Obesity complicates the treatment of patients with chronic myeloid leukemia (CML), and bariatric surgery may impact how patients respond to their medications. This review examines the limited research on how obesity and weight loss surgeries affect the effectiveness of tyrosine kinase inhibitors (TKIs), which are commonly used to treat CML. The findings suggest that certain surgeries, like gastric bypass, could reduce drug absorption due to changes in gastric acidity, potentially making treatments less effective. Patients who have had these surgeries may need different dosing strategies for their TKIs and should avoid certain weight loss medications and herbs that can interfere with drug absorption. Careful planning and counseling are essential for patients with CML considering bariatric surgery to ensure they achieve deep remission before the procedure. Overall, a collaborative clinical approach is recommended for managing obesity in CML patients, while more research is needed on optimal dosing and treatment strategies.

Obesity is a chronic health condition that is increasingly prevalent across various age groups that affects one in eight individuals and contributes to approximately 300,000 deaths annually, making it the second leading cause of preventable mortality (1, 2). Furthermore, obesity in adulthood is significantly associated with increased risk of chronic myeloid leukemia (CML) and other hematological malignancies (3–6). Even after adjusting for various risk factors, obesity remained significantly linked to CML across all age groups (3, 7, 8). For instance, weight gain over 1 kg annually between ages 25 and 40 quadrupled the CML risk, possibly negating the effects of any preclinical weight loss (8).

In addition, obesity can alter several physiological functions that influence the pharmacodynamics (PD) and pharmacokinetics (PK) of medications, as summarized in Figure 1 (9). For instance, obesity may affect drug absorption by altering gastric emptying and gut permeability; however, oral bioavailability is not significantly affected in most cases (10). Moreover, the volume of distribution (Vd) correlates with the adipose body weight of lipophilic drugs. Therefore, a high percentage of adipose tissue in obesity is associated with a higher Vd of lipophilic drugs (9, 11).

Furthermore, obesity can alter drug clearance (CL) (9). In normal-weight patients, the typical ratio between lean, which typically increases CL, and adipose body weight was 4:1; however, in obesity, an increase in adipose tissue leads to an alteration of this ratio to 3:2, which decreases drug CL (9). Obesity can also impact various metabolic processes, including liver function, which is crucial for drug CL and metabolism. For example, obese patients have lower CL of drugs metabolized by cytochrome P450 (CYP) 3A4, which is the main metabolic pathway for all tyrosine kinase inhibitors (TKIs), i.e., the mainstay treatment for CML (11). On the other hand, obese patients tend to have higher CL and, hence, lower plasma concentrations of drugs metabolized via other metabolic pathways, such as uridine diphosphate glucuronosyltransferase (UGT), glomerular filtration, xanthine oxidase, N-acetyltransferase, CYP2E1, CYP1A2, CYP2C9, CYP2C19, and CYP2D6 (12). Obesity can also cause fatty changes in the liver, alter hepatic blood flow and reduce drug CL (13).

While the kidneys also play a significant role in drug elimination, the effects of obesity on these functions are unclear. Initially, obesity increases glomerular filtration rate (GFR) and renal drug CL due to higher cardiac output and renal perfusion (11). However, later in life, owing to persistently elevated intra-glomerular pressure and a strong correlation with chronic kidney disease (CKD), obesity is associated with a decline in renal drug CL (14, 15).

Given the differences in responses to treatment, dosage, and associated comorbidities, managing patients with obesity and bariatric surgeries has become a challenging task for CML patients. Several studies indicated that obesity can adversely affect treatment outcomes in CML patients by reducing the efficacy of TKIs (16). Furthermore, obesity-related comorbidities, such as cardiovascular diseases and diabetes mellitus, can complicate CML management and increase the risk of treatment-related adverse events (17). Consequently, healthcare providers are increasingly recognizing the importance of addressing weight management as an integral component of comprehensive care for CML patients. In addition, treatment modalities for obesity have varied from lifestyle changes to pharmacological therapies and weight-reducing surgical interventions. It remains unclear how the different modalities may affect the safety and efficacy of TKIs.

Current recommendations for CML treatment do not consider patient weight and body mass index (BMI) as factors when deciding which TKI doses are required for the patient (18). Furthermore, there is a scarcity of information on the management of patients with CML who have undergone obesity-related surgeries. This review aimed to scope and summarize the current evidence on the effects of obesity and obesity related surgeries in patients with CML and propose guidance for the management in this patient population.

The review did not limit the research to a specific period, but rather aimed to provide a comprehensive, in-depth overview of the topic and to answer the following three specific clinical questions:

Studies included in the review were identified through keyword searches of PubMed, Scopus, Web of Science, Web of Conferences, and grey literature. Keywords searched included ‘obesity,’ ‘chronic myeloid leukemia,’ or ‘CML,’ ‘TKI therapy,’ ‘Tyrosine kinase inhibitors,’ and ‘CML therapy.’ In addition, tertiary evidence published on different TKIs and their PK, as well as manual searches of reference lists from primary articles found in the initial searches, were also conducted. Only research papers written in English were included. If the paper contained data relevant to answering our focused clinical questions, it was considered relevant and included in the review. B.E., M.Y., R.G., M.B., G.S., and J.C. were involved in conducting the research for this review.

