#amyloidosisJC 11/4/15 @ 9 pm EST: examining the prognostic and predictive relevance of cytogenetics in AL amyloidosis

CLICK HERE FOR A LINK TO THE FULL TEXT OF THE ARTICLE

Background

Light chain (AL) amyloidosis is a rare plasma cell dyscrasia which causes morbidity and mortality through deposition of toxic amyloid fibrils. Although the prognostic significance of specific cytogenetic aberrations in the plasma cell malignancy multiple myeloma is established, the relevance of cytogenetics in AL amyloidosis is still being defined. Several recent retrospective studies including this study by Bochtler et al., have attempted to characterize the significance of chromosome aberrations in AL amyloidosis. This paper seeks to establish translocation t(11;14), as a predictive marker of poor response to bortezomib. This is important because bortezomib-based regimens (such as Vel/Dex) are often used as front-line treatment for AL amyloidosis. In this disease where patients often have progressive multi-organ damage, selection of an efficacious regimen to rapidly establish disease control is crucial. This paper raises the question of whether cytogenetic studies could guide treatment of AL amyloidosis.

Methods

·      Retrospective, single-center study of 101 consecutive transplant ineligible AL amyloidosis patients who received Vel/Dex as first-line therapy. These patients had high-risk clinical features such as severe cardiac or kidney involvement. Patients with concurrent stage II/III MM or IgM paraprotein were excluded.

·      Outcomes assessed included hematologic response after 3 cycles (by consensus criteria for PR, VGPR), hemEFS (hematologic relapse, hematologic progression, start of a second-line therapy, death) and OS. Early deaths counted as remission failures on intent-to-treat basis.

·       High-risk aberrations were defined as t(4;14), t(14;16) and deletion 17p13.

·      After backward variable selection, validation and calibration of the final multivariable model was done using a CyBorD-treated cohort (32 patients).

Results

Patient Characteristics 

Most patients in Vel/Dex and CyBorD cohorts had cardiac involvement (91% vs 88%) and around half had renal involvement in both cohorts

HemEFS

·      Median hemEFS 4.7 mo with median F/U of 24.0 months and hematologic events in 84/101 patients. The t(11;14)-positive group had inferior hemEFS (median hemEFS 3.4 months vs 8.8 months in t(11;14)-negative group; p=.002). Median hemEFS in high-risk group was 10.3 months vs 3.9 months in patients without high-risk aberrations (P=.15).

Overall Survival (OS)

·      Median OS was 15.7 mo with median F/U time of 24.1 months and 53 observed deaths. t(11;14) predicted for shorter OS with median OS 8.7 months vs 40.7 months in t(11;14)-negative group (P=.05). High risk aberrations conferred favorable prognosis (median OS = NR for high-risk v 10.6 months for absence of high-risk aberrations; P=.04).

Remission Rates

·      95/101 (94%) pt had initial dFLC >50mg/L and thus evaluable for ≥VGPR

·      30 (32%) achieved ≥VGPR after 3 cycles, 24 (25%) attained PR and 21 (22%) did not achieve remission, 20 (21%) had early death before remission assessment. ≥VGPR rates worse in t(11;14)-positive patients compared with t(11;14)-negative patients [14/61 (23%) versus 16/34 (47%) patients, P=.02].  High-risk aberrations had favorable remission rates compared to those without [8/12 (67%) versus 21/80 (26%), P=.008]

Multivariable testing in Vel/Dex Cohort with Clinical and Cytogenetic Factors

·      By Cox regression, t(11;14) and dFLC were the only two statistically significant prognostic markers for both OS and hemEFS. NT-pro-BNP reached statistical signification for OS. Thus t(11;14) is an independent negative risk factor in the Vel/Dex treated cohort. 

    A final model developed: hemEFS, t(11;14), sex, dFLC, NT-proBNP and dose reduction. For OS, t(11;14), dFLC and NT-proBNP. For outcome remission ≥VGPR, t(11;14) and age.

External validation using CyBorD cohort

·      ≥VGPR rate after 3 cycles, 24% (4/17) in t(11;14)-positive compared with 80% (8/10) in t(11;14)-negative patients. Median hemEFS 5.7 months in all 32 patients, 4.0 months in t(11;14)-positive and NR in t(11;14)-negative patients (P=.01). Median OS for both groups NR. Median F/U was 7.5 months. Calibration analysis of final models performed which showed that all trained predictors had a trend for better prediction of the outcome in the CyBorD validation cohort.

Authors’ Conclusions

• Cytogenetic aberrations are important independent prognostic factors in AL.
• Bortezomib is less beneficial to patients with t(11;14) 
• Bortezomib overcomes the poor prognosis of patients with high-risk aberrations.

