Stephen Opat

Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions

BACKGROUND The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions. METHODS We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival. RESULTS The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased. CONCLUSIONS Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.).

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.

ADAMTS13 antibody depletion by bortezomib in thrombotic thrombocytopenic purpura.

In some patients with refractory thrombotic thrombocytopenic purpura (TTP), efforts to reduce the causative antibody to ADAMTS13 by depleting B cells with rituximab are often effective. In a patient in whom such therapy failed, bortezomib was effective.

Obinutuzumab for the First-Line Treatment of Follicular Lymphoma

BACKGROUND Rituximab‐based immunochemotherapy has improved outcomes in patients with follicular lymphoma. Obinutuzumab is a glycoengineered type II anti‐CD20 monoclonal antibody. We compared rituximab‐based chemotherapy with obinutuzumab‐based chemotherapy in patients with previously untreated advanced‐stage follicular lymphoma. METHODS We randomly assigned patients to undergo induction treatment with obinutuzumab‐based chemotherapy or rituximab‐based chemotherapy. Patients with a response received maintenance treatment for up to 2 years with the same antibody that they had received in induction. The primary end point was investigator‐assessed progression‐free survival. RESULTS A total of 1202 patients with follicular lymphoma underwent randomization (601 patients in each group). After a median follow‐up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab‐based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab‐based chemotherapy (estimated 3‐year rate of progression‐free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval [CI], 0.51 to 0.85; P=0.001). Similar results were seen with regard to independently reviewed progression‐free survival and other time‐to‐event end points. Response rates were similar in the two groups (88.5% in the obinutuzumab group and 86.9% in the rituximab group). Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events resulting in death were similar in the two groups (4.0% in the obinutuzumab group and 3.4% in the rituximab group). The most common adverse events were infusion‐related events that were considered by the investigators to be largely due to obinutuzumab in 353 of 595 patients (59.3%; 95% CI, 55.3 to 63.2) and to rituximab in 292 of 597 patients (48.9%; 95% CI, 44.9 to 52.9; P<0.001). Nausea and neutropenia were common. A total of 35 patients (5.8%) in the obinutuzumab group and 46 (7.7%) in the rituximab group died. CONCLUSIONS Obinutuzumab‐based immunochemotherapy and maintenance therapy resulted in longer progression‐free survival than rituximab‐based therapy. High‐grade adverse events were more common with obinutuzumab‐based chemotherapy. (Funded by F. Hoffmann–La Roche; GALLIUM ClinicalTrials.gov number, NCT01332968.)

A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma

Background:Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear.Methods:We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP ‘group 1’; R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX ‘group 2’; dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX ‘group 3’.Results:Overall, 217 patients were identified (49, 125 and 43 in groups 1–3, respectively). With median follow-up of 3.4 (range 0.2–18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1–3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5–33.1%), 6.9% (3.5–13.4%) and 2.3% (0.4–15.4%) in groups 1–3, respectively (P=0.009).Conclusions:The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma

BACKGROUND The optimal treatment strategy in patients with aggressive B cell central nervous system lymphoma suitable to receive intensive therapy is unknown. The benefit of incorporating rituximab in systemic therapy remains unclear. We performed a retrospective study examining the impact of rituximab in the context of concomitant therapies, including methotrexate, cytarabine, and radiotherapy, in patients treated with curative intent at 4 university teaching hospitals during 1996-2011. METHODS A retrospective study of CNS lymphoma cases treated at the participating institutions was performed in accordance with institutional ethical guidelines. Patients were included if they received a diagnosis of primary diffuse large B cell lymphoma of the CNS, were HIV negative, and were treated with curative intent. RESULTS One hundred twenty patients aged 21-81 years were identified. Rituximab recipients and nonrecipients were similar, except for rituximab recipients being more likely to have received a diagnosis after 2004. The median follow-up of surviving patients was 30 months. The 5-year overall survival was 46%. Univariate analysis revealed age ≤60 years, ECOG performance status ≤1, normal lactate dehydrogenase, diagnosis after 2004, and treatment with cytarabine and rituximab as predictive of favorable overall survival. Multivariate analysis identified age to be an independent predictor of overall survival, with a trend toward improved survival from the other variables that were significant in univariate analyses. CONCLUSIONS In this retrospective analysis, the addition of rituximab to high-dose methotrexate-based chemotherapy in patients with aggressive B cell CNS lymphoma was associated with improved overall survival. Further studies are underway to prospectively validate these findings.

