High-Grade B-Cell Lymphoma

Presentation and Diagnosis

A 64-year-old male with no major health issues except for obesity presented to his PCP with a 5-week history of bilateral neck swelling, fevers, night sweats, and an unintentional weight loss of 20 pounds. CT scan of the neck and chest demonstrated diffuse adenopathy in the cervical, axillary, and hilar regions. An excisional biopsy was obtained of a left cervical node that measured 3 cm. This demonstrated a germinal center B-cell lymphoma (GCB; using the Hans algorithm). Immunohistochemistry (IHC) CD20+, CD10+, BCL2+, MYC+, and Ki67 was >85%. Fluorescence in situ hybridization (FISH) demonstrated a rearrangement of MYC and BCL2 with no BCL6 rearrangement, consistent with a double-hit lymphoma (DHL). He then underwent a complete workup in which an FDG-PET demonstrated hypermetabolic diffuse lymphadenopathy above and below the diaphragm. Bone marrow biopsy was positive. His lactate dehydrogenase (LDH) was elevated. He had stage IVB Age-Adjusted International Prognostic International stage 2 (LDH, stage IV) and CNS-International Prognostic Index (CNS-IPI) of 4 (age, LDH, stage, extranodal sites) DHL, also referred to as a high-grade B-cell lymphoma (HGBL).  

Initial Treatment

He was treated with six cycles of dose-adjusted (DA) R-EPOCH (rituximab and etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) with methotrexate intrathecal prophylaxis. He had a dose delay following his first cycle due to prolonged neutropenia. He had an end-of-treatment PET complete response (CR; Deauville 2).  

Relapse and Treatment in Setting of Double Hit Lymphoma

Sixteen months later, he developed night sweats and increased abdominal pain. FDG-PET demonstrated extensive hypermetabolic diffuse lymphadenopathy with a large abdominal mass. This was biopsied and again demonstrated GBC lymphoma; IHC CD20+, CD10+, BCL2+, MYC+, and Ki67 was >55%. FISH was consistent with DHL due to the presence of MYC and BCL2 gene rearrangement.  

He received three cycles of RICE (rituximab, ifosfamide, carboplatin, etoposide) with a good partial response (PR; Deauville 3) demonstrating chemosensitive disease. He then underwent an autologous stem cell transplant (ASCT) with BEAM (carmustine [BCNU], etoposide, cytarabine, melphalan). Transplant complications included esophagitis and neutropenic fever. End-of-treatment PET demonstrated stable disease (SD; Deauville 4). 

Relapsed/Refractory Treatment

Two months later, he developed recurrent symptoms with swelling in his neck. Repeat PET demonstrated progressive disease (PD; Deauville 5). The APP discussed treatment options including the role of allogeneic stem cell transplant, clinical trials, and other novel therapies. He opted for CAR T-cell therapy with lisocabtagene maraleucel (liso-cel) with lymphodepleting treatment with fludarabine and cyclophosphamide. Approximately 48 hours after his CAR-T infusion, he developed a grade 2 cytokine release syndrome (CRS) due to fever and hypotension. He received one dose of tocilizumab. He had a resolution and had no further CRS or immune effector cell–associated neurotoxicity syndrome (ICANS). End-of-treatment PET demonstrated complete metabolic response (Deauville 3). 

Discussion

Pathobiology of Distinct Subtypes of DLCBL 

Diffuse large B-cell lymphoma (DLBCL) is heterogeneous in pathologic characteristics, biology, and clinical behavior. Gene expression profiling has identified distinct subtypes within DLBCL not otherwise specified based on cell of origin: GCB subtype and activated B-cell (ABC, also known as non-GCB). These subtypes are different both molecularly and clinically.^1-3 GCB usually has a better prognosis than the ABC subtype.  

Increased MYC protein (>40%) expression by IHC has been reported in 5% to 8% of patients with DLBCL and often correlates with GCB phenotype and higher risk for progression. Patients with an expression of MYC and either BCL2 and/or BCL6 gene rearrangements in IHC should undergo If the FISH or karyotype is positive for MYC, BCL2, and/or BCL6, this is called a double-hit/triple-hit lymphoma (DHL/THL), which are often referred to as high-grade B-cell lymphomas.^1-4

Patients with DHL/THL have a poor prognosis to standard chemoimmunotherapy and have an increased risk of CNS involvement.^2,3 This can occur at the time of diagnosis or at the time of relapse. The CNS-IPI is a useful clinical tool to predict the risk for central nervous system (CNS) relapse in patients with aggressive lymphomas.⁵

