Resolving to Close the Gap

January of any new year finds newspapers, social media, and family dinners full of conversations about the accomplishments of the previous year (not to mention, the previous decade). For our community of hematologists, the past 10 years have brought about a dazzling acceleration in therapies.

Basic science discoveries from the end of the last century and beginning of this one have now entered the clinic. Diseases where there was considerable therapeutic nihilism (think multiple myeloma, acute myeloid leukemia in the elderly, or sickle cell disease) are now arenas in which novel agents are becoming commonplace. A quick review of U.S. drug approvals since 2009 shows:

1. A remarkable increase in the sheer quantity of approvals of new drugs or indications for hematologic conditions. By my quick count, there were 27 such approvals for the first 5 years of the last decade and 75 approvals between 2015 and now.

2. An increasing number of novel therapies for exceedingly rare hematologic conditions — diseases like Erdheim-Chester disease, Castleman’s disease or paroxysmal nocturnal hemoglobinemia, for example. Applied knowledge has changed the outcomes for patients who previously were sidelined as “orphans.”

3. Multiple agents available in the same disease, despite the fact that this condition may be uncommon. For example, since 2010, there have been five agents approved for use in chronic myeloid leukemia.

4. Drugs are now commonly approved for molecularly defined subsets of patients. The implications being, of course, that their applicability, even in a common disease, will be limited.

In this issue of The Hematologist, we continue a tradition started by my predecessor, Dr. Jason Gotlib, where our panel of Contributing Editors outline some of what they believe to be the most impactful discoveries of the year prior. We also conducted a casual survey of participants at the annual meeting in December to get their opinions on the year’s most important discoveries, and DOACs in cancer patients took the top honors in that poll. I won’t steal their thunder by listing out what our CEs have selected, but suffice to say, it was a tough year to choose between so many good options.

As I thought about all the developments, with gratitude and excitement, I also was thinking about how much work we still need to do. Tremendous challenges continue to impede translation of science into the public good. It’s a little presumptuous, but this is also a time for resolutions, so I thought it would be a good time to propose, in no particular order, a few pledges that I believe could help our patients as we go forward.

Resolution #1: Improve our clinical trial designs such that the results can be deployed in diverse populations.

One of the high points of the 2019 ASH Annual Meeting was the number of abstracts that illustrated disparities in the treatment of blood diseases. A portion of such disparities results from clinical trial designs that needlessly exclude patients. Two examples come to mind. In one study, investigators from the Cleveland Clinic looked at more than 1,000 patients with acute myeloid leukemia and found that African Americans were more likely to have evidence of abnormal kidney functioning than whites, but this was not associated with any difference in overall survival.¹  Trials that exclude patients with signs of kidney dysfunction may disproportionately (and unnecessarily) exclude minorities as a result. In another abstract, authors looked at the post-approval use of anti-CD-19 chimeric antigen receptor T-cell (CAR-T) therapy.²  The authors used Medicare claims data to look at patients treated after approval, and their comorbidities. Despite medical conditions that would have made them ineligible for the studies, the patients seemed to benefit from the agent. So why exclude them from the protocols? Overly conservative inclusion and exclusion criteria slow down progress in medicine and also hinder precision since we need heterogeneous populations to identify which groups may or may not benefit from a given therapy.

Resolution #2: Actively work to mitigate the gap in care between rural and urban communities.

Having trained in Boston and Chicago, I have been aware throughout my time as a physician of the many ways in which poverty hinders health. Moving to Wisconsin, however, has illuminated for me some of the challenges facing rural patients. Access to care, logistical burdens from long commutes to specialty centers, health literacy, and socioeconomic status have all been cited as some of the myriad reasons that individuals from rural areas have worse outcomes compared to those who live in, near, or around cities. Can this be mitigated? An abstract presented at the annual meeting by clinical investigators at the Levine Cancer Institute³  hints that the use of a patient navigator program may help ethnic minorities achieve outcomes similar to those of white patients when they are treated for diffuse large B-cell lymphoma. These parallels bolster research published in 2018 in which investigators looked at more than 36,000 patients treated on cooperative group trials and showed that rural and urban patients with cancer experience similar outcomes when receiving treatment in the context of randomized clinical trials.⁴  It seems to me that just as we need to address gaps of care between the poor and the wealthy, between white and minority patients, we need to also devise strategies that equalize care for the urban and rural areas of our communities.

Resolution #3: Report the costs of our treatment strategies.

I’m saying nothing groundbreaking when I point out that in the United States at least, the cost of cancer drugs is one of the factors that will play a role in the inevitable financial reckoning of our health care system. This short essay is no place to explore all our options, but I recently listened to a grand rounds given in March of 2019 by Dr. Vincent Rajkumar — one of the great voices on this topic in our community. In this talk, available on YouTube for those who would like to watch it, Dr. Rajkumar describes the problem of prescription drug costs and the causes behind this trend, and then outlines some difficult but possible solutions. There are definitely steps we can take as individual providers and as voters, and I would also argue that we can make an impact when we design studies. I think, at the earliest stages, we should be considering and be transparent about the costs of the regimens that we are concocting. We should think carefully about dosing strategies and indefinite therapy. And finally, at the reporting and publication stage, our documents should reflect the cost of the regimens and the value that these regimens deliver.

As I say, these are only three possible resolutions. I’m sure you can suggest many, many more. If we consider the last decade to be the period in which we learned how to move molecular medicine from the laboratory to the clinic, perhaps we can make the next decade one in which we learn how to rationally, thoughtfully employ the agents we have in an effective, sustainable, and just manner.