Coverage of, evaluation for, and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of primary systemic amyloidosis are identified in the grids below.
Any use of short tandem repeat (STR) markers for the treatment of primary systemic amyloidosis is considered experimental, investigational and unproven.
High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) transplant (HSCT) or stem-cell support (SCS) (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, umbilical cord blood, or bone marrow stem-cells.
Initially, this policy was based on a search of peer reviewed literature and included information on Waldenstrom Macroglobulinemia, which has been removed from this policy. The most recent update on primary amyloidosis was performed for the period of 2009 through 2013. Following is a summary of key references to date.
Conventional therapy for primary systemic amyloidosis usually combines oral melphalan with prednisone (MP), which has been shown to yield higher response rates and longer survival than colchicine or prior therapies. (1-3) Median survival after MP (approximately 18 months) is longer than for untreated patients or those given older therapies (10–14 months), but more effective regimens have been sought. Combination therapy with vincristine, doxorubicin, and dexamethasone (VAD), a well-established regimen for myeloma, has been investigated. (1, 2) However, because of its toxicity, VAD therapy usually is limited to patients without peripheral neuropathy or cardiomyopathy, both common complications of amyloidosis. Because conventional regimens rarely cure systemic amyloidosis, and because of the close biologic similarity to multiple myeloma, myeloablative chemotherapy with HSCT was investigated for this disease.
Autologous SCS (AuSCS)
Initial results of AuSCS in uncontrolled patient series were published in 1998. (4, 5) Clinical response rates (50% to 60%) were nearly twice those reported for conventional therapy, and 2-year survival reportedly ranged from 56% to 68%. (2, 6) However, procedure-related mortality rates of 15% to 43% were substantially higher than those observed in myeloma patients, usually in cases that involved more than 2 organ systems or had symptomatic cardiac involvement. (5, 7, 8)
A subsequent retrospective study analyzed outcomes of conventional therapy for primary amyloidosis in patients who would have been eligible for AuSCS. (6) Inclusion required age younger than 70 years, cardiac interventricular septal thickness less than 15, left ventricular ejection fraction (LVEF) more than 55%, serum creatinine less than 2 mg/dL, and direct bilirubin less than 2.0 mg/dL. Patients eligible for transplantation 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% - 65% survival at 24 months after AuSCS.
In the same report, survival of 39 patients given AuSCS at their institution was compared with survival of a matched cohort (n=78; 2 controls for each case) selected from their database of conventionally treated amyloidosis patients.(6) 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%, all respectively).
A follow-up report to the matched-pair analysis cited above included a larger group of cases (n=63) treated with AuSCS and used parameters measuring severity of organ involvement to select matched controls (n=63). (9) Factors used for matching were age, gender, time to presentation, LVEF, 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 (OS) for those given autotransplants (p=0.004). The survival rates for the high dose and standard treatment groups at 1, 2, and 4 years were 89% and 71%; 81% and 55%; and 71% and 41%, respectively.
In addition to longer survival, evidence suggests improvement in symptoms for amyloidosis patients treated with AuSCS. In a large retrospective series of amyloidosis patients eligible for transplant (n=394), 63 patients declined treatment and 19 lost eligibility when they progressed before treatment started.(10) 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, defined as no evidence of plasma cell dyscrasia at 1 year after transplant. The authors reported functional improvement in at least 1 affected organ for 44% of evaluable patients: 66% of 73 patients with complete hematologic response, and 30% of 108 patients with an incomplete or no hematologic response. Among 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 one-half (n=196) had 3 or more organs involved and 43% had some cardiac involvement. Median survival for those with cardiac involvement (n=137) was significantly shorter (1.6 vs. 6.4 years, respectively; p<0.001) than for those without cardiac involvement (n=175).
A subsequent report based on the dataset from the large retrospective series outlined in the preceding paragraph provided an analysis of outcomes of risk-adjusted myeloablative melphalan and AuSCS in patients aged 65 years and older versus outcomes in those younger than 65 years, with up to 10 years of follow-up.(11) Patients younger than 65 years with LVEF of 45% or greater and adequate stem-cell yield (n=280; median age 55 years, range 29–64 years) received melphalan 200 mg/m2; those aged 65 years and older, those with reduced LVEF (40–45%), or those with lower stem-cell yield (n=65; median age 68 years, range 65–79 years) received risk-adjusted melphalan 140 mg/m2. No difference was observed in early treatment-related mortality (10.3% in patients 65 years or older vs. 13.4% in those younger than 65 years, p=0.665). A trend toward a lower rate of hematologic complete response (CR, defined as the absence of clonal plasma cells in the bone marrow by immunohistochemical staining and of monoclonal gammopathy by immunofixation electrophoresis of serum and urine) was observed in the older patients (27.6% for patients 65 years or older) versus 13.4% in those younger than 65 years (p=0.882). However, the median survival after AuSCS did not differ according to age (4.0 years for patients aged 65 years and older vs. 4.85 years for those younger than 65 years; log-rank p=0.28).
