As I thought about what to write for this column, I went back to much of the exciting data presented during the 64th ASH Annual Meeting and Exposition this past December, and what data will be presented this summer at the ASCO Annual Meeting and the EHA Hybrid Congress. As I pondered the depth of the data, with many new targets, I could not help but wonder what the take-home lessons would be for clinicians who seek to apply that data to the treatment of the patients in front of them. One of the strengths of the SOHO Annual Meeting is the ability to share a vast array of data and provide insights into how we can use it in our clinics.
A theme I noted from recent meetings was the breadth of targeted treatments, either genomic or immune in nature, which are rapidly changing the landscape for patients with relapsed blood cancers. While the overall response rates are quite high, the duration of remission still leaves much to be desired, and this is where Harry Potter comes into play.
To quote a well-known exchange from the final Harry Potter movie, “it’s complicated.” In the cinematic context, that phrase refers to the location of the famous sword of Gryffindor. It could easily, however, refer to blood cancers—and to cancer in general.
Over four decades ago, when the curative potential for combination chemotherapy using CHOP or MOPP in lymphomas was realized, it was based on the idea that blood cancers are complicated and that a single drug was unlikely to result in a long-term cure. Thus, highly effective agents might have a deep and durable response but are not likely to limit clonal evolution or the development of resistance. In the intervening years, the fields of HIV and infectious diseases further validated this concept of combination antivirals that is now so commonplace it shows up on television commercials.
Fast-forward to today, when we have single agents that are highly effective (bispecific antibodies, chimeric antigen receptor T cells, antibody-drug conjugates, and molecularly targeted agents), but we are still seeing issues with long-term administration. These issues include the development of resistant clones that evade the targeted agent via mutation or deletion of the target and infectious complications associated with the suppression of important immune targets over time.
Remember our line from the movie: “it’s complicated.” The problems with single agents do not arise in chronic myeloid leukemia (CML), which can be controlled with a single, molecularly targeted agent for a very long time in most patients (CML is less complicated on average). Unfortunately, this is simply not the case in most other cancers, where mechanisms of selective pressure when a single targeted agent is used chronically result in clonal selection and drug resistance.
Back in 2012, Jonathan Kaufman, MD, and I wrote an editorial for the Journal of Clinical Oncology titled “The Era of Combination Therapy in Myeloma.” We heralded the end of doublets as therapy and welcomed in a time where we now use at least triplets for induction and early relapse. This mindset shift has helped the field move from a median overall survival of three years to over a decade. The notion of combinations of noncross-reactive agents that also have nonoverlapping toxicities was highly innovative back then and, with limited agents to work with, made significant inroads in hematology.
In the current era, we have far more powerful targeted agents, as well as immune agents, but we should not forget the lessons of the past. I issue this challenge to my colleagues in hematology: combine our best new drugs in ways that are based on preclinical rationale and outstanding science, and that will allow us to create the next generation of curative therapies. We owe this to those who paved the way for us over the past 50 years in blood cancer research, we owe this to the scientists who led the way with innovative discovery, and we owe this to our patients, who are the reason we do what we do every day.
Go forth and cure!
Sagar Lonial, MD, FACP, is Chair and Professor in the Department of Hematology and Medical Oncology, the Anne and Bernard Gray Family Chair in Cancer, and Chief Medical Officer of Winship Cancer Institute at Emory University School of Medicine in Atlanta, Georgia.