Top 10 Advances in Large B-Cell Lymphomas in the Past 10 Years

Sarah Rutherford, MD

Over the past 10 years, treatment options for patients with large B-cell lymphomas (LBCLs) have expanded with the approval of several new classes of treatment.

Many clinicians believe the most significant advance in LBCL treatment in this time is the development of chimeric antigen receptor (CAR) T-cell therapy.

“I definitely think that this is the most notable agent in the last 10 years,” said Sarah Rutherford, MD, an assistant professor of medicine and the John P. Leonard, MD/Gwirtzman Family Research Scholar in Lymphoma at Weill Cornell Medical College, Cornell University, in an interview with Targeted Therapies in Oncology™.

Brian T. Hill, MD, PhD

Brian T. Hill, MD, PhD, director of the Lymphoid Malignancies Program and a staff physician at Cleveland Clinic Taussig Cancer Institute, agreed. “Because there are now patients 5 years out without any signs of relapse with a single treatment of cell therapy 5 years ago, I think it’s pretty clear that is curative therapy in a proportion of patients who otherwise wouldn’t be alive. The clinical impact on patients who received it really can’t be understated.”

Many subtypes of LBCL have been recognized.^1,2 Their clinical and pathologic heterogeneity contributes to variations in prognosis and response to treatment.^3,4

In 2012, standard treatment was chemoimmunotherapy with the anti-CD20 monoclonal antibody rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Response rates in this “rituximab era” were 80% to 90% in low-risk diffuse LBCL (DLBCL), but 5-year overall survival (OS) rates were only 30% to 50%, indicating a need for additional personalized therapies to improve outcomes, especially following standard R-CHOP therapy.³

1. CAR T-Cell Therapies

CAR-T cells are produced from autologous patient T cells transduced with CARs engineered to bind to a specific tumor antigen via an extracellular domain, CD19 for B-cell malignancies, and containing costimulatory molecules.5 These agents have been welcomed into the treatment paradigm due to high response and survival rates.

Axicabtagene ciloleucel (Yescarta) received FDA approval in 2017 for the treatment of relapsed/ refractory (R/R) DLBCL, primary mediastinal B-cell lymphoma (PMBCL), high-grade BCL, and transformed follicular lymphoma (FL). In 2019, the agency approved the drug for patients with LBCL that had progressed on 2 prior therapies; in 2021, for R/R FL, and in April 2022, for LBCL refractory to or relapsing within 12 months of first-line chemoimmunotherapy (TIMELINE). ^5-7

Tisagenlecleucel (Kymriah) was approved in 2018 for adult R/R LBCL, including DLBCL, highgrade BCL, and DLBCL arising from FL.^5,8

In 2021, the FDA approved lisocabtagene maraleucel (Breyanzi) for patients with R/R LBCL, including DLBCL, high-grade BCL, PMBCL, and FL grade 3B after at least 2 lines of systemic therapy.^5,9 Then in June 2022, the agency approved the CAR T-cell therapy for those with LBCL refractory to or relapsing within 12 months of first-line chemoimmunotherapy.¹⁰

CAR T-cell therapy is associated with potentially life-threatening toxicities, including cytokinerelease syndrome and neurologic toxicities, although advances in management have improved outcomes. Loss of the target antigen, CD19, renders treatment ineffective.^1,11,12

Although CAR-T therapy results in effective and durable clinical responses for about 40% of patients, not all patients are even candidates due to age, comorbidities, or lack of chemotherapysensitive disease. The length of time required to manufacture this individualized therapy may be too long for those with rapidly progressive disease to wait.^11,12 Further, few facilities are able to administer CAR T-cell therapy, as they must be accredited by the Foundation for the Accreditation of Cellular Therapy, making access also an issue.

