Brentuximab vedotin therapy followed by autologous peripheral stem cell transplantation as a viable treatment option for an older adult with transformed lymphoma: a case report and literature review

Abstract

This report presents a case involving a woman aged >65 years who had been diagnosed with marginal zone lymphoma 3 years prior. The patient was hospitalized with enlarged inguinal lymph nodes, and pathological examination revealed that the lymphoma had transformed into diffuse large B-cell lymphoma. After two cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP) chemotherapy, the patient achieved complete remission. This treatment was followed by autologous hematopoietic stem cell transplantation and lenalidomide maintenance therapy. At the last follow-up, the patient had been in continuous remission for 24 months. This case study suggests that the utilization of BV and R-CHP in conjunction can result in rapid remission, and it can be followed by autologous hematopoietic stem cell transplantation and maintenance therapy with lenalidomide. This treatment approach exhibits potential as a viable option for older individuals with transformed lymphoma.

Introduction

Transformed lymphoma (TL) refers to the transformation of low-grade inert lymphoma to other highly aggressive lymphoma subtypes. TL exhibits a high degree of malignancy, rendering it susceptible to relapse following remission. It also displays an increased propensity for multi-drug resistance, thereby posing a significant threat to patient survival. ¹ Few reports have discussed the transformation of marginal zone lymphoma (MZL) into diffuse large B-cell lymphoma (DLBCL), and there is currently a lack of standardized treatment guidelines for TL. This article presents a case involving an older adult diagnosed with MZL that subsequently transformed into DLBCL and provides a comprehensive review of the existing literature on this subject. The reporting of this study complies with the CARE guidelines. ²

Case presentation

In September 2018, a woman in her 60s of Chinese descent was diagnosed with MZL (stage IV A, International Prognostic Index score: 2). The immunohistochemical results for lymphoma cells of the left cervical lymph nodes were as follows: CD20(+), CD79a(+), Bcl-2(+), Ki-67(6%+), cyclin D1(−), and sparse positivity for CD3, CD5, CD15, CD21, CD23, and CD43. Epstein–Barr encoding region (EBER) in situ hybridization was negative. The results of immunoglobulin gene rearrangement and immunoglobulin heavy chain variable region (IGHV) mutation detection were as follows: IGH VH-JH: FR1 (positive), FR2 (positive), and FR3 (positive). Fluorescence in situ hybridization results were as follows: t(14;18)(q32;q21) negative. Flow cytometry immunophenotyping showed mature B-cell lymphoma, with the lymphocyte population accounting for 66.51%, mainly expressing CD19, CD20, and HLA-DR and showing minimal expression of CD5. Multiple lymphadenopathies on both sides of the mediastinum with high uptake of 18 F-fluorodeoxyglucose (FDG) were revealed by positron emission tomography–computed tomography (PET-CT), and the maximum standardized uptake value (SUVmax) was 4.0. The patient achieved a partial response as assessed by PET-CT after six cycles of rituximab (375 mg/m² on day 1, followed by one cycle every 21 days). No further treatment was administered.

In June 2021, the patient was admitted to our department because of recurrent enlargement of multiple lymph nodes. PET-CT showed a soft tissue mass (3.0 × 2.9 cm) in the right inguinal area with increased FDG uptake (SUVmax of 12.8) as well as increased FDG uptake in the bilateral parotid glands (SUVmax of 11.2). We performed a pathological biopsy on the soft tissue mass in the right inguinal region. The immunohistochemical results for the lymphoma cells of right inguinal lymph nodes were as follows (Figure 1): CD20(+), CD79a(+), Bcl-2(+), CD30(+), C-myc(50%+), p53(+), Ki-67(90%+), MUM-1(90%+), CD5(−), Bcl-6(−), CD10(−), CD21(−), CD3(−), CD38(−), and ALK(−). EBER in situ hybridization was negative. Negative rearrangement of BCL2 and MYC was demonstrated by fluorescence in situ hybridization. Next-generation sequencing of the paraffin-embedded lymphoma tissues was performed using the Illumina high-throughput sequencing platform technology (Illumina, Inc., San Diego, CA, USA). The results showed that many gene mutations were present, including mutations of TP53, MYD88, IRF4, FAT1, PRDM1, and TET2. The clonal relationship between MZL and transformed DLBCL was assessed through a comparison of IGHV-D-J gene rearrangements, leading to the confirmation of homologous clonal transformation of the lymphoma.

Figure 1.

