Sections

Treatment

Approach Considerations

Unless contraindicated because of significant pre-existing comorbid conditions, the treatment of diffuse large B-cell lymphoma (DLBCL) should include the use of rituximab- and anthracycline-based multiagent chemotherapy, possibly followed by radiation therapy, and the goal should be to achieve a durable complete remission (ie, cure). The treatment is subsequently tailored according to stage or bulk of disease and response to therapy. In general, the frontline management of DLBCL can be divided according to disease stage in 2 groups: localized and advanced.

Therapy for aggressive non-Hodgkin lymphoma (NHL) has evolved significantly in the last 30 years. For example, high-dose chemotherapy in the setting of autologous hematopoietic stem cell transplantation, and chimeric antigen receptor (CAR) T-cell therapy, have become options for DLBCL.

Chemotherapy is usually given on an outpatient basis, although patients should be admitted to the hospital if a treatment complication arises. Transfer to an appropriate facility may be necessary for further diagnostic evaluation and medical or surgical interventions.

In general, the role of surgery in the treatment of DLBCL is limited. Treatment of these tumors is primarily with cytotoxic agents, with or without radiation therapy. However, surgery can be helpful in obtaining tissue for diagnosis or, rarely, to palliate a complication.

A study by Kim et al determined that although the quality of life (QOL) of patients with intestinal DLBCL who underwent surgery and chemotherapy was lower than that of patients who underwent chemotherapy alone, the difference was acceptable.^[70]Thus, surgical resection followed by chemotherapy may be an effective treatment strategy for these patients.

R-CHOP regimen

R-CHOP—rituximab in combination with cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone—is the standard immunochemotherapy regimen for DLBCL.^{[71, 72, 73, 74]} It achieves cures in approximately two thirds of patients with DLBCL.^[74] R-CHOP may be administered in a 14-day or a 21-day cycle,^[75] and may be followed by radiation therapy.^{[73, 76]}

In patients with an absolute contraindication to anthracyclines, etoposide can be substituted for doxorubicin (ie, R-CEOP rather than R-CHOP). A long-term study found that R-CEOP is a valid alternative to R-CHOP in this setting, offering a potential for cure.^[77]

Relapse therapy

Options for relapsed disease continue to make progress. Second-line chemotherapy regimens vary, depending on whether autologous hematopoietic stem cell transplantation (ASCT) is being considered.^{[73, 75]}

Options for relapsed or refractory disease in patients being considered for ASCT include the following:

DHAP (dexamethasone, high-dose cytarabine [Ara-C], and cisplatin [Platinol]) with or without rituximab
GDP (gemcitabine, dexamethasone, cisplatin or carboplatin) with or without rituximab
ICE (ifosfamide, carboplatin, etoposide) with or without rituximab

Anti-CD19 CAR T-cell therapy may be considered for patients with DLBCL that relapses less than 12 months after first-line therapy, or that is refractory to first-line therapy.

Second-line therapy options for patient who are not candidates for ASCT include the following:

GemOx (gemcitabine plus oxaliplatin) with or without rituximab
Polatuzumab vedotin-piiq with or without bendamustine and/or rituxima
Tafasitamab-cxix plus lenalidomide

Venous access devices

Because multiple chemotherapy cycles are usually administered, consult a surgeon regarding implantation of a venous access device, which is helpful for chemotherapy infusions and for the repeated blood samples required to monitor treatment toxicity.

Patient monitoring

Monitor patients very carefully while they are receiving chemotherapy, which is administered every 3 weeks. Order complete blood count (CBC) and chemistries frequently for outpatient monitoring. Immediately see patients if they develop any chemotherapy-related adverse effects.

Red blood cell transfusions or administration of hematopoietic growth factors (eg, erythropoietin, epoetin alfa, darbepoetin alfa) may be required for patients with persistently low hemoglobin values due to disease or chemotherapy.

Management of Early-Stage DLBCL

Approximately 25% of diffuse large B-cell lymphoma (DLBCL) cases present as early stage. Localized DLBCL is defined as Ann Arbor stage I or II nonbulky disease. The management of such patients requires an abbreviated course of combined systemic chemoimmunotherapy with R-CHOP, typically followed by involved-site radiation therapy (ISRT) or involved-field radiation therapy (IFRT).^{[78, 79, 80]}

While also recommending R-CHOP for patients with low-risk disease, European guidelines include the use of rituximab with doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone R-ACVBP) for 6 cycles as an option for patients age 60 years or younger with bulky low-risk or low-intermediate risk DLBCL.^[75] An open-label phase III trial in patients aged 18-59 years with low-intermediate risk DLBCL reported significantly improved survival with R-ACVBP compared with standard R-CHOP; however, hematologic toxicity is greater with R-ACVBP, and vindesine is not commercially available in the United States.

