Search

Application of B-cell receptor (BCR) pathway inhibitor ibrutinib for chronic lymphocytic leukemia (CLL) is a major breakthrough, yet the downstream effects following inhibition of BCR signaling and during relapse await further clarification. By comparative phosphoproteomic profiling of B cells from patients with CLL and healthy donors, as well as CLL B cells collected at multiple time points during the course of ibrutinib treatment, we provided the landscape of dysregulated phosphoproteome in CLL and its dynamic alterations associated with ibrutinib treatment. Particularly, differential phosphorylation events associated with several signaling pathways, including BCR pathway, were enriched in patient CLL cells. A constitutively elevated phosphorylation level of KAP1 at serine 473 (S473) was found in the majority of CLL samples prior to treatment. Further verification showed that BCR activation promoted KAP1 S473 phosphorylation, whereas ibrutinib treatment abolished it. Depletion of KAP1 in primary CLL cells decelerated cell-cycle progression and ectopic expression of a KAP1 S473 phospho-mimicking mutant accelerated G2–M cell-cycle transition of CLL cells. Moreover, temporal phosphoproteomic profiles using a series of CLL cells isolated from one patient during the ibrutinib treatment revealed the dynamic changes of several molecules associated with BCR signaling in the ibrutinib responsive and recurrent stages.Implications:This phosphoproteomic analysis and functional validation illuminated the phosphorylation of KAP1 at S473 as an important downstream BCR signaling event and a potential indicator for the success of ibrutinib treatment in CLL.

Supplementary Data from Phosphoproteomics Reveals the Role of Constitutive KAP1 Phosphorylation by B-cell Receptor Signaling in Chronic Lymphocytic Leukemia

Supplementary Table 1 from Nucleophosmin Mutations in De novo Acute Myeloid Leukemia: The Age-Dependent Incidences and the Stability during Disease Evolution

Nucleophosmin (NPM) mutations have been found in a significant proportion of adults with de novo acute myeloid leukemia (AML), especially in those of a normal karyotype. These results provide a basis for studies of the pathogenesis in this specific subgroup of AML. In this study, NPM mutations were analyzed in 173 Chinese patients of de novo AML, including adults and children. We found that NPM mutations were present in 19.1% of the overall population and 40.3% of those with a normal karyotype. Adults had a significantly higher incidence of NPM mutations than children [32 of 126 (25.4%) versus 1 of 47 (2.1%), P < 0.001]. NPM mutations were closely associated with normal karyotype (P < 0.001) and internal tandem duplication of FLT3 (P = 0.002), but negatively associated with CEBPA mutations (P = 0.032) and expression of CD34 (P < 0.001) and HLA-DR (P = 0.003). Serial analyses of NPM mutations showed the mutation disappeared at complete remission, but the same mutation reappeared at relapse, except for one who lost the mutation at the second relapse, when new cytogenetic abnormalities emerged. None acquired novel mutations during the follow-up period. In conclusion, NPM mutations occur in an age-dependent fashion. Moreover, the findings that NPM mutations are stable during disease evolution and closely associated with disease status make it a potential marker for monitoring minimal residual disease. (Cancer Res 2006; 66(6): 3310-6)

Application of B-cell receptor (BCR) pathway inhibitor ibrutinib for chronic lymphocytic leukemia (CLL) is a major breakthrough, yet the downstream effects following inhibition of BCR signaling and during relapse await further clarification. By comparative phosphoproteomic profiling of B cells from patients with CLL and healthy donors, as well as CLL B cells collected at multiple time points during the course of ibrutinib treatment, we provided the landscape of dysregulated phosphoproteome in CLL and its dynamic alterations associated with ibrutinib treatment. Particularly, differential phosphorylation events associated with several signaling pathways, including BCR pathway, were enriched in patient CLL cells. A constitutively elevated phosphorylation level of KAP1 at serine 473 (S473) was found in the majority of CLL samples prior to treatment. Further verification showed that BCR activation promoted KAP1 S473 phosphorylation, whereas ibrutinib treatment abolished it. Depletion of KAP1 in primary CLL cells decelerated cell-cycle progression and ectopic expression of a KAP1 S473 phospho-mimicking mutant accelerated G2–M cell-cycle transition of CLL cells. Moreover, temporal phosphoproteomic profiles using a series of CLL cells isolated from one patient during the ibrutinib treatment revealed the dynamic changes of several molecules associated with BCR signaling in the ibrutinib responsive and recurrent stages. Implications: This phosphoproteomic analysis and functional validation illuminated the phosphorylation of KAP1 at S473 as an important downstream BCR signaling event and a potential indicator for the success of ibrutinib treatment in CLL.

