Current Frontline Treatment of Diffuse Large B-Cell Lymphoma

News
Article
OncologyONCOLOGY Vol 36, Issue 1
Volume 36
Issue 2
Pages: 51-58

This review article discusses which frontline treatment are best for diffuse large B-cell lymphoma.

Abstract

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is an aggressive and biologically heterogeneous disease. Risk stratification and treatment algorithms vary based on stage of disease and bulk along with other clinical and biological factors, including the International Prognostic Index, cell of origin, and other molecular subsets. Rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the current standard of care and cures more than 60% of patients. The role of radiotherapy is largely restricted to patients with limited-stage disease. In elderly patients, geriatric assessments of baseline fitness and functional status help optimize therapy based on the balance of efficacy and toxicity. While numerous randomized trials have failed to improve upon R-CHOP, a recent press release from the POLARIX trial (NCT03274492) suggests that adding polatuzumab vedotin (Polivy) to rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) improves progression-free survival and may replace R-CHOP in selected patients. Ongoing trials are exploring frontline therapy that integrates other novel agents, including various small molecules, bispecific antibodies, and chimeric antigen receptor T-cell therapy, with promising preliminary results. Defining a population of patients with high-risk disease in whom R-CHOP is not effective is critical. Patient selection based on refining molecular subsets, quantitative PET metrics such as metabolic tumor volume, and dynamic risk assessments using interim PET and circulating tumor DNA analysis may allow for a personalized, response-adapted approach that will further improve outcomes in DLBCL.

Keywords: DLBCL, diffuse large B-cell lymphoma, non-Hodgkin lymphoma, R-CHOP, pola-R-CHP

Oncology (Williston Park). 2022;36(1):51-58.
DOI: 10.46883/2022.25920940

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), constituting 25% to 30% of cases, with approximately 150,000 patients diagnosed annually wordwide.1 The median age at diagnosis is 66 years, with a male-to-female ratio of 1.5 to 1.2,3 Incidence is higher in Caucasian individuals than in those of African or Asian descent.2,3 While DLBCL is an aggressive subtype of NHL, more than 60% of patients are cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).1 Improvements in the understanding of DLBCL biology and molecular genetics have refined disease taxonomy, which is reflected in the 2016 World Health Organization (WHO) classification (Table 1).4 This review focuses on the frontline treatment of de novo DLBCL, not otherwise specified.

TABLE 1. 2016 WHO Classification of Aggressive LBCLs

TABLE 1. 2016 WHO Classification of Aggressive LBCLs

Current Standards For Diagnosis

A definitive diagnosis of DLBCL requires an excisional or core biopsy and assessment of morphology, immunophenotyping, and fluorescence in situ hybridization.5,6 Histologically, there is a diffuse architectural pattern with sheets of large B cells positive for CD19, CD20, and CD22 by immunohistochemistry (IHC). Additional stains—including CD5, CD10, BCL2, BCL6, MUM1, MYC, CD30, EBER, and Ki67—lead to greater diagnostic precision.6 Approximately 5% to 8% of cases are associated with gene rearrangements of MYC with concurrent BCL2 and/or BCL6 rearrangements.7,8 The latter cases are now recognized as a distinct entity in the 2016 WHO classification (high-grade B-cell lymphoma, also known as “double-hit” or “triple-hit” lymphoma) and historically have poorer outcomes with R-CHOP.7,8 Up to 30% of cases have overexpression of MYC (>40%) and BCL2 (>50%) by IHC, termed “double-expressor” immunophenotype.9 The latter is not a distinct entity in the WHO classification, and controversies exist regarding optimal management.

A complete staging evaluation includes imaging with a baseline PET/CT and bone marrow biopsy.6 PET/CT has variable sensitivity in detecting bone marrow involvement (60%-94%), but may miss marrow involvement by DLBCL or more commonly an underlying low-grade lymphoma.10,11 An echocardiogram or multigated acquisition scan is required if an anthracycline-based regimen is planned.

Molecular Testing

Gene expression profiling using DNA microarrays initially identified 2 molecularly distinct subtypes of DLBCL with differing cell of origin (COO).12 The germinal center B-cell (GCB) type lacks expression of postgerminal center differentiation markers while the activated B-cell (ABC) type is derived from postgerminal center plasmablasts and demonstrates enhanced B-cell receptor signaling and NF-kB activation.13 Outcomes differ for patients with GCB vs ABC DLBCL, with 5-year progression-free survival (PFS) of 75% vs 40%, respectively, after R-CHOP.14 The COO can be assessed using IHC for CD10, BCL6, and MUM1 (Hans algorithm), with 70% to 80% concordance with gene expression profiling.15,16 Newer technologies such as NanoString can identify COO with greater accuracy than IHC using paraffin-embedded tissue.17

While GCB COO typically carries a favorable prognosis, important exceptions include high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements (enriched for GCB COO) as well as GCB DLBCL with double-hit signature. The latter category, based on a 104-gene model, showed an inferior 5-year PFS of 57% vs 81% in those without double-hit signature.18 Results of a study from the Lunenburg Consortium suggest that the negative prognostic impact of MYC rearrangement is largely observed in patients with a concurrent BCL2 and/or BCL6 rearrangement and when MYC is translocated to an immunoglobulin partner.19

The biological heterogeneity of DLBCL has been further refined beyond COO using whole exome sequencing, which has identified at least 6 distinct genomic subgroups (Table 2).20-22 In the recently proposed LymphGen classification, GCB DLBCL is composed of 2 main genomic subgroups: EZB (enriched for EZH2 mutation/BCL2 translocation) and ST2 (enriched for SGK1/TET2 mutations), with more favorable prognosis in the latter group. ABC DLBCL is comprised of 3 subgroups: A53 (aneuploidy/TP53 mutation), N1 (NOTCH1 mutation), and MCD (MYD88/CD79B mutations), with a strong association with extranodal disease including central nervous system (CNS) involvement in the latter.23,24 A sixth subgroup termed BN2 (BCL6 translocation/NOTCH2 mutation) includes most cases with unclassifiable COO.

