MP 8.01.29

Hematopoietic Stem-Cell Transplantation for Hodgkin Lymphoma

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Medical Policy
Section Therapy	Original Policy Date 12/1/99	Last Review Status/Date Reviewed with literature search/6:2008
Issue 6:2008		Return to Medical Policy Index

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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

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Description

Hematopoietic Stem Cell Transplantation
Hematopoietic stem-cell transplantation (SCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole-body radiation therapy. Bone-marrow stem cells may be obtained from the transplant recipient (autologous SCT) or from a donor (allogeneic SCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft–versus-host disease. Cord blood is discussed in greater detail in policy No. 7.01.50.
Immunologic incompatibility between infused stem cells and the recipient is not an issue in autologous SCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic SCT. 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 HLA A, B, and DR loci on each leg of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.
Conventional Preparative Conditioning for Hematopoietic Stem Cell Transplantation
The conventional practice of allogeneic SCT involves administration of myelotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow failure. The beneficial treatment effect in this procedure results from chemotherapeutic eradication of malignant cells with an associated immune-mediated graft-versus-malignancy effect. While such treatment may eliminate the malignant cells, patients are as likely to die from opportunistic infections, graft-versus-host disease, and organ failure as from the underlying malignancy.
Autologous SCT necessitates myeloablative chemotherapy to eradicate cancerous cells from the blood and bone marrow, thus permitting subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic progenitor cells. As a consequence, autologous SCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous SCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not graft-versus-host disease.
Reduced-Intensity Conditioning for Allogeneic Stem-Cell Transplantation
Reduced-intensity conditioning (RIC) refers to chemotherapy regimens that seek to reduce adverse effects secondary to bone marrow toxicity while retaining the beneficial graft-versus-malignancy effect of allogeneic transplantation. These regimens do not eradicate the patient’s hematopoietic ability, thereby allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less) even without a transplant. Patients who undergo RIC with allogeneic SCT 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. A number of different cytotoxic regimens, with or without radiotherapy, may be used for RIC allotransplantation. They represent a continuum in their effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation.
Hodgkin Lymphoma (HL)

HL is a relatively uncommon B-cell lymphoma. In 2008, an estimated 8,220 new diagnoses and 1,350 deaths will occur in the U.S. (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 and older.

The 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 (NLPHL)

In Western countries, CHL accounts for 95% of cases of HL and NLPHL only 5%. (1) Classic HL is characterized by the presence of neoplastic Reed-Sternberg cells in a background of numerous non-neoplastic inflammatory cells. NLPHL lacks Reed-Sternberg cells, but is characterized by the presence of lymphocytic and histiocytic cells termed "popcorn cells". (1)

The following staging system for HL recognizes the fact that the disease is thought to typically 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.

Staging for Hodgkin Lymphoma

Staging for HL is based on the Ann Arbor staging system. Each stage is subdivided into A and B categories. "A" indicates no systemic symptoms are present and "B" indicates the presence of systemic symptoms including unexplained weight loss of more than 10% of body weight, unexplained fevers or drenching night sweats. (1)

Stage I
Involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE).
Stage II
Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph node(s) with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of lymph node regions involved should be indicated by a subscript (e.g., II2)
Stage III
Involvement of lymph node regions or structures on both sides of the diaphragm. These patients are further subdivided as follows:
III-1: disease limited to spleen or upper abdomen
III-2: periaortic or pelvic node involvement
Stage IV
Disseminated (multifocal) involvement of one or more extralymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.
Patients with HL are generally classified into 3 groups: early-stage favorable (stage I–II with no B symptoms 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). (1)
Patients with nonbulky stage IA or IIA disease are considered to have clinical early stage disease. These patients are candidates for chemotherapy, combined modality therapy, or radiation therapy alone. (3) Patients with obvious stage III or IV disease, bulky disease (defined as a 10-cm mass or mediastinal disease with a transverse diameter exceeding 33% of the transthoracic diameter), or the presence of B symptoms will require combination chemotherapy with or without additional radiation therapy. (3)
HL is highly responsive to conventional chemotherapy, and up to 80% of newly diagnosed patients can be cured with combination chemotherapy and/or radiation therapy. 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 4–6 cycles of anthracycline-containing chemotherapy, disease progression during induction therapy, or progression within 90 days after the completion of first-line treatment. (4)
In patients with relapse, the results of salvage therapy vary depending upon a number of prognostic factors, as follows: the length of the initial remission, with approximately 70% of patients with late first relapse being salvaged by autoSCT, but not more than 40% with early first relapse.(early and late relapse being defined as less or more than 12 months from the time of remission, respectively). (5) Other prognostic factors include stage at recurrence and severity of anemia at the time of relapse. (6) Of patients with refractory HL, only 20–35% may achieve long-term survival with autoSCT.