The use of monoclonal antibodies, particularly rituximab, changed the treatment paradigm of patients with B-cell non-Hodgkin lymphoma, including DLBCL. Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen present on normal and most malignant B-cells. The mechanisms by which rituximab elucidates its antitumor activity has been characterized and includes antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CMC), and activation of intracellular pathways leading to apoptosis. Preclinical models demonstrated that rituximab potentiates the effect of several chemotherapeutic agents.^[81] The addition of rituximab to standard doses of chemotherapy in DLBCL resulted in improved clinical outcomes without adding significant toxicity.^{[82, 83]}

Various protocols are in use. It is important to stress that the approach to early-stage DLBCL should be tailored according to site of disease involvement (eg, mediastinum, stomach), disease response, and patient comorbid conditions, in an attempt to optimize the achievement of a complete response, which can translate into improved survival. For example, in patients with DLBCL who are older than 80 years but have a good performance status, the use of rituximab with reduced doses of chemotherapy agents—so-called R-mini-CHOP—has proved effective.^[84]

For early-stage DLBCL, a 21-day R-CHOP cycle is typically used, involving different numbers of chemoimmunotherapy cycles. One recommended approach for stage I-II nonbulky disease consists of three 21-day cycles of R-CHOP followed by radiation therapy (RT)^[73]; four cycles and six cycles are also used.^[75] Tomita et al demonstrated that in limited-stage DLBCL, three cycles of R-CHOP followed by involved-field radiation therapy (IFRT) could be effectively replaced by six cycles of R-CHOP alone, with IFRT used only in patients with a partial response to R-CHOP. In this retrospective study, which included 190 previously untreated patients with limited-stage DLBCL (5 of whom received IFRT), the 5-year progression-free survival (PFS) and overal survival (OS) were 84% and 90%, respectively.^[85]

Imaging studies to determine response to R-CHOP can guide the decision whether to use RT. In a National Clinical Trials Network (NCTN) study, 128 patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received three cycles of standard R-CHOP therapy, then underwent an interim positron emission tomography/computed tomography (PET/CT) scan. Those patients with a negative scan received one additional cycle of R-CHOP, whereas those with a positive scan received IFRT followed by radioimmunotherapy with ibritumomab tiuxetan. radioimmunotherapy. On median follow-up of almost 5 yearst, the estimated 5-year PFS was 87% and the estimated OS estimate was 89%, with similar outcomes in patients with positive and negative PET/CT scans.^[86]

Historical perspective

The use of systemic chemotherapy to successfully eradicate DLBCL was first described in the early 1970s.^{[87, 88]}After these original reports, CHOP (given every 21 days—ie, CHOP-21) became the standard of care for aggressive lymphomas in the United States.

In the late 1990s, results from clinical trials evaluating rituximab as monotherapy in aggressive lymphomas and the results reported by Czuczuman et al in patients with follicular lymphomas^[89] prompted research into the combination of rituximab and CHOP (R-CHOP) for aggressive B-cell lymphomas.^[90]This yielded practice-changing results.

The landmark study validating the addition of rituximab to CHOP chemotherapy was conducted by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) and presented by Coiffier et al. It enrolled patients with newly diagnosed stage I-IV aggressive B-cell lymphomas who were older than 60 years and randomized them to receive eight cycles of either CHOP or R-CHOP at 21-day intervals.^[91] Compared with CHOP, R-CHOP chemotherapy resulted in higher response rates (76% vs 63%, respectively, P = 0.005) and, on 18-month follow-up, significantly better PFS and OS (P < 0.001 and P = 0.007, respectively).

Analysis of the study after 5 and 10 years of follow-up continued to show a clear benefit of R-CHOP in DLBCL.^{[91, 92, 93]} On 10-year follow-up, the PFS rate following therapy with R-CHOP or CHOP was 36.5% and 20%, respectively, and OS rates were 43.5% versus 27.6%.^[93]

Similarly, a study by Habermann et al in untreated DLBCL patients who were 60 years or older found that the 3-year failure-free survival rate was 53% with R-CHOP versus 46% for CHOP. However, no benefit was seen with maintenance rituximab after R-CHOP.^[94] A study by the MabThera International Trial (MInT) group in 824 young patients with good-prognosis DLBC reported that after a follow-up period of 3 years, patients randomized to receive R-CHOP had higher event-free survival (79% vs 59%, P< 0.0001) and OS (93% vs 84%; P = 0.0001) than patients assigned to chemotherapy alone.^[82] The benefit of adding rituximab in high-intermediate and high-risk DLBCL patients younger than 60 years had been extrapolated from the results of the GELA and MInT studies.

A 14-day (so-called dose dense) R-CHOP cycle has been studied for its potential to improve the worse prognosis in elderly patients with advanced-stage DLBCL. The RICOVER-60 trial conducted by the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) demonstrated the benefit of six cycles of R-CHOP-14 in elderly patients with DLBCL.^[95] On the other hand, in the randomized LNH03-6B trial by the GELA group in elderly patients with untreated DLBCL and at least one adverse prognostic factor, R-CHOP-14 did not improve efficacy compared with R-CHOP-21.^[96] However, that trial was criticized for high treatment-related mortality and low dose intensities in the R-CHOP-14 arm. An analysis by Kühnl et al of the RICOVER-60, LNH03-6B, and UK NCRI R-CHOP14v21 (in patients aged 18–88 years) trials concluded that ^[97]

Additional clinical trials have explored the combination of rituximab with other chemotherapy regimens. Wilson et al, from the National Cancer Institute, studied dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone in combination with rituximab (DA-EPOCH-R) in previously untreated DLBCL.^[98]In this regimen, the EPOCH doses are adjusted with each cycle to achieve an absolute neutrophil count nadir of 500 cells/µL. The study enrolled 72 consecutive patients with untreated DLBCL who were aged at least 18 years and had stage II or higher disease. Patients received 6-8 cycles of DA-EPOCH-R. IFRT was not permitted. At 5 years, PFS and OS were 79% and 80%, respectively.^{[98, 99]}

In a randomized Alliance/Cancer and Leukemia Group B (CALGB) phase III study comparing R-CHOP-21 with DA-EPOCH-R in previously untreated DLBCL, DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. However, while the trial design assumed a 55% 3-year PFS rate with R-CHOP, the observed 3-year PFS rate in the study was significantly better, at 72% The authors concluded that the more favorable results with R-CHOP may reflect more favorable patient characteristics, so the study results may not be generalizable to specific risk subgroups.^[100]

