Medical Policy Title: HDC Progenitor Cell ARBenefits Approval: 02/08/2012 Support AL Amyloidosis (Light Chain Amyloidosis) Effective Date: 01/01/2013 Document: ARB0413:01 Revision Date: 10/24/2012 Code(s): 38230, Bone marrow harvesting for transplantation 38240, Bone marrow or blood-derived peripheral stem cell transplantation; allogenic 38241, Bone marrow or blood-derived peripheral stem cell transplantation; autologous 38242, Bone marrow or blood-derived peripheral stem cell transplantation; allogeneic donor lymphocyte infusions Public Statement: Administered by: Autologous stem cell transplant for light chain amyloidosis is covered in patients with authorization through case management by American Health Holding at 877-815-1017 (option 2). Medical Policy Statement: High dose chemotherapy with autologous stem cell support for treatment of AL amyloidosis is considered medically necessary and is covered when amyloid deposits that result in significant organ dysfunction have occurred in no more than 2 organs, and if there is cardiac involvement, the patient s cardiac ejection fraction is greater than 45%. Limits: High dose chemotherapy with allogeneic stem and/or progenitor cell support is not covered following autologous stem and/or progenitor cell transplantation. Tandem high dose chemotherapy with autologous stem and/or progenitor cell support is not covered for any diseases other than multiple myeloma and Waldenstrom s macroglobulinemia. Page 1 of 9
A second or subsequent course of high dose chemotherapy with allogeneic or autologous stem cell and/or progenitor cell support for treatment of relapsed disease is covered only for patients who have shown a complete response to the initial high dose chemotherapy/transplant regimen. Coverage of high dose chemotherapy with allogeneic or autologous stem and/or progenitor cell support for a patient with two active malignant diseases is covered only if both diseases have a specific coverage policy and the patient meets all criteria for both high dose chemotherapy with stem and/or progenitor cell treatment regimens. Background: Amyloidosis is the generic term for a group of systemic protein deposition diseases in which serum proteins misfold and polymerize, forming fibrils that deposit in multiple organs of the body, leading to organ dysfunction and death. Amyloidosis can be inherited (AF [familial amyloidosis]) or secondary to chronic inflammatory or infectious disease (AA [due to deposition of serum amyloid A protein. The most common systemic form, however, is AL [light chain amyloidosis]. In AL amyloidosis, a low grade clonal proliferation of bone marrow plasma cells secrets a monoclonal Ig Light Chain into the circulation that forms fibrillar deposits, which can impair the function of the heart, liver, kidneys, gastrointestinal tract, nervous system or lungs. Primary amyloidosis is not a malignancy, although it is related to multiple myeloma, also a plasma cell disorder. Clonal plasma cells are found in the marrow of patients with either disease. However, in those with primary amyloidosis, the proportion of marrow cells that are plasma cells does not change much with time. Initial results of HDC/AuSCS in uncontrolled patient series were published in 1998 (Comenzo, 1998; Moreau, 1998). Clinical response rates (50% to 60%) were nearly twice those reported for conventional therapy, and 2-year survival reportedly ranged from 56% to 68%. However, two issues tempered initial enthusiasm for these favorable results. First, early series reported procedure-related mortality of 15% to 43%, substantially higher than after HDC/AuSCS for multiple myeloma (<5%). Studies that evaluated risk factors for early death identified involvement of more than 2 organ systems and symptomatic cardiac involvement as significant predictors of treatmentrelated mortality (Moreau, 1998; Gertz, 2000b; Saba, 1999). The second concern with early results of HDC/AuSCS for amyloidosis was the lack of controlled studies and the possibility that patient selection bias may contribute to longer survival of those selected for transplant, when compared with the general population of amyloidosis patients managed conventionally. To address this concern, Dispenzieri, et al (2001) retrospectively analyzed outcomes of conventional therapy for primary amyloidosis in patients who would have been eligible for HDC/AuSCS. Inclusion required age younger than 70 years, cardiac interventricular septal thickness less than 15, cardiac ejection fraction more than 55%, serum creatinine less than 2 mg/dl, and Page 2 of 9
