Table of Contents

    Topic review

    Diffuse Large B-Cell Lymphoma

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    Submitted by: Leonard Harris

    Definition

    The most common type of non-Hodgkin lymphoma in adults is diffuse large B-cell (DLBCL). There is a historical unmet need for more effective therapies in the 2nd and 3rd line setting. Emerging immunochemotherapies have shown activity in small studies of heavily pre-treated patients with prolonged remissions achieved in some patients. Anti-CD19 CAR (chimeric antigen receptor) T cells are potentially curative in the 3rd line and beyond setting and are under investigation in earlier lines of therapy. Antibody-drug conjugates (ADC’s) such as polatuzumab vedotin targeting the pan-B-cell marker CD79b has proven effectiveness in multiply-relapsed DLBCL patients. Tafasitamab (MOR208) is an anti-CD19 monoclonal antibody producing prolonged remissions when combined with Lenalidomide (LEN) in patients who were not candidates for salvage chemotherapy or autologous stem cell transplant. Selinexor, an oral, small-molecule selective inhibitor of XPO1-mediated nuclear export (SINE), demonstrated prolonged activity against heavily-pretreated DLBCL without cumulative toxicity and is being investigated as part of an oral, chemotherapy-free regimen for relapsed aggressive lymphoma. This article reviews current strategies and novel therapies for relapsed/refractory DLBCL.

    1. Introduction

    Diffuse large B-Cell Lymphoma (DLBCL) is an aggressive subtype accounting for 25–30% of Non-Hodgkin lymphoma (NHL) with an incidence of 5.6 per 100,000 persons per year [1][2]. DLBCL is usually symptomatic at presentation with either nodal or extranodal disease. Diagnosis is made when large, transformed B cells (CD19+, CD20+, CD79+) with prominent nucleoli, diffuse growth pattern, and a high proliferation fraction are seen on tissue biopsy [1]. The World Health Organization (WHO) schema classifies by cell of origin (COO) classification including germinal B-cell (GCB) subtype or activated B cell (ABC) subtype, but more recent transcriptome sequencing techniques have identified five distinct subtypes that improve the differentiation among prognostic groups in DLBCL [3][4]. Genomic instability is demonstrated by a median of 17 (range: 0–48) genetic drivers that were clustered into these 5 distinct genetic signatures. In the 2017 revision of WHO classifications, DLBCL with translocations of MYC and BCL2 and/or BCL6—double-hit (DHL) or triple-hit (THL)—are reclassified as Diffuse Aggressive B-Cell Lymphomas, with more intense therapeutic regimens such as DA-EPOCH-R with CNS prophylaxis in the first line setting having a 4 year overall survival of 72.2% [5]. Despite multiple studies attempting to improve upon the outcomes, R-CHOP remains the first line treatment for DLBCL regardless of IPI score, COO, or gene expression profile except for DHL.

    DLBCL cases that do not fit a specific subtype have an overall survival rate of 65% when treated with standard R-CHOP (Rituximab, Cyclosporine, Vincristine, Prednisone) therapy [1]. The Standard International Prognostic Index (IPI) is widely used for risk stratification with aggressive B-cell lymphoma, and has been validated with continued prediction of risk in the Rituximab era [6]. Patients with a high IPI score have poor prognosis with an OS as low as 20–25%. Certain mutations and pathways are common in the GCB subtype such as EZH2, BCL2 and PI3K. In the ABC subtype, NF-KB activation, MYD88 mutations and JAK-STAT pathways are more common [7].

    While most patients respond, 30–40% of patients with DLBCL relapse or are unable to achieve remission with first-line treatment. In these cases, the prognosis is poor [8]. Approximately 50% of patients with relapsed or refractory (R/R) DLBCL have a response to second-line chemotherapy; up to 50% of these patients proceed to undergo autologous hematopoietic stem-cell transplantation in some settings, and of these, approximately 30 to 40% remain progression-free 3 years after transplantation [8][9][10][11][12]. Median survival for primary and secondary refractory DLBCL is 5–7 months [8].

    Patients who progress after receiving R-CHOP receive combination salvage chemotherapy. Commonly used regimens, including R-ICE, R-DHAP, R-GDP, R-GemOx, O-DHAP, O-ICE, and DR-ICE, have similar treatment effects [13][14]. However, analysis of real-world data from 126 community-based hematology/oncology practices in the US between 2010–2016 demonstrated that only 13% of patients who received salvage regimens intended for ASCT eventually underwent ASCT [15].

    The unmet need for more effective regimens is highlighted by the wide heterogeneity in regimens used in clinical practice with consistently poor outcomes [13]. Pts that are not candidates for ASCT and those who never make it or have failed CAR-T therapy have poor outcomes with salvage chemotherapy regimens. Response rate comparisons between studies are unreliable due different rates of enrollment of primary refractory disease. In the phase III CORAL trial (n = 396) comparing R-ICE and R-DHAP followed by autologous hematopoietic cell transplant (HCT) for chemosensitive patients, the overall response was 63%, and the three year overall survival was 47%. Median overall survival of R/R DLBCL who failed second-line regimens in CORAL was 4.4 months [8]. The LY.12 trial (n = 619) compared the platinum-containing regimens R-GDP and R-DHAP followed by autologous HCT and had response rate 45% [12]. SCHOLAR-1 is the most comprehensive analysis of pooled outcomes from several large studies of relapsed and refractory DLBCL (n = 636) treated with various standard of care chemotherapy regimens, and the ORR was 26%, CR rate of 7%, and median overall survival was 6.2 months [16][17].

    A cost-effectiveness analysis of DLBCL regimens from the Truven database with claims data from US government and private payers highlighted the direct costs associated with the 2/3 of patients with DLBCL who received subsequent 2nd-line regimen after completing R-CHOP [18]. More effective treatment options for this resource intensive condition has the potential to both decrease mortality and reduce the costs of subsequent lines of therapy including ASCT [18][19]. Several innovative treatment modalities are already receiving regulatory approvals (Table 1).

    Table 1. Novel Regimens with FDA Approval.

    Agent Year of FDA Approval Regimen Population Relapse < 1 year of DLBCL Diagnosis Refractory to Last Regimen DHL/THL Efficacy Outcomes
    Axicabtagene ciloleucel
    (axi-cel)
    2017 Flu/Cy LD R/R DLBCL refractory