Limfom malign non-Hodgkin difuz cu celulă mare B avansat – un caz clinic atipic, boală refractară și provocări terapeutice în practica curentă

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in adults, accounting for approximately 30-40% of these neoplasms⁽¹⁾. The combination of immunotherapy, the anti-CD20 monoclonal antibody rituximab, in the first-line treatment with standard chemotherapy, led to an increase cure rate for these patients, and the R-CHOP protocol (rituximab – cyclophosphamide – doxorubicin – vincristine – prednisone⁽¹⁾) has become the gold standard for first-line treatment. However, the R-CHOP protocol is insufficient for some patients to achieve complete remission⁽¹⁾. These patients are classified as refractory⁽²⁾ or relapsed (R/R), and conventional therapeutic options, such as salvage chemotherapy⁽²⁾ followed by autologous stem cell transplantation, have limited efficacy. In these patients, the prognosis remains extremely poor, and most data illustrate a median survival of approximately six months⁽²⁾ in those with refractory disease⁽²⁾. In recent years, innovative therapies⁽⁴⁾, such as CAR-T⁽⁴⁾ and bispecific antibodies, have emerged, offering promising results in some refractory cases, but in the current practice, having access to these treatments may be difficult. Therefore, the early identification of high-risk patients and the development of effective therapeutic strategies remain increasingly important challenges.

We present the case of a 37-year-old woman with no significant medical history, who had a nodular lesion in the right breast for approximately four months. She underwent breast ultrasound and magnetic resonance imaging (MRI). The patient did not experience B symptoms (fever, weight loss or night sweats), and her general condition at diagnosis was good, with an ECOG performance status of 1.

A biopsy of the breast tumor with axillary extension was performed. Histopathological and immunohistochemical examination established the diagnosis of diffuse large B-cell non-Hodgkin lymphoma, not otherwise specified (NOS), germinal center B-cell-like (GCB-like) subtype. The immunophenotype was strongly positive for CD45, CD20, CD10 and BCL6, with a Ki-67 proliferation index of approximately 95%, indicating a high proliferative activity. For complete staging, PET-CT imaging and bone marrow biopsy were subsequently performed.

PET-CT revealed a bulky, metabolically active lymphadenopathic mass (SUV=24.97) measuring approximately 108×76×122 mm, located in the right axilla and extending into the retropectoral and interpectoral regions. The mass was indistinguishable from the pectoralis major and minor muscles, and exerted a mass effect on the right breast. A large, partially necrotic, metabolically active tumor mass (SUV=22.25), measuring approximately 110×80 mm, was also identified, involving the shoulder girdle muscles and causing lytic destruction of the right scapula. Bone marrow biopsy showed no evidence of malignant lymphoid infiltration.

Based on clinical, histopathological, immunohistochemical and imaging findings, the diagnosis of diffuse large B-cell non-Hodgkin lymphoma, not otherwise specified (NOS), germinal center B-cell-like (GCB-like) subtype, stage IVA bulky, was established.

First-line treatment was initiated with the R-CHOP protocol, consisting of rituximab 375 mg/m² i.v., cyclophosphamide 750 mg/m², doxorubicin 50 mg/m² and vincristine 1.4 mg/m², administered on day 1, together with prednisone 100 mg daily on days 1-5. The regimen was administered every 21 days.

After three cycles of treatment, an interim PET-CT evaluation was performed. The scan demonstrated a reduction in both size and metabolic activity of the axillary lymphadenopathic mass, now measuring 50×48 mm, with SUV=3.74 (previously 108×76 mm; SUV=24.97), showing central necrosis. The right scapular osteomuscular tumor mass also decreased in size to 80×40 mm (previously 110×80 mm), but remained metabolically unchanged, with SUV=22.21 (previously 22.25). The overall metabolic response corresponded to a Deauville score of 5.

Given the discordant treatment response and the lack of metabolic improvement in the right scapular lesion, a biopsy was performed. Histopathological and immunohistochemical findings were consistent with diffuse large B-cell lymphoma.

The disease was considered refractory, and the treatment was switched to R-DHAP (rituximab, dexamethasone, cisplatin and cytarabine) as salvage chemotherapy, followed by autologous hematopoietic stem cell (HSC) collection and transplantation. Imaging reassessment after three cycles of R-DHAP demonstrated disease progression, with both dimensional and metabolic enlargement of the scapular musculoskeletal tumor mass.

Given the lack of response to treatment and the fact that the patient changed her mind, refusing the autologous stem cell transplantation, it was decided to submit the patient’s file to the Cell Therapy Commission. Until a harvest date could be established, we continued with ACVBP chemotherapy protocol.

In the next period, the patient’s clinical course was marked by deterioration of her general condition and progressive worsening of symptoms, including pain in the scapulohumeral tumor area, which was refractory to symptomatic management. She developed functional impairment of the right arm and suppurative lesions within the tumor mass. Due to the associated local infection, the case was reevaluated, and the decision was made to postpone CAR-T cell harvesting⁽⁴⁾ and continue chemotherapy. The clinical course was characterized by progressive deterioration of clinical and laboratory parameters and rapid tumor growth. Approximately 13 to 14 months after diagnosis, the patient died from fulminant progression of lymphoma, refractory to all lines of therapy administered.

Discussion and brief review
of the literature

The case presented illustrates a rare and therapeutically challenging situation: diffuse large B-cell lymphoma (DLBCL) refractory to standard treatment. Although DLBCL is an aggressive subtype of non-Hodgkin lymphoma, approximately 60-70% of patients achieve complete remission following first-line R-CHOP therapy⁽¹⁾. However, there is a subset of patients with no response and early relapse⁽²⁾, and these cases are associated with a poor prognosis.

