Single-agent panobinostat for relapsed/refractory diffuse large B-cell lymphoma: clinical outcome and correlation with genomic data. A phase 2 study of the Fondazione Italiana Linfomi

Francesco Zaja; Flavia Salvi; Maura Rossi; Elena Sabattini; Andrea Evangelista; Giovannino Ciccone; Emanuele Angelucci; Gianluca Gaidano; Manuela Zanni; Marco Ladetto; Annalisa Chiappella; Umberto Vitolo; Pier Luigi Zinzani; Catello Califano; Alessandra Tucci; Caterina Patti; Stefano A Pileri; Valentina Lenti; Pier Paolo Piccaluga; Federica Cavallo; Stefano Volpetti; Giulia Perali; Sarit Assouline; Koren Kathleen Mann; Ryan Morin; Miguel Alcaide; Kevin Bushell; Renato Fanin; Alessandro Levis

doi:10.1080/10428194.2018.1452208

Single-agent panobinostat for relapsed/refractory diffuse large B-cell lymphoma: clinical outcome and correlation with genomic data. A phase 2 study of the Fondazione Italiana Linfomi

Leuk Lymphoma. 2018 Dec;59(12):2904-2910. doi: 10.1080/10428194.2018.1452208. Epub 2018 Apr 4.

Authors

Francesco Zaja¹, Flavia Salvi², Maura Rossi³, Elena Sabattini⁴, Andrea Evangelista⁴, Giovannino Ciccone⁵, Emanuele Angelucci⁶, Gianluca Gaidano⁷, Manuela Zanni⁷, Marco Ladetto², Annalisa Chiappella⁸, Umberto Vitolo⁸, Pier Luigi Zinzani⁹, Catello Califano¹⁰, Alessandra Tucci¹¹, Caterina Patti¹², Stefano A Pileri¹³, Valentina Lenti¹⁴, Pier Paolo Piccaluga³, Federica Cavallo¹⁵, Stefano Volpetti¹⁶, Giulia Perali¹⁶, Sarit Assouline¹⁷, Koren Kathleen Mann¹⁸, Ryan Morin¹⁹, Miguel Alcaide¹⁹, Kevin Bushell¹⁹, Renato Fanin¹, Alessandro Levis¹⁴

Affiliations

¹ a Clinica Ematologica ed Unità di Terapie Cellulari 'Carlo Melzi', DAME , University of Udine , Udine , Italy.
² b S.C. Ematologia , A.O. SS. Antonio e Biagio e C. Arrigo , Alessandria , Italy.
³ c Unit of Haemolymphopathology, Department of Experimental, Diagnostic and Specialty Medicine , University Hospital of Bologna , Bologna , Italy.
⁴ d Unit of Haemolymphopathology, Department of Hematology and Oncology , University Hospital of Bologna , Bologna , Italy.
⁵ e Unit of Clinical Epidemiology , AOU Città della Salute e della Scienza di Torino and CPO Piemonte , Torino , Italy.
⁶ f U.O.C. Ematologia , IRCCS A.O.U. San Martino-IST , Genova , Italy.
⁷ g Division of Hematology, Department of Translational Medicine , Amedeo Avogadro University of Eastern Piedmont , Novara , Italy.
⁸ h S.C. Ematologia , A.O.U. Città della Salute e della Scienza , Torino , Italy.
⁹ i Institute of Hematology "L. e A. Seràgnoli" , University of Bologna , Bologna , Italy.
¹⁰ j U.O. Medicina-Oncoematologia , Ospedale Umberto I , Nocera Inferiore , Italy.
¹¹ k S.C. Ematologia e Dipartimento Oncologia Medica Spedali Civili , Brescia , Italy.
¹² l U.O.C. di Ematologia , Ospedale V. Cervello , Palermo , Italy.
¹³ m Haematopathology Unit, European Institute of Oncology , Milano/University School of Medicine , Bologna , Italy.
¹⁴ n Fondazione Italiana Linfomi , Alessandria , Italy.
¹⁵ o University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza , Torino , Italy.
¹⁶ p Clinica Ematologica ed Unità di Terapie Cellulari 'Carlo Melzi' , Azienda Sanitaria Universitaria Integrata , Udine , Italy.
¹⁷ q Division of Hematology , Jewish General Hospital, McGill University , Montreal , QC , Canada.
¹⁸ r Lady Davis Institute, Jewish General Hospital, McGill University , Montreal , QC , Canada.
¹⁹ s Department of Molecular Biology and Biochemistry, School of Computing Science , Simon Fraser University , Vancouver , BC , Canada.

PMID: 29616865
DOI: 10.1080/10428194.2018.1452208

Abstract

We investigated panobinostat 40 mg three times weekly in 35 adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Overall response rate and complete response were 17.1% and 11.4%, respectively. Median progression-free survival (PFS) and overall survival were 2.4 and 7.6 months, respectively. Calculated 12, 24 and 36 months PFS were 26%, 11% and 11%, respectively. Four patients who achieved a sustained CR, continued receiving panobinostat for an overall period of 44, 48, 50, 62 months. Thrombocytopenia grade 3 (5 patients) and 4 (24 patients) represented the main toxic effect, causing dose reduction or treatment suspension in 19 patients. Genomic analysis was unable to identify any relationship between mutations and response; TP53 mutation appeared not to impact the clinical outcome. Overall, panobinostat has a modest activity in R/R DLBCL patients, however it can induce very long lasting responses in some cases. Thrombocytopenia frequently limits the use of this agent.

Keywords: Diffuse large B-cell lymphoma; genomic; panobinostat; relapsed/refractory.

Publication types

Clinical Trial, Phase II
Multicenter Study

MeSH terms

Aged
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / adverse effects
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Resistance, Neoplasm
Female
Humans
Italy / epidemiology
Lymphoma, Large B-Cell, Diffuse / drug therapy*
Lymphoma, Large B-Cell, Diffuse / genetics
Lymphoma, Large B-Cell, Diffuse / mortality
Lymphoma, Large B-Cell, Diffuse / pathology
Male
Mutation
Neoplasm Recurrence, Local / drug therapy*
Neoplasm Recurrence, Local / genetics
Neoplasm Recurrence, Local / mortality
Neoplasm Recurrence, Local / pathology
Panobinostat / administration & dosage*
Panobinostat / adverse effects
Progression-Free Survival
Prospective Studies
Thrombocytopenia / chemically induced
Thrombocytopenia / epidemiology*
Time Factors
Tumor Suppressor Protein p53 / genetics

Substances

Antineoplastic Agents
TP53 protein, human
Tumor Suppressor Protein p53
Panobinostat