A multicenter phase II trial of 4'-IODO-4'-deoxydoxorubicin (IDOX) in primary amyloidosis (AL)

M. A. Gertz, M. Q. Lacy, A. Dispenzieri, B. Cheson, B. Barlogie, R. A. Kyle, G. Palladini, S. Geyer, G. Merlini

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INTRODUCTION: AL is a plasma cell disorder with a median survival of 17 months. Death occurs from deposition of amyloid in tissues and not progressive increase in the plasma cell tumor mass. Prior therapies for amyloidosis have been directed at interrupting the synthesis of the amyloid precursor protein, the immunoglobulin light chain. Previously no agents were available capable of dissolving amyloid deposits. IDOX produces responses by binding to and leading to the catabolism of amyloid deposits. This multicenter study attempted to develop a dosing schedule to confirm those initial results. METHODS: Protocol eligibility required an ejection fraction (EF) greater than 50%, ventricular septal thickness <20 mm, a serum creatinine less than 2.5 mg/dL, a total bilirubin <2.1 mg/dL, neutrophils of 1,500/nL and platelets of 100,000/uL. Patients with myeloma, second or third degree AV block, atrial fibrillation or nonsustained ventricular tachycardia were excluded. IDOX was administered IV over 1 hour at a dose of 15 mg/m2 once a week for four consecutive weeks, followed by 8 weeks of observation. The four weekly treatments and 8 weeks of observation were considered one course. Up to four courses were given. RESULTS: Twenty-five previously treated and 15 untreated patients with biopsy-proven AL were entered into this protocol. The median age was 66 years (range 50-80). There were 23 women. Fifteen patients had > 3 g of protein per day in the urine. Eleven patients had an EF <60%. One, two, three, four and five organ systems were involved in 22,10,4, 3 and 1 patient respectively. The median time between diagnosis and initiation of IDOX was 17.4 months. There were 5 responses (12.5%) at the twelve-week evaluation. One patient had reduction in the severity of neuropathy proven by EMG and healing of skin lesions. A second patient had urinary protein loss of 52.85 g/d fall to 23.92 g/d and albumin rose 0.5 to 2.1 g/dL. In one patient the alkaline phosphatase fell from 374 to 254 (normal <250). This patient had no change in his nephrotic-range urinary protein excretion. The fourth patient had resolution of microvascular angina and jaw claudication. The fifth response was in a patient whose liver ultrasound showed a reduction in liver size from 17 to 13.5 cm with reduction in alkaline phosphatase level 1,029 to 783. Eight of the patients have died, of cardiac causes (N=2) not treatment-related or progressive amyloidosis (N=6). Twelve patients experienced grade 3+ non-hematologic toxicities, but only 2 had adverse events attributable to the study treatment. CONCLUSION: Despite the low incidence of toxicity, IDOX administered in this protocol was deemed to be insufficiently active at the current dose to warrant further investigation. Reassessment of the dose based on in vivo pharmacokinetic studies are underway.

Original languageEnglish
Issue number11 PART II
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Hematology


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