Seema Bhat

Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas

Bcl‐2 proteins represent a rheostat that controls cellular viability. Obatoclax, a BH3‐mimetic, has been designed to specifically target and counteract anti‐apoptotic Bcl‐2 proteins. We evaluated the biological effects of obatoclax on the anti‐tumour activity of rituximab and chemotherapy agents. Obatoclax induced cell death of rituximab/chemotherapy‐sensitive (RSCL), ‐resistant cell lines (RRCL) and primary tumour‐cells derived from patients with B‐cell lymphomas (N = 39). Obatoclax also enhanced the activity of rituximab and had synergistic activity when combined with chemotherapy agents. The ability of Obatoclax to induce PARP cleavage varied between patient samples and was not observed in some RRCL. Inhibition of caspase activity did not affect obatoclax activity, suggesting the existence of caspase‐independent death pathways. Autophagy was detected by LC3 conversion and/or electron microscopy in RRCL and in patient‐derived tumour cells. Moreover, obatoclax activity was inhibited by Beclin‐1 knockdown. In summary, obatoclax is an active Bcl‐2 inhibitor that potentiates the activity of chemotherapy agents and, to a lesser degree, rituximab. Defining the molecular events triggered by obatoclax is necessary to further its clinical development and identify potential biomarkers that are predictive of response.

Galiximab: a review

Importance of the field: A significant number of patients relapse or do not respond to rituximab due to intrinsic or acquired resistance. Hence, mAbs targeting other cell surface antigens on B-cell lymphomas are being studied. CD80 is a glycoprotein expressed on Hodgkins lymphoma, mature B-cell lymphomas and immunoeffector cells which may have T-regulatory, in addition to direct antitumor activity. CD80 serves as an attractive target in the continued development of mAbs against lymphoma. Areas covered in this review: Preclinical studies with galiximab, an anti-CD80 primatized mAb, have been encouraging and have demonstrated antitumor activity against various B-cell lymphoma models, both as a single agent as well as in combination with rituximab. Data were reviewed from a PubMed literature search from 1975 to 2009 and also included a review of abstracts from published proceedings of annual meetings from the American Society of Hematology and International Conference of Malignant Lymphoma, Lugano. What the reader will gain: Readers will gain a better understanding of mechanisms of action (both documented and proposed) of galiximab. An update of currently available clinical data will be presented. Take home message: Data from completed clinical trials are promising and galiximab is being studied in both upfront and relapsed settings with the potential of being incorporated into the future treatment of B-cell lymphoma.

Bing-Neel Syndrome in a Patient with Waldenstrom's Macroglobulinemia: A Challenging Diagnosis in the Face of Normal Brain Imaging