Pathological examination (hematoxylin and eosin staining, immunohistochemistry staining) showed lymph node alterations. (a) 100× and (b) 200× magnifications showed the morphology of the lymph nodes before transformation. (c) Immunohistochemistry staining detected the expression of CD34 before transformation (200×). (d) 100×, (e) 200×, (f) and 200× magnifications of hematoxylin and eosin staining showed the morphology of the lymph nodes after transformation. (g) 200×, (h) 200×, and (i) 200× magnifications of immunohistochemistry staining showed the expression of CD20, CD30, and p53, respectively. Scale bar: 200 µm.

The patient was ultimately diagnosed with DLBCL (non-germinal center B-cell type, CD30+, MZL transformation, Stage IV A, International Prognostic Index score: 4). After obtaining the patient’s consent, we began treatment. The patient rapidly achieved complete remission (Figure 2) as shown by PET-CT evaluation after two cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP) chemotherapy (BV 1.8 mg/kg on day 1, rituximab 375 mg/m² on day 2, cyclophosphamide 750 mg/m² on day 2, liposome doxorubicin 40 mg/m² on day 2, and prednisone 90 mg/day on days 2–6). Mobilization was conducted on 1 September 2021, followed by collection of peripheral blood hematopoietic stem cells on 18 and 19 September 2021. Subsequently, two cycles of R-CHOP regimen consolidation therapy were administered. On 13 December 2021, autologous peripheral stem cell transplantation (ASCT) was conducted with a peripheral blood mononuclear cell count of 4.6 × 10⁸ cells/kg and a CD34+ cell count of 3.3 × 10⁶ cells/kg. The pretreatment regimen consisted of bendamustine in conjunction with cytarabine, etoposide, and melphalan (Be-EAM) (bendamustine 200 mg/m² on days −8 and −7; cytarabine 400 mg/m² on days −6, −5, −4, and −3; etoposide 200 mg/m² on days −6, −5, −4, and −3; and melphalan 140 mg/m² on day −2). Neutrophil engraftment was achieved on day 9, and thrombocyte engraftment was achieved on day 13 post-transplantation. Following the transplantation, lenalidomide was administered as regular maintenance therapy. At the time of this writing, a 24-month follow-up had been conducted, and the disease was still in remission. Importantly, the circulating tumor DNA analysis indicated that the mutation of TP53 was persistently negative (Supplementary Figure 1). A flow chart of the diagnosis and treatment is shown in Supplementary Figure 2.

Figure 2.

18F-Fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) findings. (a) 18F-FDG PET-CT after two cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP) chemotherapy showed complete metabolic resolution of the disease with non-FDG-avid residual soft tissue. (b) The 18 F-FDG PET-CT study for initial staging showed nodal involvement above and below the diaphragm in the patient with transformed lymphoma before treatment. Coronal fusion images of 18 F-FDG PET-CT showed changes in focal uptake by the bilateral parotid glands (d) before and (c) after treatment. Coronal fusion images of 18 F-FDG PET-CT showed changes in focal uptake by the right inguinal lymph node (f) before and (e) after treatment.

Discussion

TL has a grave prognosis, with rapid disease progression and a median survival time of only 1.7 years. ³ A key risk factor for this adverse prognosis in patients with MZL is histological transformation. ⁴ The transformation of MZL to aggressive, large-cell lymphoma significantly worsens patient outcomes and overall survival.^5–7 The progression from MZL to DLBCL complicates the management of these typically indolent lymphomas. ⁸ All types of MZL are susceptible to this transformation, which markedly increases morbidity and mortality. ⁹

PET-CT scans are essential to confirm the transformation from MZL to DLBCL and to apply PET-CT-based criteria for identifying transformed MZL. ¹⁰ In our case, the patient’s PET-CT also indicated this transformation. Additionally, immunohistochemical staining of the patient’s lymph nodes revealed partial CD5 positivity. Research indicates that CD5-positive extranodal MZL, which is known for its aggressive behavior, is more likely to undergo transformation into DLBCL.^11,12 Sequencing results from our case revealed a TP53 mutation. Genetic studies have revealed rapid progression to aggressive lymphoma in some cases, highlighting the complexity of these transformations. ¹³ Genomic studies have shed light on the high-grade transformation of MZL and the role of TP53 mutations in these processes. ⁹

Standardized first-line recommendations or international guidelines for TL are currently lacking. However, some researchers suggest that a combination of high-dose chemotherapy and ASCT can significantly improve the prognosis for younger patients, with 5-year overall survival rates ranging from 47% to 62%.^14,15 In our case, given the patient’s age of >65 years at TL diagnosis, her tolerance of high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation would have been low and stem cell mobilization would have been challenging.