Venetoclax and obinutuzumab in chronic lymphocytic leukemia

To the editor: In chronic lymphocytic leukemia (CLL), the median age at diagnosis is 72 years, and most patients requiring therapy have coexisting medical conditions. Venetoclax is a potent BH3-mimetic compound that selectively antagonizes BCL-2 and has shown efficacy as monotherapy and with

E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis

Neoplastic transformation requires the elimination of key tumor suppressors, which may result from E3 ligase-mediated proteasomal degradation. We previously demonstrated a key role for the E3 ubiquitin ligase E6AP in the regulation of promyelocytic leukemia protein (PML) stability and formation of PML nuclear bodies. Here, we report the involvement of the E6AP-PML axis in B-cell lymphoma development. A partial loss of E6AP attenuated Myc-induced B-cell lymphomagenesis. This tumor suppressive action was achieved by the induction of cellular senescence. B-cell lymphomas deficient for E6AP expressed elevated levels of PML and PML-nuclear bodies with a concomitant increase in markers of cellular senescence, including p21, H3K9me3, and p16. Consistently, PML deficiency accelerated the rate of Myc-induced B-cell lymphomagenesis. Importantly, E6AP expression was elevated in ∼ 60% of human Burkitt lymphomas, and down-regulation of E6AP in B-lymphoma cells restored PML expression with a concurrent induction of cellular senescence in these cells. Our findings demonstrate that E6AP-mediated down-regulation of PML-induced senescence is essential for B-cell lymphoma progression. This provides a molecular explanation for the down-regulation of PML observed in non-Hodgkin lymphomas, thereby suggesting a novel therapeutic approach for restoration of tumor suppression in B-cell lymphoma.

Clinical and Immunohistochemical Features Associated with a Response to Bortezomib in Patients with Multiple Myeloma

Purpose: Multiple myeloma is an incurable disease with heterogeneous clinical behavior. Bortezomib has offered some patients with relapsed and refractory disease an opportunity for prolonged survival. However, there remains a paucity of data in patients treated with bortezomib that accurately delineates and identifies such patients. This information is crucial to guide management. Experimental Design: In this study, we aimed to identify the patients most likely to respond to bortezomib salvage therapy. We analyzed the baseline clinical variables and profiled the baseline expression of a broad range of immunohistochemical markers of cell cycle activity, apoptosis, and angiogenesis in a large cohort of multiply relapsed myeloma patients recruited to one of two prospective multicentre trials assessing the efficacy of bortezomib salvage therapy. Results: Using the European Group for Bone Marrow Transplantation criteria, response (complete or partial) to bortezomib salvage therapy was associated with a previous history of complete response to alternative antimyeloma treatment. Patients who expressed cyclin D1 were more likely to achieve a response. In contrast, patients who expressed p16INK4A, cytoplasmic p53, and the highest intensity of Bcl-2 staining had a poor response. Patients who achieved a response to bortezomib and those patients who expressed cyclin D1 at baseline showed a significant survival advantage. Patients who expressed FGFR3, a poor prognostic marker, responded equally well and had similar outcomes with bortezomib compared with FGFR3-negative patients. Conclusions: Baseline clinical variables and selective immunohistochemical markers expressed by patients may be used effectively to identify patients that are most likely to achieve a meaningful clinical response to bortezomib salvage therapy.

Failure of rituximab monotherapy in lymphomatoid granulomatosis.

To the Editor: We note with interest Jordan et al. s description of the use of single agent rituximab as salvage therapy in a patient with lymphomatoid granulomatosis (LYG) who had failed first line treatment with valganciclovir and interferon alpha (1). While we appreciate the successful outcome in their patient, we report a similar case in which rituximab monotherapy was ineffective. Our patient was a 42-year-old woman who presented with the insidious development of respiratory insufficiency secondary to bilateral pulmonary infiltrates, and a widespread papular rash affecting predominantly the face and upper limbs. Biopsies of skin, lung, and spleenwere taken, and the former two demonstrated a polymorphic lymphoid infiltrate with angiitis and granulomatosis consistent with LYG stage 4b. Immunohistochemistry was performed, and the cells were found to express CD20 and CD30. Immunoperoxidase stains for EBV with LMP1 were negative, and the patient’s peripheral blood EB viral load was 130 copies/lL. Imaging with positron emission tomography (PET) showed multiple foci of intense FDG activity throughout both lung fields and extending along the pleura, small foci of increased activity in the skin corresponding to the area of her rash, and two metabolically active lesions at the upper and lower poles of the left kidney (Fig. 1A). There was no radiological evidence of disease elsewhere, and a bone marrow aspirate and trephine was normal. Treatment with rituximab at 375 mg/m weekly for 4 wk was commenced, with a fifth dose 1 month later. Following this, restaging with PET showed a heterogenous response, with some improvement of the lesions in the left upper lobe, right lower lobe, and right hilum. However, there was marked progression of the skin lesions, and new areas of increased tracer uptake developed in the left chest wall and lower lobe of the left lung (Fig. 1B). Treatment with interferon alpha was commenced, but within 2 wk the patient’s clinical condition deteriorated with further radiological evidence of disease progression and the development of an intercurrent pneumocystiis jiroveci (PCP) respiratory tract infection. A thrombophilic predisposition also developed, manifested as spontaneous deep venous thromboses of both legs and the right upper limb, with subsequent pulmonary emboli; this has not previously been described in association with LYG. At the time of writing, she continues to require invasive cardiorespiratory support. Further treatment with multi-agent chemotherapy is planned once her condition improves. Any emerging treatment for lymphomatosis granulomatosis must be evaluated in the context of the condition’s highly variable clinical course, including some reports of spontaneous remission (2). Given the two positive case reports to date (1, 3), we agree that further investigation of the potential therapeutic role of rituximab in LYG is warranted, perhaps in combination with multiagent chemotherapy. However, in view of the lack of response to rituximab monotherapy in our patient we suggest that clinicians exercise caution in considering this treatment outside the setting of clinical trials.