Current practice

R-CHOP remains the regimen of choice for advanced-stage DLBCL. It may be given for six or eight cycles, and both 14-day and 21-day cycles are used.^{[73, 75]} R-CHOP can usually be used in fit patients up to 80 years of age in fit patients, but modulation of treatment according to geriatric assessment is recommended. In elderly patients who are unfit or frail or have cardiac dysfunction, other agents can be substituted for doxorubin (eg, gemcitabine, etoposide, liposomal doxorubicin). More intensive regimens (eg, R-CHOP plus etoposide) may be considered in selected patients.^[75]

Treatment of Relapsed/Refractory DLBCL

Treatment options for relapsed or refractory DLBCL include the following:

Alternative chemotherapy regimens
High-dose chemotherapy with autologous stem cell suppport (HDC-ASCS)
CAR T-cell therapy

In patients who are not candidates for HDC-ASCS, recommended chemotherapy regimens include the following^[73]:

GemOx (gemcitabine plus oxaliplatin) with or without rituximab
Polatuzumab vedotin-piiq with or without bendamustine and/or rituximab
Tafasitamab-cxix plus lenalidomide

High-dose chemotherapy with autologous stem cell suppport

The role of HDC-ASCS in the treatment of relapsed/refractory DLBCL was confirmed by an international randomized phase III clinical trial, the PARMA study.^[101]In this study, patients with relapsed/refractory DLBCL underwent salvage chemotherapy for 2 cycles. Patients with chemotherapy-sensitive DLBCL were randomized to further salvage chemotherapy with cytarabine/platinum-based chemotherapy alone or in combination with ASCS. Event-free survival (EFS) and overall survival (OS) at 5 years in the transplant arm were 46% and 53%, respectively, compared with 12% and 32% in the chemotherapy alone arm.

Moreover, subset analysis revealed that response to salvage chemotherapy was associated with a 5-year progression-free survival (PFS) rate of 43%, in contrast to a 1-year OS rate of 22% for patients with chemotherapy-resistant disease.^[101]Based on these results, salvage chemotherapy followed by HDC-ASCS has been adopted as the standard of care for transplant-eligible DLBCL patients.

Subsequent work focused on the development of tools to predict which patients were most likely to benefit from HDC-ASCS, such as the value of the age-adjusted International Prognostic Index (IPI) score or positron emission tomography (PET) scanning after salvage chemotherapy.^{[102, 103, 104]}

Rituximab in relapsed/refractory DLBCL

As rituximab changed the treatment paradigm of DLBCL, it has been postulated that the subset of patients with refractory or relapsed DLBCL represent a different patient population than the one studied in pre-rituximab clinical trials. Investigators have questioned whether the response to second-line chemotherapy or the value of HDC-ASCS in patients with relapsing or primary refractory DLBCL previously treated with R-CHOP has decreased compared with historical controls.

Martin et al, on behalf of the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO Cooperative Group), reported results from a retrospective analysis on the outcome of patients with DLBCL, evaluating the influence of rituximab on response rate to rituximab in combination with etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) as salvage therapy.^[105]Martin and colleagues studied 163 consecutive patients with relapsed/refractory DLBCL who received R-ESHAP as second-line therapy; 94 patients were previously treated with rituximab chemotherapy (R+ group) in the frontline setting and 69 patients received only chemotherapy alone (R- group).

Response rates were higher in patients who were not previously exposed to rituximab in a univariate analysis but not in a multivariate analysis. The OS and complete response rates to R-ESHAP were 67% and 37% for DLBCL patients previously treated with R-CHOP versus 81% and 56% for patients previously treated with CHOP (P = 0.045, P = 0.015), respectively. In addition, the PFS and OS rates at 3 years were significantly higher for the patients in the CHOP group (57% and 64%) compared with those patients in the R-CHOP group (38% and 17%) (P< 0.0001, P = 0.0005). Of note, the same percentage of patients in both groups subsequently underwent HDC-ASCS.

In a multivariate analysis, prior exposure to rituximab was found to be a prognostic indicator of worse PFS and OS.^[105]The results of this retrospective study suggest that DLBCL in patients who relapse or do not respond to rituximab chemotherapy as first-line therapy is a more resistant type of disease and represents a challenge for clinicians treating aggressive B-cell lymphomas. It also stresses the need to further study and define at the molecular level the mechanisms by which DLBCLs develop resistance to chemoimmunotherapy.

On the other hand, it is uncertain whether rituximab can enhance the antitumor activity of systemic chemotherapy in the salvage setting or to what extent the use of HDC-ASCS improves the cure rates in previously R-CHOP–treated relapsed/refractory DLBCL. Investigators have shown improved response rates by adding rituximab to salvage regimens such as ICE or DHAP compared with historical controls.^{[106, 107]}However, the majority of the patients included in those clinical trials had not been previously exposed to rituximab in the frontline setting.