direct bilirubin less than 2.0 mg/dl. Patients eligible for HDC/AuSCS but managed conventionally reportedly had median survival of 42 months after conventional treatment, compared to median survival of only 18 months for all patients with primary amyloidosis. Survival of conventionally managed patients (n=229) at 24 months was 61%, which was similar to 56% to 65% survival at 24 months after HDC/AuSCS in 2 small series. In the same report, (Dispenzieri, 2001) also compared survival of 39 patients given HDC/AuSCS at their institution with survival of a matched cohort (n=78; 2 controls for each case) selected from their database of conventionally treated amyloidosis patients. Factors used to match patients were limited to age (within 5 years), gender, and number of involved organs. They reported similar survival of cases and controls at 6 (85% versus 83%), 12 (77% versus 74%), and 24 months (68% and 60%). Dispenzieri et al. concluded that randomized trials were needed to assess the efficacy of HDC/AuSCS. In a subsequent study (Dispenzieri, 2004) followed up their earlier matched-pair analysis. The new analysis included a larger group of cases (n=63) treated with HDC/AuSCS, and utilized parameters measuring severity of organ involvement to select matched controls (n=63). Factors used for matching were age; gender; time to presentation; left-ventricular ejection fraction; serum creatinine; cardiac septal thickness; nerve involvement; 24-hour urinary protein excretion; and serum alkaline phosphatase. At a median follow-up of 3.5 years from diagnosis for each group, 16 transplanted patients and 44 controls had died. Kaplan-Meier analysis showed significantly greater overall survival for those given autotransplants (p=0.004). Actuarially estimated survival at 4 years was 71% for transplanted patients and 54% for those managed conventionally. The survival curves also showed little to no difference in early mortality for the 2 groups. In addition to longer survival, there is evidence suggesting improvement in symptoms and quality of life for amyloidosis patients treated with HDC/AuSCS. Skinner et al, 2004) reported the largest retrospective series of amyloidosis patients eligible for transplant (n=394). Of the 394 eligible patients, 63 declined treatment and 19 lost eligibility when they progressed before treatment started. Estimated median survival for 312 patients who initiated stem-cell mobilization was 4.6 years, but median follow-up was not reported. Of 181 evaluable patients (alive and followed up for 1 year or more), 40% achieved complete hematologic response (CHR), defined as no evidence of plasma cell dyscrasia at 1 year after transplant. They reported functional improvement in at least 1 affected organ for 44% of evaluable patients: 66% of 73 patients with CHR and 30% of 108 patients with an incomplete or no hematologic response. Skinner et al. (2004) also reported that of 277 patients who completed the transplant protocol, 36 (13%) died of treatment-related toxicity before day 100 post-transplant, 21 (8%) died between day 100 and 1 year, and 39 were alive but had not reached 1 year since transplant. This series included all patients transplanted between July 1994 and June 2002, of which half (n=196) had 3 or more organs involved and 43% had some cardiac involvement. Patients with these poor prognostic features predominated among Page 3 of 9
the 21% who died within the first year. For example, median survival for those with cardiac involvement (n=137) was significantly shorter (1.6 versus 6.4 years; p<0.001) than for those without cardiac involvement (n=175) Two reports in 2004 from investigators with extensive experience in the use of high dose chemotherapy and stem cell support for amyloidosis recommended selection criteria for patients for whom high dose melphalan and peripheral blood stem cell transplant has been proposed. Dispenzieri, Lacy, Kyle, et al (2004) from the Mayo Clinic recommended that pat.ents with a cardiac ejection fraction less than 55% should be excluded. Skinner, Sanchorawala, Seldin, et al (2004) recommended that patients under 65 years of age have an ejection fraction of at least 45%. Medicare issued a national coverage decision on high dose chemotherapy stem cell support which excluded coverage for patients if there was presence of amyloid in more than 2 organs. Gertz, et al (2004) reported a multicenter phase 2 Eastern Cooperative Oncology Group study of 30 patients. Patients with advanced hepatic renal, or cardiac failure were excluded. The