Follicular Lymphoma Transformed to DLBCL

Presentation and Diagnosis

A 64-year-old male with a past medical history of hypertension presented with multiple enlarged lymph nodes (LNs) in his neck and right groin. He was asymptomatic and had no B symptoms present. Laboratory was normal including his lactate dehydrogenase. An excisional biopsy on his right inguinal LN revealed follicular lymphoma (FL) grade 1-2. PET/CT scan demonstrated diffuse adenopathy above and below the diaphragm with the largest node measuring 2.5 x 3.0 cm (standardized uptake value [SUV]max 2.5). Bone marrow biopsy was negative. The diagnosis of stage IIIA FL, grade 1-2 was made, Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 (age >60, stage III, nodal involvement ≥4). He underwent a watch-and-wait approach, every-3-months lab, and clinical surveillance.   

Transformation to DLBCL and Treatment

Twenty-two months later, the patient developed increased LNs in his neck and shortness of breath, and his right leg was swollen. The venous Doppler was negative for deep-vein thrombosis. Chest CT was negative for pulmonary embolus but demonstrated a 5-cm mediastinal mass, multiple lymphadenopathy in the cervical region, and 3-cm enlarged LN in the right axillary. A biopsy of the right axillary demonstrated that his FL had transformed to diffuse large B-cell lymphoma (DLBCL), germinal center B-cell subtype, positive for BCL2 rearrangement, and MYC negative. PET/CT concurred with the CT findings but also demonstrated diffuse adenopathy in the abdomen and groin.  

He received 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone). His course was complicated with neutropenic fevers following cycles 1 and 3, requiring delays in treatment and hospitalizations. Interim and end-of-therapy PET/CT demonstrated a metabolic complete response (CR; Deauville score 2). He then underwent active surveillance. 

Disease Relapse and Second-Line Treatment

Six months after the completion of treatment, at a routine follow-up visit, the patient reported increased fatigue and unintentional weight loss of 10 pounds. A CT scan demonstrated relapse adenopathy above and below the diaphragm.  

The APP and patient discussed second-line treatment options. Due to his persistent neuropathy and not feeling well, there was a question if he would be an autologous stem cell transplant (ASCT) candidate. The decision was made for the patient to undergo salvage therapy and, based on his response, discuss the options. He received two cycles of R-ICE (rituximab, ifosfamide, carboplatin, and etoposide). A PET/CT demonstrated progressive disease (Deauville score 5).  

Refractory Disease and Third-Line Treatment

The patient was found to have chemotherapy-refractory disease, therefore, ASCT was not an option. CAR T-cell therapy was then discussed; however, the patient lived 55 miles from a healthcare facility, didn’t have reliable transportation, and was going through a divorce in which he would not have continuous caregiver support, all of which would make CAR T-cell therapy difficult. After a long discussion about next-line therapies, the patient opted to proceed with tafasitamab/lenalidomide.  

Discussion

Follicular Lymphoma 

FL is an indolent subtype of non-Hodgkin’s lymphoma (NHL) that accounts for 25% to 40% of all NHL.¹ Clinical outcomes for patients with FL grade 1 vs grade 2 are not different, and treatment recommendations are similar, so the World Health Organization classification grouped these two grades as a single grade of 1-2.²

FLIPI is a prognostic scoring system that divides patients into low-, intermediate-, or high-risk groups based on age, hemoglobin level, longest diameter of the largest involved LN, beta-2 macroglobulin level, and bone marrow involvement. It is useful for assessing a patient’s prognosis and discussing treatment options.³

Based on National Comprehensive Cancer Network (NCCN) Guidelines for the treatment of grade 1-2 FL, immediate treatment at initial diagnosis is not necessary unless the patient presents with specific indications based on the modified GELF criteria.⁴

