Imatinib versus newer generation <scp>TKIs</scp> for upfront therapy in chronic phase <scp>chronic myeloid leukemia</scp>: What is the rationale for paying more to get the same survival benefit?

To the Editor: In this issue of the American Journal of Hematology, there is an interesting analysis of a study involving an exciting, very effective newly marketed, targeted therapy for chronic myeloid leukemia (CML).1 The authors raise some interesting questions about utility and positioning of this drug in therapy. A quote from Warren Buffett, reputedly one of the 10 richest individuals in the world, is "Price is what you pay. Value is what you get." Over the past three decades, there have been amazing strides in the therapy of CML. From a time when the only potential cure, not without issues itself, was a bone marrow transplant, now known as allogeneic stem cell transplant (SCT) if you were young and healthy enough and had a donor,2 to a period when CML is felt to be a chronic, potentially curable disease, with a survival of newly diagnosed patients equivalent to that of age-matched controls.3 With an average age of diagnosis in the western world of around 65 years (it is around 40 years in the developing world), before any of the other issues of donor availability and patient eligibility even came into play, the maximum age for and SCT even if available, was 40 years and with families getting smaller, and fewer sibling matches available, most people were not even candidates. Although changes in SCT have now pushed transplant maximum age into the 70's, mismatched and unrelated donors available and better supportive care the norm, alloSCT for CML may be now paradoxically underutilized in most geographies because of the fascination with TKIs. It is a safe, highly curative, cost-effective one-time procedure compared with third generation TKIs, once patients are resistant to second generation TKIs. Other than work with herceptin for breast cancer, imatinib became the poster child for targeted therapy and this was followed with newer generation drugs.4, 5 I can remember when imatinib or what was originally called STI571 (signal transduction inihibitor 571) came into use, one wag categorically stated that STI stood for "stop transplant immediately" later restated as "select transplant intelligently." For most patients, he was right on the money. One of the somewhat controversial concepts is that of what is the goal of CML therapy. This is discussed in recommendations from the NCCN and ELN.6 The ideal or optimal outcome with no argument, is a deep molecular remission with successful treatment-free remission (TFR). This is not the result for the majority of patients and they remain on indefinite therapy or need to restart therapy on relapse.7 The other goal is survival and for virtually all patients this has been met if they have had a complete cytogenetic (MR2) response to therapy. Response is not universal and measuring this is complicated by issues such as compliance, believed to be the major cause of failure. The latter can be due to many reasons including intolerance, patient belief, quality of life or social/financial issues. We must remember that all patients do not have full coverage or live in a society with universal health care. In the early days of TKI, a sailing enthusiast CML treater stated that when in a storm, having got to a safe haven is important regardless of how long it takes. What that safe haven is has multiple opinions, but it is at least a complete cytogenetic response (CCyR) or MR2 or 1% on the international standard. Deeper than that is great, but has minimal impact on survival.8 Other definitions of response have been used in studies that compare treatments. Sometimes, these have been mandated by the FDA, evolve as a disease gets harder to treat and the optimal response is no longer possible, or newer technology becomes available. They are used to get studies published and get products approved for use and marketing and to determine if patients are TFR eligible. The bottom line however is, does the patient survive which appears to be true, and goes on eventually to die from something else (a practical definition of cure), or can go on to a successful TFR, that is, survival off therapy versus survival on therapy (a functional cure often quoted). Newer drugs have not improved survival. Given that first line imatinib has brought survival of CML patients to that of age-matched controls, we cannot do better.9 Immortality is just not one of the end points of therapy. With newer drugs, more patients may get to responses where TFR attempts are possible, but the success rate is roughly the same. We only have data on imatinib, nilotinib, and dasatinib. There is no TFR data on any other drugs on the market—bosutinib, ponatinib, and now asciminib. There is not a lot of data on why some patients on different drugs and with the same apparent responses, will relapse. Identifying and successfully targeting this would make a big difference. We do know that there is an improved TFR outcome the longer a patient is on therapy before attempting, but how long and does it matter with which