Medical Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Hodgkin Lymphoma (HL)

Number:SUR703.040

Effective Date:07-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Autologous myeloablative (high-dose chemotherapy [HDC]) or allogeneic hematopoietic myeloablative stem-cell transplantation (HSCT) may be considered medically necessary in patients with primary refractory or relapsed Hodgkin lymphoma (HL).

Tandem autologous HSCT may be considered medically necessary for:

Patients with primary refractory HL; or

Patients with relapsed disease with poor risk features who do not attain a complete remission to cytoreductive chemotherapy prior to transplantation.

Non-myeloablative or reduced-intensity allogeneic HSCT may be considered medically necessary to treat HL in patients:

Who have failed a prior autologous HSCT used to treat primary refractory or relapsed disease; or

Who would otherwise qualify for a myeloablative allogeneic transplant, but would be unable to tolerate a standard myeloablative HDC conditioning regimen; or

When insufficient stem-cells are collected for an autologous HSCT.

Second autologous HSCT for relapsed lymphoma after a prior autologous HSCT is considered experimental, investigational and/or unproven.

Allogeneic HSCT is considered experimental, investigational and/or unproven when using myeloablative HDC allogeneic HSCT regimen to treat HL relapsing after an autologous HSCT used to treat primary or refractory disease.

Other uses of autologous or allogeneic HSCT in patients with HL are considered experimental, investigational and/or unproven, including, but not limited to, initial therapy or upfront therapy for newly diagnosed disease to consolidate a first complete remission.

NOTE 1: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.

Description:

Hematopoietic Stem-Cell Transplantation (HSCT)

HSCT refers to a procedure in which hematopoietic stem-cells are infused to restore bone marrow function in patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiation therapy. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). 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 (GVHD).

Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

Hodgkin Lymphoma (HL)

HL is a relatively uncommon B-cell lymphoma. In 2017, the estimated number of new cases in the U.S. 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 (WHO) classification divides HL into 2 main types (2):

1. “Classical” HL (CHL)

Nodular sclerosis,

Mixed cellularity,

Lymphocyte depleted,

Lymphocyte rich;

2. Nodular lymphocyte-predominant HL (NLPHL).

In Western countries, CHL accounts for 95% of cases of HL and, for NLPHL, only 5%. (3) CHL is characterized by the presence of neoplastic Reed-Sternberg cells in a background of numerous non-neoplastic inflammatory cells. NLPHL lacks Reed-Sternberg cells but is characterized by the presence of lymphocytic and histiocytic cells termed “popcorn cells”. (3)

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). (3)

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 extra lymphatic 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 extra lymphatic organ or site and its regional lymph node(s) with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of lymph node regions involved should be indicated by a subscript (e.g., II2).

III

Involvement of lymph node regions or structures on both sides of the diaphragm. 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 extra lymphatic organs, with or without associated lymph node involvement, or isolated extra lymphatic 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 or large mediastinal lymphadenopathy),

Early-stage unfavorable (stage I-II with large mediastinal mass, with or without B symptoms; stage IB-IIB with bulky disease), and

Advanced-stage disease (stage III-IV). (3)

Treatment

Patients with non-bulky 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. (4) 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. (4)

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 first-line treatment. (5)

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. (6) 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 HSCT but not more than 40% with early first relapse. (7)

Only 25% to 35% of patients with primary progressive or poor-risk recurrent HL achieve durable remission after autologous HSCT, 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.

In the Morschhauser et al. (2008) study of risk-adapted salvage treatment with single or tandem autologous HSCT for first relapse or refractory HL poor-risk relapsed HL was defined as 2 or more of the following risk factors at first relapse (8):

Time to relapse less than 12 months,

Stage III or IV at relapse, and

Relapse within previously irradiated sites.

The primary refractory disease was defined as disease regression less than 50% after 4 to 6 cycles of doxorubicin-containing chemotherapy or disease progression during induction or within 90 days after the end of first-line treatment.

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

The ideal allogeneic donors are HLA?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 GVHD and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, parts 1270 and 1271. (9) Hematopoietic stem-cells are included in these regulations.

