Introduction: Infectious complications represent a major cause of morbidity and mortality in hairy cell leukemia (HCL) patients. Due to the immunosuppressive nature of the disease, these patients are frequently affected by opportunistic infections and rare pathogens. Furthermore, cytotoxic chemotherapy might lead to poor or even fatal outcomes in the setting of an active infection. Case Presentation: We report the case of a 62-year-old HCL patient who presented with recurrent fever episodes, pancytopenia, and mediastinal lymphadenopathy. A treatment decision against purine analogs and for rituximab mono was made as lymph node tissue revealed disseminated Mycobacterium kansasii infection. Together with specific antimycobacterial treatment, rituximab mono led to complete hematologic remission after 6 months without aggravating the accompanying infection. Conclusion: Here, we demonstrate successful treatment of HCL with rituximab in a patient with concomitant disseminated M. kansasii infection.
Hairy cell leukemia patients are susceptible to rare opportunistic infections, including nontuberculous mycobacterial infections.
First-line cytotoxic agents like purine analogs should not be administered in HCL patients with active infection.
Rituximab monotherapy was well tolerated in a patient with disseminated Mycobacterium kansasii infection and led to complete remission at 6-month follow-up.
Hairy cell leukemia (HCL) is a rare B-cell lymphoid neoplasm which can be identified by the distinct hairy appearance of lymphocytes in the peripheral blood or bone marrow. Patients typically present with unspecific symptoms, fatigue, weakness, and abdominal discomfort. Laboratory findings usually show pancytopenia. The diagnosis is established by cytomorphology, immunophenotyping, and molecular genetics. In asymptomatic patients, “watch and wait” may represent an appropriate strategy. As cytopenia or splenomegaly progresses or infectious complications occur, treatment is indicated. Symptomatic patients can be treated effectively with purine analogs (e.g., cladribine or pentostatine). In a state of ongoing active infection, cytostatic therapy with cladribine should not be initiated [1, 2]. Nontuberculous mycobacteria can be found ubiquitously in our environment and can cause opportunistic infections in immunocompromised patients. Mycobacterium kansasii accounts for about 5% of all nontuberculous mycobacteria isolates in Europe but shows severe differences in local distribution .
A 62-year-old male was referred to our hematology department from a peripheral clinic with persisting fever episodes after cholecystectomy. Four years prior to admission, the patient was diagnosed with a classic form of HCL, based on a CD19+, CD20+, CD25+, CD103+, CD11c+ phenotype with kappa light chain restriction in flow cytometry of bone marrow blood. Bone marrow biopsy demonstrated diffuse infiltration of a lymphoid cell type expressing CD19, CD20, CD25, CD79a, and CD103. Furthermore, BRAF V600E mutation was detected. So far, therapeutic intervention had not been required, and the patient was regularly seen by our outpatient department. Two weeks prior to admission, cholecystectomy had been performed due to fever and right upper quadrant abdominal pain. Histopathologic examination of the gall bladder revealed lymphocytic infiltrations as well as patchy granulocytic inflammation. Fever persisted after surgery, and despite an extensive workup including blood cultures, transthoracic echocardiography, transesophageal echocardiography, abdominal ultrasound, abdominal and chest CT, and esophagogastroduodenoscopy, a fever origin could not be found. However, chest CT revealed slight mediastinal lymphadenopathy which was not further pursued. The patient was subsequently transferred to our center for further workup.
