Managing Swallowing Difficulty/Dysfunction Among Patients with Chronic Lymphocytic Leukemia/Waldenström Macroglobulinemia Receiving BTK Inhibitor

Clinical Pearl: The liquid suspension formulation of the novel covalent BTK inhibitor ibrutinib is a compelling option for use in patients with swallowing difficulty or dysfunction.

MB is a 68-year-old female who is homeless and presents to the local emergency department after having a choking event while eating dinner at a homeless shelter. On exam, she has bulky lymphadenopathy throughout her body and, in particular, large cervical nodes (7 to 8 cm lymph node conglomerates bilaterally).

Her labs show:

• WBC 224,000
• ALC 218,000
• Hemoglobin 10.2
• Platelet count 132,000
• LDH 330

Flow cytometry on her blood revealed a monoclonal B cell population positive for CD5, CD19, and CD23, consistent with a diagnosis of chronic lymphocytic leukemia (CLL).

Inpatient oncology is then consulted, and the AP orders FISH and cytogenetic testing, which were notable for del(17p) and del(11q). IGHV testing revealed unmutated IGHV. A PET scan was additionally performed to rule out a Richter transformation given the elevated LDH and bulky adenopathy, although all SUVs were low and thus more consistent with CLL. Past medical history assessment was limited, as MB had not been seen by a medical professional in more than 10 years, but she reports no medical diagnoses prior to that.

Based on MB’s aggressive cytogenetic features and bulky lymphadenopathy, the AP recommended treatment with a BTK inhibitor. Long-term data shows durable efficacy of this drug class, even in patients with high-risk features.^1,2 Unfortunately, MB’s cervical disease was extremely bulky, resulting in dysphagia with pill swallowing, and per her report, she has long-standing anxiety regarding swallowing pills. Given this information, the AP recommends ibrutinib liquid suspension, as this will eliminate the need for taking a pill treatment and effectively and optimally treat MB’s CLL.

Within 2 weeks of starting treatment, MB returns to the outpatient oncology clinic. She reports to the AP that she feels well on treatment but has noted some new minor bruises on her arms and a few days of diarrhea after starting treatment, which resolved without intervention. Her lymph nodes have significantly reduced in size, with the cervical node conglomerates now measuring 2 to 3 cm on exam. MB’s labs are notable for stable anemia and thrombocytopenia and a significant rise in ALC to 368,000, which, as the AP reviewed with her, is due to lymphocyte redistribution, a normal phenomenon that occurs early in treatment with BTK inhibitors.³ She is counseled that her ALC should start to downtrend and normalize over the next weeks or months. MB plans to continue on ibrutinib oral suspension indefinitely moving forward for management of her CLL.

References

1. Woyach JA, Ruppert AS, Heerema NA, et al. Long-term results of Alliance A041202 show continued advantage of ibrutinib-based regimens compared with bendamustine plus rituximab (BR) chemoimmunotherapy. Blood. 2021;138(suppl 1):639.
2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of Elevate-TN. Blood. 2023;142(suppl 1):636.
3. Herman SE, Niemann CU, Farooqui M, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: Correlative analyses from a phase II study. Leukemia. 2014;28:2188-2196.

Management of Resistance Mutations in Chronic Lymphocytic Leukemia

Clinical Pearl: When a patient with CLL experiences disease progression while on a covalent BTKi, it is recommended to repeat cytogenetic and molecular testing including next-generation sequencing tests to determine the presence of acquired BTK resistance mutations to guide next-line treatment selection.

DW is a 62-year-old male who was incidentally found to have mild lymphocytosis of 20,000 at an annual wellness visit with his primary care provider in 2016. Flow cytometry revealed an absolute monoclonal B cell count of 19,000 (CD5+, CD19+, and CD23+), consistent with a chronic lymphocytic leukemia (CLL) diagnosis. At that time, he was asymptomatic and otherwise had no laboratory abnormalities. Additional prognostic workup revealed unmutated IGHV and TP53 mutation.

By 2019 his ALC had increased to 350,000 and he had progressive cytopenias (hemoglobin [Hgb] 9.8, platelets 92,000). He had modest lymphadenopathy on exam. At this time, he met criteria to initiate CLL treatment as per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines¹ and was started on ibrutinib 420 mg daily.

After 6 months of treatment, DW’s ALC normalized, and by 1 year on treatment, his cytopenias had resolved. He was tolerating treatment well with only minor occasional bruising and continued to follow up in clinic every 3 months for routine labs.

After 5 years of ibrutinib treatment, he returned to clinic reporting new palpable axillary lymph nodes and WBC 36,000 (up from 6,000 the prior visit). His Hgb was 13.0 and platelets are 130,000. DW’s AP recognizes that these are signs of disease progression on therapy and is aware that often when patients progress on a covalent BTK inhibitor such as ibrutinib, it is due to the patient acquiring a new BTK resistance mutation.² The AP orders a next-generation sequencing test, which reveals a BTK^C481S mutation—the most common type of BTK resistance mutation.³ Along with resistance mutation testing, the AP repeats cytogenetic and FISH testing to evaluate for other new mutations and chromosomal abnormalities, which DW does not have.

Given that DW continues to feel well and has not developed significant cytopenias, the AP recommends he continue on ibrutinib therapy with close observation (i.e., monthly visits) for the next few months before switching to new treatment. After 3 months of follow-up, DW’s WBC is now up to 80,000 and he has new mild anemia. At this time, the AP recommends a change in treatment.

When weighing the options, the AP considers DW’s aggressive disease features (i.e., unmutated IGHV, TP53 mutation) and young age and understands that durability on any treatment needs to be maximized to provide DW with the longest lifespan possible. The AP is also aware of data showing that patients with a C481S mutation will be resistant not only to ibrutinib but also other covalent BTK inhibitors, including acalabrutinib and zanubrutinib.²

With this information, DW’s treatment options are to switch to a new drug class altogether (e.g., venetoclax, a BCL-2 inhibitor) or a noncovalent BTK inhibitor such as pirtobrutinib, as CLL cells with C481S mutations are still sensitive to pirtobrutinib despite the C481S mutation.⁴ After discussing the treatment options, DW and the AP agree to pursue treatment with venetoclax and rituximab as per the MURANO study and will reserve treating with pirtobrutinib as a later line of treatment.⁵

References

1. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745-2760.
2. Robak T, Witkowska M, Smolewski P. The role of Bruton's kinase inhibitors in chronic lymphocytic leukemia: Current status and future directions. Cancers (Basel). 2022;14:771.
3. Bödör C, Kotmayer L, László T, et al. Screening and monitoring of the BTK^C481S mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia during ibrutinib therapy. Br J Haematol. 2021;194:355-364.
4. Montoya S, Thompson MC. Non-covalent Bruton's tyrosine kinase inhibitors in the treatment of chronic lymphocytic leukemia. Cancers (Basel). 2023;15:3648.
5. Seymour JF, Kipps TJ, Eichhorst BF, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140:839-850.