cord Blood as a Source of Stem Cells' (Policy #012 in the Surgery Section).

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 critical for achieving a good outcome with allo-HCT. Compatibility is establishedby typing of human leukocyte antigen (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (except umbilical cord blood).

Conditioning for HCT

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (eg, 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 effect mediated by non-self-immunologic effector cells that develop after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower graft-versus-malignancy 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 patients who are sufficiently fit medically to tolerate substantial adverse events 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 allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which also increase susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiotherapy 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 before undergoing bone marrow ablation. Patients who undergo autologous HCT are susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus-host disease.

Reduced-Intensity Conditioning for Allo-HCT

RIC refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiotherapy than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden but also to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of nonrelapse mortality and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally 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, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells.

For this policy, the term RIC refers to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

Regulatory Status

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.

Related Policies

• Hematopoietic Cell Transplantation for Non-Hodgkin Lymphomas (Policy #040 in the Treatment Section)

I. The guiding principle of this policy is the New Jersey State Mandate on High Dose Chemotherapy and Autologous Bone Marrow (ABMT) or Peripheral Stem Cell Transplant (PSCT).

The ensuing statements represent the interpretation of the law by Horizon Blue Cross Blue Shield of New Jersey (Horizon BCBSNJ) which must be strictly observed when handling pre-authorizations, claims, inquiries, and other matters pertaining to high-dose chemotherapy with stem cell support:

A. The law only applies to autologous bone marrow or peripheral stem cell transplant for the treatment of cancer. Medical necessity criteria must NOT be applied to these cases. They are automatically eligible for coverage under the law.

[INFORMATIONAL NOTE: Please note that self-insured accounts are exempt from the law. However, they have the option to adopt the law upon renewal of the contract.

Policy Statement II of this policy deals with eligibility and medical necessity criteria which must be applied specifically to those self-insured accounts which opted NOT to adopt the law.]

B. In cases of multiple, repeat, or tandem autologous bone marrow or peripheral stem cell transplant procedures for the same member, the first or initial transplant is automatically covered under the law. However, subsequent transplant procedures are NOT automatically covered under the law but are subject to medical necessity criteria.

C. The law applies to contracts delivered, issued, executed or renewed in New Jersey. Services rendered outside New Jersey are covered by the law as long as the member has a contract that is written or issued in New Jersey.

D. Exclusions to the law:
Policy Statement II of this policy addresses medical necessity criteria as it applies to the following requests for:
• an allogeneic bone marrow or peripheral stem cell transplant.
• treatment of non-cancerous conditions even if it involves autologous bone marrow or peripheral stem cell transplant.
• mini-transplants or non-myeloablative transplants since they are allogeneic transplants.

A. This procedure is subject to the specific terms of the member's contract.
[Also refer to a separate policy on Transplant Donor and Recipient Policy (Policy #003) under the Surgery Section.]

B. Medical necessity is established based on review of the following information:
1. Stage to which the malignancy has progressed;
2. Clinical history of the member including results of diagnostic procedures performed (i.e., laboratory, pathology, radiology), and previous modes of therapy with results;
3. Treatment protocol of the facility where the procedure is being performed.

C. Autologous hematopoietic cell transplantation (HCT) is considered medically necessary in members with primary refractory or relapsed Hodgkin lymphoma.

D. Allogeneic HCT, using either myeloablative or reduced-intensity conditioning regimens, is considered medically necessary in members with primary refractory or relapsed Hodgkin lymphoma.

E. Tandem autologous HCT is considered medically necessary:
• in members with primary refractory Hodgkin lymphoma or
• in members with relapsed disease with poor risk features who do not attain a complete remission after cytoreductive chemotherapy prior to transplantation (see Policy Guidelines section).

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

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

[INFORMATIONAL NOTE: Before making a determination that this procedure is investigational, please refer to Policy Statement I of this policy for the applicability of the New Jersey State Law on High Dose Chemotherapy (HDC) and Autologous Bone Marrow Transplant (BMT) or Peripheral Stem Cell Transplant (PSCT).]