BACKGROUND/PURPOSE Decorin is a small leucine-rich proteoglycan rich in extracellular matrix with potential antitumor activity. However, the role of decorin in hematological malignancies remains unclear, especially in the case of multiple myeloma (MM), a bone marrow (BM) stroma-dependent plasma cell neoplasm. METHODS We measured decorin levels in BM plasma samples from 270 patients with newly diagnosed MM (NDMM) using enzyme-linked immunosorbent assays. RESULTS Patients were divided into high decorin (H-DCN, > 18.99 ng/mL) and low decorin (L-DCN

BackgroundThe prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is poor. Glofitamab is a bispecific antibody that recruits T cells to tumor cells.MethodsIn the phase 2 part of a phase 1-2 study, we enrolled patients with relapsed or refractory DLBCL who had received at least two lines of therapy previously. Patients received pretreatment with obinutuzumab to mitigate cytokine release syndrome, followed by fixed-duration glofitamab monotherapy (12 cycles total). The primary end point was complete response according to assessment by an independent review committee. Key secondary end points included duration of response, survival, and safety.ResultsOf the 155 patients who were enrolled, 154 received at least one dose of any study treatment (obinutuzumab or glofitamab). At a median follow-up of 12.6 months, 39% (95% confidence interval [CI], 32 to 48) of the patients had a complete response according to independent review. Results were consistent among the 52 patients who had previously received chimeric antigen receptor T-cell therapy (35% of whom had a complete response). The median time to a complete response was 42 days (95% CI, 42 to 44). The majority (78%) of complete responses were ongoing at 12 months. The 12-month progression-free survival was 37% (95% CI, 28 to 46). Discontinuation of glofitamab due to adverse events occurred in 9% of the patients. The most common adverse event was cytokine release syndrome (in 63% of the patients). Adverse events of grade 3 or higher occurred in 62% of the patients, with grade 3 or higher cytokine release syndrome in 4% and grade 3 or higher neurologic events in 3%.ConclusionsGlofitamab therapy was effective for DLBCL. More than half the patients had an adverse event of grade 3 or 4. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, .)

The increased expression of programmed death-ligands 1 and 2 (PD-L1 and PD-L2, respectively) on tumour cells contributes to immune evasion, suggesting that these proteins are attractive therapeutic targets. This study aimed to evaluate the validity of cerebrospinal fluid (CSF) soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2) as biomarkers for primary central nervous system lymphoma (PCNSL). We determined the CSF concentrations of sPD-L1 and sPD-L2 in 46 patients with PCNSL using enzyme-linked immunosorbent assays (ELISAs). A control group comprised 153 patients with other brain tumours, inflammatory/infectious status, or neurodegenerative diseases. Only CSF sPD-L1 levels were significantly higher in patients with PCNSL relative to the controls. CSF sPD-L1 also exhibited superior overall discrimination performance compared to CSF sPD-L2 in diagnosing PCNSL. Compared with patients with PCNSL with low CSF sPD-L1 levels, more patients with high levels had high serum lactate dehydrogenase levels, leptomeningeal involvement, and deep-brain involvement. Furthermore, CSF sPD-L1 could predict poor survival in PCNSL but CSF sPD-L2 could not. Intriguingly, CSF sPD-L1 levels were correlated with disease status and their dynamic changes post treatment could predict time to relapse. In conclusion, this study identified CSF sPD-L1 as a promising prognostic biomarker, indicating a therapeutic potential of PD-L1 blockade in PCNSL.

Smartwatch allows easy detection of arrhythmia. Such an approach is widely used for detecting atrial fibrillation. However, there has been no consensus on the diagnostic power of smartwatch-detected supraventricular tachycardia (SVT). We reported three patients of SVT presenting with infrequent palpitations. Their SVTs were not documented with single-lead or standard ECG in hospital before, but only recorded by the single-lead ECG on smartwatches. Electrophysiological studies confirmed the mechanisms of these SVTs and led to successful catheter ablations. In conclusion, in patients with recurrent symptomatic tachycardia and a smartwatch-detected SVT, an electrophysiological study is indicated rather than to wait for a standard ECG for clinical decision. This approach might prevent the delay for successful treatment.

