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In this episode Mazen Hanna, MD, Arianne Agdamag, MD, Preethi William, MD, and Jack Khouri, MD, discuss the treatment of ATTR amyloidosis.

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Talking Tall Rounds: Treatment of Amyloidosis

Podcast Transcript


Welcome to the Talking Tall Rounds series, brought to you by the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic.

Mazen Hanna, MD:

Good morning, everyone. My name's Dr. Mazen Hanna, and I am the co-director of the Amyloidosis Center here at the Cleveland Clinic. Welcome this morning to our Tall Rounds titled Treatment of Cardiac Amyloidosis. For those of you who joined us in the fall, we had a previous Tall Rounds on the diagnosis of cardiac amyloidosis. And then later in the spring we're going to have a third one in this series, really how to follow patients over time. Without further ado, we're going to start with a case. Dr. Arianne Agdamag, who's part of our Heart Failure section.

Arianne Agdamag, MD:

Good morning. I will be presenting a case of biopsy proven ATTR and AL cardiac amyloid. This is a case of a 51-year-old Caucasian male who initially presented to our clinic with exertional dyspnea. His past medical history was significant for carpal tunnel syndrome, spinal stenosis, bicep tendon rupture, and coronary artery disease. Pertinent in his physical exam included periorbital purple discoloration as well as trace lower extremity edema. Initial workup for his dyspnea on exertion included a transthoracic echocardiogram which showed severe concentric LVH with interventricular septal thickness of 1.92 cm and posterior wall thickness of 1.9 cm, with concern for infiltrative disease. With this, an amyloid evaluation was started. His laboratory tests were significant for an elevated troponin, NT-proBNP, lambda light chain proteinuria, and very low kappa/lambda ratio. His EKG showed normal sinus rhythm, low voltage EKG in the left anterior fascicular block. Imaging testing included a PYP scan which showed a visual score grade of zero with no uptake. His cardiac MRI showed evidence of diffuse, abnormal, patchy mid-wall left ventricular late gadolinium enhancement as well as elevated extracellular volume. His bone marrow biopsy showed no evidence of amyloid deposition. Fluorescence in situ hybridization was normal. Given these above findings, he was recommended to undergo endomyocardial biopsy for further evaluation. His endomyocardial biopsy was significant for amyloid deposits. This was confirmed on both immunohistochemistry as well as typing with mass spectrometry, which show a lambda immunoglobulin light chains as well as transthyretin. With this, he underwent genetic testing which was negative, indicating wild-type ATTR amyloidosis. He was eventually started on daratumumab plus CyBorD regimen with noted good response. He was eventually transitioned to a single agent daratumumab and was started on tafamidis. He has been following on outpatient basis and has been doing well, tolerating all his medications. This rare case of biopsy-proven AL and ATTR amyloidosis highlights the importance of a thorough investigation as well as a stepwise treatment.

Mazen Hanna, MD:

Preethi William will talk about management of cardiac amyloidosis.

Preethi William, MD:

Management of cardiac amyloidosis. There are several kinds of amyloidosis, and the two main types that we're looking into are the AL, due to a bone marrow disorder, and the ATTR due to misfolded proteins from the liver due to acquired status called wild-type or a genetic mutation called as the hereditary type. Subsequently, either of these deposit in the heart. When the biopsy is done or a tissue sample is analyzed, the pathology shows diffuse involvement of multiple structures. And as a result, you have altered mechanics and heart failure. This subpectoral representation of an epidemiological view of cardiac amyloidosis, the tip of the iceberg represents clinical stage C and D heart failure. Below the waterline, you see the obvious arrhythmias and valvular heart disease. However, in most instances this is an unidentified cardiac amyloidosis, and at stage A you see the extra cardiac amyloid deposits.

