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Case Reports
. 2024 Jan 19:13:1254256.
doi: 10.3389/fonc.2023.1254256. eCollection 2023.

Brentuximab vedotin as a bridge to combination chemotherapy in gray zone lymphoma with severe liver impairment: a case report

Roshan Asrani  1 , Turgot Bora Cengiz  2 , Bruce E Petersen  3 , Theodora Anagnostou  1 , Joshua D Brody  1
Affiliations
Case Reports

Brentuximab vedotin as a bridge to combination chemotherapy in gray zone lymphoma with severe liver impairment: a case report

Roshan Asrani et al. Front Oncol. .

Abstract

Background: Gray zone lymphoma (GZL) is a rare lymphoma subtype characterized by features intermediate between diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (cHL). The optimal first-line treatment for GZL remains undefined, particularly for patients with poor performance status or baseline organ impairment. Brentuximab vedotin (BV), a targeted therapy that binds to CD30, a TNFR superfamily member involved in NF-kB signaling, has shown promise in the treatment of CD30-positive lymphomas. However, its use in GZL, especially in patients with severe liver impairment, has not been reported previously.

Case description: We present a case of a 37-year-old male with GZL and severe liver impairment at initial presentation. The patient initially received monotherapy with BV, which resulted in a marked improvement in liver enzymes and bilirubin levels. Subsequently, combination cytotoxic chemotherapy consisting of dose-adjusted etoposide, prednisone, cyclophosphamide, and doxorubicin (DA-EP_CH) was added. Repeat imaging revealed near complete resolution of lymphadenopathy and significant reduction in hepatosplenomegaly. The patient completed a full course of chemotherapy and achieved a complete response. Follow-up examinations showed no evidence of recurrent disease, and the patient resumed full-time work.

Discussion: GZL poses diagnostic challenges due to its overlapping features with DLBCL and cHL. Accurate diagnosis relies on comprehensive histopathological evaluation, immunophenotyping, and molecular analysis. The optimal first-line treatment for GZL remains uncertain. BV shows promise as an addition to chemotherapy in GZL, even in the presence of severe liver impairment. The molecular pathogenesis of GZL is complex and heterogeneous, frequently involving aberrant NF-kB signaling and impaired apoptosis regulation via loss of TP53 expression. Understanding the underlying molecular mechanisms is essential for developing targeted therapies and identifying predictive biomarkers for treatment response.

Conclusion: This case demonstrates the successful use of BV as a bridge to cytotoxic chemotherapy in a GZL patient with severe liver impairment, highlighting its potential safety and efficacy even in the setting of end-organ failure. Further investigation is warranted to define optimal treatment strategies, identify predictive biomarkers, and improve outcomes for patients with this rare and challenging lymphoma subtype.

Keywords: CD30+ lymphoma; IKBKE; Mdm4; hyperbilirubinemia; targeted therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Case Pathology. (A–E) H&E stain of initial core biopsy of left cervical lymph node showing atypical lymphocytic infiltrate consisting of isolated large, pleomorphic, atypical lymphoid cells, including cells with features of Hodgkin/Reed-Sternberg cells (A), positive for CD30 (B), CD15 (C), strongly positive for PAX5 (D); with equivocal weak labeling for OCT2 (E). (F, J) H&E stain of core biopsy of subsequent left axillary lymph node showing similar-appearing atypical lymphoid cells in confluent sheets (F), positive for CD30 (G), CD15 (H), PAX5 (I), OCT2 (J). (A, F, X1000; B–E, H–J X400).
Figure 2
Figure 2
Coronal maximum-intensity-projection (MIP) images of 18F-FDG PET-CT at baseline post-treatment initiation interval at 69 days later and surveillance follow-up 629 days later. At +69 days post-treatment initiation there is significant decrease in splenomegaly (33.7 cm to 21.7 cm) and hepatomegaly (23.1 cm to 20.8 cm) with interval resolution of bulky FDG avid lymphadenopathy in the bilateral cervical and left axillary regions. The patient was treated with G-CSF prior to the 2nd panel image which likely explains diffuse osseous uptake which was noted. Follow-up examination >1.5 years later continues to show no evidence of disease.
Figure 3
Figure 3
Serum biomarker response. Depicts serum bilirubin levels (A) and lactate dehydrogenase (LDH) (B) noted on presentation and following administration of Brentuximab Vedotin (BV) on day 12 of admission.
Figure 4
Figure 4
Proposed oncogenesis of gray zone lymphoma with IKBKE and MDM4 alteration. (A). Constitutive Nuclear factor kappa B (NF-κB) activation by canonical and noncanonical signaling. Aberrant canonical activation of NF-κB signaling can occur via increased cell surface receptor activation (e.g. CD30) leading to phosphorylation of the IKK complex. Non-canonical activation can occur via direct phosphorylation by IKBKE. Increased NF-κB activity promotes anti-apoptotic and pro-proliferative target genes leading to oncogenesis. (B) Loss of p53 tumor suppressor. The MDM2/MDM4 dimer targets p53 for Ubiquitylation and p53 proteasomal degradation. Overexpressed or amplified MDM4 inhibits p53 target gene transcription in the nucleus and targets p53 protein for proteasomal degradation. Decreased p53 tumor suppressor leads to loss of malignant cell apoptotic regulation.
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References

    1. Qasrawi A, Swofford B, Abughanimeh O, Hildebrandt GC. Trends and outcomes of gray zone lymphoma in the United States: A population-based registry study. Biol Blood Marrow Transplant (2020) 26(3):S230. doi: 10.1016/j.bbmt.2019.12.471 - DOI
    1. Evens AM, Kanakry JA, Sehn LH, Kritharis A, Feldman T, Kroll A, et al. . Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort. Am J Hematol (2015) 90(9):778–83. doi: 10.1002/ajh.24082 - DOI - PubMed
    1. Pilichowska M, Pittaluga S, Ferry JA, Hemminger J, Chang H, Kanakry JA, et al. . Clinicopathologic consensus study of gray zone lymphoma with features intermediate between DLBCL and classical HL. Blood Adv (2017) 1(26):2600–9. doi: 10.1182/bloodadvances.2017009472 - DOI - PMC - PubMed
    1. Dunleavy K, Wilson WH. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach? Blood (2015) 125(1):33–9. doi: 10.1182/blood-2014-05-575092 - DOI - PMC - PubMed
    1. Mallipudi RM, Alquran L, Shenoy VA, Leslie LA, Conti JA. A rare case of grey zone lymphoma successfully treated with brentuximab vedotin and R-CHP chemotherapy. Case Rep Oncol Med 2019 (2019) 2019:4121234. doi: 10.1155/2019/4121234 - DOI - PMC - PubMed

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