overall response rate was 64% with 3 treatment related deaths. Median follow-up was only 30 months, but median survival had not been reached. Schonland, and the European Cooperative Group for Blood and Marrow Transplantation (2006) reported on a retrospective study of high dose chemotherapy-allogeneic transplantation (n=7) and non-myeloablative chemotherapy-allogeneic transplantation (n=8) performed at multiple centers. The treatment related mortality was 40%, and selection criteria were variable. Complete remission occurred in 8, partial remission in 2, and organ response in 8. Seven of 10 patients in remission were long-term survivors. The authors noted that A prospective phase 2 study for allo-sct using reduced intensity conditioning was planned by the EBMT. The first randomized controlled trial comparing high dose melphalan followed by autologous peripheral blood stem cell support as compared to standard dose melphalan and high dose dexamethasone was reported by the Myelome Autogreffe and Intergroupe Francophone du Myelome Intergroup (Jaccard, et al, 2007). Fifty patients were enrolled in each group, with overall survival as the primary end point. The outcome in the transplant group was not superior to the outcome with standard-dose melphalan plus dexamethasone. (There were 4 patients in the control group, and 6 in the treated group whose ejection fraction was between 50% - 30%). On the basis of the Mayo Clinic criteria, 59 patients were at low risk for an adverse outcome of intensive treatment, and 41 were at high risk, mainly because of severe cardiac disease. The estimated 3-year overall survival rates were 70% among patients with low-risk disease and 25% among patients with high-risk disease. There were a number of concerns submitted as Letters to the Editor in response to the outcomes of this trial. Comenzo, Stigert, and Cohen from Memorial Sloan Kettering opined that the transplantation criteria were not stringent enough for patients with multiorgan failure (Comenzo, 2008). Lokhorst, et al. (2008) felt that the inferior survival of patients treated with high-dose melphalan was due to treatment delay. Kumar, Dispenzieri, and Gertz from the Mayo Clinic (2008) thought that the excessive mortality of the high-dose chemotherapy group Page 4 of 9
was due to the fact that 36% had involvement of three or more organs and poor cardiac status. Lachmann, Wechalekar, and Gillmore (2008) from the U.K. National Amyloidosis Centre supported the Jaccard study and stated, Chemotherapy without transplantation has been favored in the United Kingdom, where the median survival exceeded 60 months and treatment-related mortality was less than 7% among 448 patients with AL amyloidosis who received such regimens. Furthermore, a complete clonal response is not always necessary for long-term survival, since one third of patients with AL amyloidosis at our center who survived for longer than 10 years had only a partial hematologic response. Gertz, et al (2007) reported on 282 consecutive patients on whom stem cell transplant was used as therapy for newly diagnosed patients with primary amyloidosis. Partial response was achieved in 38%, and 33% achieved complete response. Survival rates were significantly different for patients with complete, partial, or no response. A univariate analysis was performed to identify factors that influenced overall survival. Survival was affected by hematologic response, BNP and serum troponin T levels, the number of organs involved, therapy intensity, serum creatinine level, and interventricular septal thickness. Sanchorawala, et al (2007b) reported their long-term outcomes in 80 patients who received high dose melphalan and PBSCT in the 1990 s. Seventeen patients died within the first year of treatment of treatment related complications or progressive disease. Of the 63 surviving evaluable patients at one year, 32 achieved a complete hematologic response. The median survival exceeded 10 years for patients achieving a complete response after high dose melphalan followed by PBSCT compared with 50 patients not achieving a complete response. This was not a randomized trial, and the results conflict with the RCT noted above, but strongly suggest that selected patients have improved outcomes following high dose melphalan and PBSCT. Whether these outcomes are better than what may be achieved with newer agents awaits appropriate trials. Recently, other drugs have been reported to be effective in the treatment of myeloma, and a study of bortezomib and dexamethasone has now been