Invasive Aspergillosis in Chronic Lymphocytic Leukemia: Therapy and Outcomes

Background: Despite the introduction of novel non-cytotoxic therapies (such as ibrutinib, idelalisib and venetoclax) for the treatment of patients with CLL, opportunistic fungal infections such as Pneumocystis jiroveci and aspergillosis are reported in these patients (Ahn, Blood, 2016; Lionakis, Cancer Cell, 2017). The clinical characteristics and outcomes of chronic lymphocytic leukemia (CLL) patients (pts) who develop invasive aspergillosis (IA) are not well described in the literature.

Methods: The Mayo Clinic CLL database was queried to identify CLL pts who had either a positive aspergillus culture or a positive galactomannan antigen test result between 1/1995-12/2016. We applied the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria to categorize pts to have either proven or probable IA. Patients who developed IA after an allogeneic stem cell transplant were excluded. The Mayo Clinic IRB approved this study.

Results: 123 CLL pts met the inclusion criteria for this study with either a positive aspergillus culture or a positive galactomannan antigen test. Among these, 93 pts had asymptomatic antigenemia or colonization and were not included in the analysis. Thirty pts (34%) had a diagnosis of clinically significant aspergillosis, 14 pts with proven IA and 16 pts with probable IA. The baseline characteristics at the time of IA diagnosis are shown in Table 1. At the time of IA diagnosis, the median serum IgG was 332 mg/dL and median ANC was 1.5 x10⁹/L.

The median time from CLL diagnosis to IA diagnosis was 7.1 years (range: 0.15-17.59 years). The diagnosis of IA was made via both culture and antigen (Ag) in 7/30 pts (23%), culture alone in 18/30 pts (60%) and Ag alone in 6/30 pts (20%). Invasive pulmonary aspergillosis was the most frequent syndrome, seen in 28 pts (93%). In addition, there were 3 pts with invasive sinus aspergillosis, including one case with both pulmonary and sinus infection.

Among those who received prior chemotherapy (N=23), the median time from last documented CLL directed therapy to diagnosis of IA was 3.5 months (range: 0.3-53.1 months). The most recent CLL treatment prior to IA diagnosis included: chemoimmunotherapy in 9 pts (39%), chemotherapy alone in 4 pts (17%), rituximab with high dose steroids in 3 pts (13%), alemtuzumab in 2 pts (9%), and ibrutinib in 5 pts (22%). Of the 5 patients diagnosed with IA while on Ibrutinib, 3 pts had proven IA and 2 pts had probable IA. The median duration between initiation of ibrutinib and diagnosis of IA was 2.5 months (0.03-21 months).

No patient received antifungal prophylaxis prior to the diagnosis of IA. Therapy for IA consisted of voriconazole monotherapy in 16 pts (53%), 5 pts (17%) received voriconazole in combination with caspofungin, 4 pts (13%) voriconazole in combination with amphotericin, 2 pts (7%) amphotericin alone, and 3 pts (7%) died prior to receiving anti-fungal therapy. The median overall survival from IA diagnosis was 11.2 months. After a median follow-up of 9.3 months, 20 pts (67%) died: 9 pts (45%) died secondary to uncontrolled IA infection, 4 (20%) due to Pseudomonas aeruginosa bacteremia, 4 (20%) due to CLL progression, 2 (10%) due to concomitant fungal infections (Cryptococcus and Mucor), and 1 (6%) due to respiratory failure. None of the CLL specific prognostic markers were associated with OS.

Conclusion: Invasive aspergillosis is a rare but devastating complication in CLL patients. In this large retrospective study, median overall survival following IA diagnosis is <1 year. Better tools at identifying potential risk factors and prophylaxis are important to prevent IA infection among CLL patients, to improve outcomes.

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