27 January, 2013

New Amyloid Fibril Nomenclature Recommendations Published

In May of 2012, at the XIIIth International Symposium on Amyloidosis in Groningen (Netherlands), the Nomenclature Committee of the International Society of Amyloidosis updated amyloid fibril nomenclature guidelines, and expanded the list of recognized amyloid fibril subtypes. The latter is shown here in 3 tables from the article
From Sipe J.D., et al. Amyloid, 2012; 19(4): 167–170

From Sipe J.D., et al. Amyloid, 2012; 19(4): 167–170
From Sipe J.D., et al. Amyloid, 2012; 19(4): 167–170

 I wanted to post the Amyloid Fibril Protein Nomenclature List because it serves as a reference for readers, and also provides context for the broad range of medical topics which will be discussed over time in this blog. Keep this post handy!

26 January, 2013

Suffering from TE

I am suffering from progressive intermittent Theralite Envy (TE), a recently-recognized condition amongst American clinicians who treat a lot of myeloma patients but do not have ready access to the Gambro HCO 1100 dialyzer filter.  The cause of TE can be debated, but my case was definitely exacerbated by recently admitting a myeloma patient with severe acute kidney injury from cast nephropathy which did not improve despite prompt recognition of the problem and initiation of effective systemic myeloma therapy. Several years ago, a consulting physician once assured me that plasmapheresis could cure my TE, but its really only made it worse (see why).

The Gambro HCO ("high cut-off") 1100 dialyzer is distinct for its 15-60 nm pore size, permitting passage of molecules with a MW of up to 45 Daltons (the size of a dimeric lambda light chain).

The Gambro HCO 1100 Dialyzer (*sigh*)
Like Charlie Brown's Little Red Haired Girl, it was a few curves with little else to go on which attracted me to the GHCO1100...


The figure above models clearance of light chains from the serum with plasma exchange and HCO hemodialysis.

Randomized studies - EuLITE and MYRE - have been ongoing (and ongoing, and ongoing...) in Europe. In both studies, myeloma patients with renal injury who are being treated with bortezomib-based therapy will be randomized to either HCO dialysis with the Gambro filter, or to conventional high flux hemodialysis.  The EuLITE trial was initiated 5 years ago, and results are expected this year.

The technology may have relevance for patients with AL amyloidosis, as well.  The mechanism of renal failure in AL is different, but disease outcome is clearly linked to prompt, deep, sustained reduction in serum light chain levels:

cited in http://www.readcube.com/articles/10.1186/1756-8722-4-47

Since the best novel agent combination regimens for AL amyloidosis typically take over a month to induce maximal light chain suppression, its reasonable to explore HCO dialysis as an adjunctive therapy, either in the initial stages of treatment, or as an ongoing part of care. Dr. Giampaolo Merlini, a world-reknowned amyloidosis specialist from Pavia, Italy is currently conducting a trial using the Gambro filter in AL amyloidosis patients with amyloid heart disease and end-stage kidney injury. In this small study, it may be hard to prove what HCO hemodialysis adds to systemic therapy in terms of light chain reduction, let alone what it adds to the likelihood of inducing an organ response. Dialyzing away the main serum marker used in chemotherapy response assessment may also present a difficulty - particularly when trying to determine the likely benefit of ongoing chemo.

Professor Giampaolo Merlini, Amyloid Guru

At this point, as a sufferer of chronic TE, my prognosis remains guarded: it feels like we have waited an eternity for the results of large and small European trials examining whether use of the Gambro HCO 1100 dialyzer will have real utility in patients with plasma cell diseases. News may come this year.  Negative results would probably relieve me of my longstanding TE, but would also certainly be a disappointment for the myeloma/amyloidosis medical and patient community. The needed prescription then for both patients suffering from light chain mediated kidney and organ disease, as well as clinicians and researchers suffering from TE? Positive results leading to accelerated availability of the filter on this side of the Atlantic. Fingers crossed.

[AUTHOR NOTE: There is no financial relationship of any sort between myself and Gambro, the maker of the product discussed above. As far as I know, I have never even met anyone associated with Gambro. Admitting this, as readers might imagine, is actually aggravating my TE a little bit]

[TE UPDATE, 2/3/13 10:00 PM EST: Have been in contact with Jeffrey R. Shideman, PhD, Director US Clinical Affairs, Gambro this last week regarding the HCO 1100 Dialyzer (AKA Theralite Filter). There is a compassionate use option for myeloma patients with acute light chain-related renal failure in the United States. This requires a little bit of work on the part of the treating physician (IRB approval, for one thing). FDA guidance on access to investigational devices is provided here. Previously discussed Theralite Envy seems somewhat eased by this information.]

20 January, 2013

9 years and counting....

The last U.S.-led randomized study comparing different treatments for newly-diagnosed AL amyloidosis was published in 2004. The one before that was published in 1999. Two randomized studies, 14 years. To put this in some perspective, despite the fact that neither of my two teenage children have expressed any particular interest in conducting large-scale studies in AL amyloidosis, they are only two behind the national medical community during their lifetimes. 

The premature closure of the ECOG-led intergroup E4A08 study, a randomized Phase III trial comparing melphalan and dexamethasone (MD) to MD + bortezomib (MD-Bz) as initial treatment for AL-amyloidosis patients who have not had prior therapy thus represents a missed golden opportunity to advance the field. This was a trial endorsed by SWOG. I served as the SWOG PI for E4A08, and have some insight as to the problems which led to the trial's closure. 

While checking out another amyloidosis-focused site (The Amyloidosis Weekly, edited by a friend and colleague, Bob Orlowski) I found a posted research abstract from the Accrual Working Group (AWG) of the National Cancer Institute's Myeloma Steering Committee which examined barriers to accrual to NCI-sponsored myeloma trials.  Dr. Matthias Weiss, the lead author of the study, provided me with a copy of the poster he presented at the 2012 American Society of Hematology meeting in Atlanta. 

The authors analyzed the results of Survey Monkey surveys returned by 246 researchers and/or support staff affiliated with cooperative oncology research groups like SWOG or ECOG-ACRIN. The surveys asked respondents to rank 10 potential barriers to accrual identified by the AWG in terms of their importance in slowing accrual in large multi-center trials. Predictably, attitudes of community-based respondents differed from those of academic/university-based ones. Dr. Weiss told me he believes barriers 3, 5 and 8 were key to the demise of E4A08, which is plausible, despite the fact that there are NO (ZERO, NADA, ZIPPO) FDA-approved therapeutic agents for initial treatment of AL amyloidosis. I believe a variation of barrier 10 was also a factor: some sites wouldn't allocate the resources needed to open a trial to which they were not likely to accrue more than 1 or 2 patients. Also, shockingly, several reputable investigators at some of the larger SWOG and ECOG centers expressed that they were uncomfortable with the control arm (melphalan plus dexamethasone), and thus wouldn't even open the study. I bet Dr. Jaccard, a leading amyloidosis specialist in France, laughs about that (see why).

Time to look in the mirror and ask ourselves whether we want to remain relevant in the arena of clinical AL amyloidosis research. The next possible standard of care for AL amyloidosis will be determined by our European colleagues who CAN get this study done (and are in the midst of proving it). Shame on us. Lets not allow another 9 years to pass before we get a big up-front AL study done in the United States.