H. Harvesting and storage of autologous hematopoietic stem cells is considered medically necessary for:
• a member who is in remission but at high risk for relapse, and the condition being treated is one of the eligible conditions for autologous peripheral blood stem cell transplantation (PBSCT) or autologous bone marrow transplantation; OR
• a member whose current clinical condition qualifies him/her for imminent transplantation (within 30 days), and the condition being treated is one of the eligible conditions for PBSCT or autologous bone marrow transplantation.

Harvesting and storage of allogeneic hematopoietic stem cells or umbilical cord blood is considered medically necessary for:
• a member whose current clinical condition qualifies him/her for imminent transplantation (within 30 days), and the condition being treated is one of the eligible conditions for allogeneic bone marrow transplantation.

[Also refer to a separate policy on Transplant Donor and Recipient Policy (Policy#003) under the Surgery Section.]

Some patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for reduced-intensity conditioning allogeneic hematopoietic cell transplantation. They include those with malignancies that are effectively treated with myeloablative allogeneic transplantation, but whose age (typically >55 or >60 years) or comorbidities (eg, 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 patient, with whom usually there is sharing of only 3 of the 6 major histocompatibility antigens. Most patients 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.


Medicare Coverage:
Autologous HSCT is considered reasonable and necessary and is covered under Medicare (NCD 110.23 effective 10/03/2016) for patients with advanced Hodgkin disease who have failed conventional therapy and have no human leukocyte antigen‒matched donor. All other indications for stem cell transplantation not otherwise listed in NCD 111.23 as covered or non-covered remain at Medicare Administrative Contractor discretion. For additional coverage information, see National Coverage Determination (NCD) for Stem Cell Transplantation 110.23. Available at: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=366&ncdver=1&bc=AAAAgAAAAAAAAA%3d%3d&.

Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy regarding second autologous HCT for relapsed lymphoma after a prior autologous hematopoietic cell transplantation (HCT), and regarding tandem autologous HCT.

Medicaid Coverage:

FIDE-SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2001 and has been updated regularly with searches of the MEDLINE database. The most recent literature review was performed through November 15, 2018.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Autologous Hematopoietic Cell Transplantation for Hodgkin Lymphoma

First-Line Therapy for Hodgkin Lymphoma

Clinical Context and Test Purpose

The purpose of autologous HCT as first-line therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with HL.

The question addressed in this policy is: does the use of autologous HCT as first-line therapy improve the net health outcomes of patients with HL?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with HL.

Interventions

The therapy being considered is autologous HCT as first-line therapy.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are overall survival (OS), disease-specific survival (DSS), change in disease status, morbid events, treatment-related mortality (TRM), and treatment-related morbidity.

Timing

Follow-up over years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using the following principles: 

·         To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

·         In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

·         To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

·         Studies with duplicative or overlapping populations were excluded.

Federico et al (2003) published results from an RCT of 163 patients with unfavorable HL who had received autologous HCT or additional standard chemotherapy for consolidation after initial conventional chemotherapy. Patients were randomized to high-dose chemotherapy (HDC) followed by autologous HCT (n=83) or to 4 additional courses of the same standard chemotherapy used in the induction phase (n=80). After treatment, complete remission (CR) was achieved in 92% of patients in the autologous HCT arm and 89% in the standard chemotherapy arm (p=0.6). Five-year survival rates (overall, failure-free, and relapse-free) did not differ between the treatment groups, and the authors concluded that HDC with autologous HCT offered no benefit in outcomes over conventional chemotherapy as first-line therapy for patients with advanced HL.^9,

Carella et al (2009) published 10-year follow-up results for the Federico study.¹⁰Ten-yearOS rates were 85% (95% confidence interval [CI], 78% to 90%) for the HDC autologous HCT group and 84% (95% CI, 77% to 89%; p=0.7) for the standard chemotherapy group. Ten-year failure-free survival rates were 79% (95% CI, 72% to 85%) for the HDC autologous HCT group and 75% (95% CI, 67% to 82%; p=0.8) for the standard chemotherapy group. The authors concluded that, after a median follow-up of 107 months, their data suggested patients who respond to induction therapy with conventional chemotherapy do not achieve superior outcomes with consolidation with HDC and autologous HCT.

