A fatal disseminated cryptococcal infection in a patient treated with zanubrutinib for Waldenström’s macroglobulinemia

Introduction

Zanubrutinib is a second generation, irreversible small-molecule Bruton tyrosine kinase inhibitor (BTK) approved for the treatment of mantle cell lymphoma, marginal zone lymphoma, and Waldenström's macroglobulinemia. Herein, we present a case of disseminated cryptococcosis in a patient with Waldenström's macroglobulinemia treated with this agent.

Case report

A 75-year-old Caucasian man was diagnosed with Waldenström's macroglobulinemia in September 2020 when routine blood work showed worsening anemia and subsequent progressive pancytopenia. Of note, the patient had previously had only a mild normocytic anemia documented between 2016–2020. Medical history included benign prostatic hyperplasia, hypertension, and obstructive sleep apnea. His medications were lisinopril and tamsulosin. He denied any history of alcohol, tobacco, or illicit substance use. There was no evidence of cancer in the immediate family. Patient spent time outdoors as he was an avid hiker and runner.

As he was asymptomatic initially, he had been monitored without any therapeutic interventions until he developed progressively worsening fatigue, dyspnea, and was unable to get through his physical activities. White blood cell count was 2.14 × 10³/μL [reference range, 3.8–10.8 × 10³/uL], with mild neutropenia and lymphopenia. Hemoglobin was 8.3 g/dL [reference range, 13.5 - 17.5 g/dL); indices were normocytic; and platelet count was 86,000/μL [reference range, 150,000–400,000/μL]. He eventually required red blood cells transfusions due to severe anemia. Serum protein electrophoresis showed M-protein of 0.3 g/dL. Immunofixation showed monoclonal IgM type kappa. Serum IgM was 986 mg/dL [reference range, 15–143 mg/dL]. Serum IgG and IgA were 543 mg/dL [603–1613 mg/dL] and 36 mg/dL [61–437 mg/dL], respectively. A bone marrow biopsy and aspiration showed a hypercellular marrow with a CD5-negative CD10-negative CD19⁺ CD20⁺ monoclonal B-cell infiltrate representing 80%. Fluorescence in situ hybridization was negative for t(11:14). Cytogenetics was normal. MYH11/CBFB gene rearrangement was negative. MYD88 testing was not done due to an insufficient sample. In the context of monoclonal gammopathy type IgM, these findings were consistent with Waldenström's macroglobulinemia. Computerized tomography (CT) demonstrated splenomegaly and mediastinal lymphadenopathy.

In July 2021, he was treated with rituximab 375 mg/m² weekly for four weeks, with only minimal symptomatic improvement and persistent cytopenias. Therefore, the decision was made to start zanubrutinib 160 mg orally twice daily in September 2021. The patient tolerated zanubrutinib well, with no adverse events. His compliance with this agent was 98%. Between September - November 2021, fatigue and energy levels continued to improve, and he began to engage in outdoor activities including yard work and hiking. By November 2021, his disease was in a good partial remission.

In December 2021, he presented with generalized weakness, subjective fevers, dyspnea, and nonproductive dry cough for seven days. On presentation, he was febrile at 103.1° F, tachycardic at 111 bpm and hypoxic with 88% oxygen saturation, thereby requiring supplemental oxygen. He had unchanged pancytopenia, with lymphopenia. Chest x-ray and CT of the chest demonstrated extensive heterogeneous ground-glass opacities scattered throughout the lungs bilaterally with mediastinal lymphadenopathy (Figures 1 and 2). Human immunodeficiency virus 1 and 2 (HIV) antigen & antibody tests were negative. Serum 1,3 beta-D-glucan was 34 pg/ml [reference range, < 60 pg/ml]. Mycoplasma pneumoniae IgG & IgM antibodies were negative. Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) polymerase chain reaction (PCR) testing was negative. Serologies for Legionella, Coccidioides, Blastomyces, Aspergillus, Pneumocystis jiroveci, and Histoplasma were negative. Serum Cryptococcal antigen was positive with a reflex titer of 1:1024. Blood cultures grew Cryptococcus neoformans in 2/2 bottles. Patient subsequently underwent lumbar puncture with cerebrospinal spinal fluid (CSF) culture. Opening pressure was normal. India ink stains showed an encapsulated yeast and culture was positive for Cryptococcus neoformans.

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Figure 1.

Ct scan demonstrating diffuse patchy and lobar consolidation with ground glass opacities, noncalcified nodules (arrows) and bilateral pleural effusions consistent radiographic findings of pulmonary cryptococcosis.

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Figure 2.

Ct scan demonstrating left hilar lymphadenopathy (arrows) in the setting of pulmonary cryptococcosis.