Rationale:

This policy was originally created in 1990, moved to this policy in 2010. The policy has been updated with reviews of the MedLine database. The most recent literature review was performed through June 2018. While the coverage of this policy does not address myeloablative (MA) (also known as high-dose chemotherapy [HDC]) or reduced intensity conditioning (RIC) prior to hematopoietic stem-cell transplantation (HSCT), discussion of HSCT outcomes may be influenced by the type of preparative conditioning completed prior to the transplantation. The following is a summary of the key literature to date for preparative conditioning (MA or RIC), allogeneic or autologous HSCT.

Medical policies assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function--including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to 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 a technology, 2 domains are examined: the relevance and the 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 HSCT

Front-Line Therapy of Hodgkin Lymphoma (HL)

Federico et al. (2003) published results from an RCT of 163 patients with unfavorable HL who had received autologous HSCT or additional standard chemotherapy for consolidation after initial conventional chemotherapy. (10) Patients were randomized to HDC followed by autologous HSCT (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 HSCT arm and 89% in the standard chemotherapy arm (p=0.6). Five-year survival rates (overall survival [OS], failure-free, and relapse-free survival [RFS]) did not differ between the treatment groups, and the authors concluded that HDC with autologous HSCT offered no benefit in outcomes over conventional chemotherapy as first-line therapy for patients with advanced HL.

Carella et al. (2009) published 10-year follow-up results for the Federico study. (11) Ten-year OS rates were 85% (95% confidence interval [CI], 78% to 90%) for the HDC autologous HSCT 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 HSCT 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 HSCT.

Section Summary: First-Line Therapy for HL

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

Relapsed/Refractory HL

A systematic review and meta-analysis of the available RCTs on HSCT for patients with relapsed or refractory HL was published by Rancea et al., in 2014. (12) Reviewers included 3 RCTs, 2 (1993, 2002) of which compared HDC plus autologous HSCT with conventional treatment. (13, 14) 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 (HR) of 0.67 for patients treated with autologous HSCT, 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 HSCT treatment, with a HR of 0.55 (95% CI, 0.35 to 0.86).

The British National Lymphoma Investigation study (1993) was the first to show that autologous HSCT offered patients with relapsed or refractory HL a PFS benefit over conventional chemotherapy. (15) Forty patients with relapsed or refractory HL were given chemotherapy without transplant (n=20) or autologous HSCT after HDC (n=20). A significantly better event-free (EFS) survival rate at 3 years (53%) was reported for patients who underwent HSCT 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 (EMBT). (14) Patients relapsing after initial chemotherapy were randomized to chemotherapy without transplant or to autologous HSCT. In the final analysis of 144 patients, freedom from treatment failure at 3 years was 55% in the transplanted group versus 34% in the non-transplanted 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. (16)

In addition to the RCTs, several large retrospective studies identified in a systematic review have reported EFS rates ranging from 25% to 60%, with OS rates from 35% to 66%, showing that disease status before autologous HSCT was the most important prognostic factor for the final outcome. (5)

Section Summary: Relapsed or Refractory HL

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

Second Autologous HSCT for Relapsed HL After Prior Autologous HSCT

Few treatment options exist for patients who relapse following an autologous HSCT; they include single-agent palliative chemotherapy or occasionally, localized radiotherapy. (16) If further remission is attained with conventional-dose chemotherapy, it is rarely durable, with a median OS of less than 1 year. (17)

There is limited experience with second autologous HSCT, and treatment-related mortality is high (25%-40%). (13) Smith et al. (2008) reported on the outcomes of 40 patients (21 with HL, 19 with non-Hodgkin lymphoma [NHL]) who underwent a second autologous HSCT for relapsed lymphoma. (18) Reported results were combined for the 2 populations, but authors stated that the outcomes for both patient groups were similar. Median age at second HSCT was 38 years (range, 16-61 years). In 82% of patients, the second HSCT was performed more than 1 year after the first. Treatment-related mortality 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 HSCT, 73% of patients had died--2% 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 HSCT 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 HSCT for Relapsed HL After Prior Autologous HSCT

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

Allogeneic HSCT

First-Line Therapy for HL

The application of allogeneic HSCT to the treatment of patients with HL appears limited, due to a high procedure-related mortality. No controlled trials evaluating allogeneic HSCT as first-line treatment for HL were identified. In addition, 2015 and 2016 systematic reviews of HSCT for HL did not discuss studies using allogeneic HSCT as first-line therapy. (19, 20)

Section Summary: First-Line Therapy for HL

No studies specifically addressing allogeneic HSCT as first-line treatment for HL were identified.

