A summary of treatment guidelines for NHL including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma can be found in the dedicated guideline recommendations section of the portal.
Refer all patients with suspected lymphoma to a clinical hematologist, medical oncologist, or general physician (if appropriate ie. in regional/rural areas) who works in association with a multidisciplinary team and has appropriate expertise in the management of lymphoma. Often, lymphoma workup, diagnosis, specialist referral, and treatment plan can all be done in the outpatient setting. However, high grade lymphomas such as Burkitt lymphoma, subsets of diffuse large B-cell lymphoma, lymphoblastic lymphoma, some mantle cell lymphomas, and peripheral T- and NK-cell are associated with high tumor proliferation rate and extensive disease burden that can result in medical emergencies. Prompt recognition of this subset is vital as medical emergencies related to aggressive lymphoma confer a worse prognosis. Recognition of potential emergencies by the generalist is important as they may be present during initial presentation and necessitate hospitalization and need immediate hematology/oncology consultation for intervention and expedited treatment.1,2
Treatments are broadly divided into the following five categories:3
The most common course of chemotherapy is CHOP (cyclophosphamide, doxorubicin, prednisone, and vincristine), often with an addition of a monoclonal antibody, either rituximab (R-CHOP) or obinutuzumab (O-CHOP). Other chemotherapy regimens include a combination with bendamustine and rituximab, fludarabine, and R-CVP (rituximab, cyclophosphamide, prednisone, vincristine).4 Recently, Pola-R-CHP, a modified drug combination that switches vincristine for polatuzumab vedotin has been approved for patients with an International Prognostic Index of >2 and has shown a significantly superior progression-free survival compared to RCHOP treatment.5 Chemotherapy is sometimes used to prepare the patient for a bone marrow transplant/stem transplant.6
This utilizes high energy beams such as X-rays or protons to destroy cancer cells. Radiation can be used alone to destroy one or two targeted spots that contain cancerous lymphoma and can be used post-chemotherapy to destroy any lymphoma cells that remain.5
Immunotherapy boosts the patient’s own immune system to fight cancer. This includes the use of modified T cells and checkpoint inhibitors. In chimeric antigen receptor (CAR) T cell therapy (CAR T), T cells are collected from the patient and modified to contain specific proteins called receptors. The receptors allow these modified T cells to recognize cancer cells that have the target protein that binds to these receptors. These modified T cells are grown in a lab and then returned to the patient’s body. An immune checkpoint inhibitor binds to PD-1 or PD-L1, receptors located on the surface of the lymphoma cell preventing it from evading the body’s immune response.4, 6
Currently available FDA-approved CAR T therapies include Axicabtagene ciloleucel, Tisagenlecleucel, Brexucabtagene autoleucel, and lisocabtagene maraleucel. Similarly, approved immune checkpoint inhibitors include pembrolizumab.4,6
Targeted therapies act against a specific component within the molecular pathway involved in tumorigenesis. Several targeted therapies are currently approved by the FDA.4,8
Bispecific antibodies (BsAbs) are novel targeted therapies that are revolutionizing the treatment landscape of B cell NHL. In the relapsed/refractory setting, salvage chemotherapy and autologous stem cell transplantation show favorable outcomes in ~50% of patients, whereas the other half will have a poorer outcome with a median overall survival of less than 12 months. This unmet need reinforced the importance of innovative therapies like the BsAbs.9
BsAbs are antibody-based molecules which target an antigen of interest and engage a host immune cell, such as T cells, to trigger immune mediated direct cell cytotoxicity or phagocytosis. The clinical use of T-cell engaging antibodies in B-cell neoplasms began with the use of blinatumomab [an anti-CD19 BsAb) in acute lymphoblastic leukemia. Recently, the US-FDA approved glofitamab and epcoritamab in relapsed or refractory (R/R) DLBCL and mosunetuzumab in R/R follicular lymphoma (FL).9,10 The table below lists major bispecific antibodies.
