Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.

TO THE EDITOR Bruton tyrosine kinase (BTK) inhibitors have improved chronic lymphocytic leukemia (CLL) outcomes and offer a chemotherapyfree option [1]. The BTK inhibitor ibrutinib, alone or with a CD20 antibody, demonstrated better efficacy versus chemoimmunotherapy in treatment-naïve (TN) CLL [2][3][4]. However, cardiovascular toxicity is a concern with continuous ibrutinib use [5,6].Acalabrutinib is a next-generation, selective BTK inhibitor approved for CLL/small lymphocytic leukemia (SLL). Acalabrutinib, alone or with obinutuzumab, showed favorable efficacy in clinical trials [7,8]. ELEVATE-TN demonstrated superior efficacy for acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil with acceptable tolerability in TN CLL [9]. We report 4-year followup results from ELEVATE-TN.ELEVATE-TN is a phase 3, randomized, multicenter, open-label study (NCT02475681) that enrolled patients aged ≥65 years, or 18-65 years with comorbidities (Cumulative Illness Rating Scale-Geriatric score >6, creatinine clearance 30-69 mL/min by Cockcroft-Gault), who had TN CLL or SLL requiring treatment, Eastern Cooperative Oncology Group performance status score of ≤2, and adequate hematologic, hepatic, and renal function [9]. Patients were randomized (1:1:1) to acalabrutinib 100 mg twice daily (until disease progression or unacceptable toxicity) with or without obinutuzumab (fixed-duration, up to 6 cycles) or obinutuzumab plus chlorambucil (up to 6 cycles). Crossover to acalabrutinib monotherapy was permitted in patients who progressed on obinutuzumab-chlorambucil. The primary study endpoint was independent review committee (IRC)-assessed progression-free survival (PFS). After primary analysis, PFS was investigatorassessed.Key secondary/exploratory endpoints were investigator-assessed PFS, investigator-assessed overall response rate (ORR), overall survival (OS), undetectable minimal residual disease (uMRD) rate, and safety. The study was not powered to compare acalabrutinib versus acalabrutinib-obinutuzumab. Informed consent was obtained from all patients before enrollment. Study details were previously published [9].In total, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; obinutuzumab-chlorambucil, n = 177). Median age was 70 years (range, 41.0-91.0); 14% had del(17)(p13.1) and/or mutated TP53 and 63% had unmutated immunoglobulin heavy chain variable (IGHV) gene (Supplementary Table 1).At a median follow-up of 46.9 months (range, 0.0-59.4), treatment was ongoing in 74.9% (n = 134) and 69.3% (n = 124) of patients in the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms, respectively (Supplementary Table 2). Sixty-

TMTV0 is more relevant than tumour bulk for predicting the outcome in patients with HL, and adds a significant prognostic insight to interim PET response assessment. The combination of TMTV0 and ΔSUVmaxPET0-2 made it possible to identify three subsets of HL patients with different outcomes. This may guide clinicians in their choice of therapeutic strategy.

In the particular setting of neutropenic leukemia patients with pulmonary infection, the presence of the RHS on CT was a strong indicator of PM. It could allow the early initiation of appropriate therapy and thus improve the outcome.