Policy

Policy Guidelines

Benefit Application

Rationale

Initially, this policy was based on a 1987 TEC Assessment focused on high-dose therapy plus autologous stem-cell support (7) and a 1990 TEC Assessment focused on high-dose therapy plus allogeneic stem-cell support. (8) Each report concluded that data showed longer survival of patients with relapsed disease after transplants than after standard therapy. Allogeneic stem cells may be preferred over autologous stem cells, if the relapse occurs in the bone marrow.

A 2000 TEC Assessment focused on HDC and allogeneic stem-cell support after a prior failed course of high-dose chemotherapy and autologous stem-cell support as treatment for various malignancies including Hodgkin’s disease. (9) The TEC Assessment found that data were inadequate to permit conclusions about outcomes of this treatment strategy.

The following data reflects the most current literature and treatment strategies as of May 2008, including the results of the relatively recent uses of RIC-alloSCTs.
Autologous SCT for HL
AutoSCT is widely considered the therapy of choice for relapsed and refractory HL. Two randomized, controlled studies showed benefit in using autoSCT in these patients:
The British National Lymphoma Investigation (BNLI) study was the first to show a progression-free survival benefit with autoSCT over conventional chemotherapy in relapsed or refractory HL patients. (10) Forty patients with relapsed or refractory HL were given chemotherapy without transplant ('n=20) or autologous transplant after high-dose chemotherapy ('n=20). (11) A significantly better event-free survival at 3 years of 53% versus 10% was reported in the patients who underwent transplant versus the group that did not.
Subsequently, these findings were confirmed in a larger trial by the GHSG and European Group for Blood and Marrow Transplantation (EBMT). (12) Patients relapsing after initial chemotherapy were randomized to chemotherapy without transplant or to autoSCT. In the final analysis of 144 patients, freedom from treatment failure at 3 years was 55% in the transplanted group, versus 34% in the nontransplanted group. This benefit was maintained in subgroup analysis, regardless of early or late relapse and the results were confirmed in follow-up data at 7 years. (13)
Several large retrospective studies have reported event-free survival rates ranging from 25–60%, with overall survival rates from 35–66%, showing that disease status before autoSCT was the most important prognostic factor for the final outcome. (4)

Limited treatment options exist for patients who relapse following an autologous SCT, and include single-agent palliative chemotherapy or occasionally, localized radiation therapy. (13) When a further remission may be attained with conventional-dose chemotherapy, it is rarely durable, with a median overall survival of less than 1 year. (14) There is limited experience with second autoSCTs, and treatment-related mortality is high (25–40%). (13) Allogeneic SCT is another possible treatment option.
Allogeneic SCT for HL
The application of alloSCT to the treatment of patients with HL initially appeared limited due to a procedure-related mortality rate of approximately 50% associated with the myeloablative conditioning regimen. (13) A small number of studies have investigated the role of RIC/alloSCT in refractory and relapsed HL, and the preliminary results have been encouraging, as detailed below. To date, most of the RIC alloSCTs have been performed in patients who have failed a previous autologous SCT for primary relapsed/refractory HL.
Peggs et al. investigated outcomes with RIC/alloSCT and T-cell depletion in multiply relapsed patients. (15) Forty-nine patients were enrolled, 90% of whom had failed a previous autologous transplant. Primary study endpoints were engraftment, toxicity, non-relapse-related mortality and graft-versus-host-disease incidence. All patients achieved engraftment. Thirty-one patients had an HLA-matched donor and 18 an unrelated donor. The cumulative incidence of non-relapse-related mortality was 4.1% at 100 days post-transplant and 16.3% at 730 days post-transplant. Patients with unrelated donors had a significantly higher non-relapse-related mortality, 34% versus 7% at 730 days. Projected 4 year overall survival and progression-free survival were 56% and 39%, respectively.
Alvarez et al. reported the results of a Spanish Cooperative Protocol using RIC/alloSCT in 40 patients with relapsed or refractory HL. (16) Seventy-three percent of patients had failed a previous autoSCT. Thirty-eight patients received hematopoietic cells from an HLA-identical sibling. One-year treatment-related mortality was 25%. Overall and progression-free survival were 48 and 32%, at 2 years, respectively. For patients who had failed a previous autoSCT, 2-year overall and progression-free survival were 75 and 70% in the subset that relapsed more than 12 months after autoSCT.
Todisco et al. evaluated the efficacy of RIC/alloSCT in 14 patients with refractory or progressive HL after high-dose chemotherapy (HDC) and autoSCT. (14) All of the patients had received at least one prior course of HDC, and 50% had undergone 2 previous. The median time from the first and second courses of HDC and the RIC/alloSCT was 15 and 8 months, respectively (range 2–34 and 2–31 months). With a median follow-up of 21 months post RIC/alloSCT (range 3–74 months), 10 of the 14 patients were alive. Estimated overall survival at 1 and 2 years was 93% and 73%, respectively, for the entire population, 83% and 44%, respectively, for patients with chemoresistant disease, and 100% for those with chemosensitive disease.

