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KOS 2007: AL Amyloidosis: Response, Assessment, and Treatment
By Morie A. Gertz, MD
Morie A. Gertz, MD
Mayo Clinic
Rochester, MN, U.S.A.
06.28.07

Mayo Clinic
Rochester, MN, U.S.A.

NOTE: THE AUDIO FOR THIS PRESENTATION IS NOT AVAILABLE DUE TO TECHNICAL PROBLEMS WITH THE RECORDING.



The ability to accurately assess the response to treatment in AL is critical, since without a consistent method, it next to impossible to assess the efficacy of competing therapies currently used for this disease. Radiolabeled amyloid P component with iodine 123 or iodine 131 is a useful imaging agent for detecting amyloid deposits. Serialized scans have been used to assess the response to therapy and have demonstrated regression of established amyloid deposits after successful interruption of immunoglobulin light chain production. The SAP scan does not distinguish AL from other forms of amyloidosis, but imaging will detect deposits in the spleen, liver, and kidneys in 87%, 60% and 25% of patients, respectively. Because of the cardiac blood pool, the SAP scan is not generally useful in detecting myocardial amyloid deposits and is usually used in conjunction with echocardiography. Plasma clearance of radiolabeled amyloid P component has been shown to correlate with survival. Rapid plasma clearance is associated with a high body burden of amyloid. Imaging studies do not correlate well with the clinical degree of organ dysfunction. As an example, hepatic involvement with an SAP component scan is common, but palpable hepatomegaly in AL is only seen in approximately 15% of patients (1).

Recently, magnetic resonance imaging has been used in an attempt to further define myocardial involvement with amyloid. The characteristic features of cardiac amyloidosis by magnetic resonance imaging include impaired biventricular systolic function, thickened atrioventricular valves, bi-atrial enlargement, increased atrioseptal thickness, and increased left ventricular mass (2). It is also presumed that serialized MRIs may be useful in monitoring the response in AL.
The immunoglobulin free light chain assay has been found to be important in both classifying the type of amyloidosis and providing a method for assessing response. It has also been found to be of prognostic value. The free light chain assay has been incorporated into the response criteria, and its high sensitivity has improved the ability to monitor the status of patients with AL. The absolute level of free light chain achieved after therapy predicts survival. Normalization of free light chain levels after transplantation predicted both organ response and complete hematologic response. In this study, the percent free light chain reduction did not predict for survival, but the absolute level of free light chain achieved after therapy did (3).

As in many malignancies, response to treatment has a profound effect on survival. Hematologic responders have superior survival to nonresponders, even in a landmark analysis to correct for early mortality. Organ responses, however, are time-dependent and renal responses have a median time to response of a year and can be delayed up to 36 months after transplantation. Hematologic responses can be seen in as many as two-thirds of patients with complete hematologic responses in a third. The definition of a complete hematologic response requires a negative immunofixation of serum and of urine as well as an immunoglobulin free light chain ratio that is in the normal range. A partial hematologic response requires a 50% reduction of a serum and urine M protein, if they are measurable, and a 50% reduction in the level of the abnormal free light chain, whether it be kappa or lambda. Response rates appear to be dependent on the dose of melphalan administered as part of conditioning. At 200 mg/m2, complete hematologic response rates are seen in 55%; and at lower doses in only 35% (4).
Response to therapy in patients with AL can be defined either by improved organ function or by hematologic responses comparable to those seen in patients with myeloma. All patients who have a measurable serum or urine monoclonal protein should be monitored for changes in the size of the peak after a therapeutic intervention. For patients who only have a free light chain, the nephelometric free light chain assay is essential in monitoring for a decrease in circulating free light chain levels. In one study (5), chemotherapy resulted in a significant reduction in amyloidogenic free light chains, and patients with a normalized kappa to lambda ratio had an improved prognosis.

Free light chain responses also seemed to parallel decreases in the NT-pro-BNP levels in cardiac responders to therapy. For patients in whom free light chains decreased by more than 50%, the NT-pro-BNP concentration decreased by a median of 48%, whereas in patients without a free light chain decrease, the NT-pro-BNP concentration increased by 47% (6). The NT-pro-BNP decrease was greater in complete responders than partial responders. A decrease in circulating free light chains and NT-pro-BNP level translates into improved survival.

Organ-based response criteria have been defined for patients with amyloidosis and reported in a consensus paper. Fundamentally, for renal amyloid, a 50% decrease in 24-hour urine albumin excretion is required, for hepatic involvement a 50% reduction in an increased serum alkaline phosphatase concentration is required. Echocardiographic response and progression of amyloid is difficult to assess because of variability in estimates of the septal wall thickness. Neurologic responses, although uncommon, can be documented by electromyography.