Waldenstrom’s macroglobulinemia (WM) is a clinicopathological entity defined by lymphoplasmacytic lymphoma in bone marrow with an immunoglobulin M (IgM) monoclonal gammopathy in blood [1]. Central nervous system (CNS) manifestations in patients with WM are usually a result of serum hyperviscosity [2]. In some patients, central neurological symptoms can be caused by direct infiltration of CNS by malignant cells, also known as Bing– Neel syndrome (BNS) [3,4]. Diagnosis of BNS is usually suspected in patients with WM who exhibit CNS symptoms and abnormal brain magnetic resonance imaging (MRI) findings, which can then be confirmed with cerebrospinal fluid (CSF) analysis and/or biopsy [5,6]. We report a case of WM with recurrent neurological symptoms and normal brain MRI where CSF flow cytometry and immunofixation electrophoresis clinched the diagnosis of BNS. A 67-year-old female developed progressive anemia and was diagnosed with WM. She achieved partial response with five cycles of rituximab and bendamustine. Eighteen months later, she developed fatigue, pancytopenia, and cognitive decline. Bone marrow biopsy showed lymphoplasmacytic (LPl) infiltration of marrow space and recurrence of WM, following which she received two cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Posttreatment marrow showed minimal residual disease and normalization of M-spike. Over a period of next 11 months, she continued to have progressive cognitive decline. Blood work showed increased levels of serum IgM, and computed tomography (CT) scan of torso showed diffuse lymphadenopathy. Given the rapidly progressive decline in cognition, brain MRI was performed, and it did not reveal any abnormality. However, subsequent comprehensive panel of CSF studies showed evidence of direct CNS LPl infiltration. Differential cell count of CSF revealed predominant lymphocytosis, flow cytometry analysis detected CD45, CD19, and lambda light chains, and CSF immunofixation electrophoresis unveiled IgM monoclonal protein. A paraneoplastic auto-antibody (PNA) panel including anti-Hu, anti-Yo, and anti-Ri antibodies was negative. Diagnosis of BNS was made based on the above findings. Thereafter, patient received salvage treatment with intravenous rituximab, dexamethasone, high-dose cytarabine, carboplatin (R-DHAC) and intrathecal methotrexate, cytarabine, and hydrocortisone. With the use of intrathecal chemotherapy, significant decrease in cognitive deficit and fatigue was noted. Mini-mental state examination (Folstein Test) score improved from 14/30 to 26/30, and 9-item fatigue severity scale (FSS) score improved from 50 to 28. In addition, CSF abnormalities resolved completely, and positron emission tomography (PET) scan after two cycles of salvage chemotherapy showed complete metabolic response with resolution of lymphadenopathy. Bone marrow biopsy after three cycles of salvage R-DHAC revealed no plasmacytic involvement, and patient underwent autologous stem cell transplant (Table 1). Our patient was recognized to have central neurological symptoms from direct tumor infiltration of the CNS, and not merely due to hyperviscosity of the CNS blood vessels, making it a case of BNS. Paraneoplastic syndrome is unlikely to be a cause of this patient’s CNS symptoms despite the evidence of increased IgM monoclonal protein in CSF. This is because (1) the plasma PNA panel (involving known PNAs) was negative, and (2) the fact that IgM auto-antibodies in plasma, if any, would lack capacity to cross blood–brain barrier. Presence of IgM in the CSF almost always occurs as a result of direct tumor infiltration of CNS. Even though our patient’s CSF was tested positive for both lymphoplasmacytic

A Phase II Trial of Rituximab Combined With Pegfilgrastim in Patients With Indolent B-cell Non-Hodgkin Lymphoma

Background To explore the role of augmenting neutrophil function in B‐cell lymphoma, we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low‐grade CD20+ B‐cell non‐Hodgkin lymphoma (B‐NHL). Patients and Methods Twenty patients with indolent B‐NHL were treated with rituximab (375 mg/m2) every other week for 4 doses, followed by every 2 months for 4 additional doses. Pegfilgrastim was administered subcutaneously 3 days before each dose of rituximab. Clinical activity and tolerability were assessed using standard criteria. Biologic monitoring included phenotype characteristics of the host neutrophils, changes in oxidative burst, and functional assays. Results The patient demographics included median age of 64 years, 70% were male, 70% had follicular lymphoma, and 90% had stage III‐IV disease. The median number of previous therapies was 2 (range, 0‐5); 90% had received previous anti‐CD20 monoclonal antibody therapy. The addition of pegfilgrastim to rituximab did not increase rituximab‐related toxicities. The overall response rate was 60% (12 of 20), with a complete response (CR) rate of 35% (7 of 20). The median progression‐free survival (PFS) duration was 17.9 months (95% confidence interval, 9.9‐27.6 months); the median overall survival was not reached. A shorter time‐to‐peak oxidative burst after the first dose of pegfilgrastim was associated with greater CR rates (P = .04) and longer PFS (P = .03). Conclusion The pegfilgrastim‐rituximab combination was well tolerated, with favorable outcomes compared with historical controls. A shorter time‐to‐peak oxidative burst was associated with higher CR rates and longer PFS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B‐NHL. Micro‐Abstract The present phase II study has demonstrated that augmenting neutrophil function by the addition of pegfilgrastim can potentiate the clinical activity of rituximab in indolent B‐cell non‐Hodgkin lymphoma while retaining the excellent safety profile. Strategies to boost the innate immune system such as this combination warrant further study, especially in the frail, elderly population for whom therapeutic options are limited owing to poor tolerance.

Hairy cell Leukemia, Version 2.2018: Clinical practice guidelines in oncology

Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL.