Interfering with amyloidosis

Comment on Dhodapkar et al, page 3520

A multicenter phase 2 clinical trial of dexamethasone and interferon shows promise for treatment of patients with AL amyloidosis.

In recent years, the attention of many in the biomedical research community has turned to a diverse group of diseases that are tied together by a remarkable pathophysiologic mechanism. Alzheimer disease and most of the other major neurodegenerative diseases and movement disorders, mad cow and the other prion diseases, α1-antitrypsin deficiency and other serpinopathies, and the systemic amyloidoses all occur because systemically or locally abundant proteins misfold and polymerize into fibrils that cause cellular and tissue destruction. The details of this process are beginning to be elucidated, and targeted therapeutic strategies are in early stages of development.

The most common systemic amyloidosis in the developed world is AL or primary amyloidosis, caused by clonal immunoglobulin light-chain deposition (in the developing world, serum amyloid A protein type [AA] amyloidosis, secondary to chronic infections and inflammation, occurs more frequently). AL amyloidosis has been considered an orphan disease, although its incidence is about one-third that of multiple myeloma, and some studies of myeloma patients have suggested that concomitant AL amyloidosis is quite common. Patients diagnosed with AL amyloidosis have a worse prognosis than patients with multiple myeloma. With traditional oral melphalan and prednisone chemotherapy, hematologic responses are difficult to document, and amelioration of the end-organ damage is not frequently observed. For hematologists and their patients, treatment options have been limited and the relentless progression of the disease disheartening.FIG1 

That grim picture has changed dramatically in recent years. In the paper by Dhodapkar and colleagues in this issue of Blood, the Southwest Oncology Group reports on S9628, a multicenter phase 2 trial of dexamethasone (DEX) and α-interferon (α-IFN) in 93 patients with AL amyloidosis. This study is the first large prospective US cooperative group trial in AL amyloidosis. The patients were enrolled between 1996 and 2003 and treated with pulse DEX followed by DEX/IFN maintenance. Complete hematologic responses were obtained in 24% of patients, organ improvements were observed in 45% of patients, and median survival was 31 months. Thirty-four institutions enrolled patients on the trial; 88 patients were actually eligible for treatment and only 1 patient withdrew from the study. Of the 87 treated patients, only two thirds were actually able to receive the 3 planned cycles of induction because of fluid retention and other treatment-related toxicities. Maintenance with DEX/IFN, planned for 2 years, was delivered for a median of only 7 months.

The authors are to be lauded for the design and conduct of their multicenter study and for their promising results. The complications and the toxicity of treatment are not surprising given those reported in other recent trials, including one in which DEX was combined with melphalan¹  and in trials with thalidomide.^2,3  Amyloid-related organ dysfunction also accounts for the excess mortality seen in trials of high-dose melphalan with peripheral blood stem cell support,^4,5  although this treatment produces high rates of complete hematologic response. These treatments, and trials of bortezomib (Velcade) and lenalidomide (Revlimid) that are underway, provide new hope for patients with this morbid plasma cell disease. With the results of these studies in hand, one will be able to design new trials that will compare effective regimens against each other; AL amyloidosis treatment is no longer futile.

Our mission as hematologists is to assist our medical colleagues with early diagnosis so patients can be treated early in the natural history of their disease; to inform our patients of the promising new treatment options and encourage them to participate in clinical trials; and to lobby health insurers to cover the costs of new treatments that we believe offer new hope and improved quality of life⁶  for patients with this formerly hopeless diagnosis.