Ibrutinib- and bortezomib-extended R-CHOP induction in elderly higher-risk patients newly diagnosed with diffuse large B-cell lymphoma – first analysis of toxicity and efficacy signals

Abstract

Diffuse large-cell B-cell lymphoma (DLBCL) is the most common lymphoid malignancy. About 30–40% of the patients will not be cured by standard Rituximab (R)-CHOP-like immune-chemotherapy, and many of them experience relapse and eventually succumb to their disease. Enhancing first-line efficacy in patients at higher risk, among them many elderly, is key to improve long-term outcomes. Numerous attempts to combine R-CHOP with targeted agents failed in large randomized phase III trials. The addition of Ibrutinib enhanced survival in younger patients, but increased toxicity across all age groups, especially in the elderly. Older DLBCL patients impose particular challenges, since they often present with more advanced disease, and exhibit treatment-relevant comorbidities. ImbruVeRCHOP trial aims at identifying patients who need that benefit from rationally augmented first-line regimens without experiencing overt toxicity and detecting their molecular signatures of response. This first analysis presents encouraging feasibility, safety, and preliminary response data in elderly high-risk DLBCL patients.

Keywords:

• Lymphoma and Hodgkin disease
• biomarker
• novel study design
• targeted therapy
• prediction
• diffuse large B-cell lymphoma

Ethical approval

Leading ethics commission: Ethics commission of the state of Berlin, Landesamt für Gesundheit und Soziales, application number: 16/0338-EK10, positive vote on 09/02/2017.

Registered: EudraCT number 2015-003429-32 (31/07/2015), ClinicalTrials.gov identifier NCT03129828 (24/04/2017).

Consent to participate

Informed consent was obtained from each subject, and all procedures were performed in accordance with the Helsinki Declaration.

Consent for publication

The study participants agreed to the publication of the results along with the study enrollment.

Author contributions

The authors were involved in all content and editorial matters and were engaged in all phases of manuscript preparation and have accepted the final version. In addition, the individual authors have made the following contributions. S.D.: coordinating investigator, preparation and realization of the trial, training of the participating study centers, protocol writing, submission to authorities, contract work, local investigator, analysis of the trial results and the accompanying translational program, writing of the manuscript. A.B.: preparation of the trial, submission to authorities. I.-K.N.: local investigator, support in project preparation and realization, contribution of expertise. J.K.: protocol writing, preparation of the trial. M.F.: preparation of the trial and submission to authorities, local investigator. U.Ke., C.B., A.H., J.D., M.J., S.M., R.M., U.Kr., L.B.: local investigator, proofreading of the manuscript. C.A.S.: representative of the sponsor, principal investigator/LKP, national coordinator, preparation and supervision of the trial, submission to authorities, protocol writing, analysis of the trial results and the accompanying translational program, writing of the manuscript.

Disclosure statement

S.D., A.B., M.F., J.K., J.H., C.T., C.B., A.H., J.D., M.J., S.M., U.Kr., I.-K.N., and L.B. had no financial relationships with Janssen-Cilag during the 36 months prior to publication. R.M. participated in an Advisory board with Janssen-Cilag during the 36 months prior to publication. U.Ke. reports personal fees from Janssen Cilag, outside the submitted work (Advisory board fees, speakers honorary, and travel support). C.A.S. receives honoraria for medical advice from Roche and Janssen-Cilag, and coordinates clinical research (namely the ImbruVeRCHOP trial) partly funded by Janssen-Cilag. No writing assistance was utilized in the production of this manuscript.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study is supported by Janssen-Cilag, and further by grants to C.A.S. from the BMBF e:Med Program Project SeneSys (No. 031L0189A), the Deutsche Forschungsgemeinschaft DFG (SCHM 1633/9-1/2), the Berliner Krebsgesellschaft (BIFF201916), the Förderverein Hämatologie und internistische Onkologie (Tyle Private Foundation, Linz, Austria), and from the Deutsche Krebshilfe to C.A.S. and I.-K.N. (No. 7011377629). This interdisciplinary work was further made possible by the Berlin Institute of Health (BIH), the BIH Clinician Scientist Program (to A.B., M.F., and J.K.), the Berlin School of Integrative Oncology (BSIO) graduate program funded within the German Excellence Initiative, and the German Cancer Consortium (GCC). S.D. is a participant in the BIH-Charité Digital Clinician Scientist Program funded by the Charité - Universitätsmedizin Berlin and the BIH.