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3.

The mass and concentration of hemoglobin per erythrocyte are important hematological parameters. Measuring these parameters from intact erythrocytes requires the value of specific refraction-index increment (RII) of oxygenated hemoglobin, which diverges in the literature. Refractive indices of hemoglobin solutions are measured directly by digital holographic microscopy on a microfluidic channel filled with hemoglobin solutions prepared by hemolysis of fresh human erythrocytes and refractive-index standards sequentially. Hemoglobin extracted from thalassemic patients shows 3–4% higher RII than that from healthy volunteers, but the difference is not significant in comparison to inter-subject variations within each group. The quantified RIIs are applied to quantify mean corpuscular hemoglobin mass of blood from 37 human subjects, and results are in accord with standard clinical test results.

Background: Atrial fibrillation (AF) increases the risk of dementia. Whether the pharmacological rhythm control of AF can reduce the risk of dementia compared to the rate control strategy remains unclear. We hypothesize that the rhythm control strategy is better than the rate control strategy in preventing dementia. Methods: AF patients aged ≥65 years were identified from the Taiwan National Health Insurance Database. Patients receiving anti-arrhythmic drugs at a cumulative defined daily dose (cDDD) of >30 within the first year of enrollment constituted the rhythm control group. Patients who used rate control medications for a cDDD of >30 constituted the rate control group. A multivariate Cox hazards regression model was used to determine the hazard ratio (HR) for dementia. Results: A total of 3382 AF patients (698 in the rhythm control group; 2684 in the rate control group) were analyzed. During a 4.86 ± 3.38 year follow-up period, 414 dementia events occurred. The rhythm control group had a lower rate of dementia than the rate control group (adjust HR: 0.75, p = 0.031). The rhythm control strategy reduced the risk of dementia particularly in those receiving aspirin (p = 0.03). Conclusions: In patients with AF, pharmacological rhythm control was associated with a lower risk of dementia than rate control over a long-term follow-up period, particularly in patients receiving aspirin treatment.

