High-dose chemotherapy (HDC) followed by hematopoietic stem-cell transplant (HSCT) or stem-cell support (SCS) (i.e., blood or marrow) is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, umbilical cord blood, or bone marrow stem-cells.
A coverage position was created in 2000; this section of the current policy has been substantially revised, and has been updated with searches of the MedLine database through August 2012. The following is a summary of the key literature to date.
When the policy was created, it was based on two Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessments, one from 1999 on autologous hematopoietic stem-cell transplantation (autologous HSCT, auto-HSCT) for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (1); the other from 2002 on allogeneic hematopoietic stem-cell transplantation (allogeneic HSCT, allo-HSCT) to treat CLL or SLL. (2) Both documents indicated that existing data were insufficient to permit scientific conclusions regarding the use of either procedure, limited by inter study 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 BCBSA TEC in 2002 to analyze allo-HSCT 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 December 2008 found no randomized trials of HSCT compared with conventional-dose therapy for CLL or SLL. Recent reviews discuss uncertainties with respect to the type of transplant (autologous vs. 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-HSCT 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.
Autologous Hematopoietic Stem Cell Transplant (auto-HSCT)
A systematic review of auto-HSCT for CLL or SLL included 9 studies (total n=361, 292 of which were transplanted) identified from a search of MedLine databases. (9) Studies were included if they were full-publication English language reports of prospective randomized, non-randomized, or single-arm design. The analysis suggested that while auto-HSCT may achieve significant clinical response rates (74-100%) with relatively low treatment-related mortality (TRM) (0–9%), molecular remissions are typically short-lived, with subsequent relapse. Overall survival (OS) ranged from 68% at 3-years’ follow-up to 58% at 6 years. Secondary myelodysplasia and myelodysplastic syndrome (MDS) that may progress to frank acute myelogenous leukemia (AML) has been reported in 5-12% of patients in some studies of auto-HSCT, which suggests caution in considering this approach, especially given the indolent nature of CLL or SLL. The authors of the review concluded that in the absence of randomized, comparative studies, it is uncertain whether auto-HSCT 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.
The conclusions of the systematic review of auto-HSCT outlined above are congruent with results of a Phase III randomized trial published in 2010 that compared auto-HSCT (n=112) or post-induction observation (n=111) for consolidation in patients with CLL who were in complete remission (CR; 59% of total) or very good partial remission (PR; 27% of total) following fludarabine-containing induction therapy. (10) Patient age ranged from 31-65 years, with Binet stage A progressive (14%), B (66%), and C (20%) disease. None were known to have 17p deletion; 45% were known to not carry 17p deletion, but that status was unknown in 54% of all patients. The primary outcome, median event-free survival (EFS), was 51 months (range: 40-62 months) in the autograft group, compared to 24 months (range: 17-32 months) in the observed group; the 5-year EFS was 42% and 24%, respectively (p<0.001). The relapse rate at 5-year follow-up was 54% in the autograft group versus 76% in the observational group (p<0.001); median time to relapse requiring therapy or to death (whichever came first) was 65 months (range: 59-71 months) and 40 months (range: 25-56 months), respectively (p=0.002). Overall survival probability at 5-year follow-up was 86% (95% confidence interval [CI]: 77-94%) in the autograft arm, versus 84% (95% CI: 75-93%) in the observation arm (p=0.77), with no evidence of a plateau in the curves. There was no significant difference in non-relapse mortality (NRM) between groups, 4% in the auto-HSCT group and 0% in the observation group (p=0.33). Myelodysplastic syndrome (MDS) was observed at follow-up in 3 patients receiving an autograft and in 1 patient in the observational group.