This is a cardiac amyloid spectrum from. Left to right, the image on the left side assimilates the ischemic cascade, and you see that there is orthopaedic manifestations that you see more of imaging biomarkers. And the images on the right portray diastolic dysfunction due to increased wall thickness and altered tissue Dopplers. And intertwined with this findings are your atrial arrhythmias or arrhythmias in general, and eventually having systolic dysfunction and cardiogenic shock. Management of cardiac amyloid eventually now has twofold mechanisms of treatment. On the right side, the disease modifying targeted therapies that my colleagues are going to go in detail with more detailed data, and this has evolved and changed the landscape in the last decade with clinical trials.

On the left side is a supportive care, which I'm going to go through. This is based predominantly on consensus and specialty guidelines. And the outcomes of most of these data are targeted therapeutics interventions that have been done after that. Management of cardiac amyloid will focus on the top two aspects of supportive care, based on these references that we have. Atrial arrhythmias are the predominant finding that we see, and then we see heart blocks, ventricular arrhythmias and device management. Most importantly, anticoagulation is recommended regardless of the CHA2DS2-VASc Score. Incidents of thrombus is seen in multiple areas of the myocardium. And in specific, you do see left atrial mechanics that are altered and can predict thrombotic events. Rhythm control is relatively tolerated. And we'll discuss the next slide as to why rate controlled drugs are not well-tolerated.

And catheter ablation is successful with less recurrence rate over the year in patients with early stages of the disease. Device management follows societal guidelines. These patients do receive appropriate ICD shocks, however, there has not been survival benefit, partly because a host of sudden cardiac death in these patients are related to pump failure, electromechanical dissociation and PEA, and higher defibrillation threshold likely related to amyloid deposition in the myocardium. An ambulatory EKG and electrophysiological study can be done on a case by case basis on a consultation. Supportive care for cardiac amyloid in the era of precision medicine and machine learning. Volume management is the mainstay of treatment with a narrow margin of tolerability using MRA, SGLT2, and diuretics. GDMT is poorly tolerated. As you know, most of these patients have restrictive cardiomyopathy and the heart rate is compensatory, and the fixed volume depends on that compensatory heart rate to produce the cardiac output. So when you suppress these patients' heart rate, they do develop decompensated heart failure.

Note on Digoxin. Our institution has a database of these patients. It can be used. Must be used with caution, with close monitoring, especially in elderly patients, patients with renal dysfunction, and those with concomitant amiodarone use. Autonomic dysfunction and hypotension is a well-known finding as well, as these patients are known to have difficulty in regulating the autonomic nervous system. And TAVR outcomes are better compared to SAVR or medical therapy in the aortic stenosis and amyloid cohort. Ultimately, a multidisciplinary team approach is required for patients with structural surgical interventions and consideration for clinical trials. That brings us to stage D heart failure where we assist the options on a multidisciplinary team basis. Heart transplantation has been considered. Mechanical circulatory support has been considered as well. I believe that the newer drugs are going to change the landscape of these advanced therapies as well. Heart transplant done in our centers are depicted here, and some of the most compelling contraindications is refractory neuropathy or uncontrolled disease, multi-organ involvement, and malnutrition associated with poor outcomes.

Mechanical circulatory support is limited by the small LV cavity size, biventricular involvement, and tolerability to anticoagulation. That brings us to palliative medicine that could be dealing from the prognosis and focused on quality of care and lifestyle to prevent symptomatic hypotension. In addition to compression stockings, most of these drugs can be tailored to patients' individual needs, although precautions and adverse effects to be of note. That brings us to the summary slide of supportive care of cardiac amyloidosis. We reviewed management of heart failure where GDMT is less tolerated and there is a narrow window of euvolemia and arrhythmias, in general, follow societal guidelines. And of note, anticoagulation is recommended in these patients due to high thrombotic risk. I will pass it on to my colleagues. Thank you.