Management & outcome

Patient was admitted to the general ward for management of severe disseminated cryptococcosis complicated by fungemia, multifocal pneumonia, and meningitis. Zanubrutinib was held. Causality assessment between zanubrutinib and the disseminated cryptococcosis via Naranjo nomogram questionnaire yielded a score of 3 (Table 1). He was initiated on intravenous liposomal amphotericin B 4 mg/kg/day in combination with oral flucytosine 100 mg/kg/day in 4 divided doses. Over the next four days, the patient's respiratory status acutely worsened, requiring noninvasive positive-pressure ventilation (NPPV). This prompted further workup with bronchoscopy and bronchoalveolar lavage by the pulmonary service. Infectious work-up did not yield any other bacterial or fungal etiologies, however, clinical suspicion for cryptococcal pneumonia lingered due to severe fungemia and multifocal involvement of lungs demonstrating heterogenous ground-glass opacities.

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Table 1.

The Naranjo adverse drug reaction (ADR) probability scale questionnaire.

To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score	Yes	No	Do not know	Score
1. Are there previous conclusive reports on this reaction?	+ 1	0	0	+ 1
2. Did the adverse event occur after the suspected drug was administered?	+ 2	−1	0	+ 2
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+ 1	0	0	0
4. Did the adverse reaction reappear when the drug was readministered?	+ 2	−1	0	0
5. Are there alternative causes (other than the drug) that could have on their own caused the reaction?	−1	+ 2	0	−1
6. Did the reaction reappear when a placebo was given?	−1	+ 1	0	0
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?	+ 1	0	0	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+ 1	0	0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+ 1	0	0	0
10. Was the adverse event confirmed by any objective evidence?	+ 1	0	0	+ 1
			Total	3

The Naranjo criteria classify the probability that an adverse event is related to drug therapy based on a list of weighted questions, which examine factors such as the temporal association of drug administration and event occurrence, alternative causes for the event, drug levels, dose – response relationships and previous patient experience with the medication. The ADR is assigned to a probability category from the total score as follows: definite if the overall score is 9 or greater, probable for a score of 5–8, possible for 1–4 and doubtful if the score is 0. The Naranjo criteria do not take into account drug-drug interactions. Drugs are evaluated individually for causality, and points are deducted if another factor may have resulted in the adverse event, thereby weakening the causal association.

After a week of hospitalization, his respiratory status deteriorated requiring intubation and transfer to the intensive care unit. Antifungal therapy was continued. Imaging studies continued to demonstrate worsening bilateral opacification, and there was a concern for superimposed hospital-acquired pneumonia, therefore, antibiotic therapy with IV meropenem and linezolid was added. Repeat blood cultures after ten days demonstrated clearance of fungemia. Despite respiratory and antimicrobial support, the patient's clinical course progressively worsened due to septic shock and multiorgan failure. After further discussion with the family members, comfort measures were initiated until the patient's demise.

Discussion/conclusion

A multitude of novel agents have become available in oncology in the last two decades. Given their fast track to clinical development and approval, providers need to be well-acquainted with their associated adverse events. Importantly, new side effects are continuously being encountered in clinical practice.

As a class, BTK inhibitors are currently approved for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström's macroglobulinemia, and marginal zone lymphoma. Side effects of BTK inhibitors include fatigue, thrombocytopenia, neutropenia, anemia, peripheral edema, nausea, atrial fibrillation, and upper respiratory tract infections. ¹ Unlike classic cytotoxic chemotherapy, these agents exert their anti-tumor effect by modifying cellular pathways and components of the immune system. ²

Cryptococcus neoformans has been identified in pigeon droppings, however, it is also found in soil worldwide. Cryptococcal infection is known to affect persons with defects of cell-mediated immunity. This involves a helper T-cell response with cytokine release including tumor including tumor necrosis factor (TNF), interferon-γ (IFNγ), and interleukin-2 (IL-2) which play a crucial role in resulting granulomatous inflammation in local lymph nodes while the yeast remains dormant but viable. ³ Thus, Cryptococcus yeast establishes a latent infection within alveolar macrophages, lying dormant in the thoracic lymph nodes within the lung parenchyma until the immune system was altered.

The cell-mediated immune response to cryptococcal infection was demonstrated in preclinical studies by Uicker et al. ⁴ After mice were exposed to cryptococcal antigen, CD4⁺ T-cells became activated leading to cytokine production and leukocytic infiltration at the site of infection. It has been established that individuals with cell-mediated immune defects as in untreated HIV patients are more susceptible to disseminated cryptococcal infection as the virus depletes CD4⁺ T-cells. A research study on immunogenomic profiling of T-cells and B-cells obtained from Waldenström's macroglobulinemia patients by Kaushal et al. ⁵ demonstrated depletion of naïve CD4⁺ T-cells and B-cells and increased clonal CD8⁺ T-cells. Notwithstanding, clinico-laboratory data examining immune alterations in patients with Waldenström's macroglobulinemia is limited due to the rarity of this malignancy.

