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Blood, 1 April 2005, Vol. 105, No. 7, pp. 2625.
Light chains ahoy: pirating Thal/Dex for AL tooMEMORIAL SLOAN-KETTERING CANCER CENTER
In patients with refractory or relapsed systemic light-chain (AL) amyloidosis, salvage therapy with thalidomide and dexamethasone in modified doses is effective albeit with manageable toxicities.
Despite the lack of a practical test to assign short-term risk of progression in AL, assays for serum free light chains (FLC) and chemical markers of myocardial strain and injury extend the promise of customized therapy. Integration of the FLC into practice allows the titration of therapy in anticipation of response, even before evidence of an organ response. The application of the myocardial markers to clinical practice is more of a work-in-progress: the utility of a screening test is a function of the prevalence of the condition in the population, the impact on clinical practice (eg, cost savings), and the measurable benefit to patients.3 The understanding of the genetics of AL also remain a work-in-progress: the majority of AL cases are caused by light chains derived from 3 lambda germ line donors (2a2, 3r, 6a), an observation that remains unexplained. Fortunately, clinical researchers continue to adopt approaches effective for myeloma and apply them to AL; usually they work if tolerated. Dexamethasone-based regimens have been shown to be highly active in AL, although a median survival of 31 months is little more than half that achieved with melphalan-based stem cell transplantation.4 Thalidomide has also been employed as a single agent for AL with the most prominent finding being its toxicity. In this issue of Blood, Palladini and colleagues report the results of a phase 2 trial of thalidomide and dexamethasone combined as salvage therapy. Thalidomide was dosed at 100 mg/day, with increments up to 400 mg, and dexamethasone at 20 mg/day on days 1 to 4 every 3 weeks. Thirty-one patients with AL refractory to or in relapse after first-line therapy were enrolled. Half had failed standard pulse dexamethasone and a third stem cell transplantation. Eleven patients (35%) tolerated 400 mg/day thalidomide for a median of 6 months; 14 could take no more than 100 or 200 mg/day for a median of 3 months. Fifteen (48%) achieved a hematologic response with 6 (19%) complete remissions and 8 (26%) organ responses; the response rate was higher in those taking higher doses of thalidomide. Overall median time to response was 3.6 months. No cases of cardiac amyloid had organ responses. There were no treatment-related deaths but two thirds experienced severe toxicity. Symptomatic bradycardia without QT prolongation was a common adverse reaction (26%), whereas neuropathic and thromboembolic complications were rare.
This clinical trial adds another regimen to the therapeutic booty. Indeed, thalidomide and dexamethasone are also currently being tested as adjuvant therapy after risk-adapted melphalan-based stem cell transplantation for AL in order to enhance hematologic responses.5 Moreover, prevailing winds are favorable and indicate that other new agents (such as bortezomib) are also being hefted aboard for clinical testing in AL. References
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