TABLE 2. Molecular Classification of DLBCL

TABLE 2. Molecular Classification of DLBCL

Stratification For Treatment Selection

Treatment selection for DLBCL varies based on disease-specific and patient-specific factors. While R-CHOP is the standard backbone for most patients, the number of treatment cycles and role of radiotherapy differ based on stage of disease and bulk.6 Scores derived from the International Prognostic Index (IPI), along with the revised IPI (R-IPI) and National Comprehensive Cancer Network (NCCN)-IPI developed in the post-rituximab era, stratify patients into specific risk groups; the 5-year PFS ranges from 91% vs 30% in the lowest- vs highest-risk disease groups, respectively.25-27 For older patients, baseline geriatric assessments of overall fitness have implications for treatment selection.28-30 Additional biological factors, including GCB vs ABC COO, double-expressor immunophenotype, and presence of MYC gene rearrangement, may also have implications for management. Increasingly, trials have focused on novel treatment approaches based on COO and for high-risk genomic subgroups as discussed further below.

Therapy Selection

Numerous randomized trials have attempted to improve upon R-CHOP by intensifying therapy, adding maintenance, or adding novel agents to an R-CHOP backbone, particularly in ABC DLBCL (Table 3). To date, none of these approaches has demonstrated superiority to R-CHOP, likely related in part include the molecular heterogeneity of DLBCL beyond the COO classification.20-22 In addition, patient selection bias seen in trials—due to lengthy screening periods that are related to central pathology review and stringent lab criteria—often preclude enrollment of the sickest patients who require treatment most urgently.31 Indeed, several studies have identified a shorter diagnosis-to-treatment interval (DTI) of less than 2 to 3 weeks (comprising a group of patients requiring urgent therapy), as an important prognostic factor associated with inferior PFS and overall survival (OS).32-34 The NCCN treatment guidelines differ for limited-stage nonbulky, limited-stage bulky, advanced-stage disease, and for elderly/infirm patients, and are discussed further below.6

TABLE 3. Randomized Phase 3 Trials Challenging R-CHOP in DLBCL

TABLE 3. Randomized Phase 3 Trials Challenging R-CHOP in DLBCL

Limited-Stage Nonbulky Disease

Combined modality therapy with 3 cycles of R-CHOP followed by 30 Gy involved field radiotherapy (IFRT) has long been a standard approach for stage I-II nonbulky DLBCL. This strategy is based on a phase 2 SWOG trial with an excellent 4-year PFS of 88%.35 Recent trials have also evaluated abbreviated chemotherapy without consolidative IFRT. The phase 3 FLYER trial randomized 592 patients with stage I to II nonbulky DLBCL and IPI 0 to receive 6 cycles of R-CHOP (standard arm) or 4 cycles of R-CHOP followed by 2 cycles of rituximab (experimental arm).36 At a median follow-up of 66 months, the 3-year PFS was not statistically different between arms (93% vs 96%), confirming noninferiority of 4 vs 6 cycles of R-CHOP. Similar results were reported in the phase 3 Lymphoma Study Association (LYSA) LNH-09-1B trial, which used a PET-adapted approach.37 A total of
650 patients with stage I to II nonbulky DLBCL and an age-adjusted IPI (aaIPI) of 0 received 2 cycles of R-CHOP followed by an interim PET scan. Patients in the standard arm received 4 additional cycles of R-CHOP regardless of interim PET results. In the experimental arm, patients with a negative interim PET scan (Deauville score 1-3) received 2 additional cycles of R-CHOP while those with a positive interim PET scan received 4 additional cycles. At a median follow-up of 61 months, the 3-year PFS was 89% vs 92% in the standard and experimental arms, respectively, establishing the noninferiority of 4 vs 6 cycles of R-CHOP in early responders.

Studies have also evaluated whether consolidative radiotherapy can be omitted in patients with a negative interim PET scan. The LYSA 02-03 trial (NCT00841945) included 334 patients with stage I to II nonbulky DLBCL treated with 4 cycles of R-CHOP given every 14 days (R-CHOP-14) followed by a PET scan.38 Of the 84% of patients who achieved a metabolic complete response (CR; Deauville score 1-2), low-risk patients (aaIPI 0) were randomized to receive 40 Gy IFRT or no further therapy, while patients with aaIPI ≥1 received 2 additional cycles of R-CHOP with or without 40 Gy IFRT. At a median follow-up of 64 months, 5-year PFS did not significantly differ in patients treated with or without consolidative IFRT (92% vs 89%; P = .18). The National Clinical Trials Network S1001 trial (NCT01359592) included 128 patients with stage I to II nonbulky DLBCL treated with 3 cycles of R-CHOP followed by an interim PET scan.39 A total of 89% of patients achieved a metabolic CR (Deauville score 1-3) and received 1 additional cycle of R-CHOP, while interim PET-positive patients received 36 Gy IFRT followed by ibritumomab tiuxetan (Zevalin). At a median follow-up of 59 months, interim PET-negative patients had an excellent 5-year PFS of 89% after 4 cycles of R-CHOP. Collectively, these studies suggest that chemotherapy can be safely abbreviated, and radiotherapy omitted, in patients with limited-stage nonbulky disease who achieve an early metabolic CR (Table 4).

