Expert Consensus on the Characteristics of Patients with Epstein–Barr Virus-Positive Post-Transplant Lymphoproliferative Disease (EBV <sup>+</sup> PTLD) for Whom Standard-Dose Chemotherapy May be Inappropriate: A Modified Delphi Study

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Abstract

Introduction

Following hematopoietic stem cell transplantation or solid organ transplantation, patients are at risk of developing Epstein–Barr virus-positive post-transplant lymphoproliferative disease (EBV ⁺ PTLD), which is an ultra-rare and potentially lethal hematologic malignancy. Common treatments for EBV ⁺ PTLD include rituximab alone or combined with chemotherapy. Given specific considerations for this population, including severity of the underlying condition requiring transplant, the rigors of the transplant procedure, as well as risks to the transplanted organ, there is a group of patients with EBV ⁺ PTLD for whom chemotherapy may be inappropriate; however, there is limited information characterizing these patients. This study aimed to reach expert consensus on the key characteristics of patients for whom chemotherapy may be inappropriate in a real-world setting.

Methods

A two-round modified Delphi study was conducted to reach consensus among clinicians with expertise treating EBV ⁺ PTLD. Articles identified in a targeted literature review guided the development of round 1 and 2 topics and related statements. The consensus threshold for round 1 statements was 75.0%. If consensus was achieved in round 1, the statement was not discussed further in round 2. The consensus thresholds for round 2 were moderate (62.5–75.0%), strong (87.5%), or complete (100.0%).

Results

The panel was composed of a total of eight clinicians (seven hematologists/hemato-oncologists) from six European countries. The panel generated a final list of 43 consensus recommendations on the following topics: terminology used to describe patients for whom chemotherapy may be inappropriate; demographic characteristics; organ transplant characteristics; comorbidities that preclude the use of chemotherapy; EBV ⁺ PTLD characteristics; and factors related to treatment-related mortality and morbidity.

Conclusions

This modified Delphi panel successfully achieved consensus on key topics and statements that characterized patients with EBV ⁺ PTLD for whom chemotherapy may be inappropriate. These recommendations will inform clinicians and aid in the treatment of EBV ⁺ PTLD.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-022-02383-z.

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Most cited references 38

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Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial.

Ralf Ulrich Trappe, Stephan Oertel, Véronique Leblond … (2012)

Post-transplantation lymphoproliferative disorder (PTLD) develops in 1-10% of transplant recipients and can be Epstein-Barr virus (EBV) associated. To improve long-term efficacy after rituximab monotherapy and to avoid the toxic effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy seen in first-line treatment, we initiated a phase 2 trial to test whether the subsequent use of rituximab and CHOP would improve the outcome of patients with PTLD. In this international multicentre open-label phase 2 trial, treatment-naive adult solid-organ transplant recipients diagnosed with CD20-positive PTLD who had failed to respond to upfront immunosuppression reduction received four courses of rituximab (375 mg/m(2) intravenously) once a week followed by 4 weeks without treatment and four cycles of CHOP every 3 weeks. In case of disease progression during rituximab monotherapy, CHOP was started immediately. Supportive therapy with granulocyte-colony stimulating factor after chemotherapy was mandatory and antibiotic prophylaxis was recommended. The primary endpoint was treatment efficacy measured as response rates in all patients who completed treatment with rituximab and CHOP, per protocol, and response duration, in all patients who completed all planned therapy and responded. Secondary endpoints were frequency of infections, treatment-related mortality, and overall survival. This study is registered at ClinicalTrials.gov, number NCT01458548. 74 patients were enrolled between Dec 12, 2002 and May 5, 2008, of whom 70 patients were eligible to receive treatment. PTLD was of late type in 53 (76%) of 70 patients, monomorphic in 67 (96%) of 70, and histologically EBV associated in 29 (44%) of 66 cases. Four of 70 patients did not receive CHOP. 53 of 59 patients had a complete or partial response (90%, 95% CI 79-96), of which 40 (68%, 55-78) were complete responses. At data cutoff (June 1, 2011) median response duration in the 53 patients who had responded to treatment had not yet been reached (>79·1 months). The main adverse events were grade 3-4 leucopenia in 42 of 62 patients (68%, 55-78) and infections of grade 3-4 in 26 of 64 patients (41%, 29-53). Seven of 66 patients (11%, 5-21) had CHOP-associated treatment-related mortality. Median overall survival was 6·6 years (95% CI 2·8-10·4; n=70). Our results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD. F Hoffmann-La Roche, Amgen Germany, Chugaï France. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Post-Transplantation Lymphoproliferative Disorders in Adults

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Author and article information

Contributors

Dhanalakshmi Thirumalai: dthirumalai@atarabio.com

Journal

Journal ID (nlm-ta): Adv Ther

Journal ID (iso-abbrev): Adv Ther

Title: Advances in Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 0741-238X

ISSN (Electronic): 1865-8652

Publication date (Electronic): 21 January 2023

Publication date PMC-release: 21 January 2023

Publication date (Print): 2023

Volume: 40

Issue: 3

Pages: 1267-1281

Affiliations

[1 ]GRID grid.412563.7, ISNI 0000 0004 0376 6589, Centre for Clinical Haematology, , University Hospital Birmingham, ; Birmingham, UK

[2 ]GRID grid.508098.c, ISNI 0000 0004 7413 1708, Atara Biotherapeutics, ; South San Francisco, CA USA

[3 ]GRID grid.412220.7, ISNI 0000 0001 2177 138X, Department of Nephrology Transplantation, , Strasbourg University Hospitals, ; Strasbourg, France

[4 ]Department of Hematology, Hospitalier Pitié Salpétrière, Paris, France

[5 ]GRID grid.439749.4, ISNI 0000 0004 0612 2754, Department of Haematology, , University College Hospital, ; London, UK

[6 ]GRID grid.418284.3, ISNI 0000 0004 0427 2257, Department of Hematology, , Institut Català d’Oncologia, IDIBELL, Universitat de Barcelona, ; Barcelona, Spain

[7 ]GRID grid.5361.1, ISNI 0000 0000 8853 2677, Department of Visceral, Transplant and Thoracic Surgery, , Medical University of Innsbruck, ; Innsbruck, Austria

[8 ]GRID grid.508098.c, ISNI 0000 0004 7413 1708, Atara Biotherapeutics, ; 2380 Conejo Spectrum St, Suite 200, Thousand Oaks, CA 91320 USA

[9 ]GRID grid.6292.f, ISNI 0000 0004 1757 1758, IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli”, ; Bologna, Italy

[10 ]GRID grid.6292.f, ISNI 0000 0004 1757 1758, Dipartimento di Medicina Specialistica, , Diagnostica e Sperimentale Università di Bologna, ; Bologna, Italy

[11 ]Department of Hematology and Oncology, DIAKO Hospital Bremen, Bremen, Germany

[12 ]Atara Biotherapeutics, Zug, Switzerland

Article

Publisher ID: 2383

DOI: 10.1007/s12325-022-02383-z

PMC ID: 9988727

PubMed ID: 36681739

SO-VID: c5f540e0-ac71-46ec-be8f-aeb3ca5dde18

License:

Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 1 September 2022

Date accepted : 17 November 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100016253, Atara Biotherapeutics;

Custom metadata

Keywords: chemotherapy,delphi panel,epstein–barr virus,post-transplant lymphoproliferative disease

Data availability:

Keywords: chemotherapy, delphi panel, epstein–barr virus, post-transplant lymphoproliferative disease