Written by: M. Yair Levy, MD
Sponsored by: BeOne Medicines
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease that has seen a remarkable treatment evolution over the past decade. Approximately one-third of CLL patients will not require treatment, with clinical observation remaining the standard for asymptomatic patients.1 For CLL patients requiring treatment, historical regimens have been limited to cytotoxic chemotherapy, administered alone or in combination with anti-CD20 immunotherapy.2 In 2016, two classes of targeted therapies entered the CLL marketplace. Most notably among these are inhibitors of the anti-apoptotic protein B-cell lymphoma 2 (Bcl2), and the B-cell proliferative regulator Bruton’s tyrosine kinase (BTK).2 Introduction of first-generation covalent BTK inhibitors (cBTKis) was followed by second-generation, as well as non-covalent BTKis.2 The rapid expansion of targeted therapies over the last decade has profoundly impacted the clinical management of CLL.
The multitude of therapeutic options in today’s CLL treatment landscape, which often includes several drugs in a single class, provides oncologists the unprecedented opportunity to weigh the entire clinical picture for each patient, and personalize their treatment strategy accordingly. Clinicians leverage decades of medical training to gauge pharmacokinetic and pharmacodynamic differences between therapies, weighing drug-specific efficacy, tolerability and safety for each patient. There is also concurrent influence from reputable medical bodies, such as NCCN guidelines and FDA approved treatments. Most importantly, every CLL patient and their disease are unique. It is imperative to protect physicians’ decision-making freedom to the degree that it permits individualized treatment approaches and the prescription of specific therapies, without undue external influence.
Step therapy is a growing utilization management strategy among health plan Pharmacy Benefit Managers (PBMs) that threatens physician autonomy. As its colloquial name “fail-first” implies, step therapy is a cost-saving approach that requires a patient to have tried, and failed, alternative drug(s), before the PBM will cover the originally prescribed drug.3 Step therapies transfer the onus of decision-making from the treating physician to a commercial entity, robbing the clinician of their ability to personalize care and maximize patient outcomes. This leads to worsening provider burnout, depersonalization, and exacerbates oncology physician shortages. Step therapies also place additional burden on clinical support staff and negatively impact CLL patient outcomes.
PBM-mandated BTKi coverage is a common scenario that exemplifies how step therapy negatively impacts CLL patient outcomes. In my clinical experience, PBMs have required frontline use of the first-generation BTKi ibrutinib. Ibrutinib is an efficacious drug that has revolutionized CLL treatment, but it is poorly tolerated, as compared with 2nd generation BTKis, which directly contributes to decreased treatment compliance and impacts patient outcomes. Ibrutinib also carries the risk of adverse cardiologic events, including atrial arrythmias, ventricular arrhythmias and sudden death.4 As a provider who has lost a patient due to this adverse event, it’s imperative that safety risks of specific drugs are weighed by an experienced clinician on a case-to-case basis. Furthermore, there is an urgent need for step therapy reform that considers clinical data in determining drug coverage. In the case of BTKi coverage, there is clinical evidence demonstrating a lower risk of adverse cardiologic events with use of second-generation BTKi agents.4 As cancer patient advocates, oncologists must continue to push back against step therapies that infringe on patient safety and well-being, and may adversely affect outcomes.
As oncology drugs continue to enter the ever-changing healthcare marketplace, it’s increasingly critical that physicians communicate the importance of preserving autonomy to PBMs and other decision-making parties. There is potential for other drug pricing provisions, such as those included in the 2022 Inflation Reduction Act (IRA),5 to impact CLL patient outcomes in a manner similar to that which is seen with PBM-mediated step therapy. Under the IRA, the government may select certain medications for which it will cap the cost of for Medicare recipients.5 While designed to reduce patient financial burden, provisions of the IRA, such as the ability to target costs of small molecules (like BTKis) years before other drug types, may have harmful effects on oncology treatment.5 This risks physicians being forced to utilize certain medications for which cost setting has been established, similar to step therapy, and has already been shown to disincentivize the development of small molecule drugs since the IRA was enacted.5 Given that CLL primarily affects elderly populations,2 drug pricing provisions affecting Medicare could impact CLL prescribing patterns, and there is precedent to surmise that commercial payers may adopt similar strategies of government-sponsored programs.
In diseases like CLL where therapeutic nuances matter, restricting access to preferred agents can have profound consequences. While the extra hours spent justifying what seems like every clinical decision, completing paperwork, appealing denials, and engaging in peer-to-peer calls may feel like “death by a thousand paper cuts”, oncologists have the responsibility as patient advocates to do no harm. We must continue to advocate for policies that prioritize patient outcomes over cost-driven algorithms, and ensure that clinical decision-making remains in the hands of those best equipped to make it: the treating physicians.
References:
- Shadman M. Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review. JAMA. 2023;329(11):918-932. doi:10.1001/jama.2023.1946.
- Sekeres S, Lamkin EN, Bravo E Jr, Cool A, Taylor J. Resistance Mutations in CLL: Genetic Mechanisms Shaping the Future of Targeted Therapy. Genes (Basel). 2025;16(9):1064. Published 2025 Sep 10. doi:10.3390/genes16091064.
- Royce TJ, Schenkel C, Kirkwood K, Levit L, Levit K, Kircher S. Impact of Pharmacy Benefit Managers on Oncology Practices and Patients. JCO Oncol Pract. 2020;16(5):276-284. doi:10.1200/JOP.19.00606.
- Moslehi JJ, Furman RR, Tam CS, et al. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Blood Adv. 2024;8(10):2478-2490. doi:10.1182/bloodadvances.2023011641.
- The Inflation Reduction Act and Medicare Drug Price “Negotiation”. Pharmaceutical Research and Manufacturers of America (PhRMA) website. https://phrma.org/policy-issues/government-price-setting/inflation-reduction-act. Accessed October 1, 2025.
