Mucormycosis in a Patient with Chronic Lymphatic Leukemia in Treatment with Ibrutinib

Case Report

J Bacteriol Mycol. 2021; 8(5): 1184.

Mucormycosis in a Patient with Chronic Lymphatic Leukemia in Treatment with Ibrutinib

Fodstad PM¹*, Lein IA² and Tjønnfjord GE³

1Department of Ear Nose Throat Surgery, Oslo University Hospital, Oslo, Norway

2Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Norway

3Department of Hematology, Oslo University Hospital, Oslo, Norway

*Corresponding author: Fodstad PM, Department of Ear Nose Throat Surgery, Oslo University Hospital, P.O. Box 4950, 0424 Nydalen, Oslo, Norway

Received: June 14, 2021; Accepted: August 04, 2021; Published: August 11, 2021


Invasive Fungal Infection (IFI) is a serious complication in patients with hematologic malignancies. We present a case of invasive Mucormycosis in a patient with Chronic Lymphatic Leukemia (CLL). This case of Mucormycosis illustrates invasive fungal infections as a complication to chronic hematologic diseases and adds to other publications that suggest a relationship with novel treatments of CLL such as ibrutinib. Treatment of the IFI was successful without having to stop ibrutinib. We present relevant publications and discuss clinical controversies that arise.

Keywords: Chronic lymphatic leukemia; Invasive fungal infection; Ibrutinib; Mucormycosis


Mucormycosis is a fungal infection caused by fungi belonging to the order Mucorales. The most common pathogenic genera in this order of fungi include Rhizopus and Mucor [1]. The disease was first described by Paltauf in 1885 [2]. The fungi in the Mucoracaeca family are widely found in organic matter such as bread, compost, and animal excrements and exposure is usually by inhalation and direct contact [3]. The most common sites of Mucormycosis infections are the sinuses (39%), followed by pulmonary (24%), cutaneous 19%), cerebral (9%) and gastrointestinal (7%). Disseminated disease was seen in 3% [4].

Mucormycosis is regarded a medical emergency. The treatment is medical combined with surgery if possible. The prognosis varies greatly on the basis of location and extent of the infection as well as the underlying health condition of the patient. Roden et al. reviewed more than 900 cases of Mucormycosis and found an overall mortality rate between 40% and 80% [4]. Ghez and colleagues found a mortality rate of 9 out of 32 patients with invasive fungal infections [5].

Chronic Lymphatic Leukemia (CLL) is the most common leukemia in Western countries. It is characterized by accumulation of mature clonal B lymphocytes in blood, bone marrow and secondary lymphoid organs. The clinical course is highly variable. In one third of the patients, the disease is asymptomatic and follows an indolent course not requiring treatment. The remaining patients suffer from active disease with progressive lymphocytosis, bone marrow failure, lymphadenopathy, hepatosplenomegaly and/or B-symptoms and may require several lines of treatment. Autoimmune thrombocytopenia and autoimmune hemolytic anemia are frequent complications of CLL, and they are primarily treated with corticosteroids. Chemoimmunotherapy and more recently treatment with signal pathway inhibitors (ibrutinib and idelalisib) and a BCL-2 inhibitor (venetoclax) have improved survival for CLL patients who require treatment. With the introduction of these novel agents, the patients may experience a new set of adverse effects. An increased frequency of mold infections has been reported in patients treated with ibrutinib, particularly when ibrutinib is combined with corticosteroids [5-7].

Case Presentation

The patient was diagnosed with CLL in 2010. He was then in his mid-forties. The CLL cells displayed a typical immunophenotype, and they used the IGHV3-53 gene which showed 100% homology to germ line. FISH-analyses disclosed homozygous del(13q14) and heterozygous del(11q22). In 2015 he received 6 courses of fludarabine, cyclophosphamide and rituximab as third line treatment for CLL. Treatment indications were progressive Binet stage B disease and autoimmune hemolytic anemia in need of high doses of corticosteroids. Complete MRD negative remission was accomplished.

In January 2017 the patient presented with progressive disease (Binet stage B) and autoimmune hemolytic anemia. Prednisolone (1mg/kg) was initiated and he received two courses of fludarabine, cyclophosphamide and rituximab with insufficient efficacy. Molecular genetics disclosed four different TP53-mutations and treatment was changed to ibrutinib 420mg daily from February 2017. Corticosteroids were continued. The patient responded favorably to the treatment, and prednisolone was tapered off to a dosage of 20mg/ day as per April 3, 2017.

In April 2017 the patient experienced moderate pain in the left maxillary area and discharge from the left nose. The condition was believed to be acute sinusitis and treatment with antibiotics and prednisolone 40mg/day was started. This did not reduce the symptoms and Endoscopic Sinus Surgery was performed at his local ENT department after approximately four weeks of symptoms. Microbiological examination revealed a positive culture of Rhizopus Mucor sensitive to amphotericin B. Liposomal amphotericin B in gauze was placed directly in the maxillary sinus and middle meatus, in addition to intravenously administration at 5mg/kg/day. The patient was transferred to the Ear Nose Throat Department at Oslo University Hospital for multidisciplinary treatment.

Investigations and treatment

At the time of admission in our hospital the patient’s general condition was good and afebrile. Examination showed crusts in the left nasal cavity, hypertrophic concha media and numbness of the left side of the upper lip. Mucosal tissue changes were seen in the posterior wall of the maxillary sinus. Computed Tomographic (CT) examination showed signs of sinusitis in the left maxillary, ethmoidal, and frontal sinuses and possible bone erosion in the dorsal maxillary sinus.

The patient was given immunoglobulin (0.4g/kg i.v.) due to hypogammaglobulinemia (3.7g/L) and a blood transfusion due to anemia (Hb 7.8g/dL). His CRP was 51mg/L. Corticosteroids were withdrawn. Ibrutinib was continued at 420mg daily. Liposomal amphotericin B was increased to 10mg/kg due to possible bone involvement.

Radical endoscopic surgery of the left sinuses was performed the day after admittance with wide opening to the maxillary sinus and ethmoids. The posterior maxillary sinus wall was surgically removed to prevent entrapment of fungi in the pterygoid fossa. The CRP continued to climb to 115mg/L while the hemoglobin was stable after the intital blood transfer with a hemoglobin around 9g/dL (Figure 1).