When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks expert oncologist Jerald P. Radich MD, MA, MS, how he would handle his own hypothetical case of chronic myelogenous leukemia (CML). Dr. Radich is the Kurt Enslein Endowed Chair in the Translational Science & Therapeutics Division of the Fred Hutchinson Cancer Center in Seattle, Washington.
Curious Dr. George: Please consider this hypothetical scenario: you are an active clinical and research oncologist in general good health, but lately you have lacked energy, have been feeling more tired than usual, have some dizziness on exertion, recent easy bruisability, have lost some weight without dieting, and are experiencing sweating at night. You decide to visit your primary care physician for a checkup. On physical examination, she notes that you are a little pale, finds arm bruises, and discovers an enlarged liver and spleen. She orders several lab tests. Your hematocrit is 38, hemoglobin 12, WBCs 120 000 with mostly mature granulocytes, a few blasts, and a normal lymphocyte count. Platelets are normal. A provisional diagnosis of chronic myelogenous leukemia is made. When you learn of this hypothetical situation, how do you proceed?
Jerald P. Radich MA, MS, MD: How ironic that I have been diagnosed with CML. On the other hand, if one is going to get the disease that they have devoted decades of studying, I guess I chose wisely.
How so, you might ask (after all, you are curious)? Because in CML, we now have an embarrassment of riches, with five approved tyrosine kinase inhibitors (TKIs) for newly diagnosed, chronic phase CML cases (which I am taking editorial license to place myself in that category, rather than advanced-phase disease, thank you very much). Taking these medications daily places you on the same natural life expectancy curve as the non-CML population. It is truly a mind-blowing example of the “bench-to-beside” paradigm so often utilized in grant writing, but so rarely attained in real life.
The current list of TKIs for newly diagnosed, chronic phase CML includes the original, imatinib, and the “second generation” TKIs, bosutinib, dasatinib, and nilotinib. Ponatinib is approved by the U.S. Food and Drug Administration (FDA) for resistant chronic phase and advanced phase disease. All these inhibitors work to block the ATP-binding domain in the tyrosine kinase of the chimeric BCR-ABL protein. Recently, a new allosteric inhibitor known as asciminib was approved for newly diagnosed CML (should we dub this a third-generation compound?). It acts outside the ATP domain by causing a structural change in the protein that abrogates kinase activity.
These TKI drugs share various degrees of common toxicity (low counts, lipase increase, potential cardiovascular events) and all have drug-specific toxicities (e.g., pleural effusions in dasatinib, diarrhea with bosutinib). In general, the second-generation TKIs are more potent, leading to faster reductions of disease, and less evolution to advanced phase disease compared to imatinib. But at the end of the day, large phase-three studies have shown that all these drugs yield near identical survival.
How then would one choose? Here are the factors I would consider, in my own order of prioritization:
- What are my goals of therapy? What do I want? First, to control the disease and put me on a normal lifespan trajectory. This requires a treatment strategy that allows for maximum compliance (the easier to take drug, the better), minimal toxicity (both preventing off-target injury and minimizing time off the TKI) and the prevention of progression to blast crisis (as noted above, the second-generation-and-beyond TKIs seem a little better than imatinib for blocking progression). If I was considerably younger, and especially if I wanted to have kids, then there would be the consideration of getting to a deeper molecular response faster, since there is ample data that roughly 25% of CML cases can successfully discontinue the drug after several years of a deep molecular response and stay in a treatment-free remission. Evidence suggests that patients taking the stronger, second-generation TKIs may have an advantage in getting a deeper molecular response, faster.
- What’s my risk of progression? The major therapeutic mission is to block progression, since once that happens, the only real path to cure is through allogeneic transplantation, and that’s not easy for a guy my age. There are various risk scores that map well to risk of progression (Sokal, Eutos, Hasford). I didn’t get my blast count, but I am worried about the large spleen, weight loss, and night sweats—all suggest a disease on the pathway towards progression. Thus, I would be hedging my bets and leaning towards the second-generation TKIs, including asciminib.
- Comorbidities and toxicity. TKIs are truly remarkable, since they are exceedingly effective, yet have relatively little toxicity compared to standard chemotherapeutic agents. A pervasive complication across all these drugs—except imatinib—is the shadow of cardiovascular events, including venous and arterial thrombosis. Hypertension is also a common problem. If I had some cardiovascular risks, I’d be leaning towards options that seem be on the lower side of the risk spectrum, such as imatinib, lower dose dasatinib, or asciminib.
- Financial toxicity. These drugs are very expensive. If I had to pay for these out of pocket, they run more than $100,000 per year, and since I’d likely have to take them the rest of my life, the overall cost would be insane. Fortunately, I have good insurance. But if not, I could go generic. For example, Mark Cuban’s drug store lists prices for generic imatinib at less than 1% of branded imatinib! A generic of dasatinib has been launched, and some new formulations of dasatinib designed for better bioavailability have been approved, though it is unclear where they are going to weigh in on cost.
No matter what drug I start with, I would be diligent about receiving routine peripheral blood testing for BCR-ABL to monitor response. If I didn’t meet the milestones (as set out in standard guidelines from the National Comprehensive Cancer Network), there are plenty of options for switching to another TKI. In general, if I need to switch because of side effects, options are open to move across generations (i.e., from a second-generation to the first-generation imatinib). However, if I need to change TKI for resistance, changes should be made within a generation (from dasatinib to nilotinib), or escalating to the next generation (dasatinib to ponatinib or asciminib).
Dr. Radich can be reached at jradich@fredhutch.org.
Related links:
- How Would an Expert Manage His Own Acute Myelogenous Leukemia: An Update
- How an Expert Would Treat His Own Glioblastoma: An Update
- How an Expert Would Manage His Own Advanced Bladder Cancer: An Update
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