Amyloidosis results from the misfolding of a protein from the native alpha helical state into a beta-pleated sheet. This equilibrium between a soluble precursor and an insoluble end product (the fibril) can be impacted by destabilizing the amyloid fibril protein, and research is under way to cause fibril dissolution, by interfering with binding of the amyloid P component or via antibodies against the fibril itself, that leads to shrinkage of amyloid tumors. These strategies are in early investigative stages, and the only available therapies in the clinic result in reduction of the precursor light chain protein supply, which leads to synthesis of the amyloid fibril. In virtually every instance, the available effective therapy is cytotoxic chemotherapy directed against the plasma cell, the source of amyloid light chain production.
When seeing a patient with newly diagnosed systemic amyloidosis, the clinician must first establish that the amyloidosis is indeed of light chain origin. An algorithm for doing this is shown in Figure 1. The clinician must be certain that the patient does not have a localized form of amyloidosis, which is not treated with chemotherapy, and that the amyloid is of immunoglobulin light chain derivation, the only form that is responsive to systemic chemotherapy. Once this has been done, the decision needs to be made on the role of systemic chemotherapy for a given patient.
According to Palladini et al, survival in patients with light chain (primary or AL) amyloidosis is best predicted by the combination of high-sensitivity cardiac troponin T (hs-cTnT) at presentation and changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) after chemotherapy. After treatment, progression of NT-proBNP and a more than 75% increase of hs-cTnT were independent prognostic determinants of survival. In primary amyloidosis, hs-cTnT is the best baseline prognostic marker. Therapy should be aimed at preventing progression of cardiac biomarkers, whereas NT-proBNP response confers an additional survival benefit.
The Role of Stem Cell Transplantation in the Management of Primary Amyloidosis
At Mayo Clinic, stem cell transplantation is the preferred intervention for patients with systemic amyloidosis who are eligible to receive this therapy. Twenty-five percent of patients receiving stem cell transplantation have been reported to be 10-year survivors, and for patients who achieve a complete response to treatment, the 10-year survival rate is 53%. Histologic regression of amyloid deposits has been seen when chemotherapy normalizes the serum free light chain, and this is most readily done with high doses of chemotherapy. The major impediment to widespread application of stem cell transplantation is the high treatment-related mortality, which we have recently reported has declined to 7%. Renal and cardiac organ responses are seen. With stem cell transplantation, complete hematologic responses were seen in 39% of patients. Organ responses were seen in 47% of patients. The most important predictor of outcome is stage. Even among patients with stage III amyloidosis (NT-proBNP > 332 pcg/mL and troponin T > 0.035 mcg/mL), the median survival was 58 months.
Validation of organ responses following stem cell transplantation has been performed using amyloid P component scans. Patients older than 65 years can receive transplants, and improved quality of life has been demonstrated. Key determinants of outcome following transplantation include excessive fluid accumulation during mobilization and the pretransplant value of the immunoglobulin free light chain. Refinement of patient selection is critical to ensure optimal outcomes. The number of organs involved and the extent of cardiac involvement do predict outcome. Reducing the dose of melphalan before transplantation reduces toxicity but also reduces response rate. A prospective randomized study of 100 patients has been reported showing no survival benefit with stem cell transplantation. A systematic review was subsequently published that also did not demonstrate the efficacy of stem cell transplantation. The high treatment-related mortality reported in these studies is a major concern.
Currently at Mayo Clinic, approximately 20% of patients with amyloidosis are eligible for stem cell transplantation. Advanced cardiac involvement and renal insufficiency are both contraindications to high-dose therapy before transplantation. It is clear from these studies[15,16] that transplantation in high-risk patients should not be undertaken, but an important question is still whether a more carefully selected cohort benefits from stem cell transplantation; we believe that the answer is yes, pending further trials. (The table outlines the transplantation eligibility criteria applied in patient selection at Mayo Clinic.)
The melphalan-prednisone combination has been shown to be superior to treatment with colchicine alone. Continuous oral low-dose melphalan provides palliation, although the response rates are low. In a seminal paper with 5 years of follow-up, outcomes in 46 patients ineligible for stem cell transplantation were reported, with organ responses in 48%, a 6-year actuarial survival rate of 50%, and a progression-free survival rate of 40%; the median overall survival time was 5.1 years. This regimen is widely considered to be the standard of therapy for patients who are not eligible for stem cell transplantation.
Others have reported far poorer results. A cohort of patients treated with oral melphalan and dexamethasone had a median survival time of only 10.5 months. A second report using parenteral melphalan with dexamethasone in 61 patients reported a median survival of 17.5 months and a 3-month all-cause mortality of 28%.
Much of the variability in outcomes is related to the proportion of patients with advanced cardiac amyloidosis who are included. Of 48 evaluable patients treated at Boston University with melphalan and dexamethasone, a com-plete hematologic response was achieved in 13% and a partial hematologic response was observed in 25%. Median survival for all 70 patients has not been reached, with a median follow-up of 17 months. The widely disparate survivals reported from these four studies[19–22] reflect the heterogeneity of amyloidosis and the importance of recognizing the proportion of patients enrolled with advanced cardiac involvement.
At Mayo Clinic, treatment with melphalan and dexamethasone is still considered a standard for nonstudy, nontransplant intervention (Figure 2). Because this combination has a relatively low toxicity profile, it can produce hematologic responses, and its oral availability makes it easy to tolerate. Because of the survival benefit seen with the use of novel agents when combined with traditional chemotherapy in patients with myeloma, novel agents have been rapidly adapted to the armamentarium of treatment of systemic amyloidosis.
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