BR-CHOP in composite angioimmunoblastic T-cell lymphoma and diffuse large B-cell lymphoma: case report

IntroductionOther Section

• Introduction
• Case presentation
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphoma (PTCL). It accounts for 1–2 % (1) of non-Hodgkin lymphomas and 18.5% of all T-cell lymphomas (2). Besides the proliferation of T-cells, it has been linked to the presence of B-cell proliferation, in the form of large B-cells, Reed-Sternberg-like cells and plasma cells. Most of the cases of AITL with B-cell proliferation, either focally or confluent, are due to the presence of Epstein-Barr virus (EBV) infection of B-cells (3). With a pre-existing EBV infection, there is a risk of virus reactivation in the setting of lymphoma, which can subsequently cause the expansion of B-cell population and development of B-cell lymphoma (3). Most patients are either EBV-positive with composite T- and B-cell lymphoma (2-7) or EBV-negative patients who had a sequential development of DLBCL after treatment of AITL (4,5). In the absence of EBV infection, AITL with B-cell lymphoma is rare with a prevalence of 1–4% (7) and an alternate cause explains B-cell proliferation in those patients. A small subset of EBV-negative patients with AITL have co-existing diffuse large B-cell lymphoma (DLBCL), a type of B-cell lymphoma. No therapeutic guidelines are available for this rare type of composite lymphoma due to limited data (8) and different variations on CHOP (cyclophosphamide, doxorubicin, prednisone) backbone of chemotherapy have been tried (2).

Here we present a rare case of composite AITL with DLBCL in an EBV-negative patient. We will also summarize a unique chemotherapy used for our patient, where brentuximab vedotin (BV) and rituximab were added to the CHOP therapy. This variation in chemotherapy proved to be effective in our patient, helped them achieve remission, and is a promising treatment option for this composite lymphoma. We present this case in accordance with the CARE reporting checklist (available at https://aol.amegroups.com/article/view/10.21037/aol-24-8/rc).

Case presentationOther Section

• Introduction
• Case presentation
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

A 71-year-old female with a past medical history of chronic hepatitis B virus (HBV) and type 2 diabetes mellitus, presented to the emergency room for acute onset shortness of breath, cough, and fever. She did not have any complaints of night sweats or weight loss but had a loss of appetite for a few days. Her family history was only significant for diabetes in her mother. She did not have any tobacco or alcohol usage. Her physical exam was significant for diffuse lymphadenopathy, skin pallor, and diminished breath sounds bilaterally. She refused to have biopsy for diffuse lymphadenopathy and was discharged after being diagnosed with legionella pneumonia and was prescribed antibiotics. Computed tomography (CT) of the chest, abdomen, and pelvis revealed mediastinal, bilateral axillary, retrocrural, retroperitoneal, periaortic, iliac, internal, and external iliac adenopathy. Most prominent lymph nodes were found in the groins with the largest one measuring 1.7 cm × 2.3 cm. Abnormalities in complete blood count at the time of admission are listed in Table 1. Lymph node biopsy was completed from the right groin lymph node and histological analysis showed that the patient had AITL with an associated EBV-negative DLBCL. The diagnosis of TCL and BCL is based on immunohistochemistry and molecular biology (8). The nodal architecture included large-sized atypical lymphoid cells. Immunohistochemical analysis showed that the atypical lymphoid cells expressed CD20, CD2, CD3, CD4, CD5, BCL6. Ki67 had a proliferative index of greater than 50%. They were negative for CD7, CD15, MuM1, TdT, ALK, TIA-1, cyclin D1, CD21, CD23, LCA, GrB, and CD56. This was consistent with AITL. An in-situ hybridization study for EBER and serological evaluation of EBV DNA were also negative. Flow cytometry was performed, and results revealed CD30⁺ B cell lymphoma consistent with large B cell lymphoma. There was a proliferation of B-cells with phenotypes of CD20⁺ and CD30⁺, supporting the diagnosis of CD30⁺ DLBCL. No M-spike was found on serum protein electrophoresis. The patient also had autoimmune hemolytic anemia, linked to the direct antiglobulin test (DAT) immunoglobulin G (IgG) that was positive in the patient. Magnetic resonance imaging (MRI) brain ruled out any abnormal parenchymal enhancement. Cerebrospinal fluid cytology was also negative for any malignancy however, positron emission tomography (PET) of the bone marrow was positive.