TABLE 4. Selected Trials in Limited Stage DLBCL

TABLE 4. Selected Trials in Limited Stage DLBCL

Bulky Disease

Bulky disease is variably defined in different studies as a maximum tumor diameter (MTD) greater than 7 to 10 cm.6 In the pre-PET era, outcomes of patients with bulky disease (MTD ≥7.5 cm) treated in the German RICOVER-60 trial (NCT00052936) with 6 cycles of R-CHOP-14 followed by 36 Gy IFRT were compared with patients treated in the
RICOVER-noRTh trial with 6 cycles of R-CHOP-14 alone.40,41 In a multivariate analysis adjusting for IPI risk factors, event-free survival (EFS) was inferior among patients with bulky disease who did not receive consolidative IFRT (HR, 2.1; 95% CI, 1.3-3.5; P = .005) with a trend toward inferior PFS (HR, 1.8; 95% CI, 1.0-3.3; P = .058).41

Currently, in the PET era, trials have focused on omitting radiotherapy in patients who achieve a metabolic CR at the end of chemotherapy. In the OPTIMAL>60 trial (NCT01478542), patients with bulky disease (MTD ≥7.5 cm) received 6 cycles of R-CHOP-14 followed by a PET scan.42 PET-positive patients (Deauville score 3-5) received IFRT while PET-negative patients were observed. Outcomes were compared with those of historical controls in the RICOVER-60 trial, who had received 6 cycles of R-CHOP followed by 36 Gy IFRT. Despite the older age and higher IPI scores in the OPTIMAL>60 cohort (no IFRT), outcomes were noninferior compared with the RICOVER-60 cohort (IFRT): The 2-year PFS was 79% vs 75%, respectively. In the retrospective study from British Columbia Cancer Agency (BCCA), patients with advanced-stage disease and bulky sites (MTD ≥10 cm) received 6 cycles of R-CHOP followed by a PET scan.43 Of 517 patients who achieved a metabolic CR (Deauville score 1-3), there was no difference in 3-year PFS between patients with initial bulky compared with those with initial nonbulky disease (82% vs 84%, respectively). Cumulatively, the results of these studies suggest that consolidative radiotherapy can be omitted without compromising efficacy in patients who achieve a metabolic CR after 6 cycles of R-CHOP.

Advanced-Stage Disease

More than 60% of patients with DLBCL present with advanced-stage disease.1 For the majority of these patients, 6 cycles of R-CHOP remains the standard of care; the results of multiple randomized trials and population-based studies have demonstrated no added benefit with 8 vs 6 cycles.40,44,45 Increasing dose density with 14-day vs 21-day cycles failed to improve outcomes while increasing toxicity and compromising dose delivery.46 In high-risk patients 65 years or older with aaIPI ≥2, consolidative autologous stem cell transplant failed to improve outcomes in a randomized phase 3 trial, with similar results in a systematic review and a meta-analysis of trials in the rituximab era.47,48 Several PET-adapted trials, escalating therapy for interim PET-positive patients, have
also failed to improve upon R-CHOP.49-51

Trials have explored various maintenance strategies after 6 cycles of R-CHOP. The randomized phase 3 HOVON, PRELUDE (NCT00332202), and PILLAR-2 (NCT00790036) studies evaluated the role of rituximab,52 enzastaurin,53 and everolimus (Afinitor) maintenance,54 respectively, all of which failed to prolong PFS. In contrast, the phase 3 REMARC trial (NCT01122472) demonstrated a potential role for lenalidomide (Revlimid) maintenance in older adults with DLBCL.55 In the latter trial, 650 patients, all aged 60-80 years, who had a CR or partial response (PR) after 6 to 8 cycles of R-CHOP were randomized to receive lenalidomide maintenance or placebo for 24 months. At a median follow-up of 39 months, PFS was significantly longer in the lenalidomide maintenance arm (HR, 0.71; 95% CI, 0.54-0.93; P = .01). Surprisingly, a greater PFS benefit was
observed in patients with GCB COO, contrary to prior reports demonstrating preferential activity of lenalidomide in ABC COO. However, there was no difference in OS, and
lenalidomide toxicity, primarily hematologic, led to premature discontinuation in 36% of patients. Currently, the NCCN guidelines include lenalidomide maintenance as a category 2B recommendation for older adults with DLBCL achieving a CR or PR after R-CHOP.6

More intensive chemoimmunotherapy with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) was compared with R-CHOP in the phase 3 CALGB 50303 trial (NCT00118209), which enrolled 524 patients with stage II to IV disease.56 At a median follow-up of 5 years, PFS did not significantly differ between R-CHOP and DA-EPOCH-R (66% vs 68%, respectively; P = .65), and hematologic toxicity was greater in the latter. In a post hoc subset analysis of high-risk patients with IPI 3-5, PFS favored the DA-EPOCH-R arm (HR, 0.63; 95% CI, 0.41-0.99) with the greatest benefit observed among patients with IPI 4-5 (HR, 0.46; 95% CI, 0.21-1.01). DA-EPOCH-R has been evaluated prospectively in a multicenter phase 2 study in 53 patients with MYC rearrangement.57 At a median follow-up of
56 months, the 2-year PFS was 71%, with favorable outcomes compared with historical data using R-CHOP.58Obinutuzumab, a glycoengineered anti-CD20 antibody with greater direct cell death and more potent antibody-dependent cellular cytotoxicity and phagocytosis than rituximab, has also been evaluated in combination with CHOP (G-CHOP) in the phase 3 GOYA trial (NCT01287741).59 A total of 1418 patients with advanced-stage disease were randomized to receive 6 to 8 cycles of G-CHOP or R-CHOP. At a median follow-up of 29 months, there was no significant difference in PFS (70% G-CHOP vs 67% R-CHOP; P = .39) and a higher incidence of serious adverse events in the G-CHOP arm.

In the last decade, research has focused on selecting patients with ABC (or non-GCB) DLBCL to evaluate whether the addition of novel agents onto an R-CHOP backbone can improve outcomes. Several agents, including bortezomib (Velcade), ibrutinib (Imbruvica), and lenalidomide, all of which have demonstrated preferential activity in ABC DLBCL in the relapsed/refractory setting, have been evaluated in the frontline setting.60-62 The REMoDL-B trial (NCT01324596) randomized 918 patients (48% non-GCB) to receive 6 cycles of R-CHOP with or without bortezomib.63 At a median follow-up of 30 months, there was no difference in PFS (70% vs 74%, respectively; P = .28), including in patients with ABC subtype. The PHOENIX trial (NCT05021536) randomized 838 patients with non-GCB DLBCL to receive 6 cycles of R-CHOP with or without ibrutinib.64 At a median follow-up of 35 months, there was no difference in EFS (HR, 0.93; 95% CI, 0.73-1.2; P = .59). In a preplanned subset analysis, age had a strong impact, with superior EFS in the R-CHOP + ibrutinib arm in patients aged less than 60 years (HR, 0.58; 95% CI, 0.38-0.88; P = .0099) and increased toxicity with compromised dose delivery in older patients. Conflicting results have been reported with the combination of R-CHOP and lenalidomide in ABC DLBCL. The randomized phase 2 ECOG-ACRIN E1412 trial (NCT01856192) demonstrated a PFS benefit with the addition of lenalidomide to R-CHOP,65 particularly in ABC DLBCL, but this benefit was not replicated in the phase 3 ROBUST trial (NCT02285062).66 The latter trial randomized 570 patients with ABC DLBCL to receive 6 cycles of R-CHOP with or without lenalidomide. At a median follow-up of 27 months, there was no difference in PFS (HR, 0.85; 95% CI, 0.63-1.14; P = .29). These conflicting results are likely due in part to the significantly longer DTI in the ROBUST trial vs the E1412 trial (31 days vs 21 days), differing lenalidomide dosing schemas (15 mg x 14 days vs 25 mg x 10 days), and heterogeneity within the ABC subsets.

