MP 8.01.15

Hematopoietic Stem-Cell Transplantation for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

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Medical Policy
Section Therapy	Original Policy Date 7/31/99	Last Review Status/Date Reviewed with literature search/9:2008
Issue 9:2008		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, auto-SCT) or from a donor (allogeneic SCT, allo-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 compatibility between infused stem cells and the recipient is not an issue in auto-SCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allo-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 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.
Conventional Preparative Conditioning for Hematopoietic Stem-Cell Transplantation

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, auto-SCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo auto-SCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not graft-versus-host disease.
The conventional (“classical”) practice of allo-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.
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 allo-SCT. 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 allo-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.
Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are neoplasms of hematopoietic origin characterized by the accumulation of lymphocytes with a mature, generally well-differentiated morphology. In CLL, these cells accumulate in the blood, marrow, lymph nodes, and spleen, while in SLL they are generally confined to the lymph nodes. The Revised European-American/WHO Classification of Lymphoid Neoplasms considers B-cell CLL and SLL a single disease entity.
CLL and SLL share many common features and are often referred to as blood and tissue counterparts of each other, respectively. Both tend to occur in older individuals and present as asymptomatic enlargement of the lymph nodes. Both tend to be indolent in nature but can undergo transformation to a more aggressive form of disease (e.g., Richter’s transformation).
Treatment regimens used for CLL are generally the same as those used for SLL, and outcomes of treatment are comparable for the 2 diseases. Both low- and intermediate-risk CLL and SLL demonstrate relatively good prognoses with median survivals of 6 to 10 years, while the median survival of high-risk CLL or SLL may be only 2 years. Although typically responsive to initial therapy, CLL and SLL are rarely cured by conventional therapy, and nearly all patients ultimately die of their disease. This natural history prompted investigation of hematopoietic stem-cell transplantation as a possible curative regimen.

Policy

Policy Guidelines

Benefit Application

Rationale

This policy initially was based on two TEC Assessments, one from 1999 on autologous hematopoietic stem-cell transplantation (auto-SCT) for CLL or SLL (1); the other from 2002 on allogeneic stem-cell transplantation (allo-SCT) to treat CLL or SLL. (2) Both documents indicated that in the absence of randomized trials, existing data were insufficient to permit scientific conclusions regarding the use of either procedure, limited by interstudy heterogeneity in patient’s baseline characteristics, procedural differences, sample size, and short follow-up. A direct comparative analysis from the International Bone Marrow Transplant Registry (IBMTR) commissioned by TEC in 2002 to analyze allo-SCT results was insufficient to permit scientific conclusions on the net health outcome of this procedure for relapsed or refractory CLL or SLL.
Literature searches conducted between 2002 and July 2008 found no randomized trials of hematopoietic stem-cell transplantation compared with conventional-dose therapy for CLL or SLL. Recent reviews discuss uncertainties with respect to the type of transplant (autologous versus allogeneic), the intensity of pretransplant conditioning, the optimal timing of transplantation in the disease course, the baseline patient characteristics that best predict likelihood of clinical benefit from transplant, and the long-term risks of adverse outcomes. (3-8) The conclusions reached in these reviews suggest that while auto-SCT may prolong survival in selected patients with CLL or SLL, for example, those with chemotherapy-sensitive malignancy who had a good response to front-line therapy and transplanted early in the course of disease, it has not yet been shown to be curative. None of the single-arm or registry studies published to date has shown a plateau in overall survival at 4 to 6 years post-transplant.
A systematic review of auto-SCT for CLL or SLL that included 9 prospective studies, none of which was randomized, further highlighted the difficulties of interstudy comparisons of this evidence on this treatment. (9) The authors of the review concluded that in the absence of randomized, controlled studies, it is uncertain whether auto-SCT is superior to conventional chemotherapy (or current chemo-immunotherapy) combinations as first-line consolidation treatment in CLL or SLL patients, regardless of disease risk, or as salvage therapy in those with relapsed disease. While auto-SCT may achieve significant clinical response rates (74–100%) with relatively low treatment-related mortality (0–9%), molecular remissions are typically short lived, with subsequent relapse. Secondary myelodysplasia and myelodysplastic syndrome that may progress to frank acute myelogenous leukemia has been reported in 5–12% of patients in some studies of auto-SCT, which suggests caution in considering this approach, especially given the indolent nature of CLL or SLL.
Several review articles also indicate that while allo-SCT has curative potential for CLL or SLL, high rates ('>10%) of treatment-related mortality discourage this approach in early or lower-risk disease. (6-8) Long-term disease control due to a low rate of late recurrences has been observed in all published series, regardless of donor source or conditioning regimen. However, current evidence is insufficient to determine the optimal approach, and heterogeneity in patients, disease characteristics, regimens used, and outcomes precludes valid interstudy comparisons and analysis of results.
A 2007 position statement from the European Group for Blood and Marrow Transplantation (EBMT) suggests allo-SCT, myeloablative or RIC, may be considered in the context of an approved clinical trial in younger, high-risk or unfavorable cases. (10) The EBMT statement suggests these cases be discussed with a transplant center as early as possible to avoid extensive cytotoxic pretreatment or disease transformation. Furthermore, because the optimum transplant strategy may vary according to the clinical situation, it should be defined in approved prospective clinical protocols.
In 1988 and 1996, a National Cancer Institute-sponsored Working group (NCI-WG) on CLL published guidelines for the design and conduct of clinical trials to facilitate comparisons between treatments and establish definitions that could be used in scientific studies on the biology of this disease. The U.S. Food and Drug Administration also adopted these guidelines in their evaluation and approval of new agents. An updated version of the NCI-WG guidelines has been published that provides management recommendations based on new prognostic markers, diagnostic parameters, and treatment options. (11)
National Cancer Institute (NCI) Clinical Trials Database (PDQ®)
The NCI Clinical Trials Database indicated more than 20 phase II/III or I/II trials that focused on a variety of hematopoietic stem-cell transplantation approaches for treatment of CLL or SLL, primarily relapsed or refractory disease, second-line therapy or more (http://www.cancer.gov/search/ResultsClinicalTrialsAdvanced.aspx?protocolsearchid=5048032).