Groupe d'Etude des Lymphomes de l'Adulte (GELA) reported a subset analysis with long-term follow up of the 202 DLBCL patients who relapsed/progressed following frontline R-CHOP or CHOP chemotherapy in the context of the landmark study. All 202 patients underwent salvage chemotherapy, of whom 31 received a rituximab-containing salvage regimen (22 and 9 previously treated with CHOP or R-CHOP, respectively). Patients treated with rituximab-containing salvage chemotherapy had a 2 years OS rate of 58%, as opposed to 24% for those treated with salvage chemotherapy alone (P =.00067). Of interest and while the numbers are small, the benefit of adding rituximab to the salvage regimen was statistically significant only for those DLBCL patients treated with CHOP chemotherapy in the frontline setting.^[92]

While this observation is of interest, the sample size of those R-CHOP patients previously treated for relapsed/refractory DLBCL receiving rituximab-containing salvage chemotherapy was extremely small (9 patients), which should limit the significance of the conclusions derived from this study.

Salvage chemotherapy regimens for DLBCL

A number of regimens are used in the treatment of patients with relapsed/refractory DLBCL, and they are primarily based on chemotherapy agents non–cross-resistant to those used in the frontline setting. They may be given with or without rituximab. The goal of salvage regimens is to achieve maximum tumor burden cytoreduction in preparation for HDC-ASCS. The current salvage regimens available for refractory/relapsed DLBCL have been evaluated in phase II studies. Investigators have also tested the efficacy of adding rituximab to established salvage regimens and compared them with pre-rituximab historical controls. Several chemotherapy regimens have been used in case of disease relapse, as follows:

DHAP (dexamethasone, high-dose cytarabine [Ara-C], and cisplatin [Platinol])
DHAX (dexamethasone, cytarabine, oxaliplatin)
GDP (gemcitabine, dexamethasone, cisplatin or carboplatin)
ICE (ifosfamide, carboplatin, etoposide)
ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin)
MIME (mesna, ifosfamide, methotrexate, and etoposide)
IMVP-16 (ifosfamide, methotrexate, and etoposide [VP-16])

Early evidence suggested that in germinal center B (GCB)-like DLBCL, the cell of origin has a better response to R-DHAP than to R-ICE.^[62]

The only randomized phase III trial that compared established salvage regimens in combination with rituximab (R-ICE vs R-DHAP) was CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma), which reported similar response rates after three cycles of either regimen (R-ICE, 63.5%; R-DHAP, 62.8%).^[108] The following factors significantly affected response rates:

Refractory disease/relapse less than versus more than 12 months after diagnosis (46% vs 88%, respectively)
International Prognostic Index (IPI) > 1 versus 0-1 (52% vs 71%, respectively)
Prior rituximab treatment versus no prior rituximab (51% vs 83%, respectively).

Patients in CORAL who responded to three cycles of chemotherapy underwent HDC-ASCS. They were then randomly assigned to either rituximab every 2 months for 1 year or observation. The 4-year EFS rates were essentially the same in both groups—52% in the rituximab arm and 53% in the observation arm, and treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100. Consequently, the CORAL researchers recommended against rituximab maintenance after ASCT.^[109]

In general, when selecting the optimal salvage regimen, consider regimens with higher response rates, especially higher CR rates, low hematological and nonhematological toxicity, and a lesser degree of stem cell damage to secure effective peripheral blood stem-cell collection (PBSC).

Types of salvage chemotherapy

Depending on the agents used, and outside of a clinical trial, salvage chemotherapy can be divided into the following 2 groups:

Platinum-based chemotherapy: Platinum-based chemotherapy yields higher response rates at the price of hematological and/or nonhematological toxicity than non–platinum-based regimens. Therefore, they are preferred in those patients who are candidates for HDC-ASCS.
Non–platinum-based chemotherapy: Non–platinum-based regimens are the treatment of choice for patients with poor bone marrow reserve (ie, relapsed after HDC-ASCS) or elderly patients who are not eligible for HDC-ASCS owing to age or previous comorbid conditions.

Platinum-based regimens in relapsed DLBCL

The antitumor effects of cisplatin, carboplatin, and, most recently, oxaliplatin, against B-cell lymphomas have been demonstrated in preclinical and clinical studies. Cisplatin has been extensively studied in combination with high-dose cytarabine- or gemcitabine-based regimens such as, rituximab plus/minus DHAP, ESHAP, or GDP, in patients with refractory/relapsed DLBCL.^{[110, 101, 105, 107, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121]}In addition, carboplatin has been combined with ifosfamide and etoposide (ICE) with or without rituximab.

In general, platinum-based regimens have response rates ranging from 43-82% and CR rates of 16-61%. Successful PBSC mobilization has been documented in the majority of patients eligible for bone marrow transplantation (BMT) treated with such regimens. On the other hand, significant grade 3 and 4 hematologic and, to a lesser degree nonhematologic, toxicity (grade 1-2) has been observed. Grade 3-4 neutropenia occurs in 50-70% of cases; grade 3-4 thrombocytopenia is observed in 30-90%. From 40-70% of the cases require at least 1 unit of red blood cell transfusion. Hospitalization for febrile neutropenia has been reported in 10-20% of the relapsed/refractory DLBCL patients receiving platinum-based salvage regimens.^{[110, 101, 105, 106, 107, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121]}

In addition nonhematologic toxicity seen with these regimens includes kidney dysfunction, cardiac toxicity (for ifosfamide-containing regimens only), neurotoxicity in the form of confusion (ifosfamide-containing regimens), and cerebellar toxicity (high-dose cytarabine-containing regimens) (< 5% of the cases). Several investigators have evaluated the possibility of replacing cisplatin/carboplatin with oxaliplatin, given its favorable toxicity profile, but this strategy failed to demonstrate significant changes in the antitumor activity or toxicity profile of currently available salvage regimens.^[118]

Non–platinum-containing salvage regimens

In the past, 4 non–platinum-containing regimens were used in the salvage regimen in preparation for HDC-ASCS:

