Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

High-dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is included in the term HDC when applicable. The most significant adverse effect of HDC is marrow ablation. Thus, HDC is followed by infusion of hematopoietic stem cells to repopulate the bone marrow. Potential donors and sources of stem cells include the following.

Autologous hematopoietic stem cells are those harvested from patients prior to myeloablative therapy.

Syngeneic hematopoietic stem cells are those harvested from an identical twin. Their use obviously is limited by the rarity of identical twins.

Allogeneic hematopoietic stem cells are those harvested from a donor, after verifying the donor and recipient are well matched with respect to human leukocyte antigens (HLA). Allogeneic cells provide two theoretical advantages: the lack of tumor contamination associated with autologous stem cells and the possibility of a beneficial graft-versus-tumor effect. Their disadvantage is the risk of graft-versus-host disease (GVHD), which increases with greater HLA disparity and recipient age.

Stem-Cell Sources

Hematopoietic stem cells can be collected from either the bone marrow or the peripheral blood of patients or donors. Stem cells may be harvested from the peripheral blood using a pheresis procedure. To increase the number of stem cells in the peripheral circulation (termed mobilization), patients providing autologous blood stem cells are pretreated with a course of chemotherapy or hematopoietic growth factors, or both. Donors providing allogeneic blood stem cells are mobilized with growth factors only.

The following discussion does not distinguish between stem cells collected from the peripheral blood or marrow, and refers to either as SCS. Therefore, HDC/AuSCS refers to high-dose chemotherapy with autologous stem-cell support, while AlloSCS refers to allogeneic stem-cell support. However, note that hematopoiesis as measured by neutrophil and platelet counts recovers more rapidly after blood stem cells than after bone marrow stem cells. On the other hand, chronic GVHD after AlloSCS is more frequent with blood than with marrow stem cells.

Note also that blood harvested from the umbilical cord and placenta shortly after delivery of neonates contains stem and progenitor cells. Although cord blood is an allogeneic source, these stem cells are antigenically naïve and apparently are associated with a lower incidence of GVHD.

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, bone marrow, lymph nodes, and spleen, while in SLL they are generally confined to the lymph nodes. The Revised European-American/World Health Organization 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 present as asymptomatic enlargement of the lymph nodes, tend to be indolent, but can undergo transformation to a more aggressive form of disease (e.g., Richter’s transformation). The median age at diagnosis of CLL is approximately 72 years, but it may present in younger individuals, often as a poor-risk disease with significantly reduced life expectancy.

Treatment regimens used for CLL are generally the same as those used for SLL, and treatment outcomes are comparable for both diseases. Both low- and intermediate-risk CLL and SLL demonstrate relatively good prognoses with median survivals of 6 to 10 years, however, 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 disease history prompted an investigation of high-dose chemotherapy as a possible curative regimen.

For coverage of HDC with hematopoietic stem cell support for the treatment of non-Hodgkins lymphoma other that small lymphocytic lymphoma please see policies 2001022 (allogeneic) or 2000010 (autologous).

Effective February 2021

High Dose Chemotherapy (HDC) with Autologous Stem-Cell Support

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

High-dose chemotherapy (HDC) with autologous stem-cell support for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma is a specific contract exclusion in most member benefit contracts.

For contracts without a specific contract exclusion, autologous stem-cell transplantation does not meet primary coverage criteria that there be scientific evidence of effectiveness.

For contracts without a specific contract exclusion and without primary coverage criteria language, autologous stem-cell transplantation is considered investigational. Investigational services are an exclusion in the member benefit contract.

Allogeneic Hematopoietic Stem-Cell Transplantation

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Allogeneic hematopoietic stem-cell transplantation for the treatment of chronic lymphocytic leukemia or small lymphocytic leukemia in patients with markers of poor-risk disease (see below) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. Use of myeloablative or non-myeloablative regimens should be individualized based on patient’s age, presence of comorbidities, and disease burden.

Note: Poor risk disease is defined as: advanced Rai or Binet stage (III or IV), IgVh wild type (unmutated), expression of ZAP-70 protein, del 11q22-q23 (loss of ATM gene), del 17q13 (loss of p53), elevated CD38, or fludarabine refractory disease (primary refractory disease, early relapse < 12 months, or progressive disease with unfavorable genetic features).