Figure 2 below summarizes the results and relevant recommendations for managing CML with obesity. Based on the current evidence, it is recommended to assess the Atherosclerotic Cardiovascular Disease (ASCVD) risk of patients before choosing the most appropriate TKI for CML treatment. This is because of the added combined risk factors for ASCVD with certain TKIs and obesity. Furthermore, according to all obesity management guidelines, lifestyle modifications are always recommended for obese patients (19). Figure 2 emphasizes that lifestyle interventions are the safest obesity management strategies and recommended, with personalization of approaches, for all obesity patients (19). However, it is recommended to assess the effects of food on the absorption of TKIs, as summarized in Figure 2 to ensure that the chosen diet plan does not affect their administration.

After establishing the importance of lifestyle interventions, as per the international guidelines for the management of obesity, patients should be assessed for their eligibility for pharmacotherapy or surgical interventions (eligibility is detailed in Figure 2 ) (20). Yet, each of those interventions may hold some risks for CML patients. These risks are summarized in Figure 2 , based on the best available evidence.

This is the first review to provide a comprehensive summary of the literature surrounding the pharmacological and surgical considerations of obesity in patients with CML. As illustrated in this review, there is a need to fill several gaps in the literature, starting with real-world clinical data and practical applications. With lifetime treatment, the majority of CML patients have achieved complete and lasting cytogenetic responses owing to the remarkable effects of TKIs on patient management. This significant shift in CML prognosis presents new clinical and scientific challenges that must be addressed. Currently, bariatric surgery is widely used, and evidence suggests a significant reduction in obesity-associated mortality (48).

It has been demonstrated that the changes resulting from these procedures can affect the bioavailability of oral drugs (49, 50). Although gastric bypass remains the most effective and long-lasting weight-loss option for individuals with severe obesity, there is a need to create customized treatment approaches tailored specifically for these patients. Based on the reported cases in the literature, gastric bypass surgery may influence clinical response to TKI therapy; hence, it is not recommended for individuals with severe obesity (38–40). In clinical practice, this underscores the need for clinicians to evaluate the dosing strategy for CML patients post-surgery actively. Adjustments such as increasing the TKI dosage may be necessary, but this must be balanced against the risk of toxicity (16, 41, 42).

Moreover, identifying the appropriate timing for TKI therapy initiation post-surgery is essential to avoid unnecessary delays, which could compromise patient outcomes. The use of TDM in obese patients becomes increasingly relevant here, as it can help clinicians optimize dosing based on the patient’s molecular response rather than relying solely on traditional PK parameters (47).

While TDM has historically been explored, particularly for imatinib, its role in routine clinical practice remains controversial. Early studies suggested a potential association between imatinib trough levels and treatment outcomes, with some recommending target trough levels ≥1000 ng/mL to optimize response (51, 52). However, subsequent investigations, failed to consistently demonstrate a direct correlation between plasma levels and treatment efficacy, particularly for second-generation TKIs (53, 54). Consequently, TDM has not been widely adopted and is not currently recommended as standard of care in most clinical settings. In our review, we highlight case-based and observational data where TDM-guided dosing was explored, particularly post-bariatric surgery. Nevertheless, these reports remain limited in number and quality. Hence, further prospective studies are warranted to clarify the clinical utility, standardization, and cost-effectiveness of TDM in optimizing TKI therapy among complex populations such as patients with obesity or gastrointestinal alterations.

In addition to the decreased absorption of TKIs in patients who have undergone bariatric surgery, other factors, such as the simultaneous use of proton pump inhibitors or the presence of comorbidities, may impact the attainment of an optimal response in patients with CML (55, 56). Therefore, it is paramount for clinicians to engage in comprehensive medication reconciliation and patient education to mitigate these risks.

The limitations of this review must be acknowledged. First, there is a lack of available data on the interactions between several weight loss medications and TKIs, such as orlistat and GLP-1 agonists. In addition, only case reports are available on the effect of bariatric surgery on the PK of TKIs, which is insufficient for drawing definitive conclusions. Furthermore, there is limited data on the delayed effects of bariatric surgery on physiological changes and how they affect drug PK in the long term. Overall, with the current scarcity of literature and the level of evidence, there is room for future research to address this gap. A multidisciplinary team, including a bariatric surgeon, CML specialist, dietitian, and clinical pharmacist, is essential for shared decision-making with the patient.

Based on our review, we recommend that postoperative patients to be closely monitored for clinical response and medication levels in the blood (if feasible); and further dose adjustment or drug switching should not be delayed if indicated. However, the lack of readily available assays for measuring TKI levels in clinical settings limits the viability of this approach. Therefore, alternative strategies include escalating TKI dosage in cases of response failure or warning signs observed during milestone monitoring. Lastly, when the decision to undergo bariatric surgery occurs post-CML diagnosis, it is advisable to enhance the response to achieve deep remission before surgery. Moreover, there may be merit in postponing the surgery to allow for a safety margin in the CML response if significant malabsorption is anticipated because of the procedure.