Febrile Reactions Occurring With Second Cycle of High Dose Melphalan and Stem Cell Transplantation in Patients With AL Amyloidosis: A “Melphalan Recall” Reaction

Systemic AL amyloidosis is a clonal plasma cell disease characterized by the wide spread deposition of amyloid fibrils into tissues and organs. Treatment for this disease is directed towards reducing the production of amyloidogenic monoclonal light chains by attacking the underlying plasma cell dyscrasia. Aggressive treatment with high dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic and clinical remissions and in extending survival. Tandem cycles of HDM/SCT have been shown to increase hematologic complete response (HCR) rates in patients with AL amyloidosis. Between April 1994 and July 2008, 57 patients with AL amyloidosis at Boston University medical center were treated with a second cycle of HDM/SCT after failing to achieve a HCR following a first transplantation. Eleven of 57 patients (19%) treated with tandem transplantation developed a high fever 12–24 hours following melphalan administration. Other clinical features noted in some of the patients include hypotension, acute renal failure, and skin rash. Among the 11 patients described, there were 7 men and 4 women. The average age was 53.5 years (range 41–60). The average peak temperature of the 11 patients was 39.1ºC (range, 38.1–39.4ºC). All patients experienced resolution of fever within 24–48 hours. Six of the 11 patients developed a rash and 5 developed hypotension that was responsive to intravenous fluids or pressors when indicated. Two of the patients developed acute renal failure that improved following resolution of the fever. In all 11 patients, workup for an infectious etiology of fever was negative. One of the 11 patients described, had cytokine measurements before, during and after the febrile reaction. The concentration of several pro-inflammatory as well as anti-inflammatory cytokines increased significantly. IL-6, a classic endogenous, pyrogenic cytokine, increased 10 fold with this reaction demonstrating a clear physiologic response correlating with the clinical findings. We conclude that an unusual febrile reaction mediated by pyrogenic cytokines can occur in patients with AL amyloidosis exposed to a second cycle of high dose melphalan. While this reaction has not been observed in patients with multiple myeloma treated in similar fashion, clinicians should be aware of this phenomenon we have termed a “melphalan recall” reaction in patients with AL amyloidosis treated with tandem cycles of HDM/SCT.