We hypothesize further that owing to immune defects in our patient, the yeast was able to multiply and disseminate outside thoracic lymph nodes leading to fungemia, pneumonia, and meningitis. The role BTK inhibitors in the pathogenesis of infections requires careful examination. The overall increased infection rates in patients treated with BTK inhibitors might be a result of: (1) inhibition of B-lymphocytes which leads to hypogammaglobinemia and (2) inhibition of interleukin-2-inducible T-cell kinase (ITK) in CD4⁺ T-cells. ⁶ Therefore, it is likely that the combination of these BTK inhibitor induced immune defects and the underlying T- and B-cell immune defects in Waldenström's macroglobulinemia contributed to our patient's fatal disseminated cryptococcal infection.

The risk of invasive fungal infections in patients who received ibrutinib has been examined in several cohorts. A retrospective study by Ruchlemer et al. ⁷ from 15 institutions across 6 countries described 28 patients with invasive fungal infections. The causative organisms were mostly aspergillus (17), but other fungal species included mucormycosis (3), cryptococcosis (7), Pneumocystis jiroveci (1). A total of 61% of these infections were fatal. Another cross-sectional study conducted by Ruchlemer et al. ⁸ and involving 22 institutions across 26 countries identified 35 patients with invasive fungal infections. The causative organisms were mostly aspergillus. However, 9 (26%) were identified as cryptococcal infections. Disseminated disease occurred in 60% patients, intracranial - in 60% and pulmonary - in 60% patients. Importantly, once an invasive fungal infection was diagnosed, mortality was 69%. This highlights the importance of heightened clinical suspicion for opportunistic infections in patients on BTKs.

Our patient was initiated on zanubrutinib, a second generation BTK, after failing to respond to rituximab, a monoclonal anti-CD20 antibody. In the ASPEN study, which compared the first-in-class BTK inhibitor, ibrutinib, to zanubritinib for the management of Waldenström's macroglobulinemia, the rate of grade 3-4 pneumonia was 7% versus 1%, respectively. There was also one report of cryptococcal sepsis in the zanubrutinib cohort. ⁹ Despite the maintained treatment efficacy of the newer BTK inhibitor zanubrutinib, it is important to note that zanubrutinib is a newer agent in its class, therefore, its side-effect profile is still evolving in clinical practice. Notwithstanding, fungal infections are rarely reported in clinical trials but have been associated with ibrutinib in several retrospective studies.^10–14

In a 3-year follow-up dose escalation and expansion study by Trotman et al. ¹⁵ in patients treated with zanubrutinib for Waldenström's macroglobulinemia, fungal infections occurred in 4/77 patients. These included bronchopulmonary aspergillosis (grade 2), cryptococcal meningitis (grade 3), esophageal candidiasis (grade 2), and disseminated Scedosporium infection (grade 4). Most of these infections resolved with antifungal treatment, except for the Scedosporium infection that recurred and was ultimately fatal. The remainder of patients restarted and completed zanubrutinib therapy.

It is difficult to establish the extent to which the risk of infection in patients receiving BTK inhibitors is attributable to the antineoplastic drug alone. The affected patients could have other factors associated with higher risk of infection which include underlying disease associated immune defects such as hypogammaglobulinemia and T-cell dysfunction.^4,16 As seen in untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the vast majority of infections are bacterial. By contrast, viral and fungal opportunistic infections are rare in untreated CLL/SLL and occur predominantly in advanced stages of disease or in the context of severe neutropenia. ¹⁷ An accurate inventory of infectious morbidity from invasive fungal infections in patients with Waldenström's macroglobulinemia is limited due to its rarity. However, in a population-based study examining patterns of infectious morbidity conducted in 2014, Lund et al. ¹⁸ demonstrated an increased risk of developing viral and bacterial infections. Data for fungal infections is not available. The authors concluded that infections represent a major cause of morbidity and mortality in patients with hematologic malignancies especially in the setting of BTK inhibitor use. This illustrates the importance of not only further investigating but appropriately reporting infectious complications in the context of newer therapies.

Undoubtedly, the context of a malignant hematologic disorder, previous rituximab administration, and frequent outdoor activities are possible contributing factors in our patient. Nonetheless, his Waldenström's macroglobulinemia was in a partial response at the time of diagnosis. A score of 3 on the Naranjo nomogram makes the causality relationship between zanubrutinib and the fatal disseminated cryptococcosis with meningitis in our patient possible. The mechanism by which zanubrutinib might trigger invasive fungal infections is yet to be fully elucidated. As this association appears likely, we expect further cases of opportunistic infections to be reported in patients on BTK inhibitors.