Relapsed or Refractory HL

In 2016, Rashidi et al. published a systematic review and meta-analysis of studies evaluating allogeneic HSCT in HL. (20) 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 (Adapted from Rashidi et al. [2016]). (20)

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)

Table Key:

CI: confidence interval.

In multivariate analysis, more recent studies (i.e., 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: Relapsed or Refractory HL

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

Allogeneic HSCT for Relapsed HL After Prior Autologous HSCT

The 2016 Rashidi meta-analysis (described above) included 38 case series assessing patients who underwent allogeneic HSCT after a prior failed autologous HSCT. (20) In a multivariate analysis of factors associated with survival outcomes, reviewers found that a previous autologous HSCT 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 HSCT.

Section Summary: Allogeneic HSCT for Relapsed HL After Prior Autologous HSCT

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

RIC with Allogeneic HSCT

In 2015, Perales et al. conducted an evidence review as part of the development of clinical guidelines on HSCT for HL. (19) Reviewers evaluated a number of studies that showed better outcomes with RIC and with MAC regimens. For example, reviewers cited a 2008 study by the EMBT reporting outcomes in 89 HL patients with relapsed or refractory disease who received a RIC with allogeneic HSCT and were compared with 79 patients who received MAC (i.e., conventional group). (21) Sixty-two percent of the RIC group had undergone a previous autologous HSCT versus 41% of the MA group. Although the incidence of relapse was nearly double in the RIC group (57% versus 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 HSCT (relative risk [RR], 1.59; 95% CI, 1.07 to 2.35; p=0.02), the use of MAC (RR=1.62; 95% CI, 1.27 to 3.29; p=0.04), and the presence of refractory disease (RR=1.51; 95% CI, 1.03 to 2.21; p=0.003). Perales et al. 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: RIC with Allogeneic HSCT

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

Tandem (Autologous-Autologous) HSCT

Fung et al. (2007) reported results from a pilot study on HL that evaluated the toxicities and efficacy of tandem autologous HSCT in patients with primary refractory or poor-risk recurrent HL. (22) 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 HSCT in 245 patients with relapsed or refractory HL. (8) 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 response [PR]or complete response [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 HSCT. 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 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 complete response), and 17 achieved a complete response after the second transplant. Outcome analysis based on the intention-to-treat sample revealed that the 5-year freedom from 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. (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 HSCT, 5-year OS rates were 86% and 37% for complete and partial responders, all respectively. (23) The findings suggested that a single autologous HSCT would be 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 concluded that a trial randomizing patients to single vs tandem autologous HSCT 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-Autologous) HSCT

There are no RCTs comparing tandem autologous HSCT 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 HSCT than with single HSCT. However, the results of this trial were not definitive, and RCTs are needed to determine the efficacy of tandem transplants.

Ongoing and Unpublished Clinical Trials: Autologous, Allogeneic, and Tandem HSCT for HL

Some currently unpublished trials that might influence this policy are listed in Table 3.

Table 3. 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 2018

NCT01203020

Once Daily Targeted Intravenous (IV) Busulfex as Part of Reduced-toxicity Conditioning for Patients with Refractory Lymphomas Undergoing Allogeneic Transplantation

32

Dec 2018

Table Key:

NCT: National Clinical Trial.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers for Autologous, Allogeneic, and Tandem HSCT for HL

In 2009, the Blue Cross Blue Shield Association requested and received clinical input from various physician specialty societies and academic medical centers.

In response to requests, input was received from 2 academic medical centers while this policy was under review. The 2 reviewers agreed with the policy statements, with the exception of the use of a second autologous HSCT after a prior autologous HSCT, which both reviewers thought would be medically necessary in certain circumstances. The data to support the use of a second autologous HSCT are extremely limited, and the coverage for this use of HSCT remains experimental, investigational and/or unproven.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) Guidelines

The NCCN guidelines for HL (v.3.2018) include a recommendation for autologous HSCT 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. (3) The guidelines do not specifically address tandem transplants.

