A clinical case of successful treatment of CD30-negative angioimmunoblastic T-cell lymphoma using brentuximab vedotin and lenalidomide followed by allogeneic hematopoietic stem cell transplantation

Introduction

The heterogeneous group of nodal T follicular helper (TFH) cell lymphomas (nTFHLs) has been introduced in the new (fifth) edition of WHO classification of Haematolymphoid Tumours. This group includes mature T-cell neoplasms with the phenotypic features and gene expression signature of TFH cells. Different patterns of tumors are recognized, i.e., angioimmunoblastic type (AI, previously designated as angioimmunoblastic T-cell lymphoma-AITL), follicular type (F, previously designated as follicular T-cell lymphoma), and not otherwise specified type (NOS, previously designated as nodal peripheral T-cell lymphoma with TFH phenotype) [1].

Nodal T follicular helper cell lymphoma, angioimmunoblastic type (nTFHL-AI/AITL) is characterized by systemic clinical features, lymphadenopathy, as well as involvement of spleen, liver, skin, and bone marrow. This malignancy is characterized by a polymorphic infiltrate of reactive cells and significant proliferation of high endothelial venules (HEVs) and follicular dendritic cells (FDCs). The reactive T cells predominate over neoplastic T-cells in most cases.

The complex tumor microenvironment plays a pivotal role in the pathogenesis and clinical trajectory of AITL, influencing both disease progression and the manifestation of clinical features such as high-grade fever, skin rash, enlarged lymph nodes, and autoimmune complications. The histomorphological features including the structure of microenvironment, immunophenotype of both reactive and neoplastic cells could be a potential predictive and/or prognostic marker for AITL.

The treatment landscape for AITL aligns with other nodal PTCLs, typically starting with CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone), often combined with etoposide in younger, fit patients [2]. Despite initial responses, the long-term outcome with these treatments is poor, with nearly 70% of patients relapsed or have refractory disease [3-4]. In the refractory or relapsed setting, treatment options include salvage chemotherapy protocols followed by autologous stem cell transplantation (ASCT), though outcomes often remain disappointing with relapse rates greater than 80% [5]. More promising results have been noted with allogeneic stem cell transplantation (allo-SCT), which shows a progression-free survival of 31% to 64% over 2 to 5 years for nodal PTCLs and as high as 81% for AITL. Thus, there remains a significant clinical need for new, active agents in both the frontline and relapsed settings. As this type of lymphoma has a rich immune microenvironment, the lenalidomide may be applied in r/r AITL demonstrating ORR of 31% in monotherapy and ability to induce complete response [6]. Cyclosporine A has been used as a therapeutic option in second- or later lines with outstanding response rates, however clinical data of AITL are based on small-scale case series, and prospective trials are scarce [7]. Bendamustine monotherapy has also demonstrated efficiency, with a reported overall response rate of approximately 50% and CR of 25% suggesting its potential as a therapeutic option [8]. One of breakthroughs in the treatment of CD30-positive variants of T-cell lymphomas, including AITL, is the conjugate of an anti-CD30 antibody with a monomethyl auristatin E, brentuximab vedotin (BV). The variable expression of CD30 on tumor cells in AITL complicates the decision to use BV [8]. However, the ECHELON-2 phase 3 clinical trial highlighted the efficacy of BV combined with CHP in PTCL at varying levels of CD30 expression, including very low levels. This trial, along with additional studies encompassing a representative number of subjects, has shown that responses to BV can occur even in tumors with low to undetectable CD30 levels [9-10]. These findings open avenues for the use of BV in CD30-negative AITL cases, where traditional therapies have failed, providing a basis for optimism in this challenging therapeutic landscape. Nevertheless, while there are reported cases of effective use of BV in patients with reduced CD30 expression, only limited observations describe the efficacy of this agent in patients with CD30-negative T-cell lymphomas [11]. Thus, a clinical case is presented of successful use of BV, lenalidomide and rituximab in a patient with CD30-negative angioimmunoblastic T-cell lymphoma, who previously demonstrated the ineffectiveness of prior therapy options and a refractory/recurrent course of the disease. It appears that achieving a complete response involves a complex impact on the whole microenvironment with lenalidomide by modifying the immune response and inhibiting the growth of tumor cells.

Figure 1. Skin lesion before therapy

Case description

The patient is a 55-year-old woman. First symptoms of the disease included fever, night sweats, rash all over the body of a petechial character, rapid enlargement of cervical lymph nodes since October 2019.