MINE (methylprednisolone, ifosfamide, mitoxantrone [Novantrone], and etoposide)
IVAD (ifosfamide, etoposide, cytarabine, and dexamethasone)
IEV (ifosfamide, epirubicin, and etoposide)
Mini-BEAM (busulphan, etoposide, cytarabine, and melphalan)

The antitumor activity of those regimens is comparable to that observed with platinum-based regimen.^{[122, 123, 124, 125]}Response rates to any of these regimens in relapsed/refractory DLBCL (never exposed to rituximab) vary from 64-75%, and the safety profile is similar to platinum-containing regimens.^{[122, 123, 124, 125]}

On the other hand, the use of these regimens has declined over time for several reasons, such as (1) the restriction of anthracyclines in salvage regimens across previously CHOP/R-CHOP–treated patients to avoid cumulative cardiotoxicity, (2) the protection of stem cells by restricting the use of melphalan or busulphan in the salvage regimen prior to stem cell collection, and (3) the need to decrease nonhematologic and hematologic toxicity from high-dose ifosfamide-containing regimens by combining this agent with a platinum compound.

Currently, the most commonly used non–platinum-containing regimens are primarily gemcitabine based. These particular regimens are well tolerated in elderly patients, in patients with limited bone marrow reserve (ie, relapsed/refractory disease after HDC-ASCT), or those patients with multiple comorbid conditions. The hematologic toxicity observed in clinical trials evaluating the efficacy and toxicity of nonplatinum gemcitabine-based regimens is significantly lower than in platinum-containing regimens. Grade 3-4 neutropenia and thrombocytopenia has been reported in only 20% and 10-25% of the patients, respectively.^{[126, 127]}

Another strategy is to modify the schedule of administration of previously used agents. A good example of this approach is the development of the infusional regimen of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH), with or without rituximab. Wilson et al demonstrated that EPOCH was highly effective (74% overall response rate, with 24% CR) in relapsed/refractory aggressive non-Hodgkin lymphoma, with acceptable hematological and nonhematological toxicity.^[128]The incident of cardiac toxicity was extremely low (3%), despite the fact that 94% of the patients enrolled had prior anthracycline exposure.^{[128, 129]}Similar antitumor activity was reported by Jermann et al in patients with refractory/relapsed B-cell non-Hodgkin lymphoma treated with rituximab-EPOCH.^[130]

The emergence of rituximab resistance is starting to be observed in patients with relapsed/refractory DLBCL. The evaluation of other biologically active monoclonal antibodies targeting CD20 (eg, ofatumumab), monoclonal antibodies directed against other key regulatory surface receptors (ie, CD40, CD22), or small-molecule inhibitors (eg, lenalidomide, proteasome inhibitors, mammalian target of rapamycin [mTOR] inhibitors) in combination with systemic chemotherapy is necessary to broaden the therapeutic armamentarium against relapsed/refractory DLBCL.

In summary, the incorporation of rituximab to standard doses of CHOP has resulted in improved clinical outcomes when compared with standard chemotherapy in patients with DLBCL and has raised the bar with respect to which new therapies are being evaluated in patients with aggressive lymphomas. While the clinical benefit of adding rituximab to CHOP or CHOP-like chemotherapy as frontline treatment of DLBCL is beyond dispute, previously accepted biomarkers of response (eg, Bcl-2 expression, IPI) also need reevaluation to raise new challenges in the therapeutic treatment of those patients in whom chemoimmunotherapy fails or who have relapse after chemoimmunotherapy.

Chemoimmunotherapy

The past several years have seen the advent of the following novel agents for treatment of relapsed or recurrent DLBCL:

Polatuzumab vedotin (Polivy)
Selinexor (Xpovio)
Tafasitamab (Monjuvi)
Loncastuximab tesirine (Zynlonta)
Epcoritamab (Epkinly)

Polatuzumab vedotin

In 2019, polatuzumab vedotin, a CD79b-directed antibody-drug conjugate, gained accelerated approval from the US Food and Drug Administration (FDA) for adults with relapsed or recurrent DLBCL in combination with bendamustine and a rituximab product (ie, rituximab or a biosimilar) after at least 2 prior therapies.^[131]

Accelerated approval of polatuzumab was based on a study in which 40% of patients (16/40) treated with polatuzumab vedotin plus bendamustine and rituximab (BR) achieved a complete response (CR) compared with 18% (7/40) of those receiving BR alone. The study also showed an OR of 45% with polatuzumab plus BR at the end of treatment compared with 18% for BR alone. Of patients who achieved a complete or partial response, duration of response was at least 6 months in 64% (16/25) of those receiving polatuzumab plus BR, compared with 30% (3/10) for BR alone. Additionally, response lasting at least 1 year was observed in 48% (12/25) of patients receiving polatuzumab plus BR compared with 20% (2/10) for BR alone.^[132]

Selinexor

Selinexor is the first oral selective inhibitor of nuclear export (SINE) compound. In 2020, the FDA granted selinexor accelerated approval for relapsed or refractory DLBCL, including DLBCL arising from follicular lymphoma, in patients previously treated with at least 2 lines of systemic therapy.^[133]

Tafasitamab

In 2020, the FDA granted accelerated approval to tafasitamab, a humanized Fc-modified cytolytic CD19-targeting monoclonal antibody, in combination with lenalidomide for the treatment of relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, in adults who are ineligible for ASCT. Approval was based on data from the phase II L-MIND study, an open label, multicenter, single-arm trial that showed an overall response rate (ORR) of 55%, including a CR rate of 37% and a partial response (PR) rate of 18%. The median duration of response (mDOR) was 21.7 months.^[134]

