John L. Berk, MD: I’d like to hear from doctor Hanna how you prognosticate, what survival metrics you use and share with your patients for both AL [immunoglobulin light chain amyloidosis] and TTR [transthyretin].
Mazen Hanna, MD: Let me start with TTR. There are 2 staging systems out there for ATTR [transthyretin amyloidosis] cardiomyopathy. One is the Mayo Clinic stage—from a publication by Martha Grogan at the Mayo Clinic—where they looked at patients with wild-type disease. They had saved blood from these patients and retrospectively looked at 2 biomarkers: NT-proBNP [N-terminal pro-brain natriuretic peptide] and troponin T and looked at the subsequent survival in these patients. They came up with 3 stages. Stage I was if you had an NT-proBNP level less than 3000 pg/mL, and if you had a troponin T level less than 0.05 nanograms per milliliter, that would make you stage I. If you had both of them above that—so an NT-pro level greater than 3000 pg/mL and a troponin T level greater than 0.05 nanograms per milliliter—that was stage III. Then, one or the other was stage II. So the patients at stage III had the worst prognosis (under 2 years), and the patients who were stage I—who were below both those biomarkers—they had the best prognosis, close to 6 years, 5 and a half to 6 years. And then you have the patients in between (about 3 1/2 years); those patients are at stage II. So, in addition to the patient’s echocardiogram results and how much diuretics they’re on and your other gestalt type of markers of how someone is going to do, using that staging system is another way we will speak to patients.
The other staging system that’s used in patients with ATTR cardiomyopathy is the Gillmore staging system. Julian Gillmore, at the National Amyloid Center in London, studied a large cohort of patients, and instead of looking at NT-proBNP and troponin levels, he looked at NT-proBNP and estimated GFR [glomerular filtration rate] (in this case, less than 45 mL per minute per meter squared). And the same thing, if you had an NT-proBNP level that was less than 3000 pg/mL and a GFR that was greater than 45 mL/min/1.73 m2, you were in stage I; if you had an NT-pro level greater than 3000 pg/mL and a GFR less than 45 mL/min/1.73 m2, you were in the worst stage, stage III. The survival rates pretty much paralleled more or less what the Mayo staging found.
So, those are the 2 staging systems that I will use in patients with ATTR cardiomyopathy to enhance the discussion that I’m having with a patient. Now, remember, these staging systems were derived without treatment. Right now, if I’m going to put somebody on tafamidis or another medication with those numbers, I can’t really give them the accurate numbers because you would assume that survival is going to be better. But that’s the best we have.
As far as AL amyloidosis, there is a Mayo Clinic staging system, I, II, III, and IV, which was revised from 2004 to a 2012 revised staging system, and again they look at 3 variables. They look at the NT-proBNP level, a troponin T level and in some cases, a troponin I level and then the difference in the involved and uninvolved free light chains. In this case, stage IV, which is the worst, would be an NT-pro level greater than 1800 pg/mL, a troponin T level greater than 0.03 ng/mL, and a difference in the involved free light chains to the uninvolved of 180 milligrams per liter, or what would be 18 milligrams per deciliter. So, again, the concept is that patients with stage IV have a very poor survival, 6 months mortality at 50%, whereas patients in stage I will have a much better prognosis, and obviously the ones in between.
Again, this is derived before daratumumab, before some of the better chemotherapy agents we have. I know doctor Witteles will hopefully talk to us about his most recent publication regarding the survival in these patients in the newer area of having daratumumab and other medications.