“For those who can’t receive CAR T-cell therapy, there are 4 other FDA-approved targeted therapies: polatuzumab vedotin [Polivy], selinexor [Xpovio], tafasitamab [Monjuvi] administered with lenalidomide [Revlimid], and loncastuximab tesirine [Lonca, Zynlonta]. We can tailor our targeted approach to each individual patient in a way much better than we could before because we have many different options,” Rutherford said.

2. Monoclonal Antibodies

R-CHOP as standard therapy has endured for 2 decades despite attempts to improve upon it with added chemotherapy or novel agents.13 More than half of patients who receive R-CHOP can be cured; the survival of those who are event free for 2 years is equivalent to that of an age- and sex-matched population; 10% to 20% have primary refractory disease that is nonresponsive to R-CHOP; and 30% to 40% experience relapse after achieving a complete response (CR) to treatment.¹⁴

In 2017, the FDA approved a new formulation of rituximab (Rituxan Hycela), allowing rituximab to be administered via subcutaneous injection in a few minutes rather than an hours-long intravenous infusion, to patients with DLBCL, among other indications.¹⁵

Tafasitamab, a cytolytic, humanized, monoclonal antibody directed against CD19, was granted accelerated approval by the agency in 2020 in combination with lenalidomide followed by tafasitamab monotherapy in adults with R/R DLBCL who were not eligible for autologous stem cell transplant. In the open-label single-arm phase 2 L-MIND trial (NCT02399085), the best overall response rate (ORR) was 57.5% (95% CI, 45.9%-68.5%) after at least 35 months of follow-up, with a 40% CR rate. Responses were durable, with a median duration of 43.9 months (95% CI, 26.1-not reached).^16,17

3. Molecular Classification and Prognostic Markers

There are 2 recognized cell of origin–based subtypes of DLBCL: germinal center B cell (GCB) and activated B cell (ABC). Classification of these distinct subtypes was added to the 2016 revision of the World Health Organization’s classification of lymphoid neoplasms.²

Patients treated with R-CHOP who have the GCB subtype, which is more common, have better outcomes than those with the ABC subtype.^18,19 The current frontline standard of care is the same for both subtypes. Immunohistochemistry (IHC) algorithms can be used to distinguish GCB from nonGCB, although the non-GCB subtype is more heterogeneous than the ABC subtype by gene expression profiling.¹

Immunophenotyping by IHC is used for risk stratification as well as diagnosis, and includes CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM1, and MYC. The presence of MYC plus either BCL2 or BCL6 by IHC should be followed by fluorescence in situ hybridization or karyotyping to detect rearrangements of these genes.¹

Lymphomas with rearrangements of MYC and BCL2 and/or BCL6 (double-hit or triplehit, usually GCB subtype) have become classified as high-grade lymphomas over the past 6 years, and account for about 4% to 8% of all LBCL cases.^2,19 Intensified induction treatment is preferred for these patients as outcomes with R-CHOP treatment are poor. When MYC and BCL2 are overexpressed (double-expressor, usually ABC subtype) rather than rearranged, prognosis may also be poor, and improved with intensified induction. Primary DLBCL of the central nervous system (typically ABC subtype) is rare, and is also associated with poor prognosis.^18,19

Although understanding molecular and genetic subtypes can enhance treatment allotment in clinical studies, a unified model appropriate for clinical practice has not yet been defined.¹⁸

4. Antibody-Drug Conjugates

Antibody-drug conjugates selectively deliver cytotoxic agents to malignant cells by linking a monoclonal antibody that targets an antigen on those cells with a cytotoxic payload.⁴

Polatuzumab vedotin combines an antiCD79b monoclonal antibody with a potent microtubule inhibitor. It was granted accelerated approval by the FDA in 2019 in combination with bendamustine and rituximab (BR) for the treatment of adults with R/R DLBCL after at least 2 prior therapies. The CR rate for polatuzumab plus BR was 40% vs 18% with BR alone, with best ORR of 63% and 25%, respectively.²⁰