DLBCL in the Elderly and Infirm

There is no standard-of-care approach for patients who are elderly (variably defined as 70 or 80 years and older) or infirm.67,68 In general, elderly patients have poorer outcomes due to impaired functional status and/or comorbidities.67,68 Comprehensive geriatric assessments and frailty scores are important tools to assess overall fitness and functional status prior to selecting a treatment regimen to optimize the balance of efficacy and toxicity.28-30 In a recent systematic review, the impact of R-CHOP dose intensity on survival outcomes varied with age.69 Reduced R-CHOP dose intensity was associated with inferior survival in patients aged less than 80 years, with no impact in patients 80 years or older. A multicenter phase 2 trial (NCT01087424) in 150 elderly patients with DLBCL (median age, 83 years; range, 80-95) evaluated attenuated dosing of R-CHOP (R-miniCHOP) for 6 cycles.70 At a median follow-up of 20 months, the 2-year PFS and OS were 47% and 59%, respectively, with a favorable balance of efficacy and toxicity. An ongoing randomized phase 2/3 trial (NCT04799275) is evaluating R-miniCHOP with or without oral azacitidine in patients 75 years and older.71 Other trials have explored novel agents, such as bispecific antibodies, as frontline treatment for elderly or infirm patients and are discussed further in the following section on emerging and novel therapies.

Various comorbidities may also preclude the use of specific chemotherapeutic agents and necessitate alternative regimens. For example, doxorubicin is contraindicated in patients with decompensated heart failure or moderate to severe left ventricular systolic dysfunction.72 In such patients, alternative agents such as etoposide, gemcitabine, or liposomal doxorubicin may be substituted for conventional doxorubicin.6 In a study of 70 patients from the BCCA treated with R-CEOP (etoposide substituted for doxorubicin), the 10-year disease-specific survival was 58% vs 67% in a case-matched control group receiving R-CHOP (P = .25).73

CNS Prophylaxis

CNS relapse of DLBCL is uncommon, occurring in less than 5% of patients treated in the rituximab era, but it is a devastating event with a poor prognosis (median OS, <6 months).74-77 Various clinical and biologic factors are associated with the risk of CNS relapse. The CNS-IPI includes the 5 clinical risk factors in the IPI along with renal or adrenal involvement as a sixth risk factor; it stratifies patients into low- (0-1 factors), intermediate- (2-3 factors), and high-risk (4-6 factors) groups with 2-year rates of CNS relapse of 0.8%, 3.9%, and 12%, respectively.78 In addition, involvement of other specific extranodal sites (ie, testicle, breast, epidural/spinal canal, paranasal sinus, and bone marrow) may also be associated with a higher risk of CNS relapse.79 Other biological factors, including double-expressor phenotype (particularly if non-GCB COO), MYC rearrangement, and MYD88 mutation, also predict a higher risk of CNS relapse.24,58,80

The optimal approach to CNS prophylaxis is not well defined. Typically, 2 to 4 cycles of high-dose methotrexate during or after chemoimmunotherapy or 4 to 8 doses of intrathecal (IT) methotrexate or cytarabine are used.6 In 2 retrospective studies comparing high-dose vs IT prophylaxis in high-risk patients, there was no difference in the incidence of CNS relapse.81,82 Data also conflict regarding the efficacy of CNS prophylaxis in preventing CNS relapse. In a retrospective study of 585 patients with DLBCL who were at high risk for CNS relapse, those who received prophylaxis had a lower 1-year incidence of CNS relapse (2% vs 7.1%), but the difference diminished over time (5-year incidence, 5.6% vs 7.5%), suggesting that prophylaxis may delay CNS relapse rather than prevent it.82 A recent systematic review also failed to demonstrate a benefit of single-route IT prophylaxis in preventing CNS relapse in the rituximab era.83 Further studies are needed to assess risk. Additionally, emerging biomarkers such as circulating tumor DNA (ctDNA) detectable in the CSF may refine the role of CNS prophylaxis.84,85

Emerging and Novel Therapies

Ongoing trials continue to explore frontline therapy that integrates other novel agents, such as small molecules, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapy. Multiple studies have identified BCL2 overexpression as a high-risk feature, particularly in ABC DLBCL, providing a rationale for
venetoclax, a BCL2 inhibitor.86,87 The phase 2 CAVALLI study (NCT02055820) treated 206 patients with R-CHOP + venetoclax, including 104 patients with BCL2 overexpression.88 Comparing outcomes with historical controls treated with R-CHOP on the GOYA trial, those receiving R-CHOP + venetoclax had better PFS (HR, 0.61; 95% CI, 0.43-0.87), particularly those patients with BCL2 overexpression. Venetoclax was also combined with DA-EPOCH-R in the phase 1 ALLIANCE 51707 trial (NCT03036904) in 30 patients with BCL2 overexpression or translocation (including double-expressor and double-hit biology), with a promising CR rate of 90%.89 Polatuzumab vedotin, an antibody-drug conjugate targeting CD79b (expressed by >95% of DLBCLs), has also been combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) as frontline therapy (omitting vincristine given the overlapping toxicity profile). Based on promising results of a phase 1b/2 trial, the phase 3 POLARIX trial randomized 879 patients with IPI ≥2 to receive 6 cycles of R-CHOP or pola-R-CHP.90 At a median follow-up of 28 months, PFS was superior in the pola-R-CHP arm (HR, 0.73; 95% CI 0.57-0.95; P< .02) with a favorable safety profile, and may become a new treatment option in eligible patients.91

