Additional MRD data were obtained for 18 of 30 patients at 3 months after randomization

Additional MRD data were obtained for 18 of 30 patients at 3 months after randomization. venetoclax irrespective of MRD; group B: MRD guided venetoclax maintenance with a maximum of 12 cycles). Here we report on a planned interim safety analysis as well as preliminary efficacy and MRD data of the first 30 patients enrolled. Downgrading of TLS risk after preinduction occurred in 25 patients: 3 from high to medium, 3 from high to low, and 19 from medium to low risk. No patient Specnuezhenide remained high risk. From these 30 patients, peripheral blood MRD data were obtained for 28 patients at the end of induction II (6 months after the last obinutuzumab dose), of whom 26 had undetectable MRD levels, and for 18 patients who reached the 3-month after-randomization point, of whom 16 had undetectable MRD levels. Obinutuzumab preinduction is usually tolerated well in these unfit patients and results in abrogating high TLS risk in all patients. Preliminary data indicate that efficacy is usually maintained with a high proportion of patients with undetectable MRD levels after combination treatment. Visual Abstract Open in a separate window Introduction First-line treatment of patients with chronic lymphocytic leukemia (CLL) unfit for fludarabine-containing chemoimmunotherapy with the Bruton tyrosine kinaseCinhibitor ibrutinib proved superior to chlorambucil monotherapy in terms of both progression-free survival and overall survival. Yet the frequency of complete remissions remained low, eradication of minimal residual disease (MRD) was not seen, and ibrutinib needs to be continued until disease relapse or unacceptable toxicity.1 Obvious disadvantages of continuous treatment are long-term exposure to at least partly unexplored adverse effects, high costs, and the inevitable selection of resistant clones. Therefore, novel safe regimens are needed that result in deep and durable responses allowing for early treatment cessation. Venetoclax is usually a highly selective inhibitor of the anti-apoptotic protein B-cell lymphoma 2, which is usually constitutively overexpressed in CLL.2 Venetoclax monotherapy has shown high efficacy in patients with heavily pretreated CLL.3 A recent study showed that a fixed duration of venetoclax treatment combined with the anti-CD20 monoclonal antibody rituximab results in undetectable levels of MRD in the majority of relapsed/refractory patients.4 Although yet to be proven for drugs such as venetoclax, MRD levels posttreatment proved to be a robust surrogate endpoint for long-term Specnuezhenide outcome after Specnuezhenide chemoimmunotherapy.5,6 It is anticipated that this combination of venetoclax with the more potent anti-CD20 antibody obinutuzumab may allow for MRD-guided instead of fixed-duration treatment, allowing a lower incidence of toxicity, as well as lower costs. Nonetheless, specific toxicities of these 2 drugs might limit their applicability in a fludarabine-unfit populace. First, venetoclax might result in potentially life-threatening tumor lysis syndrome (TLS), specifically in patients with high tumor burden and impaired kidney function,7 and necessitates frequent admissions in patients at high risk.3 Second, occurrence of severe infusion-related reactions (IRRs) has been reported during obinutuzumab infusion, especially at the first dose.8 The current phase 3 trial of the German CLL study group (CLL14) compares chlorambucil combined with obinutuzumab with venetoclax and obinutuzumab as first-line treatment in patients with CLL with significant comorbidities. Rabbit polyclonal to KATNB1 In this protocol, venetoclax is added to obinutuzumab around the 22nd day of the first treatment cycle. A recently reported safety and efficacy analysis of the first 12 patients included in the run-in phase of the CLL14 trial showed grade 3 laboratory TLS in 2/12 patients (16.7%), 1 during venetoclax ramp-up, and occurrence of obinutuzumab-related IRRs in 9/12 patients (75.0%) during the first obinutuzumab administration.9 Within the Dutch-Belgian Cooperative Trial Group for Hemato-oncology (HOVON) study group, we currently perform the randomized phase 2 HOVON 139/GIVE trial (Netherlands Trial Registry ID number #NTR604).