The R-CHOP regimen is frequently employed in the treatment of TL. However, the 5-year progression-free survival rate is only 37%. This disparity underscores the ongoing concern regarding the recurrence of both indolent and invasive components. ¹⁶ A University of Miami Health System/Jackson Memorial Hospital database analysis indicated that approximately 21% of patients with DLBCL expressed CD30, with 52% of these showing high expression levels. ¹⁷ A pathological feature of the cancer in our case was also CD30 positivity. BV, a novel antibody-conjugated drug, specifically targets CD30, which is abundantly expressed in tumor tissues. Through antibody-mediated endocytosis, BV effectively delivers cytotoxic agents to target cells, resulting in complete tumor eradication. In comparison to conventional drugs, this therapeutic approach demonstrates superior anti-tumor efficacy and reduced systemic toxicity. ¹⁸ Numerous studies have validated the efficacy of BV in the treatment of CD30-positive non-Hodgkin’s lymphoma, with favorable safety profiles observed.^19–22 In addition, no significant correlation was observed between the level of CD30 expression and the response to treatment. ²³

We employed BV in conjunction with CHP chemotherapy as the initial treatment, resulting in a substantial reduction in the patient’s enlarged lymph nodes following one treatment cycle. Complete remission was achieved after two cycles of treatment without any notable occurrences of neurotoxicity, bone marrow suppression, or other adverse events. This outcome indicates the safety and efficacy of this therapeutic approach.

In addition, peripheral blood stem cell mobilization and ASCT were successfully performed. Importantly, our case study contributes additional evidence that BV does not hinder the mobilization or implantation of stem cells, reinforcing its viability as a treatment option. Supporting this observation, previous reports have noted the effectiveness of BV as a second-line therapy, particularly regarding its ability to bridge patients to ASCT without negatively impacting stem cell mobilization or engraftment. ²⁴ These findings align closely with those in our case, consistent with previous research that underscores the drug’s efficacy and safety in similar clinical scenarios.^25,26

We also made some optimizations in the preconditioning regimen. The Be-EAM regimen stands out as a highly effective DLBCL preconditioning regimen, exhibiting a 3-year overall survival rate of 58%. ²⁷ Nevertheless, the occurrence of carmustine-induced interstitial pneumonitis is considerably high, ranging from 7% to 17%, and is dependent on dosage. Given the advanced age of our patient and our aim to minimize pretreatment toxicity, we opted for the utilization of Be-EAM as a preconditioning regimen. This treatment yielded no significant adverse events such as delayed implantation or interstitial pneumonitis.

In this case, the rapid induction of remission through the combination of BV and R-CHP, subsequently followed by bridging ASCT, was both safe and efficacious. The subsequent administration of maintenance lenalidomide post-transplantation also showed safety and efficacy, with no observed disease progression throughout the subsequent 24 months. Consequently, this treatment approach exhibits potential as a promising therapeutic option for TL. Prospective clinical trials are needed to further substantiate the efficacy of this treatment approach.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241258597 - Supplemental material for Brentuximab vedotin therapy followed by autologous peripheral stem cell transplantation as a viable treatment option for an older adult with transformed lymphoma: a case report and literature review

Supplemental material, sj-pdf-1-imr-10.1177_03000605241258597 for Brentuximab vedotin therapy followed by autologous peripheral stem cell transplantation as a viable treatment option for an older adult with transformed lymphoma: a case report and literature review by Jiewen Tan, Jinman Zhong, Wanzhen Hu, Guobiao Wu, Chong Zeng and Dan Xiong in Journal of International Medical Research

Supplemental Material

sj-pdf-2-imr-10.1177_03000605241258597 - Supplemental material for Brentuximab vedotin therapy followed by autologous peripheral stem cell transplantation as a viable treatment option for an older adult with transformed lymphoma: a case report and literature review

Supplemental material, sj-pdf-2-imr-10.1177_03000605241258597 for Brentuximab vedotin therapy followed by autologous peripheral stem cell transplantation as a viable treatment option for an older adult with transformed lymphoma: a case report and literature review by Jiewen Tan, Jinman Zhong, Wanzhen Hu, Guobiao Wu, Chong Zeng and Dan Xiong in Journal of International Medical Research