It is a tough time to stay focused on what makes work worthwhile. Even before the pandemic, there were growing burdens facing the profession, with burnout always just around the corner. Yet, most days, I wake up energized. This is due in part to my personality — I am a “half-full” individual. But I also owe my energy and optimism to having discovered a passion at work and to being lucky enough to have a workplace where that can blossom. My passion is working on novel treatments for patients with rare diseases such as blastic plasmacytoid dendritic cell neoplasm (BPDCN). Treating patients who have this orphan disease has helped me think of my work as a calling rather than a job. Perhaps in part because the patients who have this condition (like many rare diseases) do not have much of a public voice because of the rarity of their cancers or lack of awareness in general.
It was my interest in orphan diseases that first drew me to the work of Dr. David Fajgenbaum, assistant professor of medicine at University of Pennsylvania and cofounder and executive director of the Castleman Disease Collaborative Network (CDCN). Dr. Fajgenbaum is also an optimist, and his memoir Chasing My Cure: A Doctor’s Race to Turn Hope Into Action. has reinforced the energy I feel about the trajectory of my own clinical research. Dr. Fajgenbaum, who has Castleman disease himself, has led an international coalition of scientists, advocates, and physicians in identifying novel therapeutics for this uncommon malady. His efforts are notable, not just because of his medical history, but also for his energy in uniting a diverse group of stakeholders His life’s work serves as an inspiration to all of us working to cure rare diseases, and he exemplifies what a public voice can accomplish.
My work throughout the past decade has been dedicated to BPDCNs — a historically “true rare” disease. We believe the incidence of BPDCNs to be only 500 to 1,000 patient cases per year in the United States. Patients with BPDCN historically have had a median overall survival of less than two years from diagnosis, despite multiagent chemotherapy regimens, often borrowed from other leukemias and lymphomas. The discovery by Dr. Craig Jordan and colleagues1 that CD123 (IL3Rα) is overexpressed in essentially all cases led to a novel drug therapy approach. I was lucky enough to be in a position to enroll patients on the seminal pilot study led by Dr. Art Frankel of a CD123-directed cytotoxin, published in 2014.2 Within five years and after a successful multicenter trial, U.S. Food and Drug Administration approval was granted. I am now collaborating with colleagues from across the country on other CD123-directed therapies and additional novel pathways. This has been one of my daily joys at my job — the ability to find and interact with a growing coalition of investigators, who, like me, are driven to find a way to help folks with such a rare condition.
While reading Dr. Fajgenbaum’s memoir, I was struck by how many lessons reverberated with me. First, the fact that academia gives us a platform from which to share our experiences. This is certainly the case for Dr. Fajgenbaum, whose proximity to researchers and clinicians at Penn allowed him to help ideas become projects (or turn “hope into action”). I cared for several patients with BPDCN at the start of my career and observed that most could not even pronounce the name of the disease much less contemplate novel therapies. Since time is limited, resources are not infinite, and there are so many who are researching the more common disease types, why not focus on areas where understanding is lacking, to hopefully address those urgent unmet medical needs? Dr. Fajgenbaum was driven to research Castleman by his own illness. However, it is how he turned that into a passion for others that is so admirable and inspiring.
The second lesson I found in this memoir is the value of mentorship. In Dr. Fajgenbaum’s case, examples were numerous. In my life it has been the support and advice of Drs. Marina Konopleva and Hagop Kantarjian. They provided guidance when I was deciding to focus on BPDCN and when I was building up the clinical and research infrastructure at our institution, and they have helped me make discoveries. This encouragement cannot be overstated as there are so many academic rejections along the way, where experienced mentors can literally point you in the right direction and say, “Hey, keep going. Keep pushing. You’ve got this.”
I think Dr. Fajgenbaum’s story is also the story of how discoveries in a rare disease field can have far-reaching applications many years later in other fields. Siltuximab, for example, was first approved for Castleman disease and is now used in a variety of settings including chimeric antigen receptor t-cell toxicity. This has opened up a new field of IL-6 disease biology and targeting. Similarly, the first-ever approved CD123-targeted agent has opened up a new area of clinical investigation. We are now actively investigating applications in a variety of lymphoid and myeloid malignancies, multiple myeloma, as well as post–stem cell transplantation and minimal residual disease settings. By focusing on a “narrow” subset of a subpopulation, one can possibly make big discoveries applicable someday to a larger population or area.
Finally, in reading Dr. Fajgenbaum’s story, I was struck by the intimacy of illness. Just because one has a rare disease, it is not rare to them. It is not rare because that person and their family must face it every day. And yet, if a disease affects one person or 1 million people, with the digital era and expansion and feasibility of research across the world, there is likely someone out there working on your rare disease. With new means of technology and connectivity, including social media,3 it is easier to connect with each other for the betterment of all health care stakeholders. Let us learn to forgo our silos for interconnected research and realize that especially for rare blood cancers, we really are in this together.
And so, like Dr. Fajgenbaum, my passion has now turned into a dedicated, sustained career focus. I hope to continue to advocate for those who do not always have voice and for those who do not have a ribbon or a footrace dedicated to them. That hope is energizing.
Dr. Pemmaraju indicated no relevant conflicts of interest.