Section Summary: Autologous HCT as First-Line Therapy for HL

A small number of RCTs have evaluated the use of autologous HCT as first-line treatment for HL, and these trials have reported no benefit above that of conventional chemotherapy.

Relapsed or Refractory HL

Clinical Context and Test Purpose

The purpose of autologous HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with relapsed or refractory HL.

The question addressed in this policy is: does the use of autologous HCT improve the net health outcomes of patients with relapsed or refractory HL?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with relapsed or refractory HL.

Interventions

The therapy being considered is autologous HCT.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, TRM, and treatment-related morbidity.

Timing

Follow-up over years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using principles described above.

A systematic review and meta-analysis of the available RCTs on HCT for patients with relapsed or refractory HL were published by Rancea et al (2014).^11, Reviewers included 3 RCTs, 2 (1993, 2002) of which compared HDC plus autologous HCT with conventional treatment.^12,13, Both trials (described below) were judged to be at moderate risk of bias using the Cochrane criteria. Combined analysis for the outcome of OS demonstrated a hazard ratio of 0.67 for patients treated with autologous HCT, which was not statistically significant (95% CI, 0.41 to 1.07). For the outcome of progression-free survival (PFS), there was a significant improvement for autologous HCT treatment, with a hazard ratio of 0.55 (95% CI, 0.35 to 0.86).

The British National Lymphoma Investigation study (1993) was the first to show that autologous HCT offered patients with relapsed or refractory HL a PFS benefit over conventional chemotherapy.^14, Forty patients with relapsed or refractory HL were given chemotherapy without a transplant (n=20) or autologous HCT after HDC (n=20).^12, A significantly better event-free survival rate at 3 years (53%) was reported for patients who underwent HCT than for those who did not (10%).

Subsequently, these findings were confirmed in a larger 2002 trial by the German Hodgkin Study Group and European Group for Blood and Marrow Transplantation.^13, Patients relapsing after initial chemotherapy were randomized to chemotherapy without a transplantor to autologous HCT. In the final analysis of 144 patients, freedom from treatment failure at 3 years was 55% in the transplanted group vs 34% in the nontransplanted group. This benefit was maintained in a 2007 subgroup analysis, regardless of early or late relapse, and the results were confirmed in follow-up data at 7 years.^15,

In addition to the RCTs, several large retrospective studies identified in a systematic review have reported event-free survival rates ranging from 25% to 60%, with OS rates from 35% to 66%, showing that disease status before autologous HCT was the most important prognostic factor for the final outcome.^6,

Section Summary: Autologous HCT for Relapsed or Refractory HL

RCTs and a meta-analysis have evaluated the use of auto-HCT for relapsed or refractory HL. The studies reported no difference in OS, but a significant improvement in PFS, for patients treated with autologous HCT.

Second Autologous HCT for Relapsed HL After Prior Autologous HCT

Clinical Context and Test Purpose

The purpose of a second autologous HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with relapsed HL after an autologous HCT.

The question addressed in this policy is: does the use of a second autologous HCT improve the net health outcomes ofpatients with relapsed HL after an autologous HCT?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with relapsed HL after an autologous HCT.

Interventions

The therapy being considered is a second autologous HCT.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, TRM, and treatment-related morbidity.

Timing

Follow-up over years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using principles described above.

