Hematopoietic Cell Transplantation in Light Chain Amyloidosis

Pathogenesis and Diagnosis of AL Amyloidosis

Free immunoglobulin light chains typically adopt a soluble protein conformation that allows them to circulate in the bloodstream. In the setting of excessive monoclonal light chain production, certain light chains will aggregate to form insoluble amyloid fibrils, which then deposit in various tissues. Involved tissues typically include the heart, kidneys, liver, and peripheral nerves, leading to manifestations such as restrictive cardiomyopathy, nephrotic syndrome, hepatomegaly, and polyneuropathy ( Fig. 23.1 ). Unfortunately, the clinical presentation of amyloidosis is variable and frequently nonspecific so a high index of suspicion is necessary for diagnosis. If AL amyloidosis is suspected, initial workup should include a serum protein electrophoresis (SPEP) and serum immunofixation, 24-hour urine protein electrophoresis (UPEP) and urine immunofixation, and serum free light chain analysis to establish the presence of a monoclonal protein. A definitive diagnosis of amyloidosis requires a tissue biopsy demonstrating the presence of amyloid fibrils. Bone marrow biopsy and abdominal fat pad biopsy together are ~85% sensitive for the diagnosis of AL amyloidosis. Biopsy of the involved organ, while more invasive and expensive, may be necessary if these tests are negative and suspicion for amyloidosis remains high. It is impossible to clinically distinguish AL amyloidosis from amyloidosis due to deposition of other proteins (transthyretin, amyloid A protein, etc.). While immunohistochemistry is sometimes used to make this determination, mass spectrometry is considered the gold standard and may be performed on any tissue type. Identifying the protein of origin is crucial as the various types of amyloidosis are managed differently. Of note, the presence of a monoclonal protein in the serum does not establish the diagnosis of AL amyloidosis as it is entirely possible to have a different type of amyloidosis in the presence of an unrelated monoclonal gammopathy of undetermined significance. It is also important to distinguish systemic amyloidosis from localized amyloidosis as these conditions have different natural histories and the latter is typically managed with local therapies alone. HCT only plays a role in the treatment of systemic AL amyloidosis. Early diagnosis is critical as the degree of organ involvement predicts outcomes and determines eligibility for therapies including HCT.

History of Hematopoietic Cell Transplantation in AL Amyloidosis

Given the similarities in their pathogenesis, treatments for AL amyloidosis have historically mirrored those used for multiple myeloma. Early treatment consisted of oral melphalan and prednisone with a median survival of only 18 months. In the mid-1990s, high-dose intravenous melphalan with autologous HCT was investigated as an alternative therapeutic option. In a seminal study of 25 patients with AL amyloidosis receiving melphalan 200 mg/m ² , over 60% achieved a strictly defined complete hematologic response and 68% were still alive with 24 months of follow-up. Nevertheless, the role of HCT in the treatment of AL amyloidosis remained controversial because of its toxicity. A 2007 randomized trial comparing autologous HCT with oral melphalan/dexamethasone chemotherapy showed inferior survival in the HCT arm (22.2 vs. 56.9 months) primarily because of treatment-related mortality of 24% in this arm. Improvements in patient selection and supportive care since that time have substantially improved outcomes, with treatment-related mortality rates of ~2.5% and 5-year survival rates of 77% reported in recent years. Randomized clinical trials comparing HCT with nontransplant approaches incorporating novel agents used for multiple myeloma are lacking. However, given its potential to induce durable remissions and improved toxicity profile, autologous HCT with high-dose melphalan conditioning remains the standard of care for appropriately selected patients with AL amyloidosis. Allogeneic HCT and autologous HCT using other conditioning agents have not been extensively studied in this disease. Thus, unless otherwise specified, HCT will refer to autologous transplant with high-dose melphalan conditioning for the rest of this chapter.

Cardiac Involvement

The extent of cardiac involvement is the primary determinant of survival in AL amyloidosis. Imaging evidence of cardiac involvement includes wall thickening and an apical-sparing strain pattern on echocardiography as well as late gadolinium enhancement on cardiac magnetic resonance imaging (MRI). However, the most commonly used clinical prognostic factors are the cardiac biomarkers troponin T and N-terminal pro-brain natriuretic peptide (NT-proBNP).