Background: FL is an indolent yet incurable disease characterized by recurrent relapses. Pts with R/R FL often have a poor prognosis and limited treatment options, particularly those who have progression of disease within 24 months of frontline treatment (POD24) or are refractory to multiple agent classes. Glofitamab is a T-cell-engaging, CD20xCD3 bispecific, full-length, 2:1 format antibody with bivalent binding to CD20 (B cells) and monovalent binding to CD3 (T cells). Glofitamab monotherapy with obinutuzumab pretreatment (Hutchings, et al. JCO 2021), or combined with obinutuzumab (Morschhauser et al, Blood 2019; NCT03075696), has shown efficacy and manageable safety in heavily pretreated R/R NHL. Here, we present updated results of glofitamab with three different step-up dosing (SUD) regimens as monotherapy (mono) or combined with obinutuzumab (combo) in R/R FL. Methods: Obinutuzumab (1000mg) was given 7 days prior to the first dose of glofitamab. For the 3 mono cohorts, intravenous glofitamab SUD was given on Days (D) 1 and 8 of Cycle (C) 1; then at target dose on C2, or as SUD on C1D1, C1D8, C2D1 and target dose on C3D1. For the combo cohort, glofitamab SUD was given on D1 and D8 of C1, then at target dose combined with obinutuzumab 1000mg from C2D1 and onwards (every 21 days for up to 12 cycles). Response rates were based on the Lugano criteria (Cheson et al. J Clin Oncol 2014). Results: As of May 18, 2021, 53 pts received glofitamab mono SUD (2.5/10/16mg, n=3; 2.5/10/30mg, n=21; 0.5/2.5/10/30mg, n=29) and 19 pts received glofitamab combo SUD (2.5/10/30mg). All pts had FL Grade (Gr) 1-3A (FLIPI 1 high risk score: mono, 28 [53%] pts; combo, 11 [58%] pts). Median age was 64 years (range 33-83) in mono cohorts and 61 years (range 41-78) in the combo cohort; median number of prior therapies was 3 (range 1-12) and 2 (range 1-5), respectively. Twenty-eight (53%) pts in the mono cohorts and 8 (42%) pts in the combo cohort were refractory to last therapy; 16 (30%) and 7 (37%), respectively, were refractory to prior CD20 and alkylating therapy (double refractory). A total of 19 (36%) pts in the mono cohorts and 10 (53%) pts in the combo cohort had experienced POD24. In the mono cohorts, overall response rate (ORR) was 81% (n=43) and complete metabolic response rate (CMR) was 70% (n=37), with 72% (n=21) CMR in the 0.5/2.5/10/30mg cohort and 67% CMR in both the 2.5/10/16mg (n=2) and 2.5/10/30mg (n=14) cohorts. In the combo cohort, ORR was 100% (n=19) and CMR was 73.7% (n=14). In the mono cohorts 87% (32/37) pts were in CMR, while in the combo cohort 71% (10/14) pts were in CMR. Median follow-up of CMR ranged from 0-14 months (mono) and 0-5 months (combo), and at this cut-off the follow-up is insufficient to assess CMR duration. High CMR rates were observed in high-risk pts (Table). The most common adverse event (AE) was cytokine release syndrome (CRS): 66% and 79% in the mono and combo cohorts, respectively. CRS rates by mono cohort were as follows: 2.5/10/16mg cohort, 100% (3/3); 2.5/10/30mg cohort, 76% (16/21); 0.5/2.5/10/30mg cohort, 55% (16/29). With mono, CRS events (Lee et al. ASTCT 2019) were mostly Gr 1 (47.2%) and 2 (17.0%); 1 pt had a Gr 3 event (2.5/10/16mg cohort). With combo, 52.6% had Gr 1 CRS and 26.3% had Gr 2 CRS. There were no Gr 3 CRS events in the combo cohort and no Gr 4 or 5 CRS with either regimen. Of pts with CRS, tocilizumab was used to treat CRS in 22.9% pts in mono cohorts and 33.3% pts in the combo cohort. All CRS events were manageable and had resolved at data cut-off. Neurologic AEs were seen in 26 pts (16 mono, 10 combo; 36%); all Gr 1 (n=17) or Gr 2 (n=9). No ICANS-like events related to glofitamab were reported. Other common AEs were infusion related reactions and pyrexia (events separate from CRS; both 28%) and neutropenia (26%) with mono, and neutropenia (58%), anemia (37%) and thrombocytopenia (32%) with combo. Conclusions: Glofitamab SUD administered as monotherapy or in combination with obinutuzumab achieved high response rates in pts with heavily pretreated R/R FL, including high-risk subgroups. Response rates were comparable to those reported for CAR-T in R/R FL. The safety profile of glofitamab was manageable; CRS events were mostly low grade and occurred mainly in C1 and C2. Considering the short duration of follow-up, additional follow-up is required to further assess the safety and efficacy of glofitamab in this heterogeneously treated population. Further analyses will be presented. Figure 1 Figure 1. Disclosures Morschhauser: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carlo-Stella: AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Dickinson: Celgene: Research Funding; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Phillips: ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Houot: Bristol-Myers Squibb: Honoraria; CHU Rennes: Current Employment; Roche: Honoraria; Kite: Honoraria; Gilead: Honoraria; MSD: Honoraria; Celgene: Honoraria; Jsnssen: Honoraria; Novartis: Honoraria. Haioun: Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding; Servier: Honoraria, Research Funding. Corradini: AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; Incyte: Consultancy; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy. Hutchings: Novartis: Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding. Sureda: GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Wrobel: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau. Lundberg: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Mulvihill: F. Hoffmann-La Roche Ltd: Current Employment, Ended employment in the past 24 months. Perez-Callejo: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Relf: Harpoon Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; F-Star Therapeutics: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Roche Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Obinutuzumab (Gazyva) is a CD20-directed cytolytic antibody indicated: in combination with chlorambucil, for the treatment of pts with previously untreated CLL; in combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of pts with FL who relapsed after, or are refractory to, a rituximab-containing regimen; in combination with chemo followed by obinutuzumab monotherapy in pts achieving at least a PR, for the treatment of adult pts with previously untreated stage II bulky, III or IV FL