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Allogeneic hematopoietic stem-cell transplantation for the treatment of chronic lymphocytic leukemia or small lymphocytic leukemia does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication not described above.

For contracts without primary coverage criteria, allogeneic hematopoietic stem-cell transplantation for the treatment of chronic lymphocytic leukemia or small lymphocytic leukemia for indications not described above is considered investigational. Investigational services are specific contract exclusion in most member benefit certificates of coverage.

Effective prior to February 2021

High-dose chemotherapy with autologous stem-cell support for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma is a specific contract exclusion in most member benefit contracts.

Allogeneic hematopoietic stem-cell transplantation is covered for the treatment of chronic lymphocytic leukemia or small lymphocytic leukemia in patients with markers of poor-risk disease (see below). Use of myeloablative or non-myeloablative regimens should be individualized based on patient’s age, presence of comorbidities, and disease burden.

For contracts without a specific contract exclusion, autologous stem-cell transplantation does not meet primary coverage criteria for effectiveness.

Effective prior to January 2012

High-dose chemotherapy with either autologous or allogeneic stem-cell support for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma is a specific contract exclusion in most member benefit contracts.

Non-myeloablative chemotherapy with allogeneic stem cell support for the treatment of chronic lymphocytic leukemia is not covered based on a member benefit contract exclusion in most member benefit contracts.

For contracts without a specific contract exclusion, these services do not meet primary coverage criteria for effectiveness.

For contracts without a specific contract exclusion and without primary coverage criteria language, these services are considered investigational. Investigational services are an exclusion in the member benefit contract.

Autologous Stem-Cell Support

This policy references a 1999 Blue Cross Blue Shield Association Technology Evaluation Center Assessment of high-dose chemotherapy (HDC) and autologous stem-cell support (AuSCS). The Blue Cross Blue Shield Association Technology Evaluation Center Assessment considered various applications of HDC, i.e., as consolidation therapy for patients in an initial complete remission; as initial therapy in patients who have not been previously treated but have poor prognostic features; and as salvage therapy in patients who have relapsed or have signs of minimal residual disease after initial chemotherapy. Since the available studies grouped patients with poor prognostic features together with those with relapsed or refractory disease, the Blue Cross Blue Shield Association Technology Evaluation Center Assessment similarly grouped these 2 categories together. The Blue Cross Blue Shield Association Technology Evaluation Center Assessment offered the following observations and conclusions:

A subsequent prospective, randomized clinical trial assessed the efficacy of autologous HSCT in previously untreated CLL patients (Sutton, 2011). 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 autologous 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 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 autologous HSCT in this setting may prolong time to progression compared with observation, but that because OS is not improved, autologous HSCT remains investigational for CLL/SLL patients (Montserrat, 2011).

Allogeneic Stem-Cell Support

A 2002 Blue Cross Blue Shield Association Technology Evaluation Center Assessment specifically focused on the use of HDC and allogeneic stem-cell support (HDC-AlloSCS) to treat CLL and SLL and offered the following observations and conclusions:

A literature search was conducted in April 2006 to update the earlier Blue Cross Blue Shield Association Technology Evaluation Center Assessments. The search found no randomized trials comparing HDC plus either AuSCS or AlloSCS with conventional-dose therapy for CLL or SLL. A search of the clinical trials database identified several ongoing Phase II trials focusing on different chemotherapy regimens. Recent reviews and editorials discuss uncertainties with respect to the type of transplant (autologous versus allogeneic), the intensity of pre-transplant conditioning, the optimal timing of HDC/SCS 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. Based on these uncertainties and the lack of randomized trials, available evidence is insufficient to alter conclusions of the previous Blue Cross Blue Shield Association Technology Evaluation Center Assessments and, therefore, the policy statement remains unchanged.

More recent data compiled in numerous review articles suggest that myeloablative allogeneic HSCT has curative potential for CLL or SLL. 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. 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 allogeneic 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. Six published nonrandomized studies involved a total of 328 patients with advanced CLL who underwent RIC allogeneic HSCT using conditioning regimens that included fludarabine in various combinations that included cyclophosphamide, busulfan, rituximab, alemtuzumab, and total-body irradiation. The majority of patients in these series were heavily pretreated, with a median 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 an 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 autologous 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) (Dreger, 2010). 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.