Few treatment options exist for patients who relapse following an autologous HCT; they include single-agent palliative chemotherapy or occasionally, localized radiotherapy.^15, If further remission is attained with conventional-dose chemotherapy, it is rarely durable, with a median OS of less than one year.^16,

There is limited experience with second autologous HCT, and TRM is high (25%-40%).^12, Smith et al (2008) reported on the outcomes of 40 patients (21 with HL, 19 with non-Hodgkin lymphoma) who underwent a second autologous HCT for relapsed lymphoma.^17,Reported results were combined for the two populations, but the authors stated the outcomes for both patient groups were similar. Median age at second HCT was 38 years (range, 16-61 years). In 82% of patients, the second HCT was performed more than 1 year after the first. The TRM at day 100 posttransplant was 11% (95% CI, 3% to 22%). At a median follow-up of 72 months (range, 12-124 months) after the second HCT, 73% of patients had died¾62% due to relapsed lymphoma. One-, 3-, and 5-year PFS estimates were 50% (95% CI, 34% to 66%), 36% (95% CI, 21% to 52%), and 30% (95% CI, 16% to 46%), respectively. Corresponding OS estimates were 65% (95% CI, 50% to 79%), 36% (95% CI, 22% to 52%), and 30% (95% CI, 17% to 46%), respectively. Study limitations included the absence of an appropriate comparison group and lack of data on how many patients were considered for a second HCT but were unable to mobilize sufficient stem cells or were otherwise unable to proceed to the second transplant. Finally, heterogeneity of the preparative regimens used in this population precluded comparison of efficacy.

Section Summary: Second Autologous HCT for Relapsed HL After Prior Autologous HCT

The evidence is limited to case series; no RCTs or nonrandomized comparative studies were identified. In 1 series, TRM at 100 days was 11%, and the mortality rate was 73% at a median follow-up of 72 months.

Allogeneic HCT for HL

First-Line Therapy for HL

Clinical Context and Test Purpose

The purpose of allo-HCT as first-line therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with HL.

The question addressed in this policy is: does the use of allo-HCT as first-line therapy improve the net health outcomes of patients with HL?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with HL.

Interventions

The therapy being considered is allo-HCT as first-line therapy.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, TRM, and treatment-related morbidity.

Timing

Follow-up over years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using principles described above.

The application of allo-HCT to the treatment of patients with HL appears limited, due to high procedure-related mortality. No controlled trials evaluating allo-HCT as first-line treatment for HL were identified. In addition, 2015 and 2016 systematic reviews of HCT for HL did not discuss studies using allo-HCT as first-line therapy.^18,19,

Section Summary: Allo-HCT as First-Line Therapy for HL

No studies specifically addressing allo-HCT as first-line treatment for HL were identified.

Relapsed or Refractory HL

Clinical Context and Test Purpose

The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with relapsed or refractory HL.

The question addressed in this policy is: does the use of allo-HCT improve the net health outcomes of patients with relapsed or refractory HL?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with relapsed or refractory HL.

Interventions

The therapy being considered is allo-HCT.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, TRM, and treatment-related morbidity.

Timing

Follow-up over years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using principles described above.

Rashidi et al (2016) published a systematic review and meta-analysis of studies evaluating allo-HCT in HL.^19, Thirty-eight studies were selected. Three studies included more than 1 series and were divided into more than 1 group; a total of 42 series were included in the meta-analysis. Sample sizes of included studies ranged from 5 to 285 patients (total n=1850 patients). Twenty-eight studies were retrospective and 14 prospective. None was an RCT. Median follow-up in the studies ranged from 11 to 104 months. Results of the meta-analyses are shown in Table 2.

Table 2. Meta-Analytic Outcomes

Follow-Up	Relapse-Free Survival (95% CI), %	Overall Survival (95% CI), %
6 months	77 (59 to 91)	83 (75 to 91)
1 year	50 (42 to 57)	68 (62 to 74)
2 years	37 (31 to 43)	58 (52 to 64)
3 years	31 (25 to 37)	50 (41 to 58)

Adapted from Rashidi et al (2016).^19,
CI: confidence interval.

In multivariate analysis, more recent studies (ie, those that started to accrue patients in 2000 or later) had significantly higher 6-month and 1-year survival rates than older studies.

