High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) (i.e., blood or marrow) transplant 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 or bone marrow stem-cells.
This policy is based on a 1986 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment that addressed the use of allogeneic stem-cell transplant (SCT) as a treatment of CML and a 1994 TEC Assessment that addressed the use of autologous SCT. The 1986 Assessment concluded that allogeneic SCT met the TEC criteria. Since that time, allogeneic transplant has emerged as the standard treatment of CML when a suitable stem-cell donor is available. It is estimated that patients in chronic phase receiving an HLA (human leukocyte antigen )-matched sibling donor transplant have a 45–75% probability of long-term disease-free survival, while those transplanted with more advanced disease have a 15%–40% long-term survival. Young, good-risk patients transplanted early in the chronic phase from HLA-matched but unrelated donors reportedly have a 40–60% probability of long-term survival, although it is lower than that of similar patients transplanted from matched sibling donors. With the availability of imatinib mesylate, allogeneic transplants may be used less often to manage patients with CML, or they may only be used when a complete molecular response to the drug fails or is not achieved. These uncertainties will be resolved only after additional clinical studies are performed and longer follow-up is available.
Obvious limitations of allogeneic stem cells are the lack of a suitable donor for many patients and the increased morbidity of allogeneic transplant in older patients. An obvious limitation of autologous stem cells is the near certainty that leukemic cells will be infused back into the patient. The 1994 TEC Assessment concluded that autologous SCT did not meet the TEC criteria. However, it is recognized that many CML patients still have normal marrow stem cells, and research has focused on ways to isolate and expand this normal clone of cells. Techniques used have included ex vivo purging, long-term culture, and immunophenotype selection. Even without such techniques, there have been isolated case reports of partial cytogenetic remissions after autologous SCT, and one study has suggested that patients undergoing such therapy may have improved survival compared with historical controls.
A 1994 article summarized the results of 200 consecutive autologous transplants using purged or non-purged marrow from eight different transplant centers. Of the 200 patients studied, 125 were alive at a median follow-up of 42 months. Of the 142 transplanted in chronic phase, the median survival had not been reached at the time of publication, while the median survival was 35.9 months for those transplanted during an accelerated phase. Other data consist of small, single institution case series using a variety of techniques to enrich the population of normal stem cells among the harvested cells.
A search for literature from 2002 on autologous transplantation found no comparative trials, but identified several new reports from small, uncontrolled studies with a total of 182 patients (range: 15–41 patients) given autotransplants for CML. Patient populations varied across these studies. Some focused on newly diagnosed patients or those in the first year since diagnosis. Others focused on patients who did not respond to or relapsed after initial treatment using interferon alfa. Finally, some focused on patients transplanted in the late chronic phase or after transformation to accelerated phase or blast crisis. Although some patients achieved complete or partial molecular remissions and long-term disease-free survival, these studies do not permit conclusions free from the influence of patient selection bias. Note also that all autotransplanted patients included in these reports were treated before imatinib mesylate (Gleevec) became available. Since this drug has been shown to induce major hematologic and, less often, cytogenetic remissions, even among patients in accelerated phase and blast crisis, future studies of autotransplants for CML may focus on patients who fail or become resistant to imatinib mesylate. Alternatively, it may be incorporated into combination regimens used for high-dose therapy.
2007 National Comprehensive Cancer Network (NCCN) Guidelines
The 2007 NCCN guidelines on CML (V.2.2007) recommend allogeneic bone marrow transplant for treatment of primary CML and CML with disease progression. Autologous bone marrow transplant for CML is not addressed in these NCCN guidelines. Since response rates with imatinib (Gleevec) have been favorable as an initial treatment option, the NCCN mentions it is not clear whether allogeneic SCT should still be included as a front line treatment. However, since allogeneic SCT has been proven to be an effective therapy, the NCCN determined that it should continue to be included as a front line treatment option. The National Cancer Institute concurs that allogeneic SCT remains the only known curative option for CML.
Additional Review of Literature Through 2008
Allogeneic SCT became the standard therapy for CML in the 1980s when the graft-versus-leukemia (GVL) effect was shown to be the critical factor for long-term disease control. Since then, this procedure has continued to evolve, with important advancements in the use of nonmyeloablative or reduced-intensity conditioning (RIC) preparative regimens. RIC regimens were initially conceptualized as a means to extend the use of allogeneic SCT to the estimated 70% of CML patients who were ineligible for myeloablative conditioning regimens because of advanced age or comorbidities. The use of RIC and allogeneic SCT is of particular interest for treatment of CML given the relatively pronounced susceptibility of this malignancy to the GVL effect of allogeneic hematopoietic progenitor cells following their engraftment in the host. Overall, among nine studies compiled in a recent review, outcomes achieved with RIC allogeneic transplants have been similar to those with conventional allotransplants, with overall survival (OS) rates ranging from 35% at 2.5 years to 85% at five years among patients in chronic phase I at transplant. Among the studies included in this review, treatment-related mortality or non relapse mortality ranged from 0% at one year to 29% at one year. In the largest experience, a retrospective European Group for Blood and Marrow Transplantation (EMBT) study of 186 patients, OS was 54% at three years using a variety of RIC regimens in patients in chronic phase I (n=118), chronic phase II (n=26), acute phase (n=30), and blast crisis (n=12). Among patients transplanted in the first chronic phase (CP1), OS was 69% at three years.
CML was once the most common malignancy for which allogeneic SCT was performed, but by 2005 it was in eighth place among hematologic transplantation indications. A retrospective analysis of data from the Center for International Blood and Marrow Transplant Research Center (CIBMTR) showed that transplantation for CML was in decline prior to FDA approval of imatinib in 2001. It is clear RIC allogeneic SCT will continue to evolve, perhaps supplanting myeloablative conditioning regimens for select patients. However, the scientific evidence available to date does not provide direct comparison of health outcomes with sufficiently long follow-up in similar patient groups to draw conclusions about the net health benefit of this therapeutic approach. It also seems unlikely that properly designed and powered trials will be conducted to compare standard allogeneic SCT with RIC allogeneic SCT in CML patients clearly eligible for transplant, largely because the two methods are applied to different patient populations and given the effectiveness and primary role of FDA-approved TKIs.
The 2008 NCCN guidelines on CML recommend allogeneic bone marrow transplant as an alternative treatment option only for the following high-risk settings:
- patients who do not achieve hematologic remission after three months of imatinib therapy;
- patients with no cytogenetic response or those in cytogenetic relapse at six, 12, or 18 months, after achieving initial hematologic remission after three months of imatinib therapy;
- patients progressing on imatinib to accelerated phase or blast crisis.
Autologous bone marrow transplant for CML is not addressed in the NCCN guidelines.
The 2008 National Cancer Institute (NCI) clinical trial database (PDQ®) identified six active randomized trials in the United States that involve stem-cell support for patients with CML.
Trials include allografting, using various conditioning regimens, as well as different stem-cell sources and mobilization protocols.
Tandem or Triple Stem-Cell Transplant and Donor Leukocyte Infusion (DLI) for CML are considered experimental, investigational, and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.
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