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CHRONIC LYMPHOCYTIC LEUKEMIA

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.

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Fig. 1: Immune profiling in each patient sample.
Fig. 2: Clustering of cell populations via viSNE analysis on immune markers in all 42 patient samples and a control.

Data availability

Deidentified data will be shared with other researchers upon reasonable request to the corresponding author (pathompson2@mdanderson.org). The sharing will require a detailed proposal to the study investigators, and a data transfer agreement must be signed.

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Acknowledgements

This was supported, in part, by M.D. Anderson Cancer Center Support Grant P30 CA016672. The study drug and funding for the study was provided by Amgen. Amgen had no role in the conduct or analysis of the study or the writing of the paper.

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Contributions

PAT designed and wrote the protocol, provided clinical care to patients, analyzed results and wrote the paper; XJ performed bioinformatic analysis of flow cytometry data and wrote the paper; KC developed the strategic plan for the computational analysis team; PB and KR designed and performed experiments and co-wrote the paper; RB performed experiments and assisted in data analysis; MK, VN and AKNC performed experiments; AF, MK and MA provided clinical care to patients; CBP provided the statistical design for the protocol; NG centrally analyzed PETCT results; WGW assisted in protocol design and planning, provided clinical care to patients and co-wrote the paper. All authors provided intellectual input, critically evaluated the final draft and approved it for submission.

Corresponding author

Correspondence to Philip A. Thompson.

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Competing interests

PAT consulted for Amgen, Genentech and AbbVie. The remainder of the authors declare no relevant conflicts of interest.

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Thompson, P.A., Jiang, X., Banerjee, P. et al. A phase two study of high dose blinatumomab in Richter’s syndrome. Leukemia 36, 2228–2232 (2022). https://doi.org/10.1038/s41375-022-01649-3

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