Current Frontline Treatment of Diffuse Large B-Cell Lymphoma
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
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
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
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
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
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