The earliest version of the Mayo cardiac staging system stratified patients based on cutoff values for these biomarkers (NT-proBNP > 332 ng/L; troponin T > 0.035 mcg/L). Stage I patients had low levels of both biomarkers, stage II patients had high levels of only one biomarker, and stage III patients had high levels of both biomarkers. In a retrospective study of 242 patients with AL amyloidosis diagnosed between 1979 and 2000, median survivals were 26.4, 10.5, and 3.5 months in patients with stage I, stage II, and stage III disease, respectively. The prognostic utility of this staging system extends to the transplant setting. In a study of 98 patients undergoing autologous HCT with melphalan conditioning between 1996 and 2003, median survival was not reached in patients with stage I and stage II disease with a median of 20-months follow-up. However, median survival was only 8.4 months in patients with stage III disease. More recently, this staging system has been updated to include the difference between involved and uninvolved free light chains as an independent predictor of overall survival. The cutoffs used for troponin T and NT-proBNP have also been adjusted. The revised Mayo staging system is shown in Table 23.1 .

Although the Mayo staging system is a useful prognostic tool, it has important limitations when used in patient selection for HCT in the modern era. In particular, stage III disease alone should not automatically exclude a patient from consideration as many patients with stage III disease can successfully undergo HCT. In a retrospective study of 47 patients who underwent HCT at Boston University between 2008 and 2011, treatment-related mortality was 4% for all patients and only 8% for patients with stage III disease, a difference, which was not statistically significant. Furthermore, 3-year overall survival and event-free survival rates did not differ significantly by disease stage. These findings are consistent with those of other recent studies and were attributed to careful patient selection and intensive pre- and posttransplant supportive care provided by a multidisciplinary team. Other studies have attempted to develop criteria, which would more specifically identify patients at high risk of early mortality with HCT. Troponin T > 0.06 ng/mL and NT-proBNP > 5000 pg/mL (for patients not on dialysis) are two such criteria, which have been proposed. In retrospective studies, patients with troponin T > 0.06 ng/mL had an all-cause mortality rate of 28% at 100 days posttransplant and patients with NT-proBNP > 5000 pg/mL had a 25% mortality rate at 10.3 months. While it is certainly important to take these biomarkers into consideration, we emphasize the importance of a comprehensive patient assessment when deciding eligibility for transplant as described later in this chapter.

Renal Involvement

Although it does not correlate as strongly with survival as cardiac involvement, the extent of renal involvement predicts the need for dialysis and early mortality from HCT. Palladini et al. proposed a renal staging system for AL amyloidosis that is based on cutoff values for renal function and proteinuria (estimated glomerular filtration rate [eGFR] < 50 mL/min; proteinuria > 5 g/24 hours). Stage I patients had neither of these risk factors, stage II patients had only one risk factor, and stage III patients had both risk factors. In their validation cohort of 271 patients, the 3-year risk of progression to dialysis was 4% in stage I patients and 85% in stage III patients. A recent retrospective study of patients who had undergone HCT found that renal stage predicted for dialysis initiation within 100 days of HCT (3% of stage I patients vs. 10% of stage II patients vs. 22% of stage III patients). Similarly, patients with impaired renal function (eGFR < 45 mL/min) had a higher 100-day mortality (14% vs. 5%) after HCT although median overall survival and progression-free survival were similar to those of patients with normal renal function. In another retrospective study, patients who were started on dialysis in the 30 days before or after autologous HCT had substantially worse overall survival than patients started on dialysis at any other time in the transplant process. Impaired baseline renal function (eGFR < 40 mL/min) and hypoalbuminemia (albumin < 2.5 g/dL) were found to be independent predictors of the need to start dialysis during this critical time period. While many patients with renal impairment do successfully undergo HCT, these findings highlight the need to consider renal function when determining transplant eligibility and planning for transplant. Concerns regarding melphalan toxicity in patients with impaired renal function have been raised and we recommend using reduced dose melphalan (e.g., 140 mg/m ² ) in patients with renal impairment.