Upon arrival in our clinic, the patient reported recurrent fever episodes and heavy night sweats during the last weeks. Laboratory results showed an elevated CRP level of 8.1 mg/dL and pancytopenia with leukopenia 0.91 G/L, neutropenia 0.43 G/L, hemoglobin 8.1 g/dL, and thrombopenia 132 G/L. Repeated blood cultures, urine cultures, and quantiferon ELISA as well as sonography, echocardiography, and CT scans were performed and did not show any source of infection. Bone marrow biopsy revealed HCL with hypercellular bone marrow with atypical megakaryocytes and borderline blasts without indication for further malignant or infectious disease. Due to pancytopenia, an indication for treatment was established. Since active infection could not be ruled out, a treatment decision was made for rituximab weekly (375 mg/m2) instead of first-line chemotherapy. During the following weeks, the patient continued to suffer from recurrent fever and night sweats. Empiric antibiotic therapy was conducted without evidence of clinical improvement. After 4 cycles of rituximab, peripheral blood cell counts normalized; however, fever spikes continued. An FDG/PET-CT was performed which showed pathologic enlargement of several lymph node levels with strong increase in FDG uptake (Fig. 1A). Partly, mediastinal, hilar, and cervical lymph nodes also showed central necrosis. Bronchoscopy with bronchoalveolar lavage and EBUS-guided transbronchial needle aspiration was performed. Ziehl-Neelsen staining of the lymph node specimen revealed acid-fast rod-like bacilli with a segmented dot-like morphology (Fig. 1B). Subsequent DNA array-based detection of PCR-amplified mycobacterial genes (Vision Array 2.0; Zytovision GmbH, Bremerhaven, Germany) and mycobacterial cultures established the diagnosis of M. kansasii infection. The patient was started on azithromycin, ethambutol, and rifampicin. A rapid clinical improvement was seen, and he was discharged on oral antibiotics 3 weeks later. A follow-up examination at 3 months revealed normal differential cell counts. Retrospectively, acid-fast bacilli staining and PCR were performed without evidence of M. kansasii infection of the bone marrow or gall bladder. At follow-up examination at 6 months, hematologic remission persisted with an erythrocyte count of 4.48 G/L, hemoglobin 13.1 g/dL, thrombocytes 195 G/L, and leucocytes 5.86 G/L with a normal count of neutrophil granulocytes. Cytomorphologic analysis was negative for hairy cells in the peripheral blood and bone marrow. However, a small subset of CD19+, CD25+, CD103+, CD11+ cells were detected within the range of detection limit in the bone marrow. Thus, a complete remission with MRD positivity was achieved.
In a study with 186 HCL patients that presented with infections, 6 patients showed pulmonary manifestation of M. kansasii . Importantly, case reports have described fatal outcomes after treatment with cladribine or alpha interferon in HCL patients with mycobacterial infection . In our case of an assumed ongoing infection, we decided against myelosuppressive therapy and started weekly courses of rituximab. Rituximab is generally not recommended as a monotherapy in HCL patients, as data for first-line monotherapy are scarce. However, it has been shown that it can induce substantial remission rates in relapsed or refractory HCL patients . Considering the current COVID-19 pandemic, experts have recommended the increased use of targeted and nonmyelosuppressive therapies in HCL . As rituximab reduces the efficacy of COVID-19 vaccines and might lead to a prolonged and more severe clinical course of COVID-19 , a valid therapeutic strategy for classical HCL may arise from targeting BRAF V600E mutation. Administration of the oral BRAF inhibitor vemurafenib may be considered as a treatment that leads to neutrophil recovery and allows a more efficient COVID-19 vaccination than during treatment with rituximab .
In our patient, treatment was well tolerated and led to an early complete remission after 4 cycles, which was sustained at 6-month follow-up. The duration of response to rituximab alone remains unclear, and further treatment will have to be evaluated. We hypothesize that rituximab may be considered as an alternative first-line treatment option in selected cases of HCL with suspected (mycobacterial) infections.
The authors would like to thank the hospital staff involved in the patient care.
Statement of Ethics
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The study is exempt from ethics committee approval since treatment decisions were based on clinical reasoning.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
No funding was received for this study.
All authors were involved in the treatment of the patient. D.Z. and C.M. summarized the case and wrote the manuscript. S.O. provided histological images and pathological expertise. A.Z., P.M., L.F., M.G., E.K., S.O., M.H.-N., M.D., S.B., and M.B. provided critical feedback and proofread the manuscript. All authors read and approved the final manuscript.
Data Availability Statement
The data are available from the corresponding authors upon reasonable request.