It is one of the first BsAbs developed for R/R FL is a full-length, humanized, immunoglobulin G1 based BsAb targeting CD20 on B-cells and CD3 on T-cells developed. A multicenter, single-arm phase II pivotal trial (NCT02500407) studied efficacy of mosunetuzumab in 90 fit adult patients with R/R FL (grade 1–3a), after at least two prior lines of treatment, including an anti-CD20 therapy and an alkylating agent. The study demonstrated a reduction in tumor size in 95% of patients after a median follow-up of 18.3 months. The ORR and CR rates were 80 and 60%, respectively, and 70% of complete responders maintained response for at least 18 months. The observed CR rate was significantly higher (P <0.0001) than the historical control CR rate of 14% reported with copanlisib therapy, thereby meeting the primary study endpoint. These data led to the regulatory approval of mosunetuzumab for patients with R/R FL after ≥2 prior lines of therapy in 2022. An updated result of this pivotal phase II study after a median follow-up of 27 months showed a 2-year PFS of 51.4% (95% CI: 39.4–63.3). Mosunetuzumab was associated with longer PFS when compared to the PFS of patients’ last prior therapy (2-year PFS: 23.5%, 95% CI: 14.5–32.5), although limitations should be noted for retrospective comparisons.9
Another phase II trial was conducted among 230 patients with Rr/R B-cell NHL and treated at different dose levels. The most common reported adverse events (AE) were neutropenia (28%), cytokine release syndrome (CRS) (27%), hypophosphatemia (23%), fatigue (23%), and diarrhea (22%). Most of them were of low grade, transient, and occurred early in the first cycle. Among 129 evaluable patients with aggressive B-NHL, the ORR was 34.9% and the complete response (CR) rate was 19.4% with a median response duration of 22.8 months in complete responders. Patients with indolent NHL had longer median progression-free survival (PFS) of 11.8 months versus 1.4 months for aggressive NHL. The clinical response was strongly associated with mosunetuzumab exposure. Overall, mosunetuzumab has a favorable safety profile and can be administered in an outpatient setting.9
Glofitamab is another potent anti-CD20-directed T-cell engager with a 2:1 molecular format to increase biological efficacy. This CD20xCD3 BsAb has a capacity to induce a 40-fold tumor lysis by high-avidity bivalent anti-CD20 and head-to-tail orientation of B- and T-cell binding domains as opposed to a classical 1:1 BsAb format. In a first-in-human phase I trial, glofitamab was administered in dose-escalation steps (0.005–30 mg) to 174 patients with R/R B-cell NHL. The participants were heavily pre-treated with a median of 3 prior therapies, and 90.6% were refractory to their last therapy. The study reported significant clinical activity starting at a dose level of 0.6 mg. Almost all patients had CRS at a dose level of 25mg and this was considered as the maximum tolerated D1 dosing. Subsequently, the recommended phase II dose followed the SUD of 2.5mg (C1D1), 10mg (C1D8) and 30mg (C2D1). The ORR and CR rates were 53.8% and 36.8% respectively in all dosed patients. The responses were higher (ORR: 65.7%, CR: 57.1%) among those who received the recommended phase II dose. Most responses occurred early during treatment, increasing substantially with dose escalation, with sustained responses in 84% of patients after a maximum observation period of 27.4 months. In part 2 of this phase II study, 39% of patients achieved a CR after a median of 42 days after a median follow-up of 12.6 months, which coincides with the first response assessment. Responses were seen across subgroups regardless of age, histology, and prior use of CAR T-cell therapy. Notably, while refractory patients presented a lower CR rate (34%) compared to non-refractory patients (70%), the response displayed remarkable durability, with 78% of responders maintaining their response at 12 months. The 1-year PFS and OS were 37 and 50%, respectively. The most common AE was CRS in 50.3% of all dosed patients, and 71.4% for patients dosed at 2.5/10/30mg recommended dosing (most were of grade 2: 25.1% and 22.9%, respectively.9