Loncastuximab tesirine

Loncastuximab tesirine, a CD19 antibody-drug complex, gained accelerated approval from the FDA in 2021 for adults with relapsed/refractory large-B-cell lymphoma following 2 or more lines of systemic therapy. The indication includes DLBCL not otherwise specified (NOS), DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. Approval was based on results from the phase II, single-arm, open-label LOTIS-2 trial (n = 145). The trial demonstrated an ORR of 48.3% (70/145 patients), which included a CR rate of 24.1% (35/145 patients) and a PR rate of 24.1% (35/145 patients). Median time to response was 1.3 months and median duration of response for the 70 responders was 10.3 months.^[135]

Epcoritamab

Epcoritamab is an IgG1-bispecific antibody designed to simultaneously bind to CD3 on T-cells and CD20 on B-cells, and induces T-cell mediated lysis of CD20+ cells. CD20 is expressed on B-cells and is a clinically validated therapeutic target in many B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). In 2023, the FDA granted accelerated approval to epcoritamab for relapsed or refractory DLBCL NOS, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after at least 2 lines of systemic therapy.

Approval was based on the phase II EPCORE NHL-1 trial. The trial's efficacy population included 148 adults with relapsed or refractory CD20+ large B-cell lymphoma who had received at least 2 prior lines of therapy, including anti-CD20 therapies. Almost 40% had undergone CAR-T cell therapy. Epcoritamab was administered initially once weekly, then every 2 weeks, and then every 4 weeks until disease progression or unacceptable toxicity. The trial had no comparator arm. At a median follow-up of 10.7 months, the overall response rate was 61% and the complete response rate was 38%. At a median follow-up of 9.8 months among responders, the median duration of response was 15.6 months.^[150]

CNS Prophylaxis in DLBCL

Central nervous system (CNS) relapse is a rare but significant complication in the management of patients with diffuse large B-cell lymphoma (DLBCL). The probability of CNS relapse after 1 year of diagnosis is estimated to be 2.3-4.5%.^{[136, 137]}The risk of CNS relapse appears to be higher in subsets of DLBCL (4- to 15-fold increase in risk), and identification of such patients is imperative in an attempt to implement prophylactic therapy.

Patients with elevated risk for CNS relapse are those with the following^{[138, 139]}:

Elevated lactate dehydrogenase (LDH) level at diagnosis
Testicular, adrenal/kidney, or uterine involvement
More than 2 extranodal sites involved by disease
MYC translocation, particularly if occurring with a BCL2 translocation (classic double-hit lymphoma) or MYC/BCL2 with a BCL6 translocation (triple-hit lymphoma)
Concomitant infection with human immunodeficiency virus (HIV)

Risk of CNS relapse/progression in DLBCL treated with R-CHOP can be estimated using the CNS International Prognostic Index in Diffuse Large B-Cell Lymphoma (CNS-IPI), which classifies patients as low, intermediate, or high risk.^[140]See the CNS International Prognostic Index in Diffuse Large B-Cell Lymphoma (CNS-IPI) calculator.

Initially, CNS prophylaxis was most often performed with intrathecal methotrexate. However, in most studies of CNS prophylaxis in DLBCL, intrathecal prophylaxis has not been protective.^[139]High-dose intravenous methotrexate, which can cross the blood-brain barrier, is advocated for CNS prophylaxis, but its efficacy is questionable.^{[141, 75, 142]}

CAR T-cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy utilizes each patient’s own T cells, extracted by leukapheresis. The T cells are sent to a processing facility, where they are genetically engineered with CD19 receptors that seek out cancer cells; the T-cell population is then expanded and infused back into the patient, who has undergone conditioning chemotherapy in preparation for the infusion.

In 2017, the FDA approved axicabtagene ciloleucel (Yescarta) for treatment of large B-cell lymphoma after at least two other kinds of therapy have failed. Approved uses include diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.^[143]

Approval was based on the results from the ZUMA-1 study, an open-label, multicenter trial enrolling of 111 patients from 22 institutions. Patients in ZUMA-1 received the target dose of axicabtagene ciloleucel (2 × 10⁶ cells/kg) after low-dose conditioning with cyclophosphamide and fludarabine for 3 days. The modified intention-to-treat population involved 101 patients who received axicabtagene ciloleucel. In adults with relapsed/refractory DLBCL, the response rates were approximately 60-80%, with complete responses seen in 40-70% of patients. At 6-month follow-up, 40% of patients had maintained their complete response. The trial had a median survival follow-up of 8.7 months.^[144]

In 2018, tisagenlecleucel gained approval for adults with relapsed or refractory large B-cell lymphoma, including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma after ≥ 2 lines of systemic therapy.^[145]Approval was based on the single-arm, open-label, multicenter, phase 2 JULIET trial in adults with relapsed or refractory DLBCL and DLBCL after transformation from follicular lymphoma. Eligible patients must have been treated with at least 2 prior lines of therapy, including an anthracycline and rituximab, or relapsed following ASCT. Patients received a single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy.

The ORR for the 68 evaluable patients was 50% (95% CI: 37.6, 62.4) with a CR rate of 32% (95% CI: 21.5, 44.8). With a median follow-up time of 9.4 months, the duration of response (DOR) was longer in patients with a best overall response of CR, as compared to a best overall response of partial response (PR). Among patients achieving CR, the estimated median DOR was not reached (95% CI: 10.0 months, not estimable [NE]). The estimated median response duration among patients in PR was 3.4 months (95% CI: 1.0, NE).^[146]

Lisocabtagene maraleucel (Breyanzi) is a CD19-directed CAR T-cell therapy for adults with R/R large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. It is not indicated for h primary CNS lymphoma.