The precise timing of HSCT for CLL/SLL is unknown and therefore the exact benefit is uncertain. Transplantation within the context of a clinical trial is encouraged in order to establish what subsets of patients with CLL/SLL are best suited and when in the course of their disease such interventions are warranted. Transplantation has not been directly compared to chemotherapy in a prospective, randomized manner making trial participation all the more important. Current clinical trials include: NCT00899431 (M.D. Anderson), NCT01027000 (National Cancer Inst.), NCT00104858 (Fred Hutchinson Inst.), and NCT00425802 (Sloan Kettering).

This policy is being updated with a literature review through January 2014. There was no literature identified that would prompt a change in the coverage statement.

A literature search conducted through January 2015 did not reveal any new information that would prompt a change in the coverage statement.

A literature search conducted through December 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

A 2015 systematic review of autologous HCT as front-line consolidation in CLL included a literature search through November 2014 (Reljic, 2015). Four RCTs in adult patients were included in the review. Outcomes included OS, PFS, EFS, and harms (adverse events, treatment-related mortality and secondary malignancies). Four studies met inclusion criteria, with 301 patients randomized to the autologous HCT arm and 299 to the control arm using front-line therapy without HCT as consolidation. Autologous HCT did not result in a statistically significant improvement in OS (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.62 to 1.33) or in PFS (HR=0.70; 95% CI, 0.32 to 1.52). There was a statistically significant improvement in EFS favoring autologous HCT (HR=0.46; 95% CI, 0.26 to 0.83). There was not a higher rate of secondary malignancy or treatment-related mortality associated with autologous HCT.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in December 2016 did not identify any ongoing or unpublished trials that would likely influence this review.

A literature search conducted using the MEDLINE database through January 2018 did not reveal any new literature that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through January 2019. No new literature was identified that would prompt a change in the coverage statement.

A literature search was conducted through January 2020. There was no new information identified that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through January 2022. No new literature was identified that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through January 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Current National Comprehensive Cancer Network guidelines (v.1.2023) for CLL and small lymphocytic lymphoma (SLL) state the following regarding HCT (NCCN, 2022):

Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement.

	HDC & Allogeneic or Autologous Hematopoietic Stem Cell Support for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Description:	High-dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is included in the term HDC when applicable. The most significant adverse effect of HDC is marrow ablation. Thus, HDC is followed by infusion of hematopoietic stem cells to repopulate the bone marrow. Potential donors and sources of stem cells include the following. Donor Types Autologous Autologous hematopoietic stem cells are those harvested from patients prior to myeloablative therapy. Syngeneic Syngeneic hematopoietic stem cells are those harvested from an identical twin. Their use obviously is limited by the rarity of identical twins. Allogeneic Allogeneic hematopoietic stem cells are those harvested from a donor, after verifying the donor and recipient are well matched with respect to human leukocyte antigens (HLA). Allogeneic cells provide two theoretical advantages: the lack of tumor contamination associated with autologous stem cells and the possibility of a beneficial graft-versus-tumor effect. Their disadvantage is the risk of graft-versus-host disease (GVHD), which increases with greater HLA disparity and recipient age. Stem-Cell Sources Hematopoietic stem cells can be collected from either the bone marrow or the peripheral blood of patients or donors. Stem cells may be harvested from the peripheral blood using a pheresis procedure. To increase the number of stem cells in the peripheral circulation (termed mobilization), patients providing autologous blood stem cells are pretreated with a course of chemotherapy or hematopoietic growth factors, or both. Donors providing allogeneic blood stem cells are mobilized with growth factors only. The following discussion does not distinguish between stem cells collected from the peripheral blood or marrow, and refers to either as SCS. Therefore, HDC/AuSCS refers to high-dose chemotherapy with autologous stem-cell support, while AlloSCS refers to allogeneic stem-cell support. However, note that hematopoiesis as measured by neutrophil and platelet counts recovers more rapidly after blood stem cells than after bone marrow stem cells. On the other hand, chronic GVHD after AlloSCS is more frequent with blood than with marrow stem cells. Note also that blood harvested from the umbilical cord and placenta shortly after delivery of neonates contains stem and progenitor cells. Although cord blood is an allogeneic source, these stem cells are antigenically naïve and apparently are associated with a lower incidence of GVHD. 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, bone marrow, lymph nodes, and spleen, while in SLL they are generally confined to the lymph nodes. The Revised European-American/World Health Organization 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 present as asymptomatic enlargement of the lymph nodes, tend to be indolent, but can undergo transformation to a more aggressive form of disease (e.g., Richter’s transformation). The median age at diagnosis of CLL is approximately 72 years, but it may present in younger individuals, often as a poor-risk disease with significantly reduced life expectancy. Treatment regimens used for CLL are generally the same as those used for SLL, and treatment outcomes are comparable for both diseases. Both low- and intermediate-risk CLL and SLL demonstrate relatively good prognoses with median survivals of 6 to 10 years, however, 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 disease history prompted an investigation of high-dose chemotherapy as a possible curative regimen. For coverage of HDC with hematopoietic stem cell support for the treatment of non-Hodgkins lymphoma other that small lymphocytic lymphoma please see policies 2001022 (allogeneic) or 2000010 (autologous).