After the initial diagnosis, the patient was administered prednisone to treat autoimmune hemolytic anemia. There was marked improvement and stabilization of her hemoglobin at 11.8 mg/dL. Patient’s chemotherapy regimen was then decided. The patient was planned to receive six cycles of 21 days of outpatient chemotherapy with BR-CHOP (BV 1.8 mg/kg, rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², prednisone 100 mg).

With close follow-up, patient’s ability to tolerate the chemotherapy was monitored, along with any adverse effects. In the third cycle, the patient experienced emerging neuropathy and BV dose was reduced to 0.9 mg/kg for that cycle. The patient completed six cycles of the chemotherapy and was suggested to take Cymbalta for chemotherapy induced neuropathy.

With the BR-CHOP chemotherapy regimen, the patient achieved remission, as confirmed by the results of PET and CT scans which were unremarkable.

The patient’s most recent imaging studies 2 years later, including fluorodeoxyglucose (FDG)-PET and CT scans, revealed concerning changes indicating potential progression of the lymphoma. Significant increases in the number, size, and uptake of supradiaphragmatic and infra-diaphragmatic lymphadenopathy were noted, along with new splenomegaly. The spleen exhibited diffuse increased uptake, and new subcutaneous and intramuscular soft tissue nodules were seen, particularly in the thighs and calves, raising concerns for lymphomatous involvement. Additionally, there was new increased uptake in the bilateral lacrimal glands, further suggestive of lymphoma progression. Soft tissue thickening was observed in the nasal cavity, specifically along the inferior turbinates and nasal septum, also demonstrating increased FDG uptake. These findings were highly indicative of the lymphoma’s progression, despite the previous remission observed with BR-CHOP chemotherapy.

Unfortunately, the patient’s condition worsened following these findings. Despite the successful remission achieved previously, the increasing lymphadenopathy, along with the new involvement of multiple sites, led to a significant decline in her overall condition. Ultimately, the patient passed away shortly thereafter.

A complete timeline of events is detailed in Figure 1.

Figure 1 Historical and current information from this episode of care organized as a timeline. BR-CHOP, brentuximab vedotin, rituximab, cyclophosphamide, doxorubicin, prednisone; CT, computed tomography; EBV, Epstein-Barr virus; PET, positron emission tomography.

DiscussionOther Section

• Introduction
• Case presentation
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

Our patient with + anti-Hep Bc had a rare case of composite AITL and DLBCL without EBV infection. AITL is the second most common of all PTCL (1). More than 80% of AITL cases also have a proliferation of large B-cells (9), Hodgkin/Reed-Sternberg (HRS)-like cells, or plasma cells (1). Most commonly, B-cell proliferation in the setting of AITL has been reported after the initial diagnosis of AITL or at the time of relapse (4,5,10); only a few cases have been shown to have B-cell lymphoma, either simultaneously (6,8) or preceding AITL (1). It is also uncommon to find AITL and DLBCL at the same anatomic site or as composite lymphomas (1,7,8) and it makes up 1–4% of all lymphoma cases (7). Amongst the rare cases of composite AITL and DLBCL, only a handful of them are negative for EBV (4,5), like our patient. Unlike EBV-positive B-cells which may be having clonal expansion due to viral infection or reactivation in the absence of immune surveillance with ongoing AITL (3,5), the EBV-negative B-cells may be carrying mutations in TET2, DNMT3A, IDH2, TP53 (7). The B-cells may have received these mutations from hematopoietic stem cells, which also give rise to the neoplastic T-cells of AITL (1,7). MYC gene rearrangements may also be implicated as four out of twelve cases of AITL and DLBCL that were negative for EBV had MYC aberrations (11). Besides genetic mutations, environmental mutagen exposures, immunosuppression caused by the dysfunctional T-cells in AITL and chemotherapy exposure (5,12) and cytokine dysregulation (4) caused by ongoing lymphoma are alternative explanations of composite B-cell lymphomas in EBV-negative patients. Other than EBV, HBV is epidemiologically associated with non-Hodgkin’s lymphoma, specifically DLBCL (13). The mechanism is not yet fully elucidated however, it is hypothesized that HBV antigen may be stimulating B-cell receptors, influencing B-cell signaling and leading to hyperproliferation. HBV virus may also be infecting B lymphocytes and integration of HBV genome into host cellular DNA may be causing mutations of oncogenes (14).