PET/CT(January, 2020) scans demonstrated enlarged cervical, supraclavicular lymph nodes, palatine tonsils, intrathoracic, axillary lymph nodes, intra-abdominal, retroperitoneal lymph nodes, iliac, inguinal lymph nodes, spleen, skin and bone marrow.

Supraclavicular lymph node biopsy showed substantial effacement of the lymph node architecture by a polymorphous cellular infiltrate consisting of T- and B-cells, both of variable sizes. Follicular and nodular B-cell rich areas contained expanded dendritic stroma. Medium to large and large B-cells were EBV-positive (EBER) and showed high proliferative activity (Ki-67). They were found in loose and dense clusters and sheets within the nodular areas and between them. Large cells were sometimes seen in the form of muffs around the vessels. A significant proportion of B-cells outside the nodules expressed CD30.

The paracortex contained T-cells, hyperplastic HEVs and FDCs forming a network mostly around the venules. Most T-cells demonstrated the CD3+, CD4+, bcl-6+, CD10+, PD-1+ phenotype - that of TFHs. They concentrated mostly along the HEVs.

Therefore the case was classified as AITL with secondary EBV+ B-cell proliferation. Key morphological diagnostic features are shown in Figure 2.

Figure 2. Key morphological features of AITL: a – proliferation of HEVs, Azur & eosin staining, x200; b – expanded meshwork of dendritic cells around the vessels, immunostaining for CD21, x200; c – abundant PD-1-positive cell infiltration, immunostaining for PD-1, x200

The first line of therapy was administered according to the CHOEP regimen (doxorubicin 50 mg/m², cyclophosphamide 750 mg/m² and vincristine 1.4 mg/m² by intravenous infusion on day 1, etoposide 100 mg/m² intravenously days 1-3 and oral prednisone days 1-5) starting from February 2020.There were no significant complications. There was a hort-term effect of disappearance of B-symptoms, regression of peripheral lymph nodes, but the appearance of facial edema and nasal blockage.The condition was assessed as progression.

The second line of therapy included cyclosporine A at a dose of 3 mg/kg for 2 weeks (end of February 2020). Against this background, there was an increase in cervical, axillary, and inguinal lymph nodes, swelling of the soft tissues of the neck, and the return of febrile fever. The condition was assessed as progression, and the administration of cyclosporine A was stopped in March 2020.

Subsequent lines of therapy included GDP chemotherapy in March 2020 (gemcitabine 1000 mg/m² intravenously on days 1 and 8, cisplatin 75 mg/m² intravenously on day 1, dexamethasone 40 mg orally once daily on days 1-4), and therapy with the hypomethylating agent azacitidine in combination with cyclosporine A in April 2020. No response was achieved with any of the therapy options. According to PET/CT in May 2020, there was progression with increased metabolic activity of the bronchopulmonary and parapancreatic groups of lymph nodes (Deauville 5). Clinically, the patient experienced increasing peripheral edema and the reappearance of a rash.

IHC review of initial biopsy of the supraclavicular lymph node was performed, confirming that among the tumor population, only 1% of cells expressed CD30. Due to the lack of alternative available and effective therapy options, a decision was made to start therapy with BV despite the low expression of CD30 by tumor cells.

During therapy with BV from May to December 2020, a partial response was achieved according to PET/CT. It is worth noting that the drug was used in monotherapy for 6 cycles, followed by a combination with bendamustine for 4 cycles (brentuximab vedotin 1.8 mg/kg on Day 1, bendamustine 70 mg/m² on Days 1,2 of a 21-day cycle), and also in combination with rituximab at a dose of 375 mg/kg over the next 3 cycles. Hematological toxicity of grades 1-2 severity was noted as a complication during therapy. Thus, the patient achieved an objective response to the therapy for the first time.

In August 2020 the repeated biopsy was taken and histological study was performed. EBV-positive B-cell proliferation with high CD30 expression was considerably reduced in the repeated specimen. Key morphological changes after combined therapy are demonstrated in Figure 3.

Figure 3. Morphological changes of lymphoid tissue in sequential specimens from the patient with AITL Left side, primary biopsy; right side, repeated biopsy after combined therapy (CHOEP, CsA, GDP, BV, BV+bendamustine). Disappearance of EBV+ B-cell clone with high CD30 expression is observed in repeated biopsy. Immunostaining for CD20, CD30, EBER antigens. Magnification 200x

Subsequently, therapy was continued with lenalidomide (25 mg orally, days 1-21, from December to March 2021), leading to a complete response according to PET/CT from February 2021.

