Amyloidosis Program: From Bench to Bedside and Back

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Written By

Giada Bianchi, MD


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Light chain (AL) amyloidosis is a plasma cell disorder characterized by deposition of immunoglobulin free light chains (FLC) organized in fibrils. The plasma cell burden in AL amyloidosis is typically low and the plasma cells are not directly pathogenic. Instead, amyloid infiltration of target organs, such as heart or kidneys, causes tissue injury, leading to progressive organ failure and eventual patient demise. Diagnostic delays are frequent, due to the insidious nature of early symptoms, and late diagnosis can severely compromise patient outcomes. If not promptly recognized, AL amyloidosis is rapidly fatal.

There is no Food and Drug Administration (FDA)-approved treatment for AL amyloidosis. However, chemotherapy approved for multiple myeloma and targeting plasma cells, such as the combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD regimen), is standard of care. Chemotherapy does not exert any direct effect on the amyloid protein; however, plasma cell cytoreduction halts progressive deposition by abating FLC secretion. In patients who achieve a complete remission, the amyloid may then be removed over a period of months to years. Thus, a hematologic response is necessary to achieve an organ response. Recognizing the pathogenesis of AL amyloidosis, research efforts have focused on developing antifibrillary antibodies to opsonize and facilitate the removal of amyloid fibrils.

The Amyloidosis Program at Dana-Farber/Brigham and Women's Cancer Center focuses on bringing to our patients a strong pipeline of innovative clinical trials predicated on lab discoveries. In the lab, we have ongoing projects focused on three main areas:

  • Understanding the role of the ubiquitin proteasome pathway in the pathogenesis of plasma cell disorders
  • Identifying novel molecular pathways to overcome proteasome inhibitor resistance
  • Preclinical validation of novel therapeutic strategies to target protein homeostasis in AL amyloidosis

Clinically, we currently have the first phase 3 randomized clinical trial in newly diagnosed AL amyloidosis comparing CyBorD with or without daratumumab. We anticipate 1-2 clinical trials in relapsed AL amyloidosis to open in late 2019-early 2020.

We work closely with the Divisions of Cardiology and Nephrology at Brigham and Women's Hospital. Rodney Falk, MD, is a world-recognized expert in cardiac amyloidosis and Program Director of the Amyloidosis Program. Sharmila Dorbala, MD, MPH, is Director of Nuclear Cardiology and a leader in the field of cardiac amyloid imaging. Together, Drs. Dorbala and Falk lead an NIH-sponsored clinical trial to investigate the use of molecular imaging in AL amyloidosis.

Finally, recognizing the ominous consequences of delayed recognition of amyloidosis, we are designing trials focusing on early detection of AL amyloidosis in asymptomatic patients, in collaboration with Helmut Rennke, MD, Director of Renal Pathology and Robert Padera, Jr., MD, PhD, of the Cardiovascular Pathology Department.

We are committed to continuing to expand the program to help develop innovative therapeutic strategies for patients affected by AL amyloidosis and improve outcomes in this devastating illness.

Figure 1. Histopathologic appearance of cardiac amyloidosis
Panel A: Congo red staining of endomyocardial biopsy specimen. Panel B: Congo red stain of same specimen observed under polarized light showing apple green birefringence of amyloid deposits. Panel C: H&E staining of endomyocardial biopsy showing an arteriole with intimal thickening. Panel D: Sulfated Alcian blue staining of endomyocardial arteriole outlining the amyloid in blue. (Images courtesy of Dr. Padera)


Figure 2. Histopathologic appearance of renal lambda light chain AL amyloidosis
Panel A: Immunofluorescent staining for kappa light chain of glomeruli showing background signal. Panel B: Immunofluorescent staining for lambda light chain of glomeruli showing bright signal. Panel C: Electron microscopy of a renal arteriole showing mesangial and subendothelial electron-dense deposits. Panel D: Electron microscopy images of a renal arteriole at higher magnification showing abundant, non-branching fibril, circa 10 nm diameter. (Images courtesy of Dr. Rennke)


Figure 3. Mission of the Dana-Farber/Brigham and Women's Cancer Center Amyloidosis Program
Venn diagram showing the three main areas of effort in the Amyloidosis Program. In blue is laboratory research focused on identifying novel molecular targets in AL amyloidosis and developing innovative treatments. In pink is clinical research focused on early diagnosis of AL amyloidosis. In yellow is research trials stemming from research efforts. At the center is the overall goal of the program: improving outcome and extending survival in our AL amyloidosis patients

 Learn more about our Amyloidosis Program