Autoimmune cytopenias (AIC) affect 5-9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs - ibrutinib, idelalisib and venetoclax - have a prominent role in the treatment of CLL, but their impact on CLL-associated AIC is largely unknown. In this study, we evaluated the characteristics and outcome of pre-existing AIC, and described the incidence, quality and management of treatment-emergent AIC during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of pre-existing AIC was reported in 104/815 patients (13%). Interestingly, 80% of patients whose AIC was not resolved at the time of targeted drug start experienced an improvement or a resolution during therapy. Treatment-emergent AIC occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib and in 7% during venetoclax, with an estimated incidence rate of 5, 6 and 69 episodes per 1000 patients per year of exposure in the three treatment groups, respectively. The vast majority of patients who developed treatment-emergent AIC carried unfavorable biological features such as an unmutated IGHV, and a del(17p) and/or TP53 mutation. Notably, despite AIC, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib and venetoclax appears to have a beneficial impact on CLL-associated AIC, inducing an improvement or even a resolution of pre-existing AIC in most cases and eliciting treatment-emergent AIC in a negligible portion of patients.
Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n=749) or at the end (n=635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT; 5.7% vs 5.8%, p=0.98, 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n=1,253). In patients with high CNS international prognostic index (n=600), 3-year CNS relapse rate was 9.1% with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk versus i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
Our results suggest that point-of-care screening is feasible in undocumented migrants and should be targeted according to provenance. Case detection of HBV infection among migrants could potentially reduce HBV incidence in migrants' contacts and in the general population by prompting vaccination of susceptible individuals and care of eligible infected patients.
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