Bortezomib-Based Chemo Ups Survival in AL Cardiac Amyloidosis

Pam Harrison

June 29, 2016

CLEVELAND, Ohio – First-line treatment with the proteasome inhibitor bortezomib (Velcade, Millennium Pharmaceuticals) plus dexamethasone and an alkylating agent (BDex+AA) improves survival in patients with symptomatic heart failure due to amyloid light-chain (AL) amyloidosis, a rapidly fatal disease, new research shows[1].

After multivariable adjustment, patients receiving BDex+AA as their initial regimen had a 20% lower mortality risk than those receiving other regimens (hazard ratio 0.20; P=0.006).

The association remained significant after adjustment for components of the Mayo staging system: troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), or serum free light-chain difference, all of which confer a poor prognosis, Dr Brett Sperry (Cleveland Clinic Foundation, OH) and colleagues reported in their study, published in the June 28, 2016 issue of the Journal of the American College of Cardiology.

"One of the most devastating diagnoses a cardiologist may give a patient is that their heart failure (HF) is due to light-chain amyloidosis because their median survival is <1 year," editorialist Dr Marc Semigran (Harvard Medical School, Boston, MA) writes[2].

"The report from Sperry et al in this issue of the Journal marks the beginning of a change in that dire prognosis."

AL amyloidosis results from a plasma-cell dyscrasia that causes unchecked production of a monoclonal immunoglobulin light chain. This excess of light chains aggregates into fibrils that deposit in the extracellular matrix and results in organ dysfunction.

Half of patients with AL amyloidosis present with symptomatic heart failure, a major factor affecting survival.

BDex+AA has emerged as the treatment of choice in all-comers with AL amyloidosis because of improved response rates, but there are no direct mortality data confirming benefit in patients with symptomatic HF.

Survival Gain

The investigators evaluated 119 consecutive patients with confirmed AL amyloidosis presenting with NYHA functional class 2–4 heart-failure symptoms at the Cleveland Clinic from 2004 to 2015.

Bortezomib was given subcutaneously or intravenously at a dose of 1.3 mg/m2 every week and dexamethasone at varying doses, again once a week in 28-day cycles. Alkylating agents included cyclophosphamide or melphalan. Thalidomide and lenalidomide (Revlimid, Celgene) were also deployed.

Of the 106 patients who received chemotherapy, 40 patients received BDex+AA as the initial regimen and 66 received other regimens.

Over a median follow-up of 465 days, 65% of patients who received any treatment died. In contrast, "all patients who did not receive any treatment died with a median of 47 days," Sperry notes.

Almost half of patients who received the BDex+AA regimen also died, but median survival in this subgroup was 821 days. This was significantly longer than patients who received other chemotherapy regimens, 76% of whom died with a median survival of 223 days (P<0.001 compared with BDex+AA).

All deaths were related to AL amyloidosis and included progressive HF, arrhythmia, autonomic dysfunction with hypotension, or failure to thrive.

"Our current report strengthens the recommendation for BDex+AA as first-line therapy in AL amyloidosis and adds to the body of data for its utility in patients with cardiac involvement," the authors state.

Further Investigation

Semigran writes that the current study "raises the hope that chemotherapy targeting plasma cells offers the possibility of mitigating the cardiac morbidity of unchecked light-chain production."

In order to determine the wider applicability of BDex+AA, however, "a prospective multicenter study in patients with a spectrum of severity of cardiac involvement, including those being 'bridged' to stem-cell or cardiac transplant, is essential to understand the efficacy and ideal patient characteristics for this therapy."

Because bortezomib administration can have transient myocardial- and renal-depressant effects, the effect of LV ejection fraction as a predictor of successful BDex+AA also needs to be assessed.

Until a comparative effectiveness study is initiated, "the ideal patient to be considered for chemotherapy would be one whose extracardiac amyloid burden is relatively small, has good functional capacity, and whose cardiac dysfunction can be medically managed," he adds.

Semigran also emphasizes that it's been their experience that the burden of gastrointestinal amyloid is often "underappreciated," leading to severe dysmotility and malnutrition with subsequent morbidity and mortality.

"Such a patient is likely to have significant adverse effects from the immunosuppression associated with BDex+AA," he warns.

Currently, two large clinical trials—VITAL and PRONTO—are under way in patients with cardiac involvement as well as in those with persistent symptoms following treatment. "Yet even in these studies, patients with an NT-proBNP above a certain level are excluded," the authors note.

Sperry reported no relevant financial relationships; disclosures for the coauthors are listed in the article. Semigran reported no relevant financial relationships.

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