DLBCL and IHC expression of MYC and BCL2 without chromosomal rearrangements is called double expressor lymphomas. It is commonly seen in the ABC subtype.^1-3

Frontline Treatment  

GCB (without gene rearrangements) is associated with an improved outcome compared to DHL/THL and ABC when treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Several ongoing randomized clinical trials are exploring whether the addition of novel targeted agents to R-CHOP will selectively improve the outcome of patients with ABC. Retrospective studies have suggested improved outcomes with intensive chemoimmunotherapy for DHL/THL. DA-R-EPOCH is the preferred treatment for patients with DHL/THL with translocations of MYC, BCL2, and/or BCL6. CNS prophylaxis should be given due to the increased risk of CNS relapse in patients with 4 to 6 risk factors on the CNS-IPI, as well as for patients with DHL/THL.⁶

Randomized trials have evaluated R-CHOP vs intensive frontline regimens in DHL/THL and these have shown to be associated with higher rates of CR and in some instances with improved progression-free survival (PFS) but not overall survival (OS).^2,6,7 In a prospective phase II trial, 53 untreated patients with MYC gene rearrangement (19 with MYC rearrangement alone and 24 also with rearrangement of BCL2, BCL6, or both) DHL/THL were treated with DA-R-EPOCH. After a median follow-up of 56 months, 48-month event-free survival (EFS) and OS rates were 71% and 77%, respectively, for all patients who received DA-R-EPOCH.⁴

Overall, studies have not found a benefit to consolidative ASCT following intensive frontline treatment in patients with DHL/THL.⁸ Patients treated with R-CHOP followed by consolidated ASCT had a similar outcome to those treated with intensive regimens.⁹

In this case, our patient was treated with six cycles of DA-R-EPOCH and received CNS prophylaxis with intrathecal methotrexate. At the end of treatment, PET was consistent with a complete metabolic response to therapy. He was not offered consolidation with ASCT. 

Relapsed/Refractory Treatment 

Relapsed/refractory (R/R) DHL/THL should be managed similarly to DLBCL. The current standard of care (SOC) is salvage chemoimmunotherapy with ASCT; however, a retrospective study evaluating outcomes in relapsed DLBCL, that also included patients with DHL undergoing ASCT, demonstrated that patients with chemosensitive disease had minimal benefit. Four-year OS of patients with DHL was 28% compared with 57% for patients who did not have DHL.¹⁰ Our patient received three cycles of RICE. He then underwent an ASCT with BEAM, and his end-of-treatment PET demonstrated SD (Deauville 4). 

Third-Line Treatment 

The management of patients with R/R disease is quite challenging given the aggressive clinical behavior of DHL/THL. Patients with DHL/THL are less likely to achieve a CR following salvage therapy. Clinical trials should be considered to evaluate novel treatments and/or combinations. Several novel therapies have emerged in the third-line setting and subsequent therapies for patients with R/R DLBCL including HGBL. For patients with disease that relapses post-ASCT, NCCN Guidelines recommend CAR T-cell therapy (axicabtagene ciloleucel [axi-cel] or liso-cel) as an option for patients achieving PR following second-line therapy (regardless of their eligibility for transplant) and for those with disease relapse after achieving CR to second-line therapy or PD.¹¹

CAR T-cell therapy is FDA approved for the treatment of R/R HGBL after ≥2 prior systemic therapy regimens.¹¹ The TRASCEND trial evaluated liso-cel in 344 patients with R/R DLBCL including HGBL. Among 256 evaluable patients, liso-cel resulted in an objective response rate of 73% with CR of 53%. With a median follow-up of 19 months, PFS was 44%, and OS was reported as 58% at 1 year.¹² The ZUMA-7 trial evaluated axi-cel against SOC, indicating improvement in EFS at 8.3 months vs 2 months, respectively. This advantage was consistent in all subgroups including patients with high-risk disease.¹³

Based on these studies, axi-cel and liso-cel resulted in responses across all of the subgroups including DHL/THL, GCB, and ABC subtypes, and patients with either relapsed or primary refractory disease. The level of CD19 expression did not correlate with response.  

Other novel therapies 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.¹¹

In this case, treatment options were discussed, and in a shared-making process, the patient opted for CAR T-cell therapy with liso-cel.   

The advanced practitioner plays an intricate role in the shared decision-making process with patients to provide the most updated information and findings available and to assist in choosing the best treatment decision for the patient.   

References

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11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.6.2023. October 10, 2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf 
12. Abramson JS, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396:839-852. 
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