Our Comments

• Study was of small sample size and would need confirmation with other studies, prospectively and multi-center ideally

• A potential criticism is the validation using a CyBord-treated cohort rather than additional Vel/Dex-treated patients. CyBorD cohort followup duration is a lot shorter than the Vel/Dex cohort. Despite this, results seen in the CyBord patients seem consistent with those described for the Vel-Dex cohort

• Paper suggests that cytogenetics may have predictive as well as prognostic significance.

Special thanks to Sandy Wong (@SandyWong02111) from Tufts University for her efforts preparing this summary. Looking forward to co-moderating this journal club discussion with her. 

Patient Page: Why is AL #amyloidosis bad for kidneys?

"Amyloidosis" refers to any one of several diseases in which abnormal protein fibrils accumulate in a person's organs. The most common type is called AL amyloidosis, and the protein fibrils are made up of fragments of antibody proteins called light chains. I posted a slide which illustrates what a light chain is in a previous post ("Why is AL amyloid bad for hearts?"). In AL amyloidosis, the levels of light chains (usually lambda type, but sometimes kappa type) in the blood and urine are elevated.  Light chains are made by plasma cells in the bone marrow, and current AL amyloid therapy targets these plasma cells. 

Any organ's function can be compromised by amyloid deposits.  The kidney is one of the most commonly affected organs, and patients with injured kidneys may have symptoms, including swelling (edema) of the legs, decreased urine output, and lightheadedness due to sudden drops in blood pressure. 

In order to understand how amyloid injures the kidneys, it is helpful to understand how the kidney works. 

A summary of kidney anatomy and function relevant to amyloidosis:

• The kidney is made up of a million microscopic filtration units called nephrons. 
• Each nephron has a filter called the glomerulus, which filters the blood.
• Some parts of the blood, namely water and electrolytes (sodium, potassium, etc), flow through this filter into a tube system where it is processed further. The material that eventually comes out of the end of all this tubing is urine. 
• Other components of the blood, like red blood cells, do not pass through the filter.  
• Although under normal circumstances there is essentially no protein in our urine, it is not because proteins do not pass through the filter. Filtered protein may be reabsorbed (taken back up into the body) in the first part of the tubing system.  The part of the tubing where this takes place is called the proximal tubule.
• The part of the tubing further down the line is called the distal tubule.
• All of these structures, as well as blood vessels within the kidney, are surrounded by tissue which serves as scaffolding to hold it all together. This is the interstitial space, or matrix.  (Its the Jell-O holding all the little pieces of fruit in place in that dessert your mother used to make on Thanksgiving) 

If you want to know more about normal kidney function, see the clear, easy-to-understand post by my friend, nephrologist Joel Topf, in his blog Precious Bodily Fluids.

Light chains can injure the kidneys in a number of ways.  Like albumin, normal light chains are filtered through the glomerulus and then taken back up in the proximal tubule.  The receptors along the lining of the tubule which do this are actually the same for albumin and light chains (cubilin and megalin, if you were wondering).  Problems develop if the light chain levels are abnormally high or if the light chains have an abnormal tendency to form clumps of strands.

• Amyloid light chains, in addition to being filtered, form deposits in the glomerulus itself. This is because these abnormal light chains are taken up by cells within the filter called mesangial cells. Mesangial cells do not take up normal light chains. After the abnormal amyloid light chains are snagged by these cells, they get processed and deposited within the matrix of the filter in strands called fibrils. When a pathologist is looking for amyloid in a kidney biopsy, s/he applies Congo Red stain, which makes these deposits look red under normal light and green under polarized light. As amyloid accumulates in the tissue around the mesangial cells in the glomerulus, the filter is damaged. It becomes "leaky" and the amount of protein lost through the filter increases. 

Kidney biopsy stained with Congo Red stain. Top image is the view under normal light, and the bottom one is the same slide viewed under polarized light.  Everything that turned fluorescent green in the second image is amyloid!
Images snagged from http://www.pathguy.com/lectures/imm-iii.htm

• Increased protein delivery to the proximal tubule is bad for one's kidneys. The receptors to reabsorb albumin and light chains can become overwhelmed. Excess albumin is lost in the urine, and it can make the urine appear "foamy."  Very low blood albumin levels are what cause the swelling (edema) and low blood pressure (hypotension) amyloidosis patients experience. Even though I.V. albumin solutions exist, it is not feasible to replace it because infused albumin suffers the same fate as the patient's "home-grown" albumin: flushed. Excess light chains can also cause problems, as they can bind to other proteins in the urine and form casts (clumps that clog up the distal tubule, which in turn causes problems upstream). Cast formation is the leading cause of kidney injury in multiple myeloma, but less of an issue in amyloidosis.  I posted about cast nephropathy previously (check that out). 
• Inflammation plays a role in amyloid kidney injury. Abnormal light chains, when taken up by the cells in the proximal tubule actually injure the cells in that part of the kidney. Excess albumin in the tubular system and abnormal amyloid light chains in the cells lining the tubular system trigger inflammation and eventually scarring of the interstitial area. This is why AL amyloidosis patient with persisting heavy albuminuria (albumin in the urine) due to filter damage may have continued worsening of their renal function even after the amyloidosis has been treated and the light chain levels are no longer elevated: albumin-mediated kidney injury. In my own practice, this is a common and frustrating problem. One glimmer of hope: it is possible that one of the treatments commonly used in the treatment of AL amyloidosis - the proteasome inhibitor bortezomib (Velcade) - targets this inflammatory pathway.  Other drugs in this same family (carfilzomib (Kyprolis) and ixazomib (MLN-9708)) are currently undergoing testing as therapy for AL amyloidosis. These drugs may not only kill bad-acting plasma cells, but also help the kidney dodge some albumin-mediated damage. Friend and colleague Meletios Dimopoulos has published extensively on this topic; check out this article describing the improvement in kidney function seen in myeloma patients who received bortezomib therapy. 