Section Summary: Allo-HCT for Relapsed or Refractory HL

A 2016 meta-analysis identified 38 case series evaluating allo-HCT for relapsed or refractory HL. The pooled analysis found a 6-month OS rate of 83% and a 3-year OS rate of 50%.

Allo-HCT for Relapsed HL After Prior Autologous HCT

Clinical Context and Test Purpose

The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with relapsed HL after an autologous HCT.

The question addressed in this policy is: does the use of allo-HCT improve the net health outcomes of patients with relapsed HL after an autologous HCT?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with relapsed HL after an autologous HCT.

Interventions

The therapy being considered is allo-HCT.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, TRM, and treatment-related morbidity.

Timing

Follow-up over years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using principles described above.

The Rashidi et al (2016) meta-analysis (described above) included 38 case series assessing patients who underwent allo-HCT after a prior failed autologous HCT.^19, In a multivariate analysis of factors associated with survival outcomes, reviewers found that a previous autologous HCT was significantly associated with higher 1-year (p=0.012) and 2-year (p=0.040) OS rates and significantly higher relapse-free survival at 1 year (p=0.005) compared with no previous autologous HCT.

Section Summary: Allo-HCT for Relapsed HL After Prior Autologous HCT

A 2016 meta-analysis found that a previous autologous HCT was significantly associated with higher OS rates and significantly higher relapse-free survival rates compared with no previous autologous HCT.

Reduced-Intensity Conditioning with Allo-HCT

Clinical Context and Test Purpose

The purpose of RIC with allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with relapsed or refractory HL.

The question addressed in this policy is: does the use of RIC with allo-HCTimprove the net health outcomes of patients with relapsed or refractory HL?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with relapsed or refractory HL.

Interventions

The therapy being considered is RIC with allo-HCT.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, TRM, and treatment-related morbidity.

Timing

Follow-up over years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using principles described above.

Perales et al (2015) conducted an evidence review as part of the development of clinical guidelines on HCT for HL.^18, Reviewers evaluated a number of studies that showed better outcomes with RIC and with myeloablative conditioning regimens. For example, reviewers cited a 2008 study by the European Group for Blood and Marrow Transplantation reporting outcomes in 89 HL patients with relapsed or refractory disease who received a RIC with allo-HCT and were compared with 79 patients who received myeloablative conditioning (ie, conventional group).^20, Sixty-two percent of the RIC group had undergone a previous autologous HCT vs 41% of the myeloablative group. Although the incidence of relapse was nearly double in the RIC group (57% vs 30%), after a median follow-up for surviving patients of 75 months (range, 12-120 months), 24 in the RIC group (26.9%) and 18 in the conventional group (22.8%) were alive. Five-year OS rates were 28% (95% CI, 18% to 38%) for the RIC group and 22% (95% CI, 13% to 31%) for the conventional group. Independent adverse prognostic factors for OS were a previously failed autologous HCT (relative risk, 1.59; 95% CI, 1.07 to 2.35; p=0.02), the use of myeloablative conditioning (relative risk=1.62; 95% CI, 1.27 to 3.29; p=0.04), and the presence of refractory disease (relative risk=1.51; 95% CI, 1.03 to 2.21; p=0.003). Perales et al (2015) concluded: “As a result, the preferred conditioning intensity in adult patients with relapsed/refractory HL is RIC, which results in acceptable TRM [treatment-related mortality] including in patients who have had a prior ASCT [autologous stem cell transplant].”

Section Summary: RICwith Allo-HCT

A 2015 systematic review assessed a number of studies, including some with comparison groups, showing acceptable outcomes after RIC with allo-HCT in patients with relapsed or refractory HL.

Tandem Autologous HCT for HL

Clinical Context and Test Purpose

The purpose of tandem autologous HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with HL.

The question addressed in this policy is: does the use of tandem autologous HCT improve the net health outcomes of patients with HL?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with HL.

Interventions

The therapy being considered is tandem autologous HCT.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, morbid events, TRM, and treatment-related morbidity.