Jack Khouri, MD:

Okay. So the main treatment for AL amyloid aims at shutting off the source of the amyloidogenic light chain in AL amyloidosis. So a lot of the treatments that we use are borrowed from the multiple myeloma armamentarium, since that's the same cell that causes the problem here. And currently, there's a lot of drugs that we can use. As you can see, a lot of them target the plasma cell. And the main aim here is to reduce the production of the actual amyloidogenic light chain. The new wave of clinical trials, as Maz discussed, for ATTR is actually also aiming at targeting the actual fibril that's deposited in the heart and the other organs in hopes to improve the organ function that many patients are left with organ dysfunction and leaning to poor survival. So the survival of AL has improved over time regardless of the treatment that people got. And this is basically due to the fact that more patients are diagnosed early and the treatments are actually improving with time.

We all know that it's really, really important to get people to a deep hematologic response. Basically dropping the light chain to a very low level, a very deep hematologic level, and rapidly. So we know that patients who achieve a very deep hematologic response, basically what we call a VGPR, so very good partial response or better, these are the patients that do best. So it's really important to drop that light chain. And VGPR is a difference of free light chains of at least less than 40. So patients who achieve that or better are the patients that fare best. And this is basically the aim of a lot of the things that we do in AL to rapidly reduce that light chain.

This diagram shows the evolution of the treatment of AL. So back in the nineties and the early 2000s, we mostly aimed at using alkylating agents. So melphalan, which is a chemotherapy drug that was used commonly in myeloma in combination with steroids, so prednisone or dexamethasone. And then studies on myeloablative dosing of melphalan, so high doses of the same chemotherapy drug in combination with a stem cell transplant was implemented in the early nineties and early 2000s in these patients. And this is more for eligible patients, so this treatment is very toxic. So the selection of patients was a problem because there was increased mortality with this treatment, which led to the development of more tolerable treatments. And the mainstay for a long time, since at least the 2010s was CyBorD, which is a combination of cyclophosphamide, bortezomib, and dexamethasone. And then more recently in 2021, the standard of care changed with the addition of the anti-CD38 monoclonal antibody, daratumumab, to CyBorD, which constitutes the main standard of care.

The way daratumumab works is it targets the CD38 protein on the surface of the plasma cell. CD38 is very important for the survival of the plasma cell, and so when the drug binds to it, it takes it for destruction by NK cells, phagocytes and complement fixation, which leads to killing of the actual plasma cell. Now, the main study that set the standard of care for amyloidosis, for AL amyloid, is the ANDROMEDA study that was published in NEJM in 2021, which led to the FDA approval of the combination of daratumumab with the standard of care at the time, which was bortezomib, cyclophosphamide, and dexamethasone. The study was a randomized phase three study of about 400 patients that randomized patients in a one-to-one fashion between VCD, which was the standard, or VCD with daratumumab.

The initial treatment consisted of six cycles of treatment and then patients continued on daratumumab maintenance, if they were on the daratumumab arm, or just observation if they did not receive daratumumab. Patients who were excluded in this study were patients who were sicker, mostly advanced cardiac patients, so stage 3A patients. Sorry, stage 3B patients who had an NT-proBNP of 8,500 or higher. So a lot of these sick people were excluded. The primary endpoint was hematologic complete response, which is basically normalization of the involved light chain, either kappa or lambda, and the ratio of kappa and lambda. These are the results of the ANDROMEDA study. So the primary endpoint, which is complete response, was definitely better with the addition of daratumumab. More than half of the patients achieved the complete response versus only barely 20% of the patients with the standard of care at the time.

Looking at deeper levels of light chains, which is better for patients' survival. Again, same thing, 70% of the patients achieved an involved free light chain level of less than 20, which is a very deep response. And the difference of free light chains of less than 10 milligrams per liter was also seen in more patients who received daratumumab. Another endpoint that was looked at in this study was the major organ deterioration progression-free survival, which was a secondary endpoint, which basically looked at patients who had no deterioration in their cardiac or renal status. So patients who did not need further intervention for their cardiac disease, so LVAD, heart transplant and such, and patients who did not have renal deterioration, so patients who did not end up on dialysis. They looked at those patients separately and again, we did see improvement with the addition of daratumumab.