A registry analysis of 107 amyloidosis patients who received transplants between 1995 and 2001 at 48 centers included 37 (35%) patients who received a transplant for initial therapy of amyloidosis, while 27 (25%) received a transplant after 2 or more prior therapies.(12) With a median follow-up of 30 months after transplant, OS at 1 and 3 years was 66% (95% confidence interval [CI]: 56–75%) and 56% (95% CI: 45–66%), respectively. For those with no or 1 organ involved at transplant, survival at 1 year was 72% (95% CI: 61–82%), while for those with 2 or more organs involved, survival at 1 year was 54% (95% CI: 38–70%). Survival at 1 year also was greater for those without (69%; 95% CI: 58–79%) than with (56%; 95% CI: 37–74%) cardiac involvement. Treatment-related mortality at 30 days was 18% (95% CI: 11–26%), mostly among patients with cardiac and/or multiple organ involvement.
Long-term survival and outcomes were evaluated in a series of 80 patients with light-chain amyloidosis (AL) amyloidosis who were treated with myeloablative full-dose or risk-adjusted melphalan according to a risk-based protocol and underwent AuSCS. (13) All patients had a histologic diagnosis of amyloidosis with evidence of plasma cell dyscrasia and met eligibility criteria for AuSCS in clinical protocols. Patients (median age 56 years, range 29–71 years) received risk-adjusted melphalan 100 mg/m2 (n=37) or full-dose melphalan 200 mg/m2 (n=43) followed by AuSCS 24–72 hours after completion of the conditioning regimen. Treatment-related mortality was reported in 11 (14%) cases, 6 of whom had received risk-adjusted melphalan, while 5 received the full-dose regimen. Median survival for all 80 patients was 57 months; 18 (23%) were alive 10 or more years after undergoing AuSCS. Hematologic CR was assessed in 63 (79%) surviving patients at 1 year following treatment. Thirty-two of those patients (51%) achieved a hematologic CR; among those, median survival had not been reached at the time the report was prepared for publication. In contrast, the median survival for patients who failed to achieve a CR was 50 months, with a 6% estimated probability of survival at 10 years (p<.001 vs. patients with complete response).
In a series of 282 consecutive patients with AL amyloidosis who underwent AuSCS, investigators sought to determine whether or not a hematologic CR, as determined by normalization of serum and urine monoclonal protein levels, provides an adequate surrogate marker for OS. (14) All patients had AL histologically verified with Congo red tissue stain, and received risk-adjusted melphalan conditioning based on the presence of numbers of organs involved, creatinine level, age, and cardiac involvement. One third (n=93) of the patients received risk-adjusted melphalan (100 or 140 mg/m2) and 67% (n=189) received full-dose melphalan (200 mg/m2). The mortality at day 100 was 11%, with 28% of the cohort dead by the time this report was prepared. Ninety-three (33%) patients achieved a CR, 108 (38%) had a partial response (PR), and 36 (13%) had no response (NR) to AuSCS. Kaplan-Meier analysis showed that median survival was reached only in the NR group, compared with the CR and partial response (PR) groups after more than 80 months of follow-up (log-rank p<0.001 for NR vs. CR and PR). An analysis (landmark analysis) focused on patients who survived for at least 6 months after AuSCS included 86 patients in the CR group, 91 who had PR, and 36 NR patients. This analysis showed that the survival curve differences remained significant between response groups as in the overall cohort, with a median survival of 40 months reached only in the NR group.
One randomized multicenter trial involving 8 centers from the Myelome Autogreffe (MAG) and Intergroupe Francophone du Myelome (IFM) Intergroup has been reported in which conventional chemotherapy with melphalan plus dexamethasone was compared with myeloablative melphalan followed by AuSCS in patients with AL amyloidosis.(15) Patients between 18 and 70 years of age had a histologic diagnosis of AL amyloidosis and either a complete hematologic response characterization of amyloid deposits or evidence of a monoclonal immunoglobulin protein in the serum or urine or a monoclonal staining pattern of bone marrow plasma cells and had received no more than 2 courses of any chemotherapy regimen. They were randomly allocated, stratified according to age (younger than 65 years or 65 years or older) and according to the affected organ system (cardiac, renal, neurological, or other). Of note, approximately two thirds of the patients had 2 or more organs affected. Patients in the melphalan plus dexamethasone group (n=50) received monthly courses of dose-adjusted (according to cytopenic status) oral melphalan, 10 mg/m2 of body-surface area, on days 1 to 4 plus oral dexamethasone, 40 mg/day on days 1 to 4, for up to 18 courses if no severe adverse events occurred. In the AuSCS patients (n=50), hematopoietic stem cells were obtained from peripheral blood with granulocyte colony-stimulating factor mobilization. Melphalan was administered intravenously on day 0, and stem cells were infused on day 2, with the dose reduced from 200 mg/m2 to 140 mg/m2 for patients aged 65 years or older and for those with an LVEF less than 30%, a calculated creatinine clearance less than 30 mL/min, or severe liver disease. According to intention-to-treat (ITT) analysis, the hematologic response rate did not differ between groups, with 12 CR (24%) and 14 PR (28%) in the melphalan plus dexamethasone recipients versus 11 CR (22%) and 7 PR (14%) in the autologous HSCT group (p=0.11). At publication of the study, the median follow-up for the entire cohort was 24 months, and for survivors it was 36 months; 20 patients in the melphalan-dexamethasone group had died versus 31 in the AuSCS group. Among 65 patients who could be evaluated, the ITT median survival for patients assigned to melphalan plus dexamethasone was 56.9 months, versus 22.2 months in the AuSCS group (p=0.04). Survival rates and duration were significantly better in responders (CR plus PR) compared to NR (p<0.0001). Analysis of patients who survived for at least 6 months and who received their assigned treatment, showed no significant difference in survival rates in patients assigned to melphalan plus dexamethasone compared to AuSCS, with neither group reaching median survival after 80 months (p=0.38).