Timing

Follow-up over years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using principles described above.

Fung et al (2007) 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.^21, 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.

Morschhauser et al (2008) 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.^22, Median follow-up time was 51 months (range, 20-110 months). 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.

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.^23, 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.^23, 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 inpartial 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.

Section Summary: Tandem Autologous HCT for HL

There are no RCTs comparing tandem autologous HCT with alternatives for treating HL. One prospective, nonrandomized study reported that patients who had not achieved a CR after conventional chemotherapy had better outcomes with tandem HCT than with single HCT. However, the results of this trial were not definitive, and RCTs are needed to determine the efficacy of tandem transplants.

Summary of Evidence

Autologous HCT

For individuals who have HL who receive autologous HCT as first-line therapy, the evidence includes RCTs. The relevant outcomes are OS, DSS, change in disease status, morbid events, and TRM and morbidity. RCTs of autologous HCT as first-line treatment have reported that this therapy does not provide additional benefit compared with conventional chemotherapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have relapsed or refractory HL who receive autologous HCT, the evidence includes RCTs, a meta-analysis, nonrandomized comparative studies, and case series. The relevant outcomes are OS, DSS, change in disease status, morbid events, and TRM and morbidity. Two RCTs in patients with relapsed or refractory disease have reported a benefit in PFS and a trend toward a benefit in OS. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have relapsed HL after an autologous HCT who receive a second autologous HCT, the evidence includes case series. The relevant outcomes are OS, DSS, change in disease status, morbid events, and TRM and morbidity. No RCTs or nonrandomized comparative studies were identified. In a case series, TRM at 100 days was 11%; at a median follow-up of 72 months, the mortality rate was 73%. The evidence is insufficient to determine the effects of the technology on health outcomes.

Allo-HCT

For individuals who have HL who receive allo-HCT as first-line therapy, the evidence includes no published studies. The relevant outcomes are OS, DSS, change in disease status, morbid events, and TRM and morbidity. No studies specifically addressing allo-HCT as first-line treatment for HL were identified. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have relapsed or refractory HL who receive allo-HCT, the evidence includes a number of case series and a meta-analysis. The relevant outcomes are OS, DSS, change in disease status, morbid events, and TRM and morbidity. A 2016 meta-analysis identified 38 case series evaluating allo-HCT for relapsed or refractory HL. The pooled analysis found a 6-month OS rate of 83% and a 3-year OS rate of 50%. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have relapsed HL after autologous HCT who receive allo-HCT, the evidence includes case series and a meta-analysis. The relevant outcomes are OS, DSS, change in disease status, morbid events, and TRM and morbidity. A 2016 meta-analysis of 38 case series found that a previous autologous HCT followed by allo-HCT was significantly associated with higher 1- and 2-year OS rates and significantly higher recurrence-free survival rates at one year compared with no previous autologous HCT. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have relapsed or refractory HL who receive RIC with allo-HCT, the evidence includes case series, cohort studies, and a systematic review. The relevant outcomes are OS, DSS, change in disease status, morbid events, and TRM and morbidity. A 2015 systematic review cited a number of studies, including some with comparison groups, showing acceptable outcomes after RIC with allo-HCT in patients with relapsed or refractory HL. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Tandem Autologous HCT

For individuals who have HL who receive tandem autologous HCT, the evidence includes nonrandomized comparative studies and case series. The relevant outcomes are OS, DSS, change in disease status, morbid events, and TRM and morbidity. One prospective, nonrandomized study reported that, in patients with poor prognostic markers, response to tandem autologous HCT might be higher than that for single autologous HCT. This study was not definitive due to potential selection bias; RCTs are needed to determine the impact of tandem autologous HCT on health outcomes in this population. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 2 academic medical centers while this policy was under review in 2009. Both reviewers agreed with the policy statements, except the use of a second autologous hematopoietic cell transplantation (HCT) after a prior autologous HCT, which both thought would be medically necessary for certain circumstances. Data to support the use of a second autologous HCT are extremely limited, and the policy statement for this use of HCT remains investigational.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network Guidelines