Policy/ Coverage:	Effective February 2021 High Dose Chemotherapy (HDC) with Autologous Stem-Cell Support Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria High-dose chemotherapy (HDC) with autologous stem-cell support for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma is a specific contract exclusion in most member benefit contracts. For contracts without a specific contract exclusion, autologous stem-cell transplantation does not meet primary coverage criteria that there be scientific evidence of effectiveness. For contracts without a specific contract exclusion and without primary coverage criteria language, autologous stem-cell transplantation is considered investigational. Investigational services are an exclusion in the member benefit contract. Allogeneic Hematopoietic Stem-Cell Transplantation Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria Allogeneic hematopoietic stem-cell transplantation for the treatment of chronic lymphocytic leukemia or small lymphocytic leukemia in patients with markers of poor-risk disease (see below) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. Use of myeloablative or non-myeloablative regimens should be individualized based on patient’s age, presence of comorbidities, and disease burden. Note: Poor risk disease is defined as: advanced Rai or Binet stage (III or IV), IgVh wild type (unmutated), expression of ZAP-70 protein, del 11q22-q23 (loss of ATM gene), del 17q13 (loss of p53), elevated CD38, or fludarabine refractory disease (primary refractory disease, early relapse < 12 months, or progressive disease with unfavorable genetic features). Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria Allogeneic hematopoietic stem-cell transplantation for the treatment of chronic lymphocytic leukemia or small lymphocytic leukemia does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication not described above. For contracts without primary coverage criteria, allogeneic hematopoietic stem-cell transplantation for the treatment of chronic lymphocytic leukemia or small lymphocytic leukemia for indications not described above is considered investigational. Investigational services are specific contract exclusion in most member benefit certificates of coverage. Effective prior to February 2021 High-dose chemotherapy with autologous stem-cell support for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma is a specific contract exclusion in most member benefit contracts. Allogeneic hematopoietic stem-cell transplantation is covered for the treatment of chronic lymphocytic leukemia or small lymphocytic leukemia in patients with markers of poor-risk disease (see below). Use of myeloablative or non-myeloablative regimens should be individualized based on patient’s age, presence of comorbidities, and disease burden. Note: Poor risk disease is defined as: advanced Rai or Binet stage (III or IV), IgVh wild type (unmutated), expression of ZAP-70 protein, del 11q22-q23 (loss of ATM gene), del 17q13 (loss of p53), elevated CD38, or fludarabine refractory disease (primary refractory disease, early relapse < 12 months, or progressive disease with unfavorable genetic features). For contracts without a specific contract exclusion, autologous stem-cell transplantation does not meet primary coverage criteria for effectiveness. For contracts without a specific contract exclusion and without primary coverage criteria language, autologous stem-cell transplantation is considered investigational. Investigational services are an exclusion in the member benefit contract. Effective prior to January 2012 High-dose chemotherapy with either autologous or allogeneic stem-cell support for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma is a specific contract exclusion in most member benefit contracts. Non-myeloablative chemotherapy with allogeneic stem cell support for the treatment of chronic lymphocytic leukemia is not covered based on a member benefit contract exclusion in most member benefit contracts. For contracts without a specific contract exclusion, these services do not meet primary coverage criteria for effectiveness. For contracts without a specific contract exclusion and without primary coverage criteria language, these services are considered investigational. Investigational services are an exclusion in the member benefit contract.