Bispecific T-cell engagers (BiTEs) and CAR T-cell therapy have been 2 of the most successful immunotherapeutic strategies in relapsed/refractory DLBCL, and they are now being explored in the frontline setting. Mosunetuzumab, an anti-CD20/CD3 BiTE, was recently evaluated in a phase 1/2 trial as frontline therapy for elderly or unfit patients with DLBCL.92 In a small cohort of 19 patients (median age, 84 years), mosunetuzumab was active as a single agent with an overall response rate (ORR) of 58% (CR rate, 42%). Treatment was well tolerated with no cases of grade ≥3 cytokine release syndrome (CRS) or neurotoxicity. Mosunetuzumab has also been combined with CHOP (M-CHOP) with an excellent ORR of 96% (CR rate, 85%) in a small cohort of 27 patients.93 Based on these favorable results, the ongoing phase 1/2 GO40515 study (NCT03677141) is evaluating M-CHOP or pola-M-CHP as frontline therapy for DLBCL (NCT03677141). Frontline anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) was also evaluated in the phase 2 ZUMA-12 trial (NCT03761056) in high-risk patients with DLBCL (IPI ≥3) or high-grade B-cell lymphoma who had residual PET-positive disease (Deauville score 4-5) after 2 cycles of R-CHOP or DA-EPOCH-R.94 In 32 patients who received axi-cel, the ORR was 85% (CR rate, 74%) and median PFS had not yet been reached at a median follow-up of 9 months. Grade ≥3 CRS and neurotoxicity occurred in 9% and 25% of patients, respectively.

Conclusions

In summary, R-CHOP remains the current standard of care for most patients with DLBCL. For limited-stage disease, radiotherapy can be omitted in patients with negative interim and end-of-treatment PET imaging. Six cycles of R-CHOP remains the standard of care for most patients with bulky or advanced-stage disease. In elderly patients, various geriatric assessment tools can help optimize therapy. While numerous randomized trials have failed to improve upon R-CHOP, a recent press release suggests that pola-R-CHP has superior PFS compared with R-CHOP without increasing toxicity and may become a new standard of care. Ongoing trials are exploring frontline therapy that integrates other novel agents, including various small molecules, antibodies, BiTEs, and CAR T-cell therapy, with promising preliminary results.

Clearly, defining a population of patients with high-risk disease in whom R-CHOP is not effective is critical. Quantitative PET metrics such as metabolic tumor volume have been shown to be prognostic independent of IPI and COO.95 Higher baseline ctDNA level has also been shown to correlate with shorter DTI and inferior outcomes.34,96 Genomic
subgroups and gene expression signatures beyond the COO classification have been shown to predict high-risk subgroups who may respond to R-CHOP + lenalidomide.97 Ultimately, dynamic risk assessment approaches that incorporate baseline, interim, and end-of-treatment metrics, and that can be used outside an academic center, will be critical. Along with innovative trial design, the smaller subgroups as a result of fine-tuning risk underscores the need for collaborative efforts.


AUTHOR AFFILIATIONS:

Michael A. Spinner, MD1; and Ranjana H. Advani, MD1

1. Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford, CA

Disclosures: None

Corresponding author

Ranjana H. Advani, MD, Saul A. Rosenberg Professor of Lymphoma, Stanford Cancer Institute, radvani@stanford.edu

References

1. Sehn LH, Salles G. Diffuse large B-cell lymphoma. N Engl J Med. 2021;384(9):842-858. doi:10.1056/NEJMra2027612

2. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66(6):443-459. doi:10.3322/caac.21357

3. Smith A, Crouch S, Lax S, et al. Lymphoma incidence, survival and prevalence 2004-2014: sub-type analyses from the UK’s Haematological Malignancy Research Network. Br J Cancer. 2015;112(9):1575-1584. doi:10.1038/bjc.2015.94

4. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390. doi:10.1182/blood-2016-01-643569

5. Cheson BD, Fisher RI, Barrington SF, et al; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute.Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3067. doi:10.1200/JCO.2013.54.8800

6. Zelenetz AD, Gordon LI, Abramson JS, et al. NCCN Guidelines insights: B-cell lymphomas, version 3.2019. J Natl Compr Canc Netw. 2019;17(6):650-661. doi:10.6004/jnccn.2019.0029

7. Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014;166(6):891-901. doi:10.1111/bjh.12982

8. Friedberg JW. How I treat double-hit lymphoma. Blood. 2017;130(5):590-596. doi:10.1182/blood-2017-04-737320

9. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3452-3459. doi:10.1200/JCO.2011.41.0985

10. Alzahrani M, El-Galaly TC, Hutchings M, et al. The value of routine bone marrow biopsy in patients with diffuse large B-cell lymphoma staged with PET/CT: a Danish-Canadian study. Ann Oncol. 2016;27(6):1095-1099. doi:10.1093/annonc/mdw137

11. Khan AB, Barrington SF, Mikhaeel NG, et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood. 2013;122(1):61-67. doi:10.1182/blood-2012-12-473389

12. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503-511. doi:10.1038/35000501

13. Pasqualucci L, Dalla-Favera R. Genetics of diffuse large B-cell lymphoma. Blood. 2018;131(21):2307-2319. doi:10.1182/blood-2017-11-764332

14. Lenz G, Wright G, Dave SS, et al; Lymphoma/Leukemia Molecular Profiling Project. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359(22):2313-2323. doi:10.1056/NEJMoa0802885

15. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-282. doi:10.1182/blood-2003-05-1545

16. Meyer PN, Fu K, Greiner TC, et al. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol. 2011;29(2):200-207. doi:10.1200/JCO.2010.30.0368

17. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014;123(8):1214-1217. doi:10.1182/blood-2013-11-536433

18. Ennishi D, Jiang A, Boyle M, et al. Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell–like diffuse large B-cell lymphoma. J Clin Oncol. 2019;37(3):190-201. doi:10.1200/JCO.18.01583

19. Rosenwald A, Bens S, Advani R, et al. Prognostic significance of MYC rearrangement and translocation partner in diffuse large B-cell lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol. 2019;37(35):3359-3368. doi:10.1200/JCO.19.00743

20. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396-1407. doi:10.1056/NEJMoa1801445

21. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679-690. doi:10.1038/s41591-018-0016-8

22. Wright GW, Huang DW, Phelan JD, et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell. 2020;37(4):551-568.e14. doi:10.1016/j.ccell.2020.03.015

23. Lacy SE, Barrans SL, Beer PA, et al. Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report. Blood. 2020;135(20):1759-1771. doi:10.1182/blood.2019003535

24. Ollila TA, Kurt H, Waroich J, et al. Genomic subtypes may predict the risk of central nervous system recurrence in diffuse large B-cell lymphoma. Blood. 2021;137(8):1120-1124. doi:10.1182/blood.2020007236

25. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993;329(14):987-994. doi:10.1056/NEJM199309303291402

26. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857-1861. doi:10.1182/blood-2006-08-038257

27. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837-842. doi:10.1182/blood-2013-09-524108

28. Park S, Hong J, Hwang I, et al. Comprehensive geriatric assessment in elderly patients with newly diagnosed aggressive non-Hodgkin lymphoma treated with multi-agent chemotherapy. J Geriatr Oncol. 2015;6(6):470-478. doi:10.1016/j.jgo.2015.10.183

29. Merli F, Luminari S, Tucci A, et al. Simplified geriatric assessment in older patients with diffuse large B-cell lymphoma: the prospective Elderly Project of the Fondazione Italiana Linfomi. J Clin Oncol. 2021;39(11):1214-1222. doi:10.1200/JCO.20.02465

30. Isaksen KT, Mastroianni MA, Rinde M, et al. A simplified frailty score predicts survival and can aid treatment intensity decisions in older DLBCL patients. Blood Advances. 2021;5(22):4771-4782. doi:10.1182/bloodadvances.2021004777

31. Khurana A, Mwangi R, Nowakowski GS, et al. Impact of organ function–based clinical trial eligibility criteria in patients with diffuse large B-cell lymphoma: who gets left behind? J Clin Oncol. 2021;39(15):1641-1649. doi:10.1200/JCO.20.01935

32. Yoshida M, Nakaya Y, Shimizu K, et al. Importance of diagnosis-to-treatment interval in newly diagnosed patients with diffuse large B-cell lymphoma. Sci Rep. 2021;11(1):2837. doi:10.1038/s41598-021-82615-4

33. Blunt DN, Smyth L, Nagamuthu C, et al. Shorter diagnosis-to-treatment interval in diffuse large B-cell lymphoma is associated with inferior overall survival in a large, population-based registry. J Natl Compr Canc Netw. 2021;19(6):719-725. doi:10.6004/jnccn.2020.7654

34. Alig S, Macaulay CW, Kurtz DM, et al. Short diagnosis-to-treatment interval is associated with higher circulating tumor DNA levels in diffuse large B-cell lymphoma. J Clin Oncol. 2021;39(23):2605-2616. doi:10.1200/JCO.20.02573

35. Persky DO, Unger JM, Spier CM, et al; Southwest Oncology Group. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group Study 0014. J Clin Oncol. 2008;26(14):2258-2263. doi:10.1200/JCO.2007.13.6929

36. Poeschel V, Held G, Ziepert M, et al; German Lymphoma Alliance. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019;394(10216):2271-2281. doi:10.1016/S0140-6736(19)33008-9

37. Bologna S, Vander Borght T, Briere J, et al. Early positron emission tomography response-adapted treatment in localized diffuse large B-cell lymphoma (AAIPI=0): results of the phase 3 LYSA LNH 09-1B trial. Hematologic Oncol. 2021;39(suppl 2):abstr 5. doi:10.1002/hon.5_2879

38. Lamy T, Damaj G, Soubeyran P, et al; LYSA Group. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018;131(2):174-181. doi:10.1182/blood-2017-07-793984

39. Persky DO, Li H, Stephens DM, et al. Positron emission tomography–directed therapy for patients with limited-stage diffuse large B-cell lymphoma: results of Intergroup National Clinical Trials Network Study S1001. J Clin Oncol. 2020;38(26):3003-3011. doi:10.1200/JCO.20.00999

40. Pfreundschuh M, Schubert J, Ziepert M, et al; German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9(2):105-116. doi:10.1016/S1470-2045(08)70002-0

41. Held G, Murawski N, Ziepert M, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014;32(11):1112-1118. doi:10.1200/JCO.2013.51.4505

42. Pfreundschuh M, Christofyllakis K, Altmann B, et al. Radiotherapy to bulky disease PET-negative after immunochemotherapy in elderly DLBCL patients: results of a planned interim analysis of the first 187 patients with bulky disease treated in the OPTIMAL>60 study of the DSHNHL. J Clin Oncol. 2017;35(suppl 15):abstr 7506. doi:10.1200/JCO.2017.35.15_suppl.7506

43. Freeman CL, Savage KJ, Villa DR, et al. Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2021;137(7):929-938. doi:10.1182/blood.2020005846

44. Sehn LH, Congiu AG, Culligan DJ, et al. No added benefit of eight versus six cycles of CHOP when combined with rituximab in previously untreated diffuse large B-cell lymphoma patients: results from the international phase III GOYA study. Blood. 2018;132(suppl 1):abstr 783. doi:10.1182/blood-2018-99-116845

45. Wästerlid T, Biccler JL, Brown PN, et al. Six cycles of R-CHOP-21 are not inferior to eight cycles for treatment of diffuse large B-cell lymphoma: a Nordic Lymphoma Group population-based study. Ann Oncol. 2018;29(8):1882-1883. doi:10.1093/annonc/mdy184