Current National Comprehensive Cancer Network guidelines for Hodgkin lymphoma (HL; v.3.2018) include a recommendation for autologous HCT in patients with biopsy-proven refractory disease who have undergone second-line systemic therapy and Deauville stages 1, 2, 3, or 4 according to restaging based on findings from positron emission tomography or computed tomography.⁴

American Society for Blood and Marrow Transplantation

In 2015, guidelines were published by the American Society for Blood and Marrow Transplantation on indications for autologous and allogeneic HCT.^24, Recommendations described the current consensus on the use of HCT in and out of the clinical trial setting. The Society recommendations on HLare provided in Table 3.

Table 3. Recommendations for Use of HCT to Treat Hodgkin Lymphoma

Indication	Allogeneic HCT	Autologous HCT
Adult
First complete response (PET negative)	N	N
First complete response (PET positive)	N	C
Primary refractory, sensitive	C	S
Primary refractory, resistant	C	N
First relapse, sensitive	S	S
First relapse, resistant	C	N
Second or greater relapse	C	S
Relapse after autologous transplant	C	N
Pediatric
First complete response	N	N
Primary refractory, sensitive	C	C
Primary refractory, resistant	C	N
First relapse, sensitive	C	C
First relapse, resistant	C	N
Second or greater relapse	C	C

C: clinical evidence available; HCT: hematopoietic cell transplantation; N: not generally recommended; PET: positron emission tomography; S: standard of care.

The Society (2015) also published guidelines on the role of cytotoxic therapy with HCT in patients with Hodgkin Lymphoma.^18, Select recommendations are shown in Table 4.

Table 4. Recommendations on Use of Cytotoxic Therapy with HCT to Treat Hodgkin Lymphoma

Recommendation	GOR	Highest LOE
Autologous HCT
Autologous HCT should not be offered as first-line therapy for advanced disease	A	1+
Autologous HCT should be offered as first-line therapy for patients who fail to achieve CR	B	2++
Autologous HCT should be offered as salvage therapy over nontransplantation (except localized disease or in patients with low-stage disease)	A	1+
Autologous HCT should be offered to pediatric patients with primary refractory disease or high-risk relapse who respond to salvage therapy	B	2++
Tandem autologous HCT 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 autologous HCT/allo-HCT	D	4
Allo-HCT is preferred over autologous HCT as second HCT (except in late relapse)	C	2+

allo: allogeneic; CR: Complete response; GOR: grade of recommendation; HCT: hematopoietic cell transplantation; LOE: level of evidence; RIC: reduced-intensity conditioning.

American College of Radiology

The American College of Radiology (2016) issued an Appropriateness Criteria on recurrent HL.^25, 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 three 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.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT00574496	Combination Chemotherapy Followed by Donor Stem Cell Transplant in Treating Patients With Relapsed or High-Risk Primary Refractory Hodgkin Lymphoma	30	Nov 2019
NCT01203020	Once Daily Targeted Intravenous (IV) Busulfex as Part of Reduced-toxicity Conditioning for Patients With Refractory Lymphomas Undergoing Allogeneic Transplantation	32	Dec 2018

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Hematopoietic Cell Transplantation for Hodgkin Lymphoma
Hematopoietic Stem Cell Transplantation for Hodgkin Lymphoma
Allogeneic Bone Marrow Transplant, Hodgkin Lymphoma
Autologous Bone Marrow Transplant, Hodgkin Lymphoma
Bone Marrow Transplant, Hodgkin Lymphoma
Conventional Preparative Conditioning, Hodgkin Lymphoma
High Dose Chemotherapy with Hematopoietic Stem Cell Support for Hodgkin Lymphoma
Hodgkin Lymphoma, High Dose Chemotherapy
Mini-Transplant, Hodgkin Lymphoma
Nonmyeloablative Allogeneic Stem-Cell Transplantation, Hodgkin Lymphoma
Reduced-Intensity Conditioning, Hodgkin Lymphoma
Stem Cell Transplant, Hodgkin Lymphoma
Transplantation, Bone Marrow/Stem Cell for Hodgkin Lymphoma

References:
1. National Cancer Institute (NCI). Adult Hodgkin Lymphoma Treatment (PDQ®)-Health Professional Version. 2017; http://www.cancer.gov/cancertopics/pdq/treatment/adulthodgkins/healthprofessional. Accessed January 9, 2018.

