High-dose melphalan and stem cell transplantation for patients with AL amyloidosis: trends in treatment-related mortality over the past 17 years at a single referral center

To the editor:

We recently reported the outcomes of 421 consecutive patients with immunoglobulin light chain (AL) amyloidosis treated with high-dose melphalan and autologous stem cell transplantation (HDM/SCT)¹  from July 1994 through December 2008. Median survival was 6.3 years and the complete response rate for evaluable patients was 43%. Treatment-related mortality (TRM) was 11.4%. In other studies of HDM/SCT in this patient population, in which cardiac, kidney, liver, gastrointestinal, and neurologic function is compromised, has ranged from 11%-43%,^2,3  exceeding that typically seen in transplantation for lymphoma or myeloma (< 5%).^4,5  Here we report trends in TRM over 17 years at a single tertiary referral center (Table 1).

Between July 1994 and December 2011, 522 patients with AL amyloidosis were treated with HDM/SCT. TRM was defined as death during stem cell mobilization and collection (SCMC), during stem cell infusion (SCI), or within 100 days of SCT (D+1 to D+100). Of 522 patients, 61 (12%) suffered TRM.

Eleven patients (2%, n = 11 of 522) died during SCMC. Deaths during SCMC were most commonly because of cardiac events (n = 8; arrhythmia, irreversible congestive heart failure, refractory hypotension, and myocardial infarction because of small vessel amyloid disease), and less commonly because of gastrointestinal hemorrhage (n = 2) or pulmonary embolism (n = 1). There were 4 deaths (1%, n = 4 of 522) during SCI because of cardiac arrhythmia (n = 3) or pulmonary embolism (n = 1).

Forty-six additional deaths occurred from D+1 to D+100 after SCT, (9%, n = 46 of 522). Deaths during this period were usually because of infection (48%, n = 22 of 46). Cardiac events were the second most common cause of death (37%, n = 17 of 46), followed by hemorrhage (11%, n = 5 of 46; includes diverticulitis rupture, liver rupture, gastrointestinal bleeding, and pulmonary alveolar hemorrhage), and pulmonary complications (7%, n = 3 of 46). One death was attributed to complications of metastatic lung cancer and 1 suffered from ischemic colitis because of superior mesenteric artery ischemia.

Overall, cardiac events were the most common cause of TRM (39%), closely followed by infectious complications (36%) and hemorrhage (12%). TRM was 12% (61 of 522) over the past 17 years, with TRM of 17% (52 of 310) during the first decade, and 4% (9 of 212) thereafter. The difference in mortality between these 2 time periods is statistically significant by χ² analysis, with a P value of .000012.

Successful treatment of AL amyloidosis remains a challenge because of organ dysfunction leading to an increased toxicity with any therapy. Particularly with HDM/SCT, TRM can be high. We and other centers have observed a decrease in TRM in recent years.⁶  These improvements are likely because of: (1) refined patient selection, particularly with respect to detection of cardiac disease using biomarkers, cardiac MRI, and functional assessment of cardiopulmonary reserve; (2) optimized transplantation techniques including elimination of cyclophosphamide as a mobilization agent and incorporation of risk-adjusted melphalan dosing; (3) careful monitoring and management during the peri-transplant period, particularly with respect to fluid status, nutritional support, and management of cardiac complications; and (4) a multidisciplinary team approach, including experienced internists, transplant hematologists, nephrologists, pulmonologists, neurologists, cardiologists, and support staff including nurse practitioners.

The treatment options for AL amyloidosis are rapidly evolving with the introduction of novel antiplasma cell agents for these patients, and antifibril therapies on the horizon. For now, treatment choices remain highly individualized, dependent on a careful assessment of performance status and organ function. HDM/SCT, with appropriate inclusion and exclusion criteria, remains an option in selected patients that offers a high rate of hematologic and organ responses and excellent overall survival. Ongoing examination of factors that impact mortality risk will continue to improve the risk-benefit ratio for this modality.