Polatuzumab showed activity in a phase 1b/2 trial (NCT01992653) as first-line therapy for DLBCL with rituximab plus cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP), eliminating vincristine from CHOP to avoid the overlapping neurologic toxicity with polatuzumab. Responses were seen in 89% of patients and CRs in 77%.²¹

The double-blind phase 3 POLARIX trial (NCT03274492) compared pola-R-CHP with R-CHOP in patients with previously untreated, intermediate, or high-risk DLBCL. At a median follow-up of 28.2 months, 76.7% of patients in the pola-R-CHP group survived without progression at 2 years vs 70.2% of the R-CHOP group (HR for progression, relapse, or death, 0.73; 95% CI, 0.57-0.95; P = .02). There was no significant difference in OS rates at 2 years (88.7% with pola-RCHP vs 88.6% with R-CHOP; HR, 0.94; 95% CI, 0.65-1.37; P = .75). The safety profile was also comparable between the groups.²²

Lonca combines a humanized anti-CD19 monoclonal antibody with an alkylating cytotoxin causing interstrand DNA crosslinks.²³

Lonca monotherapy received accelerated approval in 2021 for patients with R/R LBCL, including DLBCL and high-grade BCL, after at least 2 lines of systemic therapy based on the results of the open-label, single-arm LOTIS-2 trial in DLBCL (NCT03589469). Participants in the phase 2 study included those with highrisk, poor prognosis, and double- and triple-hit lymphoma after at least 2 prior regimens. The ORR was 48.3% (95% CI, 39.9%-56.7%), including a CR rate of 24.1%. The median duration of response was 10.3 months.^23,24

Responses in patients who had received prior CD19-directed CAR T-cell therapy (n = 13) were similar to those of study patients overall (n = 145), although enrollment required persistent CD19 expression. Treatment with Lonca also did not interfere with response to subsequent CAR T-cell therapy (n = 15; ORR, 47%), suggesting Lonca could be used either as salvage therapy after CAR T-cell therapy or as an alternative or bridging therapy for those with rapidly progressing disease without compromising subsequent CAR T-cell therapy.²³

Recently, the addition of lenalidomide to brentuximab vedotin (Adcetris), an antiCD30 monoclonal antibody with a tubulin disrupting agent, was explored in a phase 1 dose-expansion trial (NCT02086604) in patients with R/R DLBCL. The combination was well tolerated, although most patients had neutropenia requiring granulocyte colony-stimulating factor support. The ORR was 57% (95% CI, 39.6%-72.5%) and the CR rate was 35%, with a median duration of response of 13.1 months.²⁵

5. Other Targeted Therapies

Selinexor is an oral, selective small molecule inhibitor of XPO1-mediated nuclear export. It received accelerated approval in 2020 for adults with R/R DLBCL after 2 to 5 prior lines of therapy, including progression after or ineligibility to undergo transplant. In the single-arm, open-label phase 2 SADAL trial (NCT02227251) in heavily pretreated patients, the ORR was 28% (95% CI, 20.7%- 37.0%) and the CR rate was 12%. The disease control rate was 37% (95% CI, 28.6%-46.0%) and the median duration of response was 9.3 months (95% CI, 4.8-23.0). The most common grade 3 or higher AEs were cytopenias.^1,26,27

The safety and efficacy of venetoclax (Venclexta), a selective BCL2 inhibitor approved for other hematologic malignancies, was assessed in the phase 2 CAVALLI trial (NCT02055820) in combination with R-CHOP in patients with treatment-naïve DLBCL overexpressing BCL2 protein by IHC. At a median follow-up of 32.3 months, the ORR was 83% and the CR rate was 69%. Treatment was associated with increased, manageable myelosuppression. A cross-trial comparison with the GOYA trial (NCT01287741) of standard R-CHOP did not show a progression-free survival advantage.²⁸

6. Enduring Roles of Chemotherapy, Radiotherapy, and Transplant

Involved-site radiation therapy (ISRT) can follow R-CHOP first-line therapy for bulky stage I and II DLBCL without extensive mesenteric disease. This form of therapy is recommended for patients who are not candidates for chemoimmunotherapy.¹

