Rates of undetectable MRD in the blood and marrow improved in these individuals. and triple mixtures of a BTK inhibitor, venetoclax, and obinutuzumab are now being pursued. The major questions facing the field at present are how best to select individuals for BTK inhibitor monotherapy versus venetoclax/obinutuzumab upfront, what to do after failure of both BTK inhibitor(s) and venetoclax, and the ideal way to integrate measurable residual disease data into decisions concerning treatment choice, duration, and discontinuation. 0.001)5. These results were virtually identical in the genomically high-risk subset of individuals (deletion 17p [del17p], mutation [alterations who Oaz1 received ibrutinib monotherapy; median time to progression (TTP) was 53 weeks9. Ibrutinib versus CIT The results of two important US Intergroup phase 3 studies comparing ibrutinib-based regimens in the frontline establishing against standard CIT Clevudine regimens in both older and younger individuals with CLL were recently published. The Alliance trial (A041202) randomized 547 older patients (65 years of age) with previously untreated CLL to receive one of ibrutinib alone, ibrutinib plus rituximab, or bendamustine plus rituximab (BR)10. At the time of publication, median PFS had not been reached in either of the ibrutinib-containing arms. Importantly, ibrutinib was continued until disease progression, while BR was given for a standard 6 cycles. The estimated 2-yr PFS rate was 74% for BR, 87% for ibrutinib only, and 88% for ibrutinib/rituximab. PFS was not significantly different between the two ibrutinib-containing organizations. No differences were apparent among the three arms in terms of OS at a median follow-up of 38 weeks. The pace of grade 3 hematologic AEs was higher in the BR arm (61%) than in the ibrutinib-containing arms (40%), but that of grade 3 non-hematologic AEs was higher in each ibrutinib-containing arm (74%) than in the BR arm (63%). The Eastern Cooperative Oncology Group (ECOG) 1912 trial randomized 529 treatment-na?ve individuals with CLL 70 years of age 2:1 to receive ibrutinib (until disease progression) in addition rituximab (6 cycles) or 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR)11. Individuals with del17p CLL were excluded from this trial given their known poor results with CIT. After a median of 33.6 months of follow-up, this trial demonstrated both a PFS and an OS advantage for ibrutinib plus rituximab over FCR (3-year PFS, 89.4% versus 72.9%; 3-yr OS, 98.8% versus 91.5%, 0.001 for both comparisons). Importantly, there was no difference in 3-yr PFS (87.7% for ibrutinib/rituximab and 88% for FCR) between the two arms when considering only the = 0.013). A total of 95 individuals discontinued ibrutinib (24% owing to disease progression or death, 51% owing to AEs or complications, and 25% owing to withdrawal of consent or additional reasons), after which the median time to disease progression or death was 23 weeks. Only an increased baseline Cumulative Illness Rating Level (CIRS) score expected discontinuation of ibrutinib for reasons other than disease progression or death. Ibrutinib addition to CIT An interesting strategy becoming pursued at MDACC to optimize FCR for more youthful individuals with 0.0001). The estimated 30-month PFS rates were 79% and 31%, respectively. Severe AEs occurred in 58% of individuals in the ibrutinib/obinutuzumab group and in 35% of individuals receiving chlorambucil/obinutuzumab. Ibrutinib toxicities and the need for more selective BTK inhibitors Overall, ibrutinib is definitely well tolerated; in an integrated security analysis of ibrutinib-treated (for up to 43 weeks) individuals from RESONATE (n = 195) and RESONATE-2 (n = 135), the most frequent AEs were diarrhea (52%, grade 3 in 5%) and fatigue (36%, grade Clevudine 3 in 3%)20. The most common grade 3/4 AEs were neutropenia (18%) and pneumonia (12%). The prevalence of hypertension improved over time. Dose reductions and discontinuation due to AEs occurred in 13% and 11% of individuals, respectively. In a real world analysis of 616 individuals having a median follow-up of 17 weeks, Clevudine an estimated 41% discontinued ibrutinib, mostly because of toxicities, after a median of 7 weeks21. Atrial fibrillation is definitely, of course, a well-established risk associated with ibrutinib therapy22. Pooled data on 1,505 CLL and mantle cell lymphoma (MCL).