Rationale:	Autologous Stem-Cell Support This policy references a 1999 Blue Cross Blue Shield Association Technology Evaluation Center Assessment of high-dose chemotherapy (HDC) and autologous stem-cell support (AuSCS). The Blue Cross Blue Shield Association Technology Evaluation Center Assessment considered various applications of HDC, i.e., as consolidation therapy for patients in an initial complete remission; as initial therapy in patients who have not been previously treated but have poor prognostic features; and as salvage therapy in patients who have relapsed or have signs of minimal residual disease after initial chemotherapy. Since the available studies grouped patients with poor prognostic features together with those with relapsed or refractory disease, the Blue Cross Blue Shield Association Technology Evaluation Center Assessment similarly grouped these 2 categories together. The Blue Cross Blue Shield Association Technology Evaluation Center Assessment offered the following observations and conclusions: There are currently no randomized trials that report the outcomes of HDC followed by AuSCS compared to conventional therapy. Comparative studies using historical controls are subject to patient selection bias, since many patients may not be candidates for HDC due to coexisting co-morbidities. An additional difficulty in studying the outcomes of any therapy of CLL or SLL is the long follow-up periods required, due to the indolent natural history of the disease. There was insufficient evidence to permit scientific conclusions regarding the use of HDC followed by AuSCS as consolidation therapy in patients in complete remission. 2012 Update A subsequent prospective, randomized clinical trial assessed the efficacy of autologous HSCT in previously untreated CLL patients (Sutton, 2011). 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 autologous 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 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 autologous HSCT in this setting may prolong time to progression compared with observation, but that because OS is not improved, autologous HSCT remains investigational for CLL/SLL patients (Montserrat, 2011). Allogeneic Stem-Cell Support A 2002 Blue Cross Blue Shield Association Technology Evaluation Center Assessment specifically focused on the use of HDC and allogeneic stem-cell support (HDC-AlloSCS) to treat CLL and SLL and offered the following observations and conclusions: No randomized trials are available that compare survival after HDC-AlloSCS to conventional dose chemotherapy in patients with CLL or SLL. One retrospective analysis compared matched historical controls given conventional dose therapy to 24 patients treated with HDC-AlloSCS. This study reported significantly longer survival in the transplanted group than in matched historical controls. However, several known prognostic factors were not used to match controls with those treated with HDC-AlloSCS. In addition, data on baseline characteristics were inadequate to verify the similarity of the 2 groups. Furthermore, the samples were small and the duration of follow-up was short relative to the natural history of the disease. Since available evidence from published reports was inadequate to permit conclusions, and since it seemed unlikely that data from prospective controlled trials would be available anytime soon, Blue Cross Blue Shield Association Technology Evaluation Center commissioned a direct comparative analysis from the International Bone Marrow Transplant Registry (IBMTR). Results of this analysis show that treatment with an allotransplant rather than with conventional-dose salvage results in a 2.6-fold higher risk of dying in the first 12 months, and suggest a 2.6-fold lower risk after 12 months. At 60 months after treatment, the adjusted probabilities of survival were 43% and 29%, respectively, for HDC-AlloSCS versus conventional therapy. This analysis suggests approximately 1.7 times greater survival at 5 years after salvage therapy with HDC/AlloSCS than after conventional-dose salvage treatment. For some patients, this difference in long-term survival may outweigh the increased risk of early mortality. However, the Cox regression model used to adjust the survival curves included only well established prognostic factors for CLL and SLL. As yet unknown and thus unmeasured covariates might widen the confidence intervals for point estimates the analysis provided. Further, few patients contributed to the last third of the survival curves. Thus it is possible that with additional follow-up the apparent plateau on the adjusted survival curve beginning 3 years after allotransplant might convert to a decline similar to that seen for conventionally salvaged patients. Consequently, evidence from this analysis is insufficient to permit conclusion on the net health outcome of HDC-AlloSCS for relapsed or refractory CLL or SLL. A literature search was conducted in April 2006 to update the earlier Blue Cross Blue Shield Association Technology Evaluation Center Assessments. The search found no randomized trials comparing HDC plus either AuSCS or AlloSCS with conventional-dose therapy for CLL or SLL. A search of the clinical trials database identified several ongoing Phase II trials focusing on different chemotherapy regimens. Recent reviews and editorials discuss uncertainties with respect to the type of transplant (autologous versus allogeneic), the intensity of pre-transplant conditioning, the optimal timing of HDC/SCS 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. Based on these uncertainties and the lack of randomized trials, available evidence is insufficient to alter conclusions of the previous Blue Cross Blue Shield Association Technology Evaluation Center Assessments and, therefore, the policy statement remains unchanged. More recent data compiled in numerous review articles suggest that myeloablative allogeneic HSCT has curative potential for CLL or SLL. 