Transformation of FL to DLBCL  

Transformation to more aggressive large-cell lymphoma occurs in 25% to 60% of patients with FL.^5,6 Although FL is initially an indolent disease, sensitive to a variety of chemotherapeutic agents, it is felt to be incurable, with a continuous pattern of relapse associated with decreasing sensitivity to chemotherapy.⁵ The overall incidence of transformed FL (tFL) is declining due to improvements in novel agents, but overall outcomes remain inferior to other non-tFL. The PRIMA trial reported more than half of transformed lymphomas occurred within the first year of diagnosis and the median time to transformation was approximately 9.6 months. A sub-analysis of this trial also demonstrated that patients with FLIPI scores of 3 to 5 had a higher risk for tFL.⁵

The best initial treatment depends on the prior therapy for the underlying indolent lymphoma and the histology at the time of transformation. Repeat biopsy for histologic confirmation at the time of suspected transformation is essential because there could be either a transformation to DLBCL or a high-grade B-cell lymphoma–double-hit lymphoma/triple-hit lymphoma.  

Initial Treatment Approach of tFL to DLBCL  

Currently, treatment for tFL is typically adopted from the same approaches for DLBCL, as there are no prospective studies evaluating treatment options for tFL only. In a study of patients with FL that also reported the outcomes of 60 patients with biopsy-proven tFL, R-CHOP was the most common treatment for tFL (n = 35; 59%), demonstrating a 5-year overall survival rate of 66% among these patients.⁶ NCCN Guidelines also recommend R-CHOP for patients with stage III-IV disease due to reduced toxicities compared to other regimens.⁴

Consolidative high-dose therapy (HDT)/autologous stem cell rescue (ASCR) following initial therapy for tFL has not been shown to be effective in treatment-naïve patients who achieve a CR following initial therapy with an anthracycline-based chemoimmunotherapy regimen.⁷ There is also no indication for the use of maintenance rituximab in tFL.  

Relapsed or Refractory Disease   

The role of HDT/ASCR following salvage therapy in patients with relapsed disease has been evaluated in several studies. Both the GELTAMO and ABMTR trials suggested that HDT/ASCR should be considered for patients who relapse with chemosensitive disease.^8,9 Second-line regimens that should be considered for patients who are transplant candidates include R-ICE, R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin), R-DHAX (rituximab, dexamethasone, cytarabine, and oxaliplatin), or R-GDP (gemcitabine, dexamethasone, cisplatin, or carboplatin).^10,11

Not a Transplant Candidate 

For patients who are not transplant candidates due to progressive or refractory disease after second-line therapy, several novel therapies have emerged. These include bispecific T-cell engager therapy with epcoritamab or glofitamab; anti-CD79b antibody-drug conjugate polatuzumab vedotin in combination with bendamustine and rituximab; anti-CD19 monoclonal antibody tafasitamab plus lenalidomide; anti-CD19 antibody-drug conjugate loncastuximab; and selective small-molecule inhibitor XPO1-medicated nuclear export selinexor.⁴

Three CAR T-cell products are currently FDA-approved for patients with relapsed/refractory disease, including tFL, after at least two lines of therapy: axicabtagene ciloleucel (axi-cel), tisagenlecleucel, and lisocabtagene maraleucel. Unfortunately, for some patients, like in this case, accessibility, functional status, and disease burden create barriers to these treatments. 

Our patient opted for anti-CD19 monoclonal antibody tafasitamab plus lenalidomide. According to data from the L-MIND trial, among patients with relapsed/refractory DLBCL that had failed ≤3 prior systemic therapy regimens who received the tafasitamab plus lenalidomide combination experienced a 57.5% overall response rate (95% CI, 45.9%-68.5%), which included a CR rate of 40.0% and a partial response rate of 17.5%.¹²

References

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2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer Press; 2008.
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4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology for B-Cell Lymphomas V.5.2023. Accessed August 8, 2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
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8. Vose JM, Zhang MJ, Rowlings PA, et al. Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol. 2001;19:406-413.
9. Rodriguez J, Caballero MD, Gutierrez A, et al. Autologous stem-cell transplantation in diffuse large B-cell non-Hodgkin's lymphoma not achieving complete response after induction chemotherapy: the GEL/TAMO experience. Ann Oncol. 2004;15:1504-1509.
10. Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012;30:4462-4469.
11. 11. Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014;32:3490-3496.
12. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21:978-988.