reported in the treatment of amyloidosis. The authors concluded from this small study of 18 consecutive patients that patients with severe cardiac or renal impairment could be managed with bortezomib and dexamethasone with a high probability of rapid response (Kastritis, 2007), Cohen, et al (Cohen, 2007) reported on a phase II trial of 45 patients who received high-doses melphalan with autologous SCT followed by adjuvant dexamethasone and thalidomide in newly diagnosed patients with = 2 organ systems involved. Follow-up was a median of 31 months. They concluded that risk-adapted SCT with adjuvant thalidomide/dexamethasone results in low treatment related mortality and high hematological and organ response. A second study, a phase II trial of lenalidomide and dexamethasone in the treatment of 24 patients with light chain amyloidosis described a complete hematologic response in 7 (29%) and a partial response in 9 (38%) (Sanchorawala, et al, 2007a). Page 5 of 9
Sanchorawala & Seldin (Sanchorawala, 2007c) reported their recommendations on treatment with high dose melphalan and stem cell transplant, and noted that patients can be stratified into three risk categories as follows: (i) good risk patients are of any age and have 1-2 organs involved, no cardiac involvement and creatine clearance > 50 ml/min; (ii) intermediate risk patients are < 71 years old and have 1-2 organs involved, one of which must include cardiac or renal with creatinine clearance < 51 ml/min; and (iii) poor risk patients have either three organs involved or advanced cardiac involvement. They further state It is clear that patients should be carefully selected for transplant, as advanced cardiac disease, more than two organ involvement, hypotension and poor performance status are poor prognostic factors for the outcome of HDM/SCT. A review of treatment of light chain amyloidosis was reported in the British J of Hematology in February 2008. The authors stated that autologous SCT achieves the highest rates of complete clonal response among the current treatments for light chain amyloidosis but go on to say that although responses to ASCT have undoubtedly been very durable in some patients, the same is true for others who have received intermediate dose regimens like oral melphalan -dexamethasone, and there is presently a paucity of clear comparative data of relapse-free survival in the literature. (Wechalekar AD, et al, 2008). The National Comprehensive Cancer Network Practice Guidelines in Oncology v2.2010 (accessed 29 July 2009) has the following statement regarding primary treatment for systemic light chain amyloidosis: There are insufficient data to indicate the optimal treatment of amyloidosis and, therefore, all patients should be treated in the context of a clinical trial when possible. Therapeutic options include: oral melphalan and dexamethasone, intermediate-dose or high-dose melphalan with stem cell transplant, dexamethasone and alpha-interferon, thalidomide and dexamethasone, bortezomib single agent, lenalidomide/dexamethasone/best supportive care. References: Cohen AD, Zhou P, Chou J, et al.(2007) Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone =/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial. Br J Haematol, 2007; 139:224-233. Comenzo RL, Gertz MA.(2002) Autologous stem cell transplantation for primary systemic amyloidosis. Blood 2002; 99(12):4276-82. Comenzo RL, Sanchorawala V, Fisher C et al.(1999) Intermediate-dose intravenous melphalan and blood stem cells mobilized with sequential GM+G-CSF or G-CSF alone to treat AL (amyloid light chain) amyloidosis. Br J Haemato 199l;104(3):553-9. Comenzo RL, Steingart RM, Cohen AD.(2008) High-dose melphalan versus melphalan Page 6 of 9
plus dexamethasone for AL amyloidosis [Letter]. New Engl J Med, 2008; 358:92 Comenzo RL, Vosburgh E, Falk RH et al.(1998) Dose-intensive melphalan with blood stem-cell support for the treatment of AL amyloidosis: survival and responses in 25 patients. Blood 1998; 91(10):3662-70. Dispenzieri A, Kyle RA, Lacy MQ, et al.(2004) Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a casecontrol study. Blood, 2004; 103:3960-3963. Dispenzieri A, Lacy MQ, Kyle RA, et al.(2001) Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival. J Clin Oncol 2001; 19:3350-56. Gertz MA, Blood E, Vesole DH, et al.(2004) A multicenter phase 2 trial of stem cell transplantation for immunoglobulin light chain amyloidosis (E4A97): an Eastern Cooperative Oncology Group Study. Bone Marrow transplant, 2004; 34:149-154 Gertz MA, Comenzo R, Falk RH, et al.