A subsequent prospective, randomized clinical trial assessed the efficacy of auto-HSCT in previously untreated CLL patients. (11) A total of 244 patients (181 males) of median age 56 years (range 31-66 years) had Binet stage B (n=185) or C (n=56) disease. Among enrollees, 237 started planned therapy, 6 of whom discontinued. All 231 patients underwent induction chemotherapy; 103 (45%) entered CR and were randomly allocated to auto-HSCT (n=52) or observation (n=53). The 3-year estimated OS rates were 98% (95% CI: 94%, 100%) in the observation arm, and 96% (95% CI: 90%, 100%) in the HSCT arm (p=0.73). The estimated hazard ration (HR) for death was 1.2 (95% CI: 0.3, 3.8) in the HSCT arm relative to the observation arm (p=0.82). During the 36 months after randomization, HSCT was associated, on average, with an extra 9 months without clinical symptoms or blood signs of CLL progression (32 ± 1 month) compared with observation (23 ± 2 months). An editorial that accompanied this report suggests using auto-HSCT in this setting may prolong time to progression compared with observation, but that because OS is not improved, auto-HSCT remains experimental, investigational and unproven for CLL or SLL patients. (12, 13)
Allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT)
Given that auto-HSCT based on myeloablative conditioning regimens has not been demonstrated to be a curative treatment of CLL or SLL, alternative modalities have been sought. Allo-HSCT has been under investigation for the past two decades based on a potent graft-versus-leukemia (GVL) effect expressed as a permanently active cellular immune therapy in the recipient, independent of chemotherapy-related cytotoxicity.
Data compiled in numerous review articles suggest that myeloablative allo-HSCT has curative potential for CLL or SLL. (6-8) Long-term disease control (33-65% OS at 3 to 6 years) due to a low rate of late recurrences has been observed in all published series, regardless of donor source or conditioning regimen. (14) However, high rates (24-47%) of treatment-related mortality (TRM) discourage this approach in early or lower-risk disease, particularly among older patients whose health status typically precludes the use of myeloablative conditioning.
The development of reduced-intensity conditioning (RIC) regimens has extended the use of allo-HSCT to older or less fit patients who account for the larger proportion of this disease than younger patients, as outlined in several recent review articles. (7, 14, 15) Six published nonrandomized studies involved a total of 328 patients with advanced CLL who underwent RIC allo-HSCT using conditioning regimens that included fludarabine in various combinations that included cyclophosphamide, busulfan, rituximab, alemtuzumab, and total-body irradiation. (16-21) The majority of patients in these series were heavily pretreated, with a median of 3-5 courses of prior regimens. Among individual studies, 27-57% of patients had chemotherapy-refractory disease, genetic abnormalities including del 17p13, del 11q22, and VH unmutated, or a combination of those characteristics. A substantial proportion in each study (18-67%) received stem-cells from a donor other than a human leukocyte antigen- (HLA-) identical sibling. Reported NRM, associated primarily with graft-versus-host disease (GVHD) and its complications, ranged from 2% at 100 days to 26% overall at median follow-up that ranged from 1.7 years to 5 years. Overall survival rates ranged from 48-70% at follow-up that ranged from 2-5 years. Similar results were reported for progression-free survival (PFS), 34-58% at 2-5 year follow-up. Very similar results were reported from a Phase II study published in 2010 of RIC allogeneic HSCT in patients (n=90; median age 53 years, range: 27-65 years) with poor-risk CLL, defined as having 1 of the following: refractoriness or early relapse (i.e., less than 12 months) after purine-analog therapy; relapse after auto-HSCT; or, progressive disease in the presence of an unfavorable genetic marker (11q or 17p deletion, and/or unmutated IgVh status and/or usage of the VH3-21 gene). (22) With a median follow-up of 46 months, 4-year NRM, EFS, and OS were 23%, 42%, and 65%, respectively. EFS was similar for all genetic subsets, including those with a 17p deletion mutation.
European Group for Blood and Marrow Transplantation (EBMT):
In June 2005, the EBMT convened a consensus panel to identify situations in which allo-HSCT is indicated for patients with CLL. (24) Information for this evidence-based consensus was based on a MedLine search; meeting abstracts, and unpublished investigator-derived data. The panel considered four key issues:
- Does graft-versus-leukemia (GVL) activity in CLL exist?
- If yes, is it effective in high-risk CLL?