Achievement of a hematologic response is an important predictor of prolonged survival after high-dose therapy for patients with AL. The degree of response is important because those people who achieve a complete response have a better survival than those who achieve a >50% reduction in light chain, and both groups do better than patients who fail to achieve a 50% reduction. The hematologic response is a good surrogate marker for survival. One unanswered question is whether patients who do not achieve a complete response should receive some form of maintenance or consolidation chemotherapy to try and further depress their light chain levels. In a study from the National Amyloidosis Center in Great Britain (7), free light chain concentrations were measured in 262 patients, 137 who received cytotoxic chemotherapy. The five-year survival in patients who had a 50% reduction was 88%. Those who did not have a 50% reduction had a five-year survival of only 39%. This suggests that a 50% reduction in the urinary protein is an important and valid endpoint in assessing outcome. Sanchorawala (8) and colleagues assessed serum free light chain responses after high-dose melphalan and autologous stem cell transplantation. A complete response rate of 41% was seen. In this study, if the free light chain concentration decreased by more than 90%, the likelihood of clinical improvement was greater and longer survival was noted regardless of whether the patient fulfilled strict complete response criteria. In a review of autologous stem cell transplantation from the UK, a reduction in the serum free light chain proteins was seen in >50% in 83% of evaluable patients. This hematologic response translated to an overall median survival of 8.5 years for those patients who survived over 100 days (9).

Therapy
A controversy in the treatment of AL is the role of stem cell transplant compared to conventional chemotherapy to suppress the amyloidogenic light chain. The Italian Amyloidosis Treatment Group reported the use of melphalan 0.22 mg/kg and dexamethasone 40 mg both for four days every 28 days. Forty-six patients were treated. The response rate was 67%, 33% complete responses, 48% organ responses, only two treatment-related deaths in the first 100 days, and a projected median survival of 5.1 years.

The IFM presented a small phase 3 study at the American Society of Hematology in 2005 randomizing patients to this regimen or to high-dose therapy with stem cell transplant. The complete response rate, objective response rate, organ response rate, and overall survival were no different between the two groups.
The combination of thalidomide with dexamethasone was reported in 31 patients to produce a 48% hematologic response rate and a 26% organ response rate. The combination of cyclophosphamide, thalidomide, and reduced dose dexamethasone has been reported in 75 patients to produce a hematologic response of 75% and an organ response of 21 to 27%. Lenalidomide, when combined with dexamethasone, has been reported to be active in amyloidosis, producing hematologic responses in 60% and organ responses in 30%. The median time on therapy is 5.3 months. Bortezomib appears to be active in amyloidosis. When 18 patients were treated, hematologic response was seen in 77%, complete in 16%, and organ responses in 27%.

Transplantation for amyloidosis has been used because it is efficacious in the treatment of multiple myeloma, and AL patients have a low tumor mass. Stringent patient selection is required, and only 25% of patients seen at Mayo Clinic are eligible for high-dose therapy. Of 270 transplanted patients, 94 achieved a complete response and 105 a partial response. Median survival is 80 months. The chemotherapy dose has an impact on survival. Patients receiving higher-dose chemotherapy tend to have higher response rates. Patients with three or more organs involved have a treatment-related mortality that approaches 30%. When the BNP is >170 picograms/mL pretransplant, the median survival is significantly shorter at 25 months. (10). Mayo 100-day mortality is 11% but has fallen to 8% in calendar year 2006. Optimal therapy for AL has yet to be defined.


References
1. Gillmore JD, Hawkins PN, Pepys MB. Amyloidosis: a review of recent diagnostic and therapeutic developments. Br J Haematol. 1997;99:245-256.
2. Cheng AS, Banning AP, Mitchell AR, Neubauer S, Selvanayagam JB. Cardiac changes in systemic amyloidosis: visualization by magnetic resonance imaging. Int J Cardiol. 2006;113:E21-23.
3. Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2006;107:3378-3383.
4. Gertz MA, Lacy MQ, Dispenzieri A, et al. Risk-adjusted manipulation of melphalan dose before stem cell transplantation in patients with amyloidosis is associated with a lower response rate. Bone Marrow Transplant. 2004;34:1025-1031.
5. Matsuda M, Yamada T, Gono T, et al. Serum levels of free light chain before and after chemotherapy in primary systemic AL amyloidosis. Intern Med. 2005;44:428-433.
6. Palladini G, Lavatelli F, Russo P, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood. 2006;107:3854-3858.
7. Lachmann HJ, Gallimore R, Gillmore JD, et al. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br J Haematol. 2003;122:78-84.
8. Sanchorawala V, Seldin DC, Magnani B, Skinner M, Wright DG. Serum free light-chain responses after high-dose intravenous melphalan and autologous stem cell transplantation for AL (primary) amyloidosis. Bone Marrow Transplant. 2005;36:597-600.
9. Goodman HJ, Gillmore JD, Lachmann HJ, Wechalekar AD, Bradwell AR, Hawkins PN. Outcome of autologous stem cell transplantation for AL amyloidosis in the UK. Br J Haematol. 2006;134:417-425.
10. Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Kumar S. Transplantation for amyloidosis. Curr Opin Oncol. 2007;19:136-141.


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