American Society for Blood and Marrow Transplantation (ABMT)

In 2015, guidelines were published by the ABMT on indications for autologous and allogeneic HSCT. (24) Recommendations describe the current consensus on the use of HSCT in and out of the clinical trial setting. The Society recommendations on HL are provided in Table 4.

Table 4. Recommendations for Use of HSCT to Treat HL

Indication

Allogeneic HSCT

Autologous HSCT

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

Table Key:

HSCT: hematopoietic stem-cell transplantation;

PET: positron emission tomography;

C: clinical evidence available;

N: not generally recommended;

S: standard of care.

In 2015, the Society also published guidelines on the role of cytotoxic therapy with HSCT in patients with HL. (19) Select recommendations are shown in Table 5.

Table 5. Recommendations on Use of Cytotoxic Therapy with HSCT to Treat HL

Recommendation

GOR

Highest LOE

Autologous HSCT

Autologous HSCT should not be offered as first-line therapy for advanced disease

A

1+

Autologous HSCT should be offered as first-line therapy for patients who fail to achieve CR

B

2++

Autologous HSCT should be offered as salvage therapy over nontransplantation (except localized disease or in patients with low-stage disease)

A

1+

Autologous HSCT should be offered to pediatric patients with primary refractory disease or high-risk relapse who respond to salvage therapy

B

2++

Tandem autologous HSCT is not routinely recommended in standard-risk patients

C

2+

Allogeneic HSCT

Allogeneic HSCT should be used for relapse after autologous HSCT 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 HSCT/allogeneic HSCT

D

4

Allogeneic HSCT is preferred over autologous HSCT as second HSCT (except in late relapse)

C

2+

Table Key:

HSCT: hematopoietic stem-cell transplantation;

HL: Hodgkin lymphoma;

CR: complete response;

GOR: grade of recommendation;

LOE: level of evidence;

RIC: reduced-intensity conditioning;

A: directly based on Level 1 evidence;

B: directly based on Level II evidence or extrapolated recommendations from Level I evidence

C: directly based on Level III evidence or extrapolated recommendations from Level I or II evidence

clinical evidence available;

D: directly based on Level IV evidence or extrapolated recommendations from Level I, II, or III evidence.

American College of Radiology (ACR)

In 2016, the ACR issued an Appropriateness Criteria on recurrent HL. (25) The criteria stated that while salvage therapy followed by autologous HSCT 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 HSCT 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.

European Society for Medical Oncology (ESMO)

In 2014, the ESMO published guidelines on the diagnosis and treatment of HL. (26) 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 (ASCT).”

Summary of Evidence

Autologous Hematopoietic Stem-Cell Transplantation (HSCT)

For individuals who have Hodgkin lymphoma (HL) who receive autologous HSCT as first-line therapy, the evidence includes randomized clinical trials (RCTs). Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. RCTs of autologous HSCT 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 HSCT, the evidence includes RCTs, a meta-analysis, nonrandomized comparative studies, and case series. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. Two RCTs in patients with relapsed or refractory disease have reported a benefit in progression-free survival and a trend toward a benefit in overall survival. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

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

Allogeneic HSCT

For individuals who have HL who receive allogeneic HSCT as first-line therapy, the evidence includes no published studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. No studies specifically addressing allo-HSCT 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 allogeneic HSCT, the evidence includes a number of case series and a meta-analysis. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. A 2016 meta-analysis identified 38 case series evaluating allogeneic HSCT for relapsed or refractory HL. The pooled analysis found a 6-month overall survival rate of 83% and a 3-year overall survival rate of 50%. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have relapsed HL after autologous HSCT who receive allogeneic HSCT, the evidence includes case series and a meta-analysis. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. A 2016 meta-analysis of 38 case series found that a previous autologous HSCT followed by allogeneic HSCT was significantly associated with higher 1- and 2-year overall survival rates and significantly higher recurrence-free survival rates at 1 year compared with no previous autologous HSCT. 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 reduced-intensity conditioning (RIC) with allogeneic HSCT, the evidence includes case series, cohort studies, and a systematic review. Relevant outcomes are overall survival, disease-specific survival, change in disease status, morbid events, and treatment-related mortality and morbidity. A 2015 systematic review cited a number of studies, including some with comparison groups, showing acceptable outcomes after reduced-intensity conditioning with allogeneic HSCT 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 HSCT

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

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. NCI/PDQ – Physician Data Query (PDQ®). Adult Hodgkin lymphoma treatment (2015 April 2). National Cancer Institute. Available at <http://www.cancer.gov> (accessed 2015 April 14).

