case report

Brentuximab Vedotin Induces Long-Term Remission in T-cell PTLD without Evidence of Graft Rejection

Authors: Wael Toama1, Andrew B Stone2, Michael A Linden2, Joseph Maakaron1*

*Corresponding Author: Joseph Maakaron, Division of Hematology and Oncology, University of Minnesota, Minneapolis, MN, USA

1Division of Hematology and Oncology, University of Minnesota, Minneapolis, MN, USA

2Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

Received Date: 19 May 2022

Accepted Date: 21 May 2022

Published Date: 24 May 2022

Citation: Toama W, Stone AB, Linden MA, Maakaron J. (2022) Brentuximab Vedotin Induces Long-Term Remission in T-cell PTLD without Evidence of Graft Rejection. Ann Case Report 7: 849. DOI: https://doi.org/10.29011/2574-7754.100849

Abstract

A 63-year-old male with a history of bilateral lung transplant in 2013 for end-stage COPD, presented with constitutional symptoms, and a paraspinal soft tissue lesion at the T10 level, lymphadenopathy, and lung and liver nodules on imaging Liver biopsy confirmed EBV-negative T-cell PTLD with positive CD30. The patient’s immunosuppressant regimen was reduced and immunochemotherapy was initiated with BV-CHP (Brentuximab vedotin, cyclophosphamide, doxorubicin and prednisone). Symptoms improved remarkably after starting chemotherapy and no change in lung function. PET scan after two cycles demonstrated a complete response (CR) which persisted on follow-up imaging after completion of 6 cycles. The physiologic role of CD30 is not fully understood in transplant recipients however, it was exploited therapeutically in this case. BV-CHP was safe, well-tolerated, and efficacious in treating patients with T-cell PTLD with positive CD30.

Keywords: PTLD; Brentuximab vedotin; CD30

Introduction

Post-transplant lymphoproliferative disorders (PTLDs) are typically of B-cell lineage and EBV-driven. However, PTLDs of T-cell or NK-cell lineage can rarely be seen, but they are less likely to be associated with EBV.

Case Description

A 63-year-old male with a history of bilateral lung transplant in 2013 for end-stage COPD, complicated by acute rejection in the peri-operative phase, presented with constitutional symptoms and a paraspinal soft tissue lesion at the T10 level, lymphadenopathy, and lung and liver nodules on imaging. LDH was 304 U/L (normal reference range 85-277 U/L). Epstein–Barr virus (EBV) was detectable in the blood at 1,324 copies/mL by quantitative PCR. A liver biopsy revealed an abnormal T cell lymphoproliferative disorder that expressed CD2 (partial), CD4, CD5, perforin, and TIA, but lacked CD3, CD7, CD8, ALK-1, and PAX-5. These cells formed abnormal sheets of large cells which were CD30positive and EBV ISH negative, establishing a diagnosis of monomorphic post-transplant lymphoproliferative disorder (PTLD) (Image 1). The International Prognostic Index (IPI) score was high-risk, with extranodal sites (involving liver and bone), in addition to elevated LDH and Ann Arbor stage IV. The patient was subsequently treated with a reduction in immunosuppression and BV-CHP (Brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone) as described in the ECHELON-2 protocol, every 3 weeks and planned for 6 cycles [1]. PET scan after two cycles revealed complete remission (Figure 1). Brentuximab vedotin was dose reduced to 1.2 mg/kg in the fourth cycle, then omitted in the last two cycles due to grade 2 neuropathy. Subsequent PET scan after completion of 6 cycles of chemotherapy demonstrated persistent complete remission (CR), and the patient remains in CR one year after completion of therapy without any evidence of lung compromise.

Discussion

PTLDs are lymphoid and/or plasmacytic proliferations that develop in patients who undergo solid-organ or allogeneic bone marrow transplantation and are on immunosuppressive agents. Only about 7-15% of PTLD are of T-cell or NK cell origin [2]. PTLDs of T/NK type are reported to be EBV-associated in 37% of cases [3]. In this case, the T lymphoproliferation had morphologic and immunophenotypic aberrancies (including loss of CD3 and CD7, as well as strong CD30 expression) and would be considered a monomorphic PTLD (resembling anaplastic large cell lymphoma, ALK-negative). The physiologic role of CD30 is not fully understood, and in transplant recipients is not defined at all. It is thought to be expressed on activated T cells, NK cells, and B cells and serves in negative selection of T-cells and secondary antibody production [4]. In this case, the tumor cells expressed CD30, and we were able to exploit that therapeutically.Treatment of PTLD represents a challenge due to patients’ transplant history, comorbidities and immunosuppression. The risk-stratified sequential treatment (RSST) trial represented a novel strategy to maximize benefit while reducing treatment-related toxicity [5]. Immunosuppression reduction alone can yield responses in about 25% of PTLDs even though that varies by type of PTLD. The addition of monoclonal antibodies can also augment these responses. Brentuximab vedotin (BV) is an antibody-drug conjugate that binds to target tumor cells expressing CD30. The linked chemotherapeutic agent, monomethyl auristatin E (MMAE), is released causing cell cycle arrest and cell death. BV has demonstrated efficacy in treatment for CD30-positive peripheral T-cell lymphomas (PTCL) in combination with cyclophosphamide, doxorubicin, and prednisone (CHP). In the ECHELON-2 study, BV-CHP regimen for 6-8 cycles was compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30- positive peripheral T-cell lymphomas. The hazard ratios for overall survival and progression-free survival favored BV-CHP (HR=0.66 and 0.71 respectively) [6]. However, there is very little data regarding the resultant immune manipulation of targeting CD30-positive cells in the post-transplant setting. Intratumoral regulatory T-cells (Tregs) have been shown to express CD30, and there was a concern about whether eliminating a significant portion would result in rejection6. After careful discussion with the transplant and the patient, we elected to give one cycle with immediate improvement in constitutional symptoms and no change in lung function. We herein present this case where BV-CHP was safe, well-tolerated, and efficacious to add to the body of literature.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

Figures




Figure 1: PET scan at diagnosis showed increased FDG-uptake in the paraspinal soft tissue lesion at the T10 level (white arrows) (A); PET scan after 2 cycles of BV-CHP (B) and 6 cycles of BV-CHP (C) showed resolution of the paraspinal mass. Coronal views on the top. Sagittal views on the bottom. 

References

  1. Horwitz S, O’Connor OA, Pro B, Illidge T, Fanale M, et al. (2019) Brentuximab Vedotin with Chemotherapy for CD30-Positive Peripheral T-cell Lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet Lond Engl. 393: 229-240.
  2. Swerdlow SH (2007) T-cell and NK-cell posttransplantation lymphoproliferative disorders. Am J Clin Pathol 127: 887-895.
  3. Allen UD, Preiksaitis JK. (2019) Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 33: e13652.
  4. van der Weyden CA, Pileri SA, Feldman AL, Whisstock J, Prince HM. (2017) Understanding CD30 biology and therapeutic targeting: a historical perspective providing insight into future directions. Blood Cancer J. 7: e603-e603.
  5. Trappe RU, Dierickx D, Zimmermann H, Morschhauser F, Mollee P, et al. (2017) Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial. J Clin Oncol Off J Am Soc Clin Oncol. 35:536-543.
  6. Heiser RA, Grogan BM, Manlove LS, Gardai SJ. (2018) Abstract 1789: CD30+T regulatory cells, but not CD30+CD8 T cells, are impaired following brentuximab vedotin treatment in vitro and in vivo. Cancer Res. 78: 1789-1789.

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