Targeting CD19 in diffuse large B-cell lymphoma: An expert opinion paper.

The ubiquitous, early-stage expression, efficient internalization, limited off-target effects, and high disease specificity of CD19 make it an attractive therapeutic target. Currently available anti-CD19 therapies have demonstrated particular promise in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Selection of the most appropriate treatment strategy should be based on individual patient characteristics and the goal of therapy. However, evidence and knowledge about the sequencing of anti-CD19 therapies are limited. Here, we review the current evidence for CD19 as a target in diffuse large B-cell lymphoma and consider approaches to the use of anti-CD19 therapy.

Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib-resistant non-nodal leukemic mantle cell lymphoma.

We herein report the case of a 73-year-old male patient who was diagnosed with leukemic non-nodal MCL. This patient had received six cycles of bendamustine, which resulted in a transient remission, and a second-line therapy with ibrutinib, which unfortunately failed to induce remission. We started a treatment with single-agent obinutuzumab at a dose of 20 mg on day 1, 50 mg on day 2-4, 330 mg on day 5, and 1000 mg on day 6. The laboratory analysis showed a rapid decrease of leukocyte count. Four weeks later, we repeated the treatment with obinutuzumab at a dose of 1000 mg q4w and started a therapy with venetoclax at a dose of 400 mg qd, which could be increased to 800 mg qd from the third cycle. This combination therapy was well tolerated. The patient achieved a complete remission (CR) after three cycles of obinutuzumab and venetoclax. To date, the patient has a progression-free survival of 17 months under ongoing obinutuzumab maintenance q4w. This is the first report about obinutuzumab and venetoclax induced CR in rituximab-intolerant patient with an ibrutinib-resistant MCL. This case suggests that obinutuzumab- and venetoclax-based combination therapy might be salvage therapy in patients with ibrutinib-resistant MCL.

Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after blinatumomab failure: No change in the level of CD19 expression.

Blinatumomab, a bi-specific T-cell engaging CD3-CD19 antibody construct, has shown significant activity in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL). Despite this improvement, most patients relapse. Here, we describe the outcome of 68 patients with R/R ALL after failure of blinatumomab therapy: 38 (56%) blinatumomab refractory; 30 (44%) relapsing after initial response. After a median follow-up of 49 months, 9 (13%) patients remained alive. The median overall survival after blinatumomab failure was 5.2 months. At the time of failure, among 61 patients evaluated for immunophenotype, 56 (92%) had CD19-positive blasts; only five (8%) had ALL recurrence with CD19-negative disease. Two patients progressed with lower CD19 expression. In summary, the outcome of patients with R/R ALL after blinatumomab failure is poor and treatment of these patients remains an unmet medical need. Our findings indicate that blinatumomab therapy would not exclude a significant number of patients from the potential benefit of subsequent CD19-directed therapies such as chimeric antigen receptor T-cell therapy.

Th17.1 cell driven sarcoidosis-like inflammation after anti-BCMA CAR T cells in multiple myeloma.

Pseudo-progression and flare-up phenomena constitute a novel diagnostic challenge in the follow-up of patients treated with immune-oncology drugs. We present a case study on pulmonary flare-up after Idecabtagen Vicleucel (Ide-cel), a BCMA targeting CAR T-cell therapy, and used single-cell RNA-seq (scRNA-seq) to identify a Th17.1 driven autoimmune mechanism as the biological underpinning of this phenomenon. By integrating datasets of various lung pathological conditions, we revealed transcriptomic similarities between post CAR T pulmonary lesions and sarcoidosis. Furthermore, we explored a noninvasive PET based diagnostic approach and showed that tracers binding to CXCR4 complement FDG PET imaging in this setting, allowing discrimination between immune-mediated changes and true relapse after CAR T-cell treatment. In conclusion, our study highlights a Th17.1 driven autoimmune phenomenon after CAR T, which may be misinterpreted as disease relapse, and that imaging with multiple PET tracers and scRNA-seq could help in this diagnostic dilemma.

CD52 and OXPHOS-potential targets in ibrutinib-treated mantle cell lymphoma.

Altered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanism of a metabolic switch to reliance on oxidative phosphorylation (OXPHOS) in surviving cells. Besides, we had shown that treatment-persisting cells were characterized by increased CD52 expression. Therefore, we hypothesized that combining ibrutinib with another agent targeting these potential escape mechanisms could minimize the risk of survival of ibrutinib-resistant cells. Concomitant use of ibrutinib with OXPHOS-inhibitor IACS-010759 increased toxicity compared to ibrutinib alone. Targeting CD52 was even more efficient, as addition of CD52 mAb in combination with human serum following ibrutinib pretreatment led to rapid complement-dependent-cytotoxicity in an ibrutinib-sensitive cell line. In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival.

The use of tafasitamab in diffuse large B-cell lymphoma.

Patients who relapse or are refractory after first-line therapy for diffuse large B-cell lymphoma (DLBCL) frequently have poor prognoses, especially when they are not candidates for autologous stem cell transplant (ASCT). Tafasitamab is a humanized monoclonal anti-CD19 antibody that has recently been approved by the FDA in combination with lenalidomide for the treatment of relapsed/refractory (R/R) DLBCL in patients who are not eligible for ASCT. Tafasitamab has an Fc region which has been modified to have an increased affinity for Fcγ receptors, to potentiate antibody-dependent cellular cytotoxicity and antibody-dependent cell-mediated phagocytosis. Here, we review the development, mode of action and clinical data for tafasitamab in combination with lenalidomide in R/R DLBCL, and discuss the various ways in which this novel antibody could be utilized in the treatment sequence to improve clinical outcomes for patients with DLBCL.

A GRP78-Directed Monoclonal Antibody Recaptures Response in Refractory Multiple Myeloma with Extramedullary Involvement.

PURPOSE: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens. EXPERIMENTAL DESIGN: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti-multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide. RESULTS: Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra- and extramedullary lesions. CONCLUSIONS: PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341-9. ©2016 AACR.