Kidney transplant has been undertaken in a limited number of patients with myeloma and/or amyloidosis. A major concern is that the same disease-related processes which caused the original kidneys to fail will recur in a transplanted kidney. Also, the fact that patients with these diseases often have limited survival independent of kidney function begs the question of whether precious  donor kidneys are best used in this situation. With newer therapies leading to higher remission rates and longer survival in both myeloma and AL amyloidosis, the idea that it may be time to revisit the conventional wisdom about organ transplantation is gaining traction (like here).

Lets call it a wrap. While I call this a "Patient Page," I used a lot of medical terminology. I tried to define everything in common language. Even so, it is probably clear I expect a lot from my readers. If there is anything in this page which requires clarification, TELL ME. Email me, or post it as a comment. I want the content of this (and every) post to be as clear and helpful as possible. 

Pomalidomide and Light Chain Amyloidosis

With the immunomodulatory drug pomalidomide (Pomalyst) recently approved for patients with multiple myeloma who have progressing disease within 60 days of the last of at least 2 prior therapies which had to have included lenalidomide (Revlimid) and bortezomib (Velcade), its an opportune time to review what we know (and don't know) about the drug in light chain (AL) amyloidosis. 

Pomalidomide, like lenalidomide, is a structural analogue of thalidomide. The structures of each are shown here:

source: http://www.readcube.com/articles/10.1186/2162-3619-1-27

The FDA-approved dose of POM in multiple myeloma is 4 mg/day for 21 out of every 28 days.

Investigators at the Mayo Clinic have studied POM (with dexamethasone) in 33 patients with previously treated AL amyloidosis. Patients had had a median of 2 prior therapies, with about half having had autologous stem cell transplant. A few (7) had previously been treated with other immunomodulatory drugs. 

The initial dose of POM in this study was 2 mg/day for 28 consecutive days each cycle (no break). DEX was given at 40 mg/week. POM dosing could be adjusted upward (if no response) and downward (for toxicity). The doses actually received are shown here: 

source: http://bloodjournal.hematologylibrary.org/content/119/23/5397.long

About half of the patients had hematologic responses, with the majority of these being partial. The median duration of response was 19 months. A handful of patients who had hematologic responses also had improvement in organ function, which is about what would be expected (based on prior work involving transplant, bortezomib, and other agents). Some of the responses observed occurred in patients who had had prior lenalidomide. 

A few notes regarding toxicity/adverse events: mild hematologic and gastrointestinal events were common. Peripheral sensory neuropathy (numbness, tingling) was documented in almost all patients - this was generally mild, but was more common than one might expect from, say, lenalidomide (at least in myeloma patients). The authors noted that the cardiac biomarker NT-pro-BNP (a marker of heart failure) sometimes worsened even in the setting of a hematologic response. Similar discordance between light chain measurements and cardiac markers have been noted previously in AL patients treated with immunomodulatory drugs (take a look).  In the present study, a 30% rise in the NT-pro-BNP in the first 3 months of therapy was associated with inferior survival, even though some such patients had concurrent light chain improvement.  

What we know: 

• POM can (and undoubtedly will) be used as treatment for AL amyloidosis. 
• Responses can be seen even in patients who have had prior autologous stem cell transplant, bortezomib, or lenalidomide.

What we don't know: 

• Optimal dose, schedule, and duration of POM in AL amyloidosis (tsk! details!) 
• Mechanism of NT-pro-BNP increase with POM therapy.

Study Spotlight: 

POM, like lenalidomide and thalidomide, will be studied in combination with other active drugs in patients with AL amyloidosis. The Karmanos Cancer Institute will be coordinating a national trial investigating the combination of POM, bortezomib, and dexamethasone in AL amyloidosis. This is the first trial prospectively studying an immunomodulatory drug combined with a proteasome inhibitor as front-line therapy for AL amyloidosis.  Participating centers will include Boston University, Duke University, the Colorado Blood Cancer Institute (Denver, CO) and Princess Margaret Hospital (Toronto).