drug, is only speculation at this point.10 This now brings into perspective, issues of side effects developing with longer therapy. Side effects or adverse events (AEs) are reported on product monographs and are based on the studies that are used to get drug approval. Post marketing monitoring has definitely shown that for some drugs the appearance of a side effect may be early and persistent, develop at a variable time point after starting the drug, worsen with ongoing therapy, or develop initially late on therapy.9 Some of these AEs do not appear on the product monograph as a result and in many cases are not brought to the attention of treating health care professionals unless, unless updates or warnings are provided or the medical literature is followed in depth. For the vast majority of treating physicians who treat a myriad of diseases, most common than CML, all requiring the same diligence, this is not possible. A recently completed encyclopedic reference publication of long-term side effects is available,9 but by no means has this captured everything. In many cases, newer drugs have resulted in more severe and less "chronic" type side effects or are too early in usage to know what the future holds. The message here is that patient monitoring includes not just following efficacy outcomes, but also following adverse event outcomes, as the majority of patients will not be eligible for TFR, may not want to attempt TFR or fail TFR and be on therapy indefinitely. A holistic overview also reveals that patients age on therapy, have co-morbidities before starting or develop co-morbidities on therapy, and may be on medications that potentially interact with their CML medications. To use the American football analogy, there has to be a quarterback who oversees things or hands off responsibility to someone else who does. My last issue is drug development and cost to the consumer, whether that is the patient, insurance, health care program, or society. We need new drugs and they must be developed in the hope of improving TFR and reducing side effects. Switching drugs for reasons of intolerance is an interesting concept. Most of us have seen patients tolerate effective drugs with minor issues until a newer product becomes available and then feel they have to switch. We are faced with this hard reality. Resistance is different but needs to be defined practically. Failing to get the optimal response is not resistance nor is failing a TFR attempt and given everything else described here, does not necessarily justify the use of a more expensive drug. Losing response unrelated to a failed TFR attempt or compliance, may very well justify the cost however. Where the big question comes is what drug should be used first line? If we take away reasons of drug approval, reimbursement approval, risky co-morbidities or life-style issues, the choice of a drug costing less than a hundred dollars a month versus tens of thousands of dollars a month, needs to be considered, given that most people will do as well on a Toyota versus the Ferrari. The Leukemia and Lymphoma Society of the United States have recently aired a webinar on patient medical debt (June 25, 2024). Apparently, nearly half of the adult American population are in medical debt that may be lifelong and legislation is pending to help deal with this. High drug costs, which may be avoidable, are a large part of this, but this was not addressed specifically in that webinar. It does not matter whether they are borne by the patient, their health care group, insurance or society in the case of socialized medical systems. Physicians must not feel that they have under-treated their patient by not ordering the Ferrari and more importantly, patients who in the era of information from the internet or social media have access to much including marketing, feel they are not getting the best (aka most expensive) option and are being short changed.11 I will now get off my soapbox and conclude. We need to be cognizant of where we are going with not just CML therapy, but medicine in general. I will be frank in stating that I am a capitalist and I believe in patient choice so long as it of value and does not contribute to backbreaking debt. I understand completely, the cost of developing new therapies, and do not think this should be done as a charitable donation. We do however, need the wide angle lens to view the impact on society and individuals and I think we have yet to dig this out of the camera bag. In summary, the four goals of CML therapy are survival, TFR, treatment value, and side effects. (1) All four TKIs (perhaps 5 soon with asciminib) fulfill OS: (2) None shown to improve TFR over imatinib. (3) Toxicities unique to each and long-term toxicities are important (e.g. 10-year SAEs AOEs with nilotinib; newer drugs are a big unknown). (4) Treatment value dictates annual prices <$30 000 to provide better treatment value than that of generic imatinib and generic second generation TKIs. The author has no conflicts and there is no funding for this publication. Data sharing not applicable—no new data generated.

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