- What is the success rate of allo-HSCT in CLL?
- Which prognostic risk level justifies allo-HSCT?
The EBMT panel concluded that there is sound evidence that GVL activity is effective and represents the main contributor to durable disease control after allo-HSCT, even in poor-risk patients. It further concluded that long-term disease-free survival and possibly cure may be achieved in 33-67% of patients who undergo allo-HSCT for poor-risk CLL. While allo-HSCT for CLL is a procedure with evidence-based efficacy for poor-risk CLL, evidence is not sufficient to identify a generally superior conditioning regimen. The optimum choice of conditioning regimens may vary: in the presence of older age, comorbidity and sensitive disease; RIC regimens might be appropriate, whereas myeloablative regimens might be preferable in younger patients with good performance status but poorly controlled disease. The EBMT statement further suggests that 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 whenever possible in approved prospective clinical protocols.
It should be noted that the consensus panel has not discussed this topic since 2005.
National Cancer Institute (NCI) Working Group on CLL:
In 1988 and 1996, a National Cancer Institute 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 (FDA) 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. (25) In August 2012, the NCI Database indicated over 130 Phase II/III trials in the treatment of CLL, first-line, second-line, relapsed or refractory disease.
National Comprehensive Cancer Network (NCCN) Guidelines:
Current NCCN Guidelines for non-Hodgkin’s lymphoma (NHL) do not include auto-HSCT as a therapeutic option in CLL or SLL. (26) NCCN indicates that allo-HSCT (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 or relapsed disease.
National Cancer Institute (NCI) Clinical Trials Database (PDQ®):
In August 2012, the NCI Clinical Trials Database indicated numerous Phase II/III trials that focused on a variety of hematopoietic SCT approaches for treatment of CLL or SLL, primarily relapsed or refractory disease, second-line therapy or more.
Summary for Auto-HSCT and Allo-HSCT
A substantial body of evidence from single-arm prospective and registry-based studies suggests allogeneic HSCT can provide long-term disease control and overall survival in patients with poor-risk CLL or SLL and otherwise dismal prognosis. This conclusion is supported by clinical input from transplant specialists as noted below. Until recently, it has been unclear what patient- and disease-specific characteristics can be used to select patients who could benefit from allo-HSCT compared to those for whom less-intense or no therapy may be indicated. This question has been addressed by investigations of cytogenetic and molecular abnormalities that can be associated with differential response to various therapies. (23)
Autologous HSCT is feasible in younger patients but is not curative, particularly in those with poor-risk CLL. None of the single-arm or registry studies of autologous HSCT published to date has shown a plateau in OS at 4 to 6 years post-transplant. It may result in prolongation of overall survival, compared with conventional therapy, but this must be considered in the context of improved outcomes using conventional chemoimmunotherapy.
Additional Infusion Treatments for CLL or SLL
Tandem or triple stem-cell transplant for CLL or SLL is considered experimental, investigational, and unproven due to lack of adequate evidence in published peer-reviewed medical literature of safety and effectiveness.
There are inadequate data regarding the efficacy of donor leukocyte infusion (DLI) for CLL or SLL. It is unlikely that sufficient prospective clinical trials will ever be conducted to rigorously compare outcome strategies using DLI for refractory hematologic malignancies post allo-HSCT other than AML or chronic myeloid leukemia (CML), since there are so few patients who would be eligible. Yet there is evidence from other types of studies that there is a graft-vs-malignancy effect after a nonmyeloablative allotransplant for these types of malignancies. While the risks of adverse outcomes are substantial, DLI may be considered a reasonable therapy for patients with hematologic malignancies who relapse after a previous medically necessary allo-HSCT. The benefit of DLI may exceed the harm for a specific selected patient.
Summary for Tandem or Triple SCT and DLI
Based on a search of peer reviewed literature in the MedLine database, through August 2012, there were no new clinical trial publications or any additional information that would change our coverage position; therefore, tandem or triple stem-cell transplant and DLI remain experimental, investigational and unproven for the treatment of CLL or SLL.
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