gms | German Medical Science

History: A now 68 years old man was diagnosed with Waldenström’s macroglobulinemia (WM) and lymphoplasmocytic lymphoma in 2010. Due to progressive anemia and increasing IgM (58 g/l), he received bendamustine/rituximab in 2011. Fludarabine was applied for progressive disease 2015; a subsequent partial remission (PR) was short-lived. In 2016, at an IgM of 34.7 g/l and a Hb of 9.8 g/dl, ibrutinib 420 mg was started and continued until March 2022 when it was stopped due to suspected heart failure after having reached and maintained a PR with elevated IgM (12–21 g/l).

Cardinal symptom by manifestation of disease: On day 2 after stopping ibrutinib, the patient reported headache, palpitations, fever (38.9°C), dry cough, shortness of breath, generalized arthralgia, and malaise. Despite antibiotic therapy, the patient’s temperature continued to range between 38.0–39.5°C.

Diagnostics: On admission mild pancytopenia, a CRP of 176 mg/l, ferritin of 351 ng/ml, and IgM of 33.1 g/l were present. An extensive workup for infectious disease was unremarkable. Serologies and PCRs for viral hepatitis, HIV, EBV, CMV, HSV-1/-2, SARS-CoV-2 were negative, as were ANA, ENA, C3, C4 ANCA. FDG-PET-CT showed bilateral tracer uptake in the pleural cavities but no evidence of malignancy, abscesses or large vessel vasculitis. Bone marrow biopsy showed 50% infiltration by lymphoplasmocytic lymphoma, no evidence of hemophagocytosis (HLH), MYD88 L265P mutation, and CXCR4 wild type. The HScore for reactive HLH was 94 points (very low probability).

Therapy: Piperacillin/tazobactam and roxithromycin were ineffective and therefore discontinued. After completing the diagnostic workup ibrutinib 420 mg/d was resumed.

Further course: All symptoms abated within 2 days after reinstitution of ibrutinib, CRP levels dropped to 26 mg/l. The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is a standard 2nd line treatment for WM. The patient’s clinical presentation was strongly suggestive of an autoinflammatory disease resembling adult-onset Still’s disease. Because of prompt recovery after reinstitution of ibrutinib, the diagnoses of ibrutinib withdrawal syndrome was established. In everyday practice, immunological withdrawal syndromes seem under-recognized and are even not mentioned in the prescribing information. Since BTK inhibitors suppress inflammatory cytokines and since WM triggers IL-1 pathways a mode of action for this disease can be provided.

Table 1 [Tab. 1]

Figure 1 [Fig. 1]