Salli Fennessey

Kidney dysfunction during lenalidomide treatment for AL amyloidosis

BACKGROUND Lenalidomide is an immunomodulatory agent used to treat plasma cell dyscrasias. We previously observed worsening of kidney function in a high proportion of patients with AL amyloidosis during lenalidomide treatment. The objective of this study is to characterize alterations in kidney function among patients with AL amyloidosis undergoing treatment with lenalidomide. METHODS This is a secondary analysis of an ongoing clinical trial at a single referral centre. Forty-one patients with AL amyloidosis received lenalidomide with or without dexamethasone in monthly cycles. Kidney dysfunction was defined as ≥ 50% increase in serum creatinine. Severe kidney dysfunction was defined as ≥ 100% increase in serum creatinine. Recovery of renal function was defined as a return of serum creatinine to within 25% of the pre-treatment value or discontinuation of dialysis. RESULTS Twenty-seven of 41 patients (66%) developed kidney dysfunction during lenalidomide treatment. The kidney dysfunction was severe in 13 of these patients (32%); four of whom required initiation of dialysis (10%). The median time to kidney dysfunction after starting lenalidomide was 44 days (interquartile range 15-108 days). Four of eight patients without underlying renal amyloidosis developed kidney dysfunction. Patients with severe kidney dysfunction were older and had a higher frequency of underlying renal amyloidosis, greater urinary protein excretion, and lower serum albumin. Recovery of renal function occurred in 12 patients (44%). CONCLUSIONS Among patients with AL amyloidosis, worsening of kidney function occurs frequently during lenalidomide treatment. While a causal role of the drug has not been established, our findings suggest that kidney function should be monitored closely during treatment with this drug.

Increases in B-type natriuretic peptide (BNP) during treatment with lenalidomide in AL amyloidosis

To the editor: The combination of lenalidomide and dexamethasone can produce hematologic responses in previously treated patients with AL amyloidosis.[1][1] Since this prospective study (ClinicalTrials.gov: [NCT00091260][2]) was initiated, NT-proBNP and BNP have been found to be useful biomarkers

Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis

To the editor: In AL amyloidosis, amyloid fibril deposits, derived from immunoglobulin light chains produced by a clonal plasma cell dyscrasia, accumulate in extracellular tissues and damage vital organs.[1][1] Novel therapies used in multiple myeloma[2][2] can be effective in AL amyloidosis.

Modified high-dose melphalan and autologous SCT for AL amyloidosis or high-risk myeloma: analysis of SWOG trial S0115

We designed a trial using two sequential cycles of modified high-dose melphalan at 100 mg/m2 and autologous SCT (mHDM/SCT) in AL amyloidosis (light-chain amyloidosis, AL), AL with myeloma (ALM) and host-based high-risk myeloma (hM) patients through SWOG-0115. The primary objective was to evaluate OS. From 2004 to 2010, 93 eligible patients were enrolled at 17 centers in the United States (59 with AL, 9 with ALM and 25 with hM). The median OS for patients with AL and ALM was 68 months and 47 months, respectively, and has not been reached for patients with hM. The median PFS for patients with AL and ALM was 38 months and 16 months, respectively, and has not been reached for patients with hM. The treatment-related mortality (TRM) was 12% (11/93) and was observed only in patients with AL after SCT. Grade 3 and higher non-hematologic adverse events were experienced by 81%, 67% and 57% of patients with AL, ALM and hM, respectively, during the first and second HDM/SCT. This experience demonstrates that with careful selection of patients and use of mHDM for SCT in patients with AL, ALM and hM, even in the setting of a multicenter study, OS can be improved with acceptable TRM and morbidity.

High-dose melphalan and autologous stem cell transplantation for AL amyloidosis: recent trends in treatment-related mortality and 1-year survival at a single institution

Treatment with high-dose melphalan chemotherapy supported by hematopoietic rescue with autologous stem cells produces high rates of hematologic responses and improvement in survival and organ function for patients with AL amyloidosis. Ongoing clinical trials explore pre-transplant induction regimens, post-transplant consolidation or maintenance approaches, and compare transplant to non-transplant regimens. To put these studies into context, we reviewed our recent experience with transplant for AL amyloidosis in the Amyloid Treatment and Research Program at Boston Medical Center and Boston University School of Medicine. Over the past 10 years, there was a steady reduction in rates of treatment-related mortality and improvement in 1-year survival, now approximately 5% and 90%, respectively, based upon an intention-to-treat analysis. Median overall survival of patients treated with this approach at our center exceeds 7.5 years. Introduction: Treatment of AL amyloidosis patients with high-dose intravenous melphalan chemotherapy and autologous hematopoietic stem cell support (HDM/SCT) produces a high rate of hematologic complete responses and improvement in organ function. Nephrotic syndrome can resolve [1], myocardial wall thickness can decline (MeierEwert et al., this volume), and quality of life improves [2]. Good outcomes are dependent upon the safe application of the therapy. Our first large patient series, published in 2004, reported a 100 day treatment-related mortality (TRM) of 14% [3]. Since then, we have refined patient selection and transplantation techniques and seen a concomitant decline in the rate of serious complications. Methods: Data on patients evaluated and treated in the Amyloid Treatment and Research Program at Boston University School of Medicine and Boston Medical Center were collected under protocols approved by the Boston University Medical Campus IRB after informed consent was signed. Data on patients enrolled into protocols using HDM/SCT from January 2000–December 2009 were reviewed retrospectively. Survival of all patients was determined through the end of December 2010, providing at least 1 year of follow-up on 100% of patients. Kaplan-Meier survival and confidence intervals for median overall and event-free survival were determined. Results and discussion: In the 10-year-period from January 2000 through December 2009, 323 patients began treatment on institutional or cooperative group protocols using HDM/SCT. The age range of enrolled patients was 28–80 years (median 57). The overall TRM was 8.4%, and the 1-year survival (1 YS) was 86.1% by intention-to-treat analysis. In the more recent 5-year-period from January 2005 through December 2009, 158 patients were treated; the age range was 28–77 years (median 57), the TRM was 5.1%, and the 1YS was 89.2%. Annual trends are plotted in Figure 1. The overall survival and progression free survival of all 323 patients are plotted in Figure 2. We attribute these improvements to two factors: firstly, rigorous selection of appropriate patients; and secondly, experienced multidisciplinary management during the peri-transplant period. Appropriate patient selection requires a comprehensive multidisciplinary clinical evaluation. The key evaluation components are summarized below. Chronological age is not a critical factor [4]. Patients who are potential candidates for HDM/SCT are assessed by sub-specialists highly familiar with the clinical manifestations of amyloidosis and with the complications of HDM/SCT. Cardiopulmonary function: Many studies have demonstrated that outcomes for patients with AL amyloidosis are driven by cardiac disease, defined by clinical parameters, echocardiographic parameters, and biomarkers for cardiac function. We use all of these to judge cardiac risk, including careful review of symptoms, physical examination for signs of heart Figure 1. Trends in TRM (lower line) and 1YS (upper line) each year in the 10-year-period from 2000 through the end of 2009, for a total of 323 patients. 127