Those with DLBCL that relapses after more than 12 months can be considered for transplant. After second-line therapy, transplant-eligible patients who experience CR or partial response can receive high-dose therapy with autologous stem cell rescue, or in some cases allogeneic hematopoietic cell transplant.¹

7. Bispecific Antibodies

Bispecific antibodies simultaneously target tumor and immune cell antigens. Several are in development for B-cell lymphomas, including blinatumomab (Blincyto), which binds CD19 and CD3, and mosunetuzumab and glofitamab, which bind both CD20 and CD3.^18,29-31 Hill said bispecific antibodies are highly active in R/R lymphomas and appear to be free of many of the toxicities seen with CAR T cells. He speculated that for patients unable to receive CAR T- cell treatment because they are unable to travel to a referral center, bispecific antibodies are likely to be widely available in the community setting, eventually.

8. Newer Cellular Therapies

Hill said, “There’s a lot of excitement about the possibility of delivering therapies that don’t require individual patient manufacturing. These could include off-the-shelf cellular therapies.”

Approaches may include adoptive transfer of cytotoxic natural killer (NK) cells, which, unlike T cells, are not associated with cytokine release syndrome or graft-vs-host disease. This will rely on pre-expanded, banked cells from different sources to allow transfer with minimal human leukocyte antigen matching.³²

In addition to NK cells, other immune effector cells such as invariant NK T cells, γ-δ T cells, and macrophages may be amenable to engineering into alternative CAR constructs to treat R/R B-cell malignancies.¹²

9. Other Biomarkers and Treatment Targets

Other biomarkers that may provide treatment targets are being investigated. TP53 mutations are frequently found in patients with R/R DLBCL and are considered a negative prognostic indicator.³³ These mutations have also been associated with acquired resistance to rituximab and R-CHOP failure.¹⁸ Currently, use of locoregional therapy shows the best survival outcomes for patients with these mutations.³³

Magrolimab, which targets CD47, a molecule that when overexpressed in tumor cells allows them to evade phagocytosis, has shown activity in an early trial.^18,19

Mutations in the histone-methyl transferase EZH2 have been reported in about 25% of GCB lymphomas. The oral EZH2 inhibitor tazemetostat (Tazverik), which is already approved for EZH2-mutation positive R/R FL after at least 2 prior therapies or if there are no other treatment options, has shown initial encouraging efficacy in combination with R-CHOP in untreated DLBCL, and should be further investigated.^34,35

10. Checkpoint Inhibitors

Pembrolizumab, a humanized anti–PD-1 monoclonal antibody, is approved for treatment of patients with R/R PMBL after at least 2 prior lines of therapy.¹ Otherwise, immunotherapy with immune checkpoint inhibitors (ICIs) has not been effective in DLBCL, although a retrospective analysis suggested ICIs could sensitize lymphomas to subsequent chemotherapy.⁴ Combinations of ICIs with R-CHOP or other agents are under investigation.¹⁸

Looking Ahead

“There are still people with really aggressive diseases that just don’t respond to anything you give them. Trying to figure out who they are and why that’s happening, and trying to figure out the better targeted approach earlier on, is what I view as the biggest unmet need,” Rutherford said.

“It’s been a fulfilling time to be a researcher and to care for these patients because we used to have not much to offer for them, and even though we do prefer clinical trials for people when we can, there are reasons why people can’t get on trials, whether it’s comorbidities or lack of availability of trials, etc. It’s been very fulfilling now to have a lot of options for people to talk about, rather than just giving [these patients] different types of chemotherapy that is unlikely to work,” Rutherford said.

Hill agreed. “It has been a very remarkable time,” he said. “I have been at this 11 years, and the treatment options that have been available in 2022 compared [with] 2012 are remarkably improved and likely to be even better in the future.”

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