These randomized trial data suggest that AuSCS may be no more efficacious than conventional chemotherapy in prolonging survival among patients with AL amyloidosis. However, the results are limited by the size of the study, a lack of assessor blinding or allocation concealment, and a large attrition post-randomization. Thus, among 50 patients assigned to AuSCS, 13 (26%) did not receive the planned treatment (1 declined, 2 had insufficient stem-cell harvest, 10 died before treatment), whereas 7 of 50 (14%) assigned to melphalan plus dexamethasone did not receive planned treatment (5 died before treatment, 1 did not tolerate treatment, 1 received incorrect treatment). Therefore, even though this was a randomized trial, the results are not sufficient to change the policy statement given the body of evidence available from other, albeit nonrandomized, studies.
A series of 421 consecutive patients treated with high-dose melphalan and AuSCS at a single referral center compared outcomes for patients with and without a CR. (16) Treatment-related mortality was about 11% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and OS were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after SCS and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with high-dose melphalan and AuSCS resulted in a high organ response rate and long OS, even for those patients who did not achieve CR. These results are compatible with others cited above.
Allogeneic SCS (AlloSCS)
Data on the use of AlloSCS to treat AL amyloidosis are sparse, with no systematic evaluation in a clinical trial. (17) Concerns about the use of AlloSCS include high treatment-related mortality (more than 40%), morbidity secondary to graft-versus-host (GVH) disease (GVHD), and questions about the efficacy of a proposed graft-versus-malignancy (GVM) effect on low-grade plasma cell dyscrasias.
National Comprehensive Cancer Network Guidelines
The 2013 National Comprehensive Cancer Network (NCCN) guidelines include AuSCS as primary therapy for systemic amyloidosis; however, they caution that the optimal therapy is not established and that such treatment would best be performed in a clinical trial. (21)
National Cancer Institute Physician Data Query (PDQ®) Database
A search of the National Cancer Institute clinical trials PDQ database identified one active Phase III study. It compares hematologic response rate in patients with primary systemic amyloidosis treated with conventional chemotherapy comprising low-dose melphalan and dexamethasone versus high-dose melphalan followed by AuSCS and compares the toxicity of these regimens in these patients. The study was listed as MAYO-MC0482 MAYO-IRB-1691-05, MC0482, NCT00477971: Phase III Randomized Study of Low-Dose Melphalan and Dexamethasone Versus High-Dose Melphalan Followed By Autologous Hematopoietic Stem Cell Transplantation in Patients With Primary Systemic Amyloidosis.
Additional Infusion Treatments for Primary Amyloidosis
Tandem or triple stem-cell transplant and donor leukocyte infusion (DLI) for primary amyloidosis are considered experimental, investigational, and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.
As with DLI, hematopoietic progenitor cell (HPC) boost has a positive response rate for relapse following AlloSCS. (25) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. However, the data is insufficient for the use of HPC Boost following AlloSCS for treatment of non-hematological malignancies to lessen post-transplant graft failures. (22, 23, 24, 25)
Short Tandem Repeat (STR) Markers
Following SCS therapy, it is important to determine whether the new blood forming system is of the donor or the recipient, based upon the proportion of donor and recipient cells. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders) has been tested initially after the SCS, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (26, 27) Without further randomized trials using STR markers prior to or post SCS therapy for treatment of primary systemic amyloidosis, the data is insufficient to determine the outcome/effect of stem-cell engraftment. (29, 30, 31, 32, 33, 34)
Chemotherapy for the treatment of AL amyloidosis was introduced in 1972 in the form of MP. (3) Median survival with this regimen was typically 12 to 18 months, with therapy remaining unchanged until the introduction of AuSCS. The use of AuSCS for AL amyloidosis rapidly eradicates the amyloidogenic light chain produced by the clonal plasma cell populations, which is the proximal cause of pathology and subsequent death. This has extended survival rates to a reported 53% at 10 years in patients with a CR to treatment. (13) Transplant-related mortality rates have declined, from as high as 40% to 7% in current studies. (18) Therefore, AuSCS is an important option for patients who are deemed eligible, and it is considered medically necessary. Data on the use of AlloSCS are sparse and it remains experimental, investigational and unproven.
Based on a search of scientific literature in the MedLine database through March 2013, HPC boost to reduce the graft failure process and STR markers to monitor engraftment chimerism for the treatment of primary systemic amyloidosis are considered experimental, investigational, and unproven due to the lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.
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