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. 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 allogeneic 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. Six published nonrandomized studies involved a total of 328 patients with advanced CLL who underwent RIC allogeneic HSCT using conditioning regimens that included fludarabine in various combinations that included cyclophosphamide, busulfan, rituximab, alemtuzumab, and total-body irradiation. The majority of patients in these series were heavily pretreated, with a median 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 an 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 autologous 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) (Dreger, 2010). 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. The precise timing of HSCT for CLL/SLL is unknown and therefore the exact benefit is uncertain. Transplantation within the context of a clinical trial is encouraged in order to establish what subsets of patients with CLL/SLL are best suited and when in the course of their disease such interventions are warranted. Transplantation has not been directly compared to chemotherapy in a prospective, randomized manner making trial participation all the more important. Current clinical trials include: NCT00899431 (M.D. Anderson), NCT01027000 (National Cancer Inst.), NCT00104858 (Fred Hutchinson Inst.), and NCT00425802 (Sloan Kettering). 2014 Update This policy is being updated with a literature review through January 2014. There was no literature identified that would prompt a change in the coverage statement. 2015 Update A literature search conducted through January 2015 did not reveal any new information that would prompt a change in the coverage statement. 2017 Update A literature search conducted through December 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below. A 2015 systematic review of autologous HCT as front-line consolidation in CLL included a literature search through November 2014 (Reljic, 2015). Four RCTs in adult patients were included in the review. Outcomes included OS, PFS, EFS, and harms (adverse events, treatment-related mortality and secondary malignancies). Four studies met inclusion criteria, with 301 patients randomized to the autologous HCT arm and 299 to the control arm using front-line therapy without HCT as consolidation. Autologous HCT did not result in a statistically significant improvement in OS (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.62 to 1.33) or in PFS (HR=0.70; 95% CI, 0.32 to 1.52). There was a statistically significant improvement in EFS favoring autologous HCT (HR=0.46; 95% CI, 0.26 to 0.83). There was not a higher rate of secondary malignancy or treatment-related mortality associated with autologous HCT. Ongoing and Unpublished Clinical Trials A search of ClinicalTrials.gov in December 2016 did not identify any ongoing or unpublished trials that would likely influence this review. 2018 Update A literature search conducted using the MEDLINE database through January 2018 did not reveal any new literature that would prompt a change in the coverage statement. 2019 Update Annual policy review completed with a literature search using the MEDLINE database through January 2019. No new literature was identified that would prompt a change in the coverage statement. 2020 Update A literature search was conducted through January 2020. There was no new information identified that would prompt a change in the coverage statement. 2021 Update Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement. 2022 Update Annual policy review completed with a literature search using the MEDLINE database through January 2022. No new literature was identified that would prompt a change in the coverage statement. 2023 Update Annual policy review completed with a literature search using the MEDLINE database through January 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below. Current National Comprehensive Cancer Network guidelines (v.1.2023) for CLL and small lymphocytic lymphoma (SLL) state the following regarding HCT (NCCN, 2022): "Allogeneic HCT can be considered for CLL/SLL refractory to small-molecule therapy in patients without significant comorbidities." "For patients with CLL/SLL with del(17p) or TP53 mutation, a discussion of allogeneic HCT could be considered for patients in remission with or after ibrutinib therapy, if complex karyotype [CK] (≥3 abnormalities) is present. However, available data suggest that CK (≥5 abnormalities) is associated with inferior overall survival [OS] and event-free survival [EFS] following allogeneic HCT with reduced-intensity conditioning in patients with high-risk interphase cytogenetics." In patients with histologic transformation (Richter's) and progression, allogeneic HCT can be considered for certain patients with disease responding to initial chemotherapy. In addition, "autologous HCT may also be appropriate for patients with disease responding to initial therapy but who are not candidates for allogeneic HCT due to age, comorbidities, or lack of a suitable donor." 2024 Update Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement.

