Clinical Case: Oropharyngeal Tumor-like Reaction During Transition from Cytostatic Therapy to a BTK Inhibitor in a CLL Patient

CT scan showing oropharyngeal lymphoid infiltration mimicking a solid tumor during tumor flare reaction in a patient with CLL on BTK inhibitor therapy.
Oropharyngeal pseudo tumor due to lymphoid infiltration during tumor flare after initiation of BTK inhibitor.

Abstract
We present a rare clinical case of a patient with chronic lymphocytic leukemia (CLL), who developed tumor-like infiltration in the base of the tongue with massive edema of the neck and occipital area after transitioning from long-term cytostatic therapy with cyclophosphamide to a BTK inhibitor (brutoncib). The reaction was reversible upon administration of methotrexate and dexamethasone. This observation highlights the need for oncologic vigilance, proper staging before therapy changes, and a multidisciplinary approach.

1. Introduction
   BTK inhibitors have become a key component of CLL therapy, particularly in patients with refractory disease or those relapsing from remission. However, transitioning from cytostatic to targeted therapy can be accompanied by acute reactivation of tumor subclones, manifesting as transient lymphadenopathy, pain, and infiltration of soft tissues. Such reactions are described as tumor flare—a phenomenon where discontinuation of cytostatics and initiation of a BTK inhibitor results in immune and cellular redistribution of tumor mass. However, localized infiltrates in the oropharyngeal region mimicking a solid tumor are rarely reported in literature and may lead to diagnostic errors. A flare reaction is a transient worsening of clinical presentation following initiation of targeted therapy, caused by redistribution of tumor cells and activation of a cytokine cascade. In CLL treatment with BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib), flare may present as lymph node enlargement, mucosal infiltration, fever, pain, or even pseudo-tumorous formations. In most cases, the reaction resolves without discontinuation of therapy, but due to lack of experience, it can be misinterpreted as disease progression or a solid tumor. Flare reaction is not a sign of therapy inefficacy. On the contrary, it may indicate the drug’s biological activity. However, the absence of clinical awareness and preventive protocols makes it a potentially dangerous decision-making zone.

2. Clinical Case
   A 79-year-old female patient with a diagnosis of CLL had been in stable remission for over five years on cyclophosphamide monotherapy (under hematologist supervision). In recent months, progressive lymphadenopathy and splenomegaly were noted. Due to worsening condition (including arrhythmias), a decision was made to transition to a BTK inhibitor—brutoncib (in coordination with regional hematologists). Approximately four weeks after therapy initiation, the patient developed a rapidly growing tumor-like mass in the tongue base, accompanied by massive neck and occipital edema, dysphagia, and an alarming clinical picture. The patient was examined by ENT specialists; squamous cell carcinoma of the tongue was considered. However, complete symptom regression occurred within 10–14 days following methotrexate and dexamethasone administration. Histology results are pending; preliminary findings indicate lymphoid tissue. An important aspect is that the patient had been treated with cyclophosphamide monotherapy for over five years—without significant disease progression, but also without improvement. During this time, she lived with the diagnosis without access to modern treatment options. Lymphadenopathy persisted, overall condition remained poor, but no decision was made to change therapy until arrhythmias and clear lymph node growth developed. At that point, transitioning her to a more advanced and effective therapy—brutoncib—became necessary. That moment was shocking for me: I realized that despite years of monitoring, the patient had not received treatment in line with current standards. Upon research, I discovered that cyclophosphamide monotherapy has long been outdated in leading clinics, and BTK inhibitors have become the standard in appropriate clinical cases. This realization brought not only confusion but also inner anger—towards the system, outdated approaches, and lack of support. I had previously written an article about the negligent physician who was managing this patient before me, prescribing BRUKINSA. But even after that, I had to go through the entire process alone. Of course, I made mistakes—not due to carelessness, but because there were no algorithms or support. I consulted leading hematologists in the region, one in Vladivostok—yet none warned me about the possibility of tumor flare or mucosal infiltration upon initiating targeted therapy. I walked this path alone, blindly, and that’s precisely why I believe it’s important to share this case—so other doctors don’t feel unsupported in similar situations.

Rationale for Therapy Choice
The BTK inhibitor was selected based on international guidelines (NCCN, ESMO), considering the patient’s age, absence of significant cytopenia, comorbidities, and long history of prior therapy. Given the limited capacity for second-line chemotherapy in the region and the drug’s availability, the transition to targeted therapy was deemed appropriate. Consultations with leading regional hematologists confirmed the validity of this approach.

3. Discussion
   3.1 Why is This Important?
   BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib, brutoncib) are known to cause transient symptom worsening during the initial weeks of therapy. This is linked to tumor cell redistribution, especially in cases with high tumor burden. Localized oropharyngeal involvement is extremely rare. Such cases may mimic solid tumors and lead to misdiagnosis, unnecessary biopsies and surgeries, premature discontinuation of effective therapy.

3.2 What Could Have Been Prevented?
In U.S. and European clinics, the switch from cytostatics to BTK inhibitors is always accompanied by full staging (CT, PET-CT, ultrasound, ENT exam), tumor flare risk assessment, temporary therapy overlap (e.g., continuing cytostatics for 2–3 weeks after BTK inhibitor initiation), prophylactic steroids, multidisciplinary board discussions. In this case, oropharyngeal staging was not performed before therapy, and no specialist warned of a potential reaction. This underscores a systemic gap in clinical training and communication.

3.3 Role of Clinical Training and Physician Education
This case highlights not only the complexity of transitioning from cytostatics to BTK inhibitors, but also systemic gaps in physician training for managing CLL patients. Despite formal adherence to protocols and interdisciplinary interaction, no specialist—including experienced regional hematologists—warned about potential tumor flare in the oropharynx. This suggests that such reactions are either underreported in educational materials or considered unlikely and not worth separate attention. In reality, such events can be clinically dramatic, lead to misdiagnosis, patient anxiety, and unnecessary invasive procedures. Modern oncohematology requires not only understanding molecular mechanisms of drugs but also clinical patterns of tumor response to treatment shifts. Interpretation of atypical symptoms requires experience and systematic education through examples, case studies, and rare situation analysis. Therefore, such cases should be included in continuing medical education programs, clinical conferences, and treatment planning frameworks—especially in institutions serving elderly and long-term patients. These cases serve as both clinical observations and signals prompting review of educational priorities to ensure reliable patient protection throughout complex therapeutic paths.

4. Conclusions
   BTK inhibitors can cause localized lymphoid infiltrates, including in the oropharynx. Physicians must be aware of tumor flare risk, especially during therapy changes in elderly patients. Staging and multidisciplinary assessment are essential before transitioning from cytostatics to targeted therapy. Patients and colleagues need to be informed about possible temporary symptom worsening.