The literature describes that 20-40% of DLBCL patients develop refractory⁽²⁾ or relapsed disease after first-line therapy, and they achieve subsequent remissions using second-line regimens, but these are often short-lived. The median survival of these patients, in the absence of innovative therapies⁽⁴⁾, is less than one year – approximately six months, according to recent studies. Thus, primary refractoriness reflects an aggressive tumor behavior, and it is associated with a markedly reduced likelihood of disease control using standard therapeutic approaches.

In our 37-year-old women, although the lymphoma had a germinal center B-cell (GCB) phenotype, its clinical course was aggressive and refractory, highlighting the biological heterogeneity of DLBCL and suggesting that unfavorable prognostic factors (such as high IPI score and large tumor burden) may outweigh phenotypic advantages in determining disease behavior.

Salvage chemotherapy followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT)⁽³⁾ has long represented the mainstay of second-line therapy. However, the success of this approach depends largely on the chemosensitivity of the tumor; therefore, in patients with chemoresistant or refractory disease, the likelihood of achieving remission in order to proceed to transplantation is minimal.

In clinical practice, more than 80% of patients with relapsed or refractory DLBCL fail to undergo hematopoietic stem-cell transplantation (HSCT), either because of inadequate response to salvage chemotherapy or because of poor clinical condition, and less than 20% may achieve long-term survival after ASCT⁽³⁾. Moreover, there is a significant proportion of patients – often elderly – who are ineligible for autologous transplantation, because of the toxicities associated with conditioning regimens.

This case, refractory to conventional regimens, reflects the limitations of standard therapy and highlights the urgent need for alternative therapeutic strategies.

New therapeutic options

Over the past decade, several innovative therapies have been developed for refractory aggressive lymphomas, reshaping the therapeutic landscape of these diseases. The most significant is represented by chimeric antigen receptor T-cell (CAR-T) therapy⁽⁴⁾ – a personalized immunotherapy that uses genetically modified autologous T cells to target the CD19 antigen expressed on malignant B cells.

In 2018, the first two anti-CD19 CAR-T⁽⁴⁾ products – tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®) – were approved by the U.S. Food and Drug Administration for adult patients with relapsed or refractory DLBCL who had received at least two prior lines of therapy. Clinical studies have shown that approximately 30-40% of these patients achieve durable remission following CAR-T therapy⁽⁴⁾, which represents a remarkable outcome, given the historical failure of conventional regimens⁽¹⁾.

For patients with primary refractory or early-relapsed (within 12 months) DLBCL after R-CHOP, the current international guidelines now recommend CAR-T therapy⁽⁴⁾ as a second-line option instead of autologous transplantation, as it has demonstrated superior survival outcomes in these high-risk subgroups⁽¹⁾. In the present case, the access to CAR-T therapy was, unfortunately, not possible.

In addition to CAR-T therapy⁽⁴⁾, several other targeted agents have been incorporated into the treatment of refractory or relapsed DLBCL:

1. Polatuzumab vedotin, an anti-CD79b antibody-drug conjugate, in combination with bendamustine and rituximab, has demonstrated clear benefits in patients ineligible for hematopoietic stem cell transplantation, significantly prolonging survival compared with stan­dard chemotherapy.

2. Loncastuximab tesirine, another anti-CD19 antibody-drug conjugate, is approved for use in third-line therapy and has shown substantial response rates in clinical trials.

3. Bispecific monoclonal antibodies (e.g., glofitamab, epcoritamab), which simultaneously target CD20 on tumor B cells and CD3 on T cells, have induced remissions even in patients previously treated with CAR-T therapy⁽⁴⁾, representing a promising option in third- or fourth-line treatment.

4. Additionally, the combination of the anti-CD19 antibody tafasitamab with the immunomodulatory agent lenalidomide has been approved as second-line therapy for patients ineligible for autologous transplantation, demonstrating effective disease control. These novel therapies provide an opportunity to achieve clinical responses in patients with refractory lymphoma. However, they are often associated with high costs and require specialized infrastructure.

This case, managed prior to the widespread availability of these novel agents, underscores the urgent need for access to modern therapies. The lack of response to conventional treatments in this atypical case of refractory GCB-like DLBCL highlights that, beyond standard protocols, the absence of validated clinical biomarkers necessitates that therapeutic decisions are largely guided by clinical factors and assessment of treatment response. This emphasizes the importance of an individualized approach in managing refractory DLBCL, with treatment strategies tailored to both the biological profile of the tumor and the characteristics of the patient.

Conclusions

This case illustrates the rapid and aggressive course of diffuse large B-cell lymphoma refractory to standard therapy and the associated therapeutic challenges. Despite modifications in the treatment regimen, the disease progressed rapidly, resulting in the patient’s death approximately one year after diagnosis, underscoring the poor prognosis associated with refractory disease. Careful monitoring of therapeutic response from the first cycles is critical, and at the earliest signs of refractoriness, prompt transition to salvage therapies is essential.

Furthermore, this case underscores the need for implementing innovative therapies in routine practice. Recent advances – including CAR-T therapy⁽⁴⁾ and other targeted agents, such as antibody-drug conjugates, bispecific antibodies, and immunotherapeutic combinations – have demonstrated potential to induce remission in patients previously considered without therapeutic options. Integrating these therapies into clinical practice and identifying appropriate candidates are key steps toward improving survival in refractory diffuse large B-cell lymphoma.

In conclusion, managing primary refractory diffuse large B-cell lymphoma remains highly challenging, requiring both prompt recognition of refractoriness and access to state-of-the-art therapeutic strategies. This case emphasizes the importance of continued medical innovation, ensuring that future patients may benefit from advanced therapies, such as CAR-T, with potential curative outcome.  

Corresponding author: Alina-Mihaela Menciu E-mail: grigoroiu.alina@gmail.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.