2. Swerdlow S, Campo E, Harris N, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4 ed. Lyon France: IARC; 2008.

3. Swerdlow SH CE, Pileri SA, Harris NL, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19;127(20):2375-90. PMID: 26980727. PMID

4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Hodgkin disease/lymphoma. Version 1.2017. https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed December 21, 2017.

5. American Cancer Society (ACS). Hodgkin Lymphoma Stages. https://www.cancer.org/cancer/hodgkin-lymphoma/detection-diagnosis-staging/staging.html. Accessed December 21, 2017.

6. Brice P. Managing relapsed and refractory Hodgkin lymphoma. Br J Haematol. Apr 2008;141(1):3-13. PMID 18279457

7. Schmitz N, Sureda A, 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. PMID 14970934

8. Schmitz N, Dreger P, Glass B, et al. Allogeneic transplantation in lymphoma: current status. Haematologica. Nov 2007;92(11):1533-1548. PMID 18024402

9. Federico M, Bellei M, Brice P, et al. High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy. J Clin Oncol. Jun 15 2003;21(12):2320-2325. PMID 12805333

10. Carella AM, Bellei M, Brice P, et al. High-dose therapy and autologous stem cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy: long-term results. Haematologica. Jan 2009;94(1):146-148. PMID 19001284

11. 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 meta-analysis. Crit Rev Oncol Hematol. Oct 2014;92(1):1-10. PMID 24855908

12. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. Apr 24 1993;341(8852):1051-1054. PMID 8096958

13. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. Jun 15 2002;359(9323):2065-2071. PMID 12086759

14. Seftel M, Rubinger M. The role of hematopoietic stem cell transplantation in advanced Hodgkin Lymphoma. Transfus Apher Sci. Aug 2007;37(1):49-56. PMID 17716946

15. Murphy F, Sirohi B, Cunningham D. Stem cell transplantation in Hodgkin lymphoma. Expert Rev Anticancer Ther. Mar 2007;7(3):297-306. PMID 17338650

16. 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. PMID 17253967

17. 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. PMID 18640574

18. 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. PMID 25773017

19. 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. PMID 26726948

20. 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. PMID 18086796

21. Fung HC, Stiff P, Schriber J, et al. Tandem autologous stem cell transplantation for patients with primary refractory or poor risk recurrent Hodgkin lymphoma. Biol Blood Marrow Transplant. May 2007;13(5):594-600. PMID 17448919

22. Morschhauser F, Brice P, Ferme C, et al. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin's lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol. Dec 20 2008;26(36):5980-5987. PMID 19018090

23. Ferme C, Mounier N, Divine M, et al. Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin's disease in relapse or failure after initial chemotherapy: results of the Groupe d'Etudes des Lymphomes de l'Adulte H89 Trial. J Clin Oncol. Jan 15 2002;20(2):467-475. PMID 11786576

24. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015;21(11):1863-1869. PMID 26256941

25. Winkfield KM, Advani RH, Ballas LK, et al. ACR Appropriateness Criteria(R) recurrent Hodgkin lymphoma. Oncology (Williston Park). Dec 15 2016;30(12):1099-1103, 1106-1098. PMID 27987203

26. Centers for Medicare & Medicaid Services. 110.23 - Stem Cell Transplantation (Formerly 110.8.1). 2016; https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/ncd103c1_Part2.pdf. Accessed January 9, 2018.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

38204
38205
38206
38207
38208
38209
38210
38211
38212
38213
38214
38215
38220
38221
38230
38232
38240
38241