The two-year follow-up of this study showed that the responses continued to deepen over time, so more patients achieved CR, complete response, with time at two years. Versus with the standard of care, the number was still the same. So daratumumab is definitely something that improved the standard of care that we had at the time. And this study basically led to the approval of this combination, the quadruple therapy for patients with AL amyloid.

Looking at response rates. Cardiac response rates also were better at six months and 18 months with the addition of daratumumab. So 50% or more of the patients at 18 months had recovered their cardiac dysfunction, versus about 20%. There was more than doubling of the response here. Same thing for renal. At six months and 18 months, more than 50% of the patients achieved organ response versus 20% for the standard of care.

Quality of life also improved with the addition of daratumumab, looking at two scores here that we use in AL, so QLQ and C30, looking at global health status and fatigue. There is definitely improvement with the addition of daratumumab with good tolerability. The unanswered questions from that study is basically for patients who have worse cardiac disease, so stage 3B patients with the NT-proBNP above 8,500. Patients who had advanced renal disease on dialysis were not included either. And again, so complete responses were seen in more than 50% of the patients, but there were still about 45% of the patients who did not really achieve that CR. So we still need more work in that area. This is a treatment algorithm for how we treat AL amyloidosis currently. So the first line is with daratumumab, bortezomib, cyclophosphamide and dexamethasone.

We need to achieve at least a PR with this. If there is no PR, if the patient is eligible, we move on to stem cell transplant. If not, then we can follow the algorithm for relapse disease. If someone achieved a CR or a very good partial remission, then we can just continue with the ANDROMEDA protocol. Now, let's say the patient did not really achieve a partial response. This is when the treatment is really... There's no standard of care and it's basically the dependent on the hematologist. But a lot of the treatments that we used are, again, borrowed from multiple myeloma. A drug that's very promising that we have published on is venetoclax, which is a BCL2 inhibitor. BCL2 is an anti-apoptotic protein. And if you block it, you can potentially help kill the plasma cell. It's been used for people with translocation 11;14, which is a chromosomal translocation that we see commonly in amyloid in about 50% of the patients. And this drug has really shown a lot of promise in this arena.

Now, moving on from targeting the plasma cell, like Maz was talking about in the ATTR, the new wave of therapies is also aiming at clearing the amyloid fibrils in hopes to improve organ dysfunction in our patients. Again, 50% of the patients are left with organ dysfunction, and so it's an unmet need in this situation. So two antibodies that we're looking at an AL amyloid, CAEL-101 and birtamimab, and they both target different epitopes, cryptic epitopes, on the surface of the misfolded light chain. And they're both in clinical trials right now. The birtamimab clinical trial, so the birtamimab drug was tested in a large phase three study called the VITAL study. The study was not successful. It did not meet its primary endpoint. However, when they did post hoc analyses on patients who were sicker, so Mayo's stage four patients, and these are the patients with elevated troponins and elevated NT-proBNP, there was a survival benefit in those patients at nine months.

So there was a signal for those patients. Currently, the drug is being tested in a large phase three study that looks at patients with stage four amyloid only. This study is only for stage four AL amyloid. We do have it open here at the clinic, and it randomizes patients to standard of care with birtamimab versus placebo. The primary endpoint is all cause mortality and there's a bunch of secondary endpoints, including six-minute walk test.

The other anti-amyloid fibril antibody is CAEL-101, which targets a different cryptic epitope on the misfolded light chain. We were involved in the testing of this drug here at the Clinic, and we did have the phase two here open. That included two parts, part A and part B, which involved giving the drug initially at four weekly doses with standard of care chemotherapy and then moving on to maintenance with biweekly dosing. The second part included daratumumab after the approval of daratumumab for AL amyloid.

If you look at the cardiac responses, so blue and green is either stable or resolved. A lot of patients achieved at least stable organ response or better. And even after cessation of anti-plasma cell therapy, we did see the same thing. So more patients achieved stable and/or resolved a response in the cardiac response. So this is very promising and there's currently two phase three studies that have fully accrued looking at this drug, and we're awaiting to read on those studies. Thanks.


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