1. Pemmaraju, Naveen MD

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Breaking news. I am talking about real, true must-see news, not the alarm-fatigue, constant alerts that bombard our eyes, EPIC inboxes, and TV airwaves. In this modern era of no chance for surprises, since everything is always available 24/7, I still find it to be exhilarating when I am learning something in an unexpected moment, when we are all learning something that can impact our patients' lives, for the first time, all together in one place.


This happened to me once at the American Society of Hematology (ASH) meeting on Dec.10, 2013, in New Orleans. I will never forget that day. I was prepared and knew how busy this ASH was going to be as compared to years past. I had marked my calendar weeks in advance to make sure that I would put my fatigue on hold until after the meeting and make it to the Late-Breaking Session, held on the last day of ASH. I am not getting on that plane back home until I see this year's late-breakers, I told myself.


The reason is that there were two abstracts that really intrigued me-a group of new letters for a new molecular mutation popped up out of the page; letters that didn't fit into my brain's archived information troves-for patients with myeloproliferative neoplasms (MPNs). This was important to me as I have dedicated a large portion of my career to treating patients with these rare hematologic malignancies. By way of some background, I had joined the field just after the discovery of the first major molecular finding in the MPNs-JAK2V671F-in 2005 (N Engl J Med 2005;352:1779-1790, Cancer Cell 2005;7:387-397, Lancet 2005;365:1054-1061, Nature 2005;434:1144-1148).


I was a newly minted intern on the Osler Internal Medicine Service at Johns Hopkins in 2005, and was just starting out in the lab of Jerry Spivak and Alison Moliterno and was only starting to understand the biologic underpinnings of Dameshek's projected unifying basis for this trio of classical hematologic diseases (Blood 1951;6:372-375). It would be a residency, a fellowship, and a few years of faculty later, some 8 years, from the time I graduated from my short white coat that intern year, to the time that I was sitting in that overcrowded ASH hall for the Late-Breaking Session, that I would fully appreciate the work of Osler, Vaquez, Dameshek, and others in the MPN field. There was a buzz that year-a real buzz-one that I had not seen in our field since the discovery of JAK2V671F. But I didn't know, nor was I prepared for, what was about to happen.


Research Revealed in Real-Time

Two fantastic presentations were given back-to-back that day. In this age of distracted listening during presentations, I found myself hanging on every word, not looking at my Twitter feed or my smartphone during the talks-a real sign of being in the zone! The first talk was presented brilliantly by Dr. Nangalia. Her team performed exome sequencing and advanced statistical methods to find that a newly discovered set of mutations, those involving calreticulin (CALR), were found very frequently throughout the JAK2-negative/MPL-negative MPN (ET and MF) patient samples, actually marking it as the second most common acquired somatic driver mutation in the MPNs after only JAK2V617F (N Engl J Med 2013;369:2391-2405).


The second presentation, delivered deftly by Dr. Klampfl, on behalf of his group, similarly wowed us in the audience. His group, also using exome sequencing among other methods, demonstrated that many different abnormalities of CALR (insertions, deletions all in exon 9 of CALR) were observed as the second most common driver mutation in JAK2-negative/MPL-negative patients with ET and MF (N Engl J Med 2013;369:2379-2390). The audience was filled with conversation, discussion, and new energy. And as we now turned anxiously to our smartphones, Twitter feeds, and each other, there they were: both presentations dropped immediately into The New England Journal of Medicine as online-first complete manuscripts. As my wife and I often struggle just to get ourselves and our kids to everywhere everyone needs to be on a daily basis, I took a moment to marvel at the sheer amount of coordination, precision planning, and hard work among many parties it took to orchestrate all of that happening simultaneously!


It is an astonishing feeling to be hearing something in real-time that you know is going to change your medical practice forever. I knew in that moment that the lives of our patients would be affected from that point forward. It meant we can start moving from "negative" as in JAK2 mutation-negative to "positive," as in CALR mutation-positive (ASCO Annual Meeting 2015;35:139-145). The MPN field is a rare cancer field and breakthroughs of this level (two NEJM articles in the same issue are not that common (N Engl J Med 2012;366:799-807, N Engl J Med 2012;366:787-789), and this particular finding was immediately widely adopted and available as part of standard pathologic testing worldwide. The elucidation of the CALR mutation has been a real boon to our field on the clinico-pathologic side, as it has assisted in previously difficult cases of distinguishing a final diagnosis in reactive versus true clonal states in JAK2-negative patient cases (Blood 2016;127:2391-2405).


Furthermore, it appears there may be prognostic significance of presence of CALR mutation (based on CALR vs. MPL vs. JAK vs. so-called "triple negative" especially in MF and based on different categories of CALR mutations) (Blood 2014;124:1062-1069, Blood 2015;126:790-797, Leukemia 2014;28:1472-1477). Finally, this finding has unlocked a new area of basic and translational research in our field, including work from Dr. Mullally's group in uncovering the underpinnings of mutant CALR mechanism via the thrombopoietin receptor (Cancer Discov 2016;6:368-381).


In this era of instantly available information, even from remote locations, this was a refreshing, stunning moment I experienced as a young investigator. I reflect on this now, 4 years later, as I gear up for yet another ASH conference, to remind all of the potential learning by staying until that last day for the Late-Breaking Sessions. Of course, if you can't make it, especially from remote parts of the world, readers of this column know I am a big proponent of Twitter and social media to convey the spirit of the meetings to anyone anywhere (Curr Hematol Malig Rep 2015;10:413).


But if you can make the time to still try to be in the room, there is the potential for a certain flourish of meaning you may gain by hearing about a new finding that you know will directly benefit and help your patients in a rare cancer field, with your colleagues, in a crowded hall, and that never gets old.


NAVEEN PEMMARAJU, MD, is Assistant Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

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