2. Swerdlow S, Campo E, Harris N, et al. WHO classification of tumors of hematopoietic and lymphoid tissues. 4th Edition. Lyon France: IARC; 2008.

3. NCCN – Hodgkin Lymphoma. NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Version. 3.2018. Available at <http://www.nccn.org> (accessed 2018 June 16).

4. ACS – Hodgkin Lymphoma Stages. American Cancer Society. Available at <https://www.cancer.org> (accessed 2018 June 17).

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

6. 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

7. Schmitz N, Dreger P, Glass B, et al. Allogeneic transplantation in lymphoma: current status. Haematologica. Nov 2007; 92(11):1533-48. PMID 18024402

8. 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):5980-7. PMID 19018090

9. Food and Drug Administration (FDA). Tissues and Tissue Products. Available at <http://www.fda.gov> (accessed 2015 September 23).

10. 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 Oncol. Jun 15 2003; 21(12):2320-5. PMID 12805333

11. 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):146-8. PMID 19001284

12. 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

13. 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 randomized trial. Lancet. 1993; 341(8852):1051-4. PMID 8096958

14. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous hemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomized trial. Lancet. 2002; 359(9323):2065-71. PMID 12086759

15. 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

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

17. 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):322-9. PMID 17253967

18. 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):904-12. PMID 18640574

19. 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):971-83. PMID 25773017

20. 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):521-8. PMID 26726948

21. 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):455-62. PMID 18086796

22. 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

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):467-75. 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):1863-9. 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):1099-103, 1106-1098. PMID 27987203

26. Eichenauer DA, Engert A, Andre M, et al. Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. Sep 2014; 25 Suppl 3:iii, 70-5. PMID 25185243

27. Hematopoietic Stem-Cell Transplantation for Hodgkin Lymphoma. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 February) Therapy 8.01.29.

Policy History:

Date Reason
7/15/2018 Document updated with literature review. Coverage unchanged. Rationale reorganized. References 4, 19-20, and 24-26 were added; numerous references removed.
6/1/2017 Reviewed. No changes.
7/15/2016 Document updated with literature review. Coverage unchanged.
7/15/2015 Document updated with literature review. Coverage unchanged. Title changed from Stem-Cell Transplant for Hodgkin Lymphoma.
6/1/2014 Document updated with literature review. The following was changed: 1) Allogeneic stem-cell support (AlloSCS) is considered experimental, investigational and/or unproven as initial therapy for newly diagnosed Hodgkin lymphoma (HL) to consolidate a few complete remission; 2) Autologous stem-cell support (AutoSCS) is considered experimental, investigational and/or unproven to perform a second AutoSCS for relapsed HL; 3) Tandem AutoSCS is considered medically necessary for patients with primary refractory HL or with relapsed disease with poor risks who do not attain complete remission to cytoreductive chemotherapy prior to transplantation; 4) expanded coverage to consider a) donor leukocyte infusion (DLI) and hematopoietic progenitor cell (HPC) boost as medically necessary for HL that has relapsed following an AlloSCS procedure, to prevent relapse in the setting of a high-risk relapse, or to convert a patient from mixed to full chimerism; b) DLI and HPC boost are considered experimental, investigational and/or unproven following an AlloSCS treatment for HL that was originally considered experimental, investigational and/or unproven for the treatment of HL OR as a treatment prior to AlloSCS; and 5) Expanded coverage to consider a) short tandem repeat (STR) markers as medically necessary when used in pre- or post-stem-cell support testing of the donor and recipient DNA profiles as a way to assess the status of donor cell engraftment; b) all other uses of STR markers as experimental, investigational and/or unproven . Description and Rationale significantly revised.
4/1/2010 New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem Cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies. Stem cell transplant continues to be medically necessary when stated criteria are met. [NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; Cord Blood as a Source of Stem Cells; Donor Leukocyte Infusion (DLI); and Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies.

Archived Document(s):

Back to Top