(2005) Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis. Am J Hematol. 2005; 79:319-328 Gertz MA, Lacy MQ, Dispenzieri A.(2000) Myeloablative chemotherapy with stem cell rescue for the treatment of primary systemic amyloidosis: a status report. Bone Marrow Transplant 2000; 25(5):465-70. Gertz MA, Lacy MQ, Dispenzieri, et al.(2007) Effect of hematologic response on outcome of patients undergoing transplantation for primary amyloidosis: importance of achieving a complete response. Haematologica, 2007; 92:1415-1418 Gertz MA, Lacy MQ, Gastineau DA, et al.(2000) Blood stem cell transplantation as therapy for primary systemic amyloidosis (AL). Bone Marrow Transplant 2000; 26(9):963-9. Gertz MA.(1999) Amyloidosis: recognition, prognosis, and conventional therapy. American Society Hematology 1999; pp. 339-47; available online at http://www.hematology.org/education/hema99/gertz.pdf. Jaccard, A, Moreau P, Leblond, V, et al for the Myelome Autogreffe and Intergroupe Francophone du Myelome (IFM) Intergroup.(2007) High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. New Engl J Med, 2007; 357:1083-1093. Kastritis E, Anagnostopoulos A, et al.(2007) Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica, 2007; Page 7 of 9
92:1351-8. Kumar S, Dispenzieri A, Gertz MA.(2008) High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis [Letter]. New Engl J Med, 2008; 358:91 Kyle RA.(1999) High dose therapy in multiple myeloma and primary amyloidosis: An overview. Semin Oncol 1999; 26:74-83. Lachmann HJ, Wechalekar AD, Gillmore JD.(2008) High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis [Letter]. New Engl J Med, 2008; 358:91. Lokhorst HM, Hazenbert BPC, Croockewit A.(2008) High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis [Letter]. New Engl J Med, 2008; 358:92 Mhaskar R, Kumar A, Behera M, et al.(2009) Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review. Biol Blood Marrow Transplant, 3009; 15:893-902 Moreau P, Leblond V, Bourquelot P et al.(1998) Prognostic factors of survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol 1998; 101(4):766-9. Palladini G, Russo P, et al.(2007) Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood, 2007; 110:787-98. Saba N, Sutton D, Ross H, et al.(1999) High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant. BMT 1999; 24(8):853-5. Sanchorawala G, Skinner M, et al.(2007) Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation. Blood, 2007; 110:3561-3. Sanchorawala V, Seldin DC.(2007) An overview of high-dose melphalan and stem cell transplantation in the treatment of AL amyloidosis. Amyloid, 2007; 14:261-269 Sanchorawala V, Wright DG, et al.(2007) Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood, 2007; 109:492-6. Schonland SO, Lokhorst H, Buzyn A, et al, for the European Cooperative Group for Blood and Marrow Transplantation.(2006) Allogeneic and syngeneic hematopoietic cell transplantation in patients with amyloid light chain amyloidosis: a report from the European Group for Blood and Marrow Transplantation. Blood, 2006; 107:2578-2584. Seldin DC, Anderson JJ, Malek K et al.(2003) Treatment of AL amyloidosis patients with high dose melphalan and autologous stem cell transplantation (HDM/SCT) produces Page 8 of 9
durable remissions and improvement in quality of life. Blood 2003; 102 (11 pt. 1):452a (abstract 1651). (Available online at http://www.abstracts2view.com/hem). Seldin DC, Anderson JJ, Sanchorawala V, et al.(2004) Improvement in quality of life of patients with AL amyloidosis treated with high dose melphalan and autologous stem cell transplant. Blood, 2004; 104:1888-1893. Skinner M, Sanchorawala V, Seldin DC, et al.(2004) High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 2004; 140(2):85-93. Vesole DH, Perez WS, Akasheh M, et al for the Plasma Cell disorders Working committee of the Center for International Blood and Marrow Transplant Research.(2006) High-dose therapy and autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis: a Center for International Blood and Marrow Transplant Research Study. Mayo Clin Proc, 2006; 81:880-8. Wechalekar AD, Goodman HJ, Lachmann HJ, et al.(2007) Safety and efficacy of riskadjusted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood, 2007; 109:457-464. Wechalekar AD, Hawkins PN, Gillmore JD.(2007) Perspectives in treatment of AL amyloidosis. Br J Hematol, 2007; 140:365-77. Application to Products This policy applies to ARBenefits. Consult ARBenefits Summary Plan Description (SPD) for additional information. Last modified by: SCS Date: 10/25/2012 Page 9 of 9