References:	Garcia-Escobar I, Sepulveda J, Castellano D et al.(2011) Therapeutic management of chronic lymphocytic leukaemia: state of the art and future perspectives. Crit Rev Oncol Hematol 2011; 80(1):100-13. Hallek M, Cheson BD, Catovsky D et al.(2008) 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. Delgado J, Milligan DW, Dreger P.(2009) Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time? Blood 2009; 114(13):2581-8. Dreger P, Corradini P, Kimby E et al.(2007) Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21(1):12-7. Dreger P, Dohner H, Ritgen M et al.(2010) Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood 2010; 116(14):2438-47. Dreger P.(2009) Allotransplantation for chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2009:602-9. Gladstone DE, Fuchs E,(2012) Hematopoietic stem cell transplantation for chronic lymphocytic leukemia, Opin Oncol. 2012 Jan 9. [Epub ahead of print]. Gribben JG.(2008) Role of allogeneic hematopoietic stem-cell transplantation in chronic lymphocytic leukemia. J Clin Oncol 2008; 26(30):4864-5. High-dose chemotherapy for chronic lymphocytic leukemia. 1999 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Vol 14, tab 20. High-dose chemotherapy plus allogeneic stem cells to treat chronic lymphocytic leukemia or small lymphocytic lymphoma. Blue Cross Blue Shield Association Technology Evaluation Center Vol 17, tab 4. High-dose chemotherapy with autologous stem cell support, treatment for chronic leukemia. Hayes Technology Assessment. August 2004. Keating MJ, Chiorazzi N, et al.(2003) Biology and treatment of chronic lymphocytic leukemia. Hematology (Am Soc Hematol Educ Program) 2003;153-7. Kipps TJ.(2009) Chronic lymphocytic leukemia: advances in assessing prognosis and therapy. American Society of Clinical Oncology (ASCO) Education Book 2009:385-93. Montserrat E, Gribben JG.(2011) Autografting CLL: the game is over! Blood 2011; 117(23):6057-8. Montserrat E.(2004) Treatment options in chronic lymphocytic leukemia. Hematol J 2004; 5 Suppl 1:S2-9. National Comprehensive Cancer Network (NCCN).(2022) NCCN clinical practice guidelines in oncology: chronic lymphocytic leukemia/small lymphocytic lymphoma. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed December 5, 2022. National Comprehensive Cancer Network.(2011) Non-Hodgkin's Lymphoma. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. V.4.2011. Pollack A.(2003) Current therapeutic options for subgroups of chronic lymphocytic leukemia. Planning risk-adapted treatment according to recognized prognostic factors. Haematologica 2003; 88:726-9. Reljic T, Kumar A, Djulbegovic B, et al.(2015) High-dose therapy and autologous hematopoietic cell transplantation as front-line consolidation in chronic lymphocytic leukemia: a systematic review. Bone Marrow Transplant. Aug 2015;50(8):1144. PMID 26242579 Rizouli V, Gribben JG.(2003) Role of autologous stem cell transplantation in chronic lymphocytic leukemia. Curr Opin Hematol 2003; 10:306-11. Sorror ML, Storer BE, Sandmaier BM et al.(2008) Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol 2008; 26(30):4912-20. Sutton L, Chevret S, Tournilhac O et al.(2011) Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood 2011; 117(23):6109-19.

	Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants. CPT Codes Copyright © 2024 American Medical Association.