Epcoritamab is a CD20xCD30 BsAb, that is administered subcutaneously with initial SUD and continued until disease progression. The dose escalation trial across all B-cell NHL subtypes, escalated doses ranging from 0.0128 mg to 60mg of single-agent epcoritamab in 68 highly refractory CD20+ mature B-cell NHL patients. The trial did not report any dose-limiting toxicities, and 48mg was selected as the recommended phase II dose as no additional responses were recorded beyond this dose. Most common AEs were CRS in 59% (all of grade 1 and 2) and injection-site reactions in 47%. Treatment with epcoritamab demonstrated an ORR and CR rates of 68 and 45% in R/R DLBCL and 90 and 50% in R/R FL, respectively. In the dose-expansion cohort of the phase I/II trial, 157 patients with R/R mature B-cell NHL received a median of 5 cycles (15 doses) at the full dose of 48mg after SUD (0.16mg on D1 and 0.8mg on D8). The ORR and CR rates were 63.1% and 38.9%, respectively. The median time to CR was 2.7 months (range, 1.2–11.1), with an estimated DOR of 12 months. The 6-month PFS rate was 44%; a longer follow-up is needed to determine whether the PFS curve will reach a “plateau”. Epcoritamab demonstrated consistent responses across several pre-specified subgroups, including age, line of therapy, primary refractory disease, and prior exposure to CAR T-cell therapy. The safety profile was as expected from the initial reports of this trial, with the most common AEs being CRS, injection-site reactions and neutropenia.9
Odronextamab is an IgG-like CD20xCD3 BsAb, studied in the ELM trials for the treatment of various B-cell malignancies, including DLBCL and FL. ELM-1, a large dose-finding phase-1 study [with FL=40, MCL=12, marginal zone lymphoma (MZL)=6]. The study reported impressive ORR of 91%, 50% and 67% in FL, MCL and MZL respectively. The CR rates were 72%, 33% and 33%, respectively. The dose for phase-2 follicular lymphomas was determined to be 80mg. The results from ELM-2 that evaluated the efficacy and safety of odronextamab in patients with relapsed/refractory FL after ≥2 prior lines of therapy maintained the response rates at a high of 82% ORR and 75% CR. Th relapsed/refractory DLBCL cohort from ELM-2 study demonstrated 52% ORR, 31% CR and 48% probability of maintaining CR for 2 years.12-14
Step-up dosing and the impact on CRS and ICANS
The initial step-up regimen in ELM-2 consisted of 1 mg split over days one and two of cycle one and 20 mg split over days eight and nine of cycle one, followed by the 80 mg full dose on day 15 of cycle one (1/20 regimen). The 1/20 regimen was revised during the study to further mitigate cytokine release syndrome (CRS) risk by adding an intermediary step-up dose. The modified regimen consisted of 0.7 mg split over day one of cycle one (0.2 mg) and day two of cycle two (0.5 mg), 4 mg split over days eight and nine of cycle one, and 20 mg split over days 15 and 16 of cycle one, followed by the 80 mg full dose on day one of cycle two (0.7/4/20 regimen). The treatment showed an acceptable safety profile with 0.7/4/20 step-up dosing compared to the other CD20xCD3 bispecific antibodies. treatment-related adverse events occurred in 86 (90%), with the most common TEAEs (>30% all grades) being CRS (51%), pyrexia (32%), anemia (31%), and infusion-related reaction (31%). In R/R DLBCL cohort, most common TEAEs (>30% all grades) were CRS (55%), anemia (43%), and pyrexia (42%). With the optimized 0.7/4/20 mg step-up regimen, 98% of CRS events were Grade 1/2, and only one Grade 3 CRS (confounded by pancreatitis) was reported. Supportive measures resolved CRS events. No ICANS events were reported with the optimized step-up regimen.12-14
Following implementation of the 0.7/4/20 step-up regimen in C1, no Grade ≥2 CRS was observed; only Grade 1 CRS was reported in 39% of pts. All CRS events resolved and only 1 pt received tocilizumab for CRS management. No ICANS was reported in the 0.7/4/20 regimen compared with 3% in the 1/20 regimen. Overall, the treatment was well tolerated and may present an important treatment option for relapsed/refractory patients with follicular lymphoma.8,10,11
Other targeted FDA-approved therapies for the treatment of NHL include:
Bone Marrow Transplant4,6
This involves using high doses of radiation and chemotherapy to suppress the patient’s bone marrow and immune system. Transplants are either autologous (patient’s own stem cells) or allogenic (donor stem cells).
Further details on each of these therapies can be accessed in the Resources section.