Considering the refractory, relapsed course of the disease, with the aim of consolidating remission, allogeneic hematopoietic stem cell transplantation (HSCT) was performed in April 2021 from HLA- mismatched unrelated donor. A reduced intensity conditioning regimen was used (FluBe: bendamustine 130 mg/m²×3, fludarabine 30 mg/m²×3). A total of 6.5×10^6 CD34+ cells were reinfused. Graft-versus-host disease (GvHD) prophylaxis included post-transplant cyclophosphamide (50 mg/kg), tacrolimus (0.03 mg/kg), and MMF (45 mg/kg). The post-transplant period was complicated by febrile neutropenia and overlap syndrome: stage 2 chronic skin GvHD, stage 3 liver GvHD (Day +124). Resolution of GvHD was noted against the background of systemic glucocorticosteroid therapy (1 mg/kg). Currently, the patient maintains the remission state since February 2021 with no evidence of GvHD, the transplant is functioning satisfactorily, and there is full donor chimerism.

Discussion

nTFHL-AI (AITL) is a rare and aggressive subtype of PTCL, which does not have successful treatment standards. It accounts for approximately 1-2% of all non-Hodgkin's lymphoma cases, but almost 1 of 5 PTCL cases per year [12]. AITL is associated with a high level of immune cell infiltration within the tumor microenvironment, including T-cells, B-cells, macrophages and dendritic cells. This immune cell infiltration is thought to be involved in the pathogenesis of AITL and may contribute to the dysregulated immune response observed in the disease. The prognosis for patients with AITL is generally poor. The rate of complete responses to first-line therapy (СHOP, СHOEP, Bv+CHP) is 39%, and the 2-year event-free survival rate does not exceed 45% [13].

The present case report demonstrates a refractory course of the disease after first-line therapy. In the International T-Cell Lymphoma Project, in which 85% of patients received CHOP-based therapy (without upfront ASCT consolidation), the 5-year failure-free survival rate for patients with AITL was only 18% [2]. In this way, treatment options include a combination of chemotherapy or single-agent chemotherapy for relapsed or refractory disease. [14] Despite undergoing combined chemotherapy, hypomethylating and immunosuppressive therapy, this patient failed to achieve a response and further disease progression was observed.

This case demonstrates the important role of the microenvironment in response to therapy. Despite the absence of CD30+ expression on tumor cells, a partial response was achieved with BV therapy. Moreover, the response deepened to complete when using the immunomodulatory agent lenalidomide, which also affects the tumor microenvironment. Thus, even in the absence of CD30 on tumor cells in AITL, a good response to BV therapy can be achieved in some cases. According to a study by Horwitz et al. on a series of CD30-positive PTCLs, CD30 expression according to IHC ranged from 0% to 95%. The series included 6 patients (17%) with undetectable CD30 expression who, nonetheless, responded to anti-CD30 therapy [15]. Thus, responses to CD30-targeted therapy can be observed in patients with extremely low or undetectable levels of CD30 expression. The possible explanation of such an effect is the diffusion of monomethyl auristatin E from the target CD30-reactive cells into the tumor microenvironment and induction of cytotoxicity [16]. Overall, the microenvironment of AITL represents a complex and dynamic system that plays a crucial role in the course of the disease. Understanding the interactions between tumor cells, immune cells, stromal cells, and cytokines in the microenvironment may provide new insights into the pathogenesis of AITL and potential therapeutic targets.

Allogeneic hematopoietic stem cell transplantation has the most compelling evidence of curative potential or the possibility of achieving long-term disease remission in patients with T-cell lymphomas [17]. It is associated with a 2- to 5-year progression-free-survival of 81% for AITL [18-20] Thus, for appropriate patients, consolidation with alloSCT should be considered at all stages of therapy as a highly effective method of consolidating remission, provided that disease control has been achieved.

In conclusion, even in cases of refractory disease progression with standard therapeutic approaches, including chemotherapy and targeted agents, the use of immunotherapy or therapies targeting the tumor microenvironment can potentially shift the balance in the tumor substrate and achieve a response. Specifically, drugs such as BV and lenalidomide can demonstrate their efficacy, even in the case of CD30-negative lymphoma, by affecting the immune component of the tumor.

Conflict of interest

The authors declare that they have no conflict of interest. Also, there is no financial relationship with any organization for this project.

Funding

This research was funded by the Russian Science Foundation research grant (project number 22-75-00117).

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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