46. Delarue R, Tilly H, Mounier N, et al. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013;14(6):525-533. doi:10.1016/S1470-2045(13)70122-0

47. Chiappella A, Martelli M, Angelucci E, et al. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017;18(8):1076-1088. doi:10.1016/S1470-2045(17)30444-8

48. Epperla N, Hamadani M, Reljic T, Kharfan-Dabaja MA, Savani BN, Kumar A. Upfront autologous hematopoietic stem cell transplantation consolidation for patients with aggressive B‐cell lymphomas in first remission in the rituximab era: a systematic review and meta‐analysis. Cancer. 2019;125(24):4417-4425. doi:10.1002/cncr.32464

49. Swinnen LJ, Li H, Quon A, et al. Response-adapted therapy for aggressive non-Hodgkin’s lymphomas based on early [18F] FDG-PET scanning: ECOG-ACRIN Cancer Research Group study (E3404). Br J Haematol. 2015;170(1):56-65. doi:10.1111/bjh.13389

50. Schöder H, Zelenetz AD, Hamlin P, et al. Prospective study of 3’-deoxy-3’-18F-fluorothymidine PET for early interim response assessment in advanced-stage B-cell lymphoma. J Nucl Med. 2016;57(5):728-734. doi:10.2967/jnumed.115.166769

51. Dührsen U, Müller S, Hertenstein B, et al; PETAL Trial Investigators. Positron emission tomography–guided therapy of aggressive non-Hodgkin lymphomas (PETAL): a multicenter, randomized phase III trial. J Clin Oncol. 2018;36(20):2024-2034. doi:10.1200/JCO.2017.76.8093

52. Lugtenberg EJ, Brown P, van der Holt B, et al. Rituximab maintenance for patients with diffuse large B-cell lymphoma in first complete remission: results from a randomized HOVON-Nordic Lymphoma Group phase III study. J Clin Oncol. 2019;37(suppl 15):abstr 7507. doi:10.1200/JCO.2019.37.15_suppl.7507

53. Crump M, Leppä S, Fayad L, et al. Randomized, double-blind, phase III trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large B-cell lymphoma. J Clin Oncol. 2016;34(21):2484-2492. doi:10.1200/JCO.2016.65.7171

54. Witzig TE, Tobinai K, Rigacci L, et al. Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial. Ann Oncol. 2018;29(3):707-714. doi:10.1093/annonc/mdx764

55. Thieblemont C, Tilly H, Gomes da Silva M, et al. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2017;35(22):2473-2481. doi:10.1200/JCO.2017.72.6984

56. Bartlett NL, Wilson WH, Jung S-H, et al. Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: clinical outcomes of the phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019;37(21):1790-1799. doi:10.1200/JCO.18.01994

57. Dunleavy K, Fanale MA, Abramson JS, et al. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study. Lancet Haematol. 2018;5(12):e609-e617. doi:10.1016/S2352-3026(18)30177-7

58. Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28(20):3360-3365. doi:10.1200/JCO.2009.26.3947

59. Vitolo U, Trněný M, Belada D, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017;35(31):3529-3537. doi:10.1200/JCO.2017.73.3402

60. Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113(24):6069-6076. doi:10.1182/blood-2009-01-199679

61. Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nature Med. 2015;21(8):922-926. doi:10.1038/nm.3884

62. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell–like than in germinal center B-cell–like phenotype. Cancer. 2011;117(22):5058-5066. doi:10.1002/cncr.26135

63. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(5):649-662. doi:10.1016/S1470-2045(18)30935-5

64. Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non–germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37(15):1285-1295. doi:10.1200/JCO.18.02403

65. Nowakowski GS, Hong F, Scott DW, et al. Addition of lenalidomide to R-CHOP improves outcomes in newly diagnosed diffuse large B-cell lymphoma in a randomized phase II US Intergroup Study ECOG-ACRIN E1412. J Clin Oncol. 2021;39(12):1329-1338. doi:10.1200/JCO.20.01375

66. Nowakowski GS, Chiappella A, Gascoyne RD, et al. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39(12):1317-1328. doi:10.1200/JCO.20.01366

67. Thieblemont C, Grossoeuvre A, Houot R, et al. Non-Hodgkin’s lymphoma in very elderly patients over 80 years. a descriptive analysis of clinical presentation and outcome. Ann Oncol. 2008;19(4):774-779. doi:10.1093/annonc/mdm563

68. Pfreundschuh M. How I treat elderly patients with diffuse large B-cell lymphoma. Blood. 2010;116(24):5103-5110. doi:10.1182/blood-2010-07-259333

69. Bataillard EJ, Cheah CY, Maurer MJ, Khurana A, Eyre TA, El-Galaly TC. Impact of R-CHOP dose intensity on survival outcomes in diffuse large B-cell lymphoma: a systematic review. Blood Adv. 2021;5(9):2426-2437. doi:10.1182/bloodadvances.2021004665

70. Peyrade F, Jardin F, Thieblemont C, et al; Groupe d’Etude des Lymphomes de l’Adulte (GELA) investigators. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12(5):460-468. doi:10.1016/S1470-2045(11)70069-9

71. Brem EA, Li H, Beaven AW, et al. A phase II/III randomized study of R-miniCHOP with or without oral azacitidine (CC-486) in participants age 75 years or older with newly diagnosed diffuse large B-cell lymphoma, grade IIIb follicular lymphoma, transformed lymphoma, and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. Blood. 2021;138(Suppl. 1 ):3565.

72. Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of anthracyclines. Front Cardiovascular Med. 2020;7:26. doi:10.3389/fcvm.2020.00026

73. Moccia AA, Schaff K, Freeman C, et al. Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines. Blood Advances. 2021;5(5):1483-1489. doi:10.1182/bloodadvances.2020002982

74. Zhang J, Chen B, Xu X. Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: a systematic review and meta-analysis. Leuk Lymphoma. 2014;55(3):509-514. doi:10.3109/10428194.2013.811239

75. Gleeson M, Counsell N, Cunningham D, et al. Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial. Ann Oncol. 2017;28(10):2511-2516. doi:10.1093/annonc/mdx353

76. Ghose A, Elias HK, Guha G, Yellu M, Kundu R, Latif T. Influence of rituximab on central nervous system relapse in diffuse large B-cell lymphoma and role of prophylaxis—a systematic review of prospective studies. Clin Lymphoma Myeloma Leuk. 2015;15(8):451-457. doi:10.1016/j.clml.2015.02.026

77. Bernstein SH, Unger JM, LeBlanc M, Friedberg J, Miller TP, Fisher RI. Natural history of CNS relapse in patients with aggressive non-Hodgkin’s lymphoma: a 20-year follow-up analysis of SWOG 8516—the Southwest Oncology Group. J Clin Oncol. 2009;27(1):114-119. doi:10.1200/JCO.2008.16.8021

78. Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34(26):3150-3156. doi:10.1200/JCO.2015.65.6520

79. Chin CK, Cheah CY. How I treat patients with aggressive lymphoma at high risk of CNS relapse. Blood. 2017;130(7):867-874. doi:10.1182/blood-2017-03-737460

80. Savage KJ, Slack GW, Mottok A, et al. Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL. Blood. 2016;127(18):2182-2188. doi:10.1182/blood-2015-10-676700

81. Orellana-Noia VM, Reed D, McCook AA, et al. Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions. Blood. Published online September 27, 2021. doi:10.1182/blood.2021012888

82. Bobillo S, Joffe E, Sermer D, et al. Prophylaxis with intrathecal or high-dose methotrexate in diffuse large B-cell lymphoma and high risk of CNS relapse. Blood Cancer J. 2021;11(6):113. doi:10.1038/s41408-021-00506-3

83. Eyre TA, Djebbari F, Kirkwood AA, Collins GP. Efficacy of central nervous system prophylaxis with stand-alone intrathecal chemotherapy in diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy in the rituximab era: a systematic review. Haematologica. 2020;105(7):1914-1924. doi:10.3324/haematol.2019.229948

84. Bobillo S, Crespo M, Escudero L, et al. Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B-cell lymphomas. Haematologica. 2021;106(2):513-521. doi:10.3324/haematol.2019.241208

85. Olszewski AJ, Chorzalska AD, Peterson M, et al. Cerebrospinal fluid (CSF) analysis of tumor-specific cell-free DNA (cfDNA) as a diagnostic and prognostic tool for central nervous system (CNS) invasion in lymphoma. Blood. 2020;136(suppl 1):21-22. doi:10.1182/blood-2020-134757

86. Iqbal J, Neppalli VT, Wright G, et al. BCL2 expression is a prognostic marker for the activated B-cell–like type of diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(6):961-968. doi:10.1200/JCO.2005.03.4264

87. Tsuyama N, Sakata S, Baba S, et al. BCL2 expression in DLBCL: reappraisal of immunohistochemistry with new criteria for therapeutic biomarker evaluation. Blood. 2017;130(4):489-500. doi:10.1182/blood-2016-12-759621

88. Morschhauser F, Feugier P, Flinn IW, et al. A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma. Blood. 2021;137(5):600-609. doi:10.1182/blood.2020006578

89. Rutherford SC, Abramson JS, Bartlett NL, et al. Phase I study of the Bcl-2 inhibitor venetoclax with DA-EPOCH-R as initial therapy for aggressive B-cell lymphomas. J Clin Oncol. 2020;38(suppl 15):abstr 8003. doi:10.1200/JCO.2020.38.15_suppl.8003

90. Tilly H, Morschhauser F, Bartlett NL, et al. Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Lancet Oncol. 2019;20(7):998-1010. doi:10.1016/S1470-2045(19)30091-9

91. Tilly H, Morschhauser F, Sehn LH, et al. The POLARIX Study: Polatuzumab Vedotin with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (pola-R-CHP) Versus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) Therapy in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma. Blood. 2021;138(Suppl. 1):LBA-1.

92. Olszewski A, Avigdor A, Babu S, et al. Single-agent mosunetuzumab is a promising safe and efficacious chemotherapy-free regimen for elderly/unfit patients with previously untreated diffuse large B‑cell lymphoma. Blood. 2020;136(suppl 1):43-45. doi:10.1182/blood-2020-136255

93. Phillips TJ, Olszewski AJ, Munoz J, et al. Mosunetuzumab, a novel CD20/CD3 bispecific antibody, in combination with CHOP confers high response rates in patients with diffuse large B-cell lymphoma. Blood. 2020;136(suppl 1):37-38. doi:10.1182/blood-2020-136295

94. Neelapu SS, Dickinson M, Ulrickson ML, et al. Interim analysis of ZUMA-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients (pts) with high-risk large B cell lymphoma (LBCL). Blood. 2020;136(suppl 1):49. doi:10.1182/blood-2020-134449

95. Kostakoglu L, Mattiello F, Martelli M, et al. Total metabolic tumor volume as a survival predictor for patients with diffuse large B-cell lymphoma in the GOYA study. Haematologica. Published online August 19, 2021. doi:10.3324/haematol.2021.278663

96. Kurtz DM, Scherer F, Jin MC, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma. J Clin Oncol. 2018;36(28):2845-2853. doi:10.1200/JCO.2018.78.5246

97. Hartert KT, Wenzl K, Krull JE, et al. Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL. Leukemia. 2021;35(2):522-533. doi:10.1038/s41375-020-0766-4



Related Videos
Some patients with large B-cell lymphoma may have to travel a great distance for an initial evaluation for CAR T-cell therapy.
Education is essential to referring oncologists manage toxicities associated with CAR T-cell therapy for patients with large B-cell lymphoma.
There is no absolute age cutoff where CAR T cells are contraindicated for those with large B-cell lymphoma, says David L. Porter, MD.
David L. Porter, MD, emphasizes referring patients with large B-cell lymphoma early for CAR T-cell therapy consultation.
It may be applicable to administer CAR T-cell therapy to patients with large B-cell lymphoma in a community or outpatient setting.