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.

Conflict of interest statement

Conflict of interest disclosure: P.A.T. consulted for Amgen, Genentech and AbbVie. The remainder of the authors declare no relevant conflicts of interest.

© 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Figures

Figure 1.

Immune profiling in each patient sample. A. Percentage of B, CD4, CD8 T cells groups in each patient sample. X axis is plotted in time order. Other cell are the cells that were CD3 and CD19 negative. B. Expression level of each immune marker in CD4 T cells for each sample. C. Expression level of each immune marker in CD8 T cells for each sample. B: baseline; Timepoints in days after treatment for each sample are shown next to the last heat map. Color bar indicates the mean arcsinh transformed value of fluorescent intensity.

Figure 2.

Clustering of cell populations via viSNE analysis on immune markers in all 42 patient samples and a control. A.ViSNE map for PhenoGraph clusters using immune markers in all samples (8 patients and 1 control). B. ViSNE map showing the expression levels of each marker. Color bar indicates the arcsinh transformed value of fluorescent intensity. C. Heatmap of mean immune cell marker expression in each cluster. The number in the brackets represents the size of cluster in percentage. D. ViSNE map separated to control, responder, transient responder, non responder groups. n denotes the number of control individuals or patients. E. Proportions of T cell subpopulations in all 8 patients at different time points and a control sample. B: baseline. Black arrow indicates that samples are collected after disease relapse in transiently responding patients.