National Comprehensive Cancer Network (NCCN) Guidelines
The 2008 NCCN Guidelines for Non-Hodgkin’s Lymphoma do not include auto-SCT as a therapeutic option in CLL or SLL. (12) NCCN indicates allo-SCT (conditioning regimen unspecified) may be considered, preferably in a clinical trial, for patients younger than age 70 years with high-risk disease (Rai High Risk or del17p) or as salvage treatment in those with progressive disease. However, the NCCN recommendation is based on a single review article (category 2A).
Based on uncertainties outlined above in this Policy, and the lack of randomized trials, available evidence is insufficient to alter the policy statement. Since the impact of this treatment on clinical outcomes is unknown, these treatments are considered investigational.

 

References:

1. 1999 TEC Assessments; Volume 14, Tab 20
2. 2002 TEC Assessments; Volume 17, Tab 4
3. Abbott BL. Chronic lymphocytic leukemia: recent advances in diagnosis and treatment. The Oncologist 2006; 11(1):21-30.
4. Brugiatelli M, Bandini G, Barosi G et al. Management of chronic lymphocytic leukemia: practice guidelines from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2006; 91(12):1662-73.
5. Dreger P, Brand R, Michallet M. Autologous stem cell transplantation for chronic lymphocytic leukemia. Semin Hematol 2007; 44(4):246-51.
6. Gine E, Moreno C, Esteve J et al. The role of stem-cell transplantation in chronic lymphocytic leukemia risk-adapted therapy. Best Pract Res Clin Haematol 2007; 20(3): 529-43.
7. Kharfan-Dabaja MA, Anasetti C, Santos ES. Hematopoietic cell transplantation for chronic lymphocytic leukemia: an evolving concept. Biol Blood Marrow Transpl 2007; 13(4): 373-85.
8. Gribben JG. The role of stem cell transplantation in chronic lymphocytic leukemia. American Society of Clinical Oncology (ASCO) Education Book 2008; pp. 291-6.
9. Kharfan-Dabaja MA, Kumar A, Behera M et al. Systematic review of high dose chemotherapy and autologous haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: what is the published evidence? Br J Haematol 2007; 139(2):234-42.
10. Dreger P, Corradini P, Kimby E et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21(1):12-7.
11. Hallek M, Cheson BD, Catovsky D et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111(12): 5446-56.
12. Non-Hodgkin’s Lymphoma. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. V.3.2008; http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf

 

Index

Policy History

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