MP 8.01.30

High-dose Chemotherapy and Hematopoietic Stem-cell Support for the Treatment of Chronic Myelogenous Leukemia

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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

Policy

Policy Guidelines

Benefit Application

Rationale

This policy was initially based on a 1986 TEC Assessment that addressed the use of allogeneic stem-cell transplant as a treatment of CML (1) and a 1994 TEC Assessment that addressed the use of autologous stem cell transplant. (2) The 1986 Assessment concluded that allogeneic stem-cell transplant 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-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. (3) Young, good-risk patients transplanted early in 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. (4, 5) 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 (6-8). These uncertainties will be resolved only after additional clinical studies and longer follow-up than presently 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 stem-cell transplant 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. (9) Even without such techniques, there have been isolated case reports of partial cytogenetic remissions after HDC with autologous stem-cell support, and 1 study has suggested that patients undergoing such therapy may have improved survival compared with historical controls. (3)

A literature search conducted in 1999 sought studies of autologous transplants for CML published after completion of the 1994 TEC Assessment. The search did not identify any comparative trials. A 1994 article summarized the results of 200 consecutive autologous transplants using purged or unpurged marrow from 8 different transplant centers. (10) 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. (3)

An updated literature search on autologous transplantation in May 2002 also 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. (11, 12) Others focused on patients who did not respond to or relapsed after initial treatment using interferon alfa. (13, 14) Finally, some focused on patients transplanted in the late chronic phase (15) or after transformation to accelerated phase or blast crisis. (16) 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. (6-8) Alternatively, it may be incorporated into combination regimens used for high-dose therapy.

2007 Update

Updated reviews of the peer-reviewed literature on MEDLINE identified no clinical trial publications that would alter existing conclusions. This finding is supported by a recent review article (17) Therefore, the policy statements are unchanged.

2007 National Comprehensive Cancer Network (NCCN) Guidelines

The 2007 National Comprehensive Cancer Network (NCCN) guidelines on chronic myelogenous leukemia (V.2.2007) recommend allogeneic bone marrow transplant for treatment of primary CML and CML with disease progression. (18) 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 frontline 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 frontline treatment option. The National Cancer Institute concurs that allogeneic SCT remains the only known curative option for CML. (19)

2008 Update
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. (20) 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 9 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 5 years among patients in chronic phase 1 at transplant. (21) In the largest experience, a retrospective EMBT study of 186 patients, OS was 54% at 3 years using a variety of RIC regimens in patients in chronic phase 1 ('n=118), chronic phase 2 ('n=26), acute phase ('n=30) and blast crisis ('n=12) (22). Among patients transplanted in CP1, OS was 69% at 3 years. Treatment-related mortality or nonrelapse mortality ranged from 0% at 1 year to 29% at 1 year.
RIC regimens have many of the same limitations as standard-intensity conditioning — relapse, GVHD (particularly chronic GVHD), and mortality from treatment-related causes other than myelotoxicity; comparison of study results is further compromised by heterogeneity among patients, treatments, outcome measures, and insufficient follow-up. Therefore, in the absence of prospective, comparative, randomized trials, only indirect comparisons can be made between the relative clinical benefits and harms associated with myeloablative and RIC regimens with allogeneic SCT. An underlying premise of this policy is that RIC allogeneic SCT is one of many conditioning regimens that can be used for which the evidence supports that allogeneic stem-cell transplant improves health outcomes. The role of RIC transplant in other settings is uncertain and requires direct comparative trials with adequate follow-up to analyze its safety and effectiveness. No such controlled trials were identified. It also seems unlikely that properly designed and powered trials will be conducted to compare standard stem-cell transplantation with nonmyeloablative transplantation in populations clearly eligible for transplant, largely because the two methods are applied to different patient populations.
CML was once the most common malignancy for which allogeneic SCT was performed, but by 2005 it was in eight 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. (23) It is clear RIC allogeneic SCT will continue to evolve and will likely supplant 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.
2008 National Comprehensive Cancer Network (NCCN) Guidelines
The 2008 National Comprehensive Cancer Network (NCCN) guidelines on chronic myelogenous leukemia (V.3.2008) have changed significantly since the 2007 update of this Policy. (24) NCCN recommends allogeneic bone marrow transplant as an alternative treatment option only for high-risk settings:

• patients who do not achieve hematologic remission after 3 months of imatinib therapy
• patients with no cytogenetic response or those in cytogenetic relapse at 6, 12, or 18 months, after achieving initial hematologic remission after 3 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.
2008 National Cancer Institute (NCI) clinical trial database (PDQ®)
A search of the National Cancer Institute (NCI) clinical trial database (PDQ®) in May 2008 identified 6 active randomized trials in the United States that involve stem-cell support for patients with CML. (http://www.cancer.gov/search/ResultsClinicalTrialsAdvanced.aspx?protocolsearchid=4624548)
Trials include allografting, using various HDC regimens, as well as different stem cell sources and mobilization protocols.

 

References:

 

Index

Policy History

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