Only a handful of cases of EBV-negative AITL and B-cell lymphoma have been reported in the literature (4-6,15). In one study, three out of 15 composite cases were EBV-negative (16). In another study, four out of 15 patients developed EBV-negative B-cell plasmacytosis with AITL without any large cell morphology expected of DLBCL (6). There was also a case of Epstein-Barr encoding region (EBER)-negative AITL with systemic lymphadenopathy and Reed-Sternberg-like B-cells, but no large B-cells were observed (15). Large B-cell morphology is rare to find in B-cell lymphomas with AITL. R-CHOP is one of the treatment options used for AITL and DLBCL (7). Rituximab with autologous peripheral blood stem cell transplantation has also been used previously (4).

For these composite lymphoma cases of AITL, the available treatments include chemotherapy, immunomodulatory therapy, and hematopoietic stem cell transplantation (8). There is no standard therapy (7) and the first line is usually CHOP or R-CHOP (7). The primary therapy used for AITL is similar to the CHOP therapy used for PTCL, including cyclophosphamide, doxorubicin, vincristine, and prednisone7 and consideration for autologous stem-cell transplant (9). Other medications that can potentially be added to the CHOP backbone include alemtuzumab, romidepsin, bortezomib, and belinostat (9). However, the addition to CHOP with the most promising results anticipated is BV, an anti-CD30 antibody-drug conjugate (9). It targets CD30, which is positive in 43–90% of AITL cases (2). In the ECHELON-2 phase III study, when BV in combination with CHP was compared with CHOP for safety and efficacy, higher response rate and progression-free survival was found (17). Amongst patients with CD30⁺ relapsed or refractory AITL, BV therapy caused a significant response in 54% of cases (9). BV, as an antibody-drug conjugate that disrupts microtubule assembly during cell division, leading to apoptosis of CD30⁺ cells (18).

So far, there has only been a single case of composite AITL and DLBCL in an EBV-negative patient who was treated with BR-CHOP regimen. However, the patient was not able to complete the entire course of treatment and succumbed soon after cycle 1 was complete. In our patient, who completed all six cycles of BR-CHOP therapy as planned, remission was achieved and maintained for 2 years after which the patient relapsed and passed away due to disease progression. There is therapeutic potential of BR-CHOP for composite lymphoma.

ConclusionsOther Section

• Introduction
• Case presentation
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

Our patient had a rare presentation of composite lymphomas, particularly AITL and DLBCL without EBV infection. A unique chemotherapy regimen, BR-CHOP, proved to be efficacious in achieving complete remission for the patient. This case adds to the limited literature on the management of composite lymphomas, where therapeutic guidelines are lacking due to the rarity of these occurrences and the variability in treatment responses. There is a need for further research and clinical trials to explore optimal treatment approaches for rare and complex lymphoma presentations, particularly those involving composite histology and negative viral associations.

AcknowledgmentsOther Section

• Introduction
• Case presentation
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

None.

FootnoteOther Section

• Introduction
• Case presentation
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://aol.amegroups.com/article/view/10.21037/aol-24-8/rc

Peer Review File: Available at https://aol.amegroups.com/article/view/10.21037/aol-24-8/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aol.amegroups.com/article/view/10.21037/aol-24-8/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

ReferencesOther Section

• Introduction
• Case presentation
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

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