No randomized trial has compared autoSCT to alloSCT prospectively. (17)

In summary, the studies using RIC/alloSCT in relapsed/refractory HL are characterized by small numbers of patients, disparate preparative and graft-versus-host disease prophylaxis regimens, and varying lengths of follow-up. (10) Nonetheless, they demonstrate reduced non-relapse mortality and some suggest a graft-versus-HL effect with favorable disease control in these poor-prognosis patients. The results seem to be more favorable in patients with chemosensitive disease, with related donors, and in the subset of patient who have undergone a previous autoSCT, those who experience disease relapse more than 12 months after transplant.

Prospective, larger, comparative studies are needed to clarify the role RIC/alloSCT will play in the treatment of patients with HL.

Autologous SCT for front-line therapy of HD

A study published by Federico and colleagues concluded that HDC with autologous stem-cell transplantation offered no benefit in outcomes over conventional chemotherapy in front-line therapy for advanced Hodgkin’s lymphoma patients. (18) This supports the above policy statement indicating HDC as initial or upfront therapy is investigational.

Guidelines and PDQ Database

The 2006 National Comprehensive Cancer Network (NCCN) guidelines on HL (19) recommend HDC with autologous stem-cell support for relapsed or refractory disease consistent with this policy. However, the NCCN guidelines are silent on the use of allogeneic stem-cell support. The NCCN guidelines also specifically indicate that “up-front” HDC is not indicated, citing evidence that this approach offers no benefit over conventional therapy, as noted here. (18)
The 2008 NCCN guidelines state that autoSCT is the best option for patients with HL that is incurable with primary treatment, even though it does not improve overall survival. (1) The 2008 NCCN guidelines state that allogeneic transplant is an option in select patients with progressive or relapsed disease.
A search of the National Cancer Institute’s Physician Data Query database identified 2 active phase III randomized studies of SCT which include patients with HL:

 

References:

1. Hodgkin Disease/Lymphoma. Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. V.2.2008. Available online at http://www.nccn.org/professionals/physician_gls/PDF/hodgkins.pdf. Last accessed June 2008.
2. Harris NL, Jaffe ES, Diebold J et al. The World Health Organization Classification of Hematological Malignancies Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Mod Pathol 13:193-207;
3. Physician Data Query. Adult Hodgkin lymphoma treatment. Modified 04/29/2008. Available online at http://www.cancer.gov/cancertopics/pdq/treatment/adulthodgkins/healthprofessional. Last accessed June 2008.
4. Brice P. Managing relapsed and refractory Hodgkin lymphoma. Br J Haematol 2008; 141:3-13.
5. Schmitz N, Dreger P, Glass B et al. Allogeneic transplantation in lymphoma: current status. Haematologica 2007; 92:1533-48.
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 2004; 31:27-32.
7. 1987 TEC Assessments; p. 36.
8. 1990 TEC Assessments; p. 178.
9. 2000 TEC Assessments; Tab 9.
10. Seftel M, Rubinger M. The role of hematopoietic stem cell transplantation in advanced Hodgkin lymphoma. Transfus Apher Sci 2007; 37:49-56.
11. 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; 341:1051.
12. Schmitz N, Pfistner B, Sextro M et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haematopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet 2002; 359(9323):2065-71.
13. Murphy F, Sirohi B, Cunningham D. Stem cell transplantation in Hodgkin lymphoma. Expert Rev Anticancer Ther 2007; 7(3):297-306.
14. 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 2007; 78:322.
15. Peggs KS, Hunter A, Chopra R et al. Clinical evidence of a graft-versus-Hodgkin’s-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet 2005; 365(9475):1934-41.
16. Alverez I, Sureda A, Caballero MD et al. Non-myeloablative stem cell transplantation is an effective therapy for refractory or relapsed Hodgkin’s lymphoma: Results of a Spanish prospective cooperative protocol. Biol Blood Marrow Transplant 2006; 12:172-83.
17. David KA, Mauro L, Evens AM. Relapsed and refractory Hodgkin lymphoma: Transplantation strategies and novel therapeutic options. Curr Treat Options Oncol 2007; 8:352-74.
18. 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 2003; 21(12):2320-5.
19. Hodgkin Disease/Lymphoma. Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. V.1.2006. http://www.nccn.org/professionals/physician_gls/PDF/hodgkins.pdf.

Index

Hematopoietic Stem-Cell Transplantation, Hodgkin Lymphoma

Policy History

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