Safety and efficacy were evaluated in the TRANSCEND trial, an open-label, multicenter, single-arm trial. Patients (n=268) with R/R large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. Study patients received a single infusion of lisocabtagene maraleucel following completion of lymphodepleting chemotherapy. Of these patients, 54% achieved CR (95% CI: 47%-61%) and 19% achieved PR (95% CI:14%-26%). Median duration of response for all responders was 16.7 months (CR was not reached; PR: 1.4 months [95% CI: 1.1-2.2 months). Among all responders, 65% had remission for at least six months and 62% had remission lasting at least nine months.^[147]

Among patients in the TRANSCEND trial, the most common adverse reactions were as follows^[147]:

Fatigue
Cytokine release syndrome
Musculoskeletal pain
Nausea
Headache
Encephalopathy
Infections (pathogen unspecified)
Decreased appetite
Diarrhea
Hypotension
Tachycardia
Dizziness
Cough
Constipation
Abdominal pain
Vomiting
Edema

For more information, see Cancer Immunotherapy with Chimeric Antigen Receptor (CAR) T-Cells

Supportive Care in Chemotherapy

Administer intravenous fluids and/or supportive care with analgesics and growth factors, as necessary. Patients often are started on allopurinol with the induction of chemotherapy to avoid acute kidney injury from tumor lysis syndrome (TLS) and uric acid nephropathy.

Antiemetics

Antiemetics are always prescribed before and after the administration of chemotherapy, for the prevention of chemotherapy-induced nausea and vomiting. Antiemetics used include the following:

The 5-hydroxytryptamine 3 (5-HT3) antagonists such as granisetron (1 mg orally [PO] q12h) or ondansetron (8 mg PO q8h) for severe chemotherapy-induced nausea and vomiting
Lorazepam
Metoclopramide (0.5-2 mg/kg PO q3-4h)
Prochlorperazine (10 mg PO q4-6h)

Another antiemetic, palonosetron (Aloxi), is a selective 5-HT3 receptor antagonist with a long half-life (40 h). The adult dose is intravenous 0.25 mg once (30 min before chemotherapy). Administer this agent intravenously over 30 seconds, and do not repeat the dose within 7 days. Palonosetron may cause headache, constipation, diarrhea, or dizziness.

Growth factors

For patients with anemia, consider erythropoietin or epoetin alfa (Procrit) at 40,000-60,000 U, administered subcutaneously once weekly, or darbepoetin alfa 300 mcg, with weekly subcutaneous administration.

Growth factors stimulate blood cell production. Endogenous erythropoietin stimulates red blood cell hematopoiesis. Recombinant human erythropoietin (epoetin alfa) stimulates erythropoiesis in anemic conditions. Colony-stimulating factors act on hematopoietic cells to stimulate hematopoietic progenitor cell proliferation and differentiation. Interleukins stimulate stem cell proliferation.

Administer growth factor support (ie, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) to patients with a previous episode of febrile neutropenia, during subsequent cycles. Patients who administer growth factors to themselves should be carefully advised on sterile techniques, and patients with fevers during periods of neutropenia should immediately seek the attention of the treating physician.

Inpatient Care

Most patients are treated in an outpatient setting. However, hospitalization may be necessary for patients with disease- or therapy-associated complications, such as tumor lysis syndrome, neutropenic fever, and anemia and thrombocytopenia.

Tumor lysis syndrome

Patients with a high tumor burden may need to be admitted to the hospital to receive prophylaxis with allopurinol and alkaline hydration for prevention of this potentially life-threatening condition

Neutropenic fever

Patients are usually expected to be neutropenic approximately 10-14 days after a dose of chemotherapy, with individuals being most susceptible to infections at this point. If febrile, they should be admitted to the hospital and treated with intravenous antibiotics.

Anemia and thrombocytopenia

Transfusions (red blood cells or platelets) should be administered as clinically indicated for anemia and thrombocytopenia.

Diet

No specific diet is recommended for patients with diffuse large cell lymphoma except a salt restriction when steroids are administered as part of the chemotherapy regimen.

Patients undergoing cytotoxic chemotherapy may develop severe neutropenia, as defined by an absolute neutrophil count of less than 500/µL. These patients should be advised to maintain a low microbial diet for the expected duration of neutropenia.

Activity

No specific limitation of activity is necessary unless the patient is thrombocytopenic, in which case activity restriction may be necessary to avoid traumatic bleeding or bruising. In addition, the patient may feel substantial fatigue due to the lymphoma, its treatment, or both.

Consultations

A surgical oncologist may be consulted if an open biopsy is needed for the diagnosis or to treat a complication, such as perforated viscus.

A radiation oncologist may be consulted if the primary therapy involves a combination of chemotherapy and radiotherapy. In addition, an initial large lymphoma mass or a large residual mass following completion of chemotherapy may be considered for involved-field radiotherapy (IFRT).

Transfer

Patients whose condition relapses after multiple treatment regimens or who have poor performance status and who are therefore not candidates for further chemotherapy should be considered for palliative management and hospice care. The following services can be sought in appropriate clinical situations:

Pain management service
Nursing home
Terminal care facility (hospice)
Home care with specialized nursing support for pain management
Rehabilitative centers

Tumor lysis syndrome and uric acid nephropathy

Tumor lysis syndrome is a potential complication following treatment of diffuse large cell lymphoma. This condition manifests as a rapid rise in potassium, phosphorus, and uric acid and a drop in calcium. TLS can lead to a sudden death from electrolyte abnormalities. Treatment that includes aggressive intravenous hydration, urine alkalinization, and administration of allopurinol usually prevents tumor lysis syndrome.

Occasionally, patients with significant tumor volume and rapidly growing disease can avoid tumor lysis syndrome by receiving dose-modified or attenuated chemotherapy as the first treatment, followed by conventional chemotherapy in subsequent treatment cycles.

Uric acid nephropathy is usually observed within 1-2 days after the initiation of chemotherapy and may occur in conjunction with tumor lysis syndrome. It usually can be prevented by administering allopurinol or alkalinizing the urine.

Neutropenic fevers and sepsis

Neutropenic fevers and sepsis are the most common potentially serious complications of chemotherapy. If not recognized and treated aggressively, these infections can cause rapid deterioration of the patient's condition, which could lead to death.

The use of cytokines (granulocyte colony-stimulating factors [G-CSFs] or granulocyte-macrophage colony-stimulating factors [GM-CSFs]) has been helpful in preventing infections by shortening, and in some cases preventing, the neutropenic period. The use of prophylactic antibiotics (especially with the fluoroquinolones [eg, ciprofloxacin, levofloxacin]) has been shown to be effective in preventing neutropenic infections.

Other complications

Chemotherapy-associated complications may also include the following:

Cardiomyopathy - Related to anthracycline
Infections - During neutropenia, postchemotherapy
Gonadal dysfunction - Sterility related to chemotherapy
Secondary leukemias - Related to alkylating agents
Alopecia
Neuropathy
Complications related to bone marrow transplantation

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Media Gallery

Biopsy of a cervical lymph node showing infiltration with a population of large cells (B cells) consistent with diffuse large cell lymphoma.
Computed tomography (CT) scan of the abdomen showing mesenteric and retroperitoneal adenopathy in a patient with diffuse large cell lymphoma.
Diffuse large B-cell lymphoma. Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture of the node is lost, with a diffuse pattern of involvement.
Patient with diffuse large B-cell lymphoma with extranodal involvement. This computed tomography (CT) scan shows an enlarged spleen and liver as a result of lymphomatous involvement.
Patient with diffuse large B-cell lymphoma with extranodal involvement (same patient as in the previous image). This patient has an enlarged spleen and liver as a result of lymphomatous involvement. Extensive retroperitoneal lymphadenopathy is also present.
This image depicts gallium scans performed as part of a staging workup for a patient with diffuse large B-cell lymphoma. The scans show extensive hepatosplenic and multiple sites of nodal involvement with a gallium-avid tumor.
Role of B-cell receptor signaling in promoting proliferation and survival of DLBCL. BCR is the main factor in B-cell biology, playing a key role in B-cell development, antigen-driven clonal selection, and humoral immunity. B-cell receptor signaling activates PI3K-mediated activation of the kinase AKT, which activates many downstream signaling pathways. All these downstream pathways are essential for the survival of B cells. PIP3 is generated as a result of BCR-dependent PI3K activation. BTK also hydrolyzes PIP2 into DAG and IP3. IP3 induces release of calcium stores from the endoplasmic reticulum. Ca and DAG activate PKC, which leads to activation of NF-k B pathyway. PI3K, phosphatidylinositide-3 kinase; AKT, protein kinase B; PTEN, phosphatase and tensin homolog; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-4,5-trisphosphate; IKK, IkB kinase; mTOR, mammalian target of rapamycin; FoxO, Forkhead box transcription factors; GSK3b, glycogen synthase 3-beta; p21, inhibitor of cyclin-dependent kinases.

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Author

Shipra Gandhi, MBBS Resident Physician, Department of Internal Medicine, University of Buffalo, State University of New York School of Medicine and Biomedical Sciences

Shipra Gandhi, MBBS is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Andre M Kallab, MD Clinical Associate Professor of Oncology, Medical College of Georgia; Consulting Staff, Department of Oncology, Northeast Georgia Diagnostic Clinic

Andre M Kallab, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Hematology

Disclosure: Nothing to disclose.

Francisco J Hernandez-Ilizaliturri, MD Professor of Medicine, Department of Medical Oncology, Associate Professor of Immunology, Department of Immunology, Chief, Lymphoma and Myeloma Section, Director, The Lymphoma Translational Research Program, Roswell Park Cancer Institute, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Francisco J Hernandez-Ilizaliturri, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Asher A Chanan-Khan, MD Assistant Professor, Department of Medicine, Division of Lymphoma and Bone Marrow Transplantation, Roswell Park Cancer Institute, State University of New York at Buffalo

Disclosure: Nothing to disclose.

Wendy Hu, MD Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center

Disclosure: Nothing to disclose.

Michael Paul Kosty, MD Associate Director, Associate Professor, Department of Internal Medicine, Divisions of Supportive Care Services and Hematology and Oncology, Ida M and Cecil H Green Cancer Center, Scripps Clinic

Disclosure: Nothing to disclose.

Clifford H Pemberton, MD Instructor in Medicine, Jefferson Medical College; Medical Director, Jefferson Hospice and Palliative Care Program; Consulting Staff, Department of Medicine, Division of Hematology/Oncology, Lankenau Hospital

Clifford H Pemberton, MD is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American College of Physicians, American Medical Association, American Society of Hematology, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Diffuse Large B-Cell Lymphoma (DLBCL) Treatment & Management