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A phase two study of high dose blinatumomab in Richter's syndrome.

ABSTRACT: Richter's Syndrome (RS) is an aggressive transformation of CLL, usually clonally-related diffuse large B-cell lymphoma (DLBCL), characterized by frequent TP53 mutations, intrinsic chemoresistance and poor survival. TP53-independent treatments are needed. We conducted a single center, phase 2, investigator-initiated study of high dose blinatumomab (maximum 112 mcg/d after initial, weekly dose escalation), NCT03121534, given for an 8-week induction and 4-week consolidation cycle. Responses were assessed by Lugano 2014 criteria. Serial multi-parameter flow cytometry from blood was performed to identify patient-specific biomarkers for response. Nine patients were treated. Patients had received a median of 4 and 2 prior therapies for CLL and RS, respectively. Five of 9 had del(17p) and 100% had complex karyotype. Four patients had reduction in nodal disease, including one durable complete response lasting >1 y. Treatment was well tolerated, with no grade >3 cytokine release syndrome and 1 case of grade 3, reversible neurotoxicity. Immunophenotyping demonstrated the majority of patients expressed multiple immune checkpoints, especially PD1, TIM3 and TIGIT. The patient who achieved CR had the lowest levels of immune checkpoint expression. Simultaneous targeting with immune checkpoint blockade, especially PD1 inhibition, which has already demonstrated single-agent efficacy in RS, could achieve synergistic killing and enhance outcomes.

SUBMITTER: Thompson PA

PROVIDER: S-EPMC9467861 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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A phase two study of high dose blinatumomab in Richter's syndrome.

Thompson Philip A PA Jiang Xianli X Banerjee Pinaki P Basar Rafet R Garg Naveen N Chen Ken K Kaplan Mecit M Nandivada Vandana V Cortes Ana Karen Nunez AKN Ferrajoli Alessandra A Keating Michael J MJ Peterson Christine B CB Andreeff Michael M Rezvani Katayoun K Wierda William G WG

Leukemia 20220808 9

Richter's Syndrome (RS) is an aggressive transformation of CLL, usually clonally-related diffuse large B-cell lymphoma (DLBCL), characterized by frequent TP53 mutations, intrinsic chemoresistance and poor survival. TP53-independent treatments are needed. We conducted a single center, phase 2, investigator-initiated study of high dose blinatumomab (maximum 112 mcg/d after initial, weekly dose escalation), NCT03121534, given for an 8-week induction and 4-week consolidation cycle. Responses were as ...[more]

PMID: 35941212

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Project description:BackgroundTransformation of B-cell chronic lymphocytic leukaemia (B-CLL) to diffuse large B cell lymphoma (DLBCL) (Richter's syndrome (RS)) is a rare (2-15% of patients) but catastrophic complication of B-CLL. Dose-intense chemotherapy regimens investigated in small single institution trials, but with the exception of bone marrow transplantation for a minority of patients, little has improved the median overall survival of patients with RS beyond eight months. Patients are often elderly, immunosuppressed, possess co-morbidities and have a deteriorating performance status. TP53 disruption is a common molecular abnormality noted in RS and contributes to the tumour's chemotherapy resistance. Ofatumumab is a fully human anti-CD20 monoclonal IgG1κ antibody that targets a unique epitope on B lymphocytes. It has displayed increased binding affinity and a longer dissociation time when compared to rituximab resulting in improved complement dependent cellular cytotoxicity (CDCC); a mechanism with the potential to overcome apoptosis-resistance in TP53 disruption. Given the prevalence of TP53 disruption in RS, Ofatumumab was considered a relatively non-toxic agent with a sound rationale to test in a prospective multicentre trial as an adjunct to CHOP induction and subsequent ofatumumab maintenance therapy in responding patients.Methods/designThe CHOP-OR study is a prospective phase II study to evaluate the safety, feasibility and activity of a CHOP chemotherapy in combination with ofatumumab in induction and subsequent maintenance for patients with newly diagnosed RS. The primary objective will be the overall response rate (ORR) in patients with RS after six cycles of CHOP-O. The secondary objectives include feasibility of recruitment, progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by exploratory analysis of the genomic landscape of RS in newly diagnosed patients.DiscussionThe CHOP-OR trial evaluates the safety, feasibility and activity of CHOP plus Ofatumumab induction and Ofatumumab maintenance in new RS patients. The study is currently recruiting and has met the interim analysis criteria, with more than 7 of the first 25 participants achieving a CR or PR after six cycles of CHOP-O. The study has the potential to identify predictive biomarkers for this treatment modality.Trial registrationNCT01171378.

Project description:BackgroundTreatment options for metastatic breast cancer (MBC) refractory to anthracyclines and taxanes are limited. In a phase III trial, eribulin demonstrated a significant improvement in overall survival compared to treatment of physician's choice, but had limited tolerability because of neutropenia and peripheral neuropathy. Based on prior studies of alternative treatment schedules with other therapies, we hypothesized that a low-dose metronomic schedule of eribulin would permit patients to remain on treatment more consistently without treatment delays, resulting in longer time to progression, and improved toxicity profile.MethodsWe conducted a multi-site single arm, phase II trial patients with MBC. All patients were treated with metronomic eribulin (0.9 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle.) Treatment was continued until the patient developed disease progression, unacceptable toxicity, or chose to stop the study. Patients must have had prior taxane exposure. The primary endpoint was progression-free survival. Secondary end points were overall survival, response rate, and clinical benefit rate. Exploratory biomarkers were performed to analyze change in levels of circulating endothelial cells (CECs), circulating endothelial precursors, and carbonic anhydrase IX (CAIX) with response to therapy.FindingsWe consented 86 patients and 59 were evaluable for final analysis. Median age was 59 years; 78% had HER2 negative tumors. The median progression-free survival (PFS) was 3.5 months with overall survival (OS) of 14.3 months. Objective response rate was 15% with clinical benefit rate of 48%. Reported grade 3 neutropenia and peripheral neuropathy were 18% and 5%, respectively. Treatment discontinuation due to toxicity was seen in 3% of patients.InterpretationMetronomic weekly low-dose eribulin is an active and tolerable regimen with significantly less myelosuppression, alopecia, and peripheral neuropathy than is seen with the approved dose and schedule, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen.

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A phase two study of high dose blinatumomab in Richter's syndrome.

Publications

A phase two study of high dose blinatumomab in Richter's syndrome.

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