Our literature search retrieved 167 articles from the three databases of which 42 were duplicate articles and 125 represented unique articles. One hundred ten articles were excluded at the title and abstract stage due to various reasons [review/commentary (n=51); non-COVID-19-related use of BTKinibs (n=42); other reasons (n=11); case reports (n=6)]. The 15 remaining articles were screened at the full text screening stage. Among those, 9 were excluded as no patient outcomes were reported and 6 articles were included in our analysis (Figure 1).
The sample size ranged from 6 patients, in a case-series of WM  to 126 subjects in an ongoing phase II randomized trial . The majority of the population consisted of patients who were hospitalized with acute COVID-19, and included patients requiring various modalities of oxygenation support and ICU admission (Table 1). The median ages of the patients in each study ranged from 61 to 72 years. The cohorts included patients with WM and CLL, as they are commonly treated with BTKinibs. Two studies focused on the use of acalabrutinib [7, 30], one on ibrutinib , and another evaluated the effect of either drug . Two other studies did not separately classify patients on the basis of which BTKinib was used (i.e., acalabrutinib, ibrutinib, or zanubrutinib), nor included the specific dosages of each drug [32, 33]. The 6 studies had a heterogeneity of clinical outcomes measured, including resolution of symptoms, hospitalization rate or duration, oxygen requirements, and overall survival (Table 1). Time to primary outcome measurement varied from 12 days to 30 days. Of note, the study by Wilkinson et al. was ongoing at the time of analysis, therefore no outcome data is available thus far .
Hospitalization was a key outcome measured in half of the studies. Scarfò et al. reported on 190 CLL patients with confirmed SARS-CoV-2 infection, and found that ibrutinib significantly lowered the hospitalization rate for severe COVID-19 compared to any other CLL-targeted treatment or no CLL-directed treatment by half (OR 0.44 [95% CI 0.20-0.96] p<0.05) . Thibaud et al. measured hospitalization duration, as all eight patients on BTKinib were hospitalized. Patient groups were stratified to BTKinib that was continued (n=6) or discontinued (n=2) during acute COVID-19. The median length of stay was 6 days (range, 3–9) for the group that continued BTKinibs, and 8.5 days (range, 5–19) for the group in which use of BTKinibs was discontinued .
Three studies reported outcome data related to improvement in oxygenation requirements. Roschewski et al. reported on 19 patients hospitalized with COVID-19, in whom acalabrutininb was administered off-label . Eighteen of these patients had increasing oxygen requirements at baseline, 11 requiring supplemental oxygen without intubation and 8 requiring mechanical ventilation. Eight out of 11 (73%) subjects requiring supplemental oxygen without intubation were discharged from the hospital on room air at the end of the 10–14-day treatment period. Four out of 8 (50%) subjects on mechanical ventilation were extubated in the same time period, including 2 (25%) who were discharged from the hospital on room air . Mato et al. reported that hospitalized CLL patients with COVID-19 who were receiving BTKinib therapy appeared to require supplemental oxygen (86% versus 92%) or mechanical ventilation (21% versus 30%) less frequently compared to those not receiving BTKinibs . In addition, the patient group that discontinued BTKinibs in the Thibaud et al. study had higher rates of oxygen requirement, with 4/6 (67%) requiring nasal cannula or more aggressive oxygenation support. Of the 2 patients who continued ibrutinib in that study, one required minimal oxygenation support via nasal cannula .
In a case series of 6 WM patients, Treon et al. observed that ibrutinib continuation favored resolution of COVID-19 symptoms . The median time with COVID-19-related symptoms prior to diagnostic testing was 5 days, whereas the median time since diagnosis (i.e., time of data collection) was 22 days. Five of the 6 subjects continued full-dose ibrutinib (420mg/day) throughout their acute SARS-CoV-2 infection. Among these, only one subject had unresolved symptoms at day 24 since diagnostic testing. In contrast, ibrutinib was held in the sixth subject. Because symptoms worsened, ibrutinib was restarted at 140mg/day on hospital day 5, along with tocilizumab. The subject was intubated on day 10. Ibrutinib was increased to full-dose (420mg/day) on day 11, which was associated with a rapid improvement in oxygenation. The patient was extubated on day 12 and discharged from the hospital on room air by day 14.
Overall survival/mortality was measured in 5 of 6 studies (Table 1). The Treon et al. study reported that all 6 WM patients survived SARS-CoV-2 infection . Scarfò et al. reported that 13/31 (41.9%) patients with severe COVID-19 died while receiving ibrutinib. One of these 13 (7.7%) patients with less severe COVID-19 died while receiving ibrutinib. Another 42 out of 146 (28.8%) patients not receiving BTKinibs died with COVID-19 in that study, however it is unclear as to which other CLL-targeted treatment was continued or discontinued in this group and what proportion of these patients had severe versus less severe COVID-19. In addition, the study did not report an overall survival between patients who remained on ibruritinib versus those in whom ibruritinib was discontinued . Roschewski et al. reported 5/19 deaths from COVID-19, one out of 11 (9%) in the supplemental oxygen group not requiring intubation and four out of 8 (50%) in the mechanical ventilation group . Mato et al. reported that patients in the BTKinib group trended towards higher survival when compared to those on other or no CLL-directed treatment, but the difference was not statistically significant (HR 0.80, 95% CI [0.47–1.4], p=0.42) . Thibaud et al. reported that both subjects who continued BTKinib therapy survived, while 2 out of 6 patients (33%) in whom BTKinibs were discontinued died .
We did not perform a pooled cohort analysis from the studies identified due to the study population heterogeneity and multiple biases that were identified during the risk-of-bias analysis (Table 2). Indeed, selection and treatment biases were significant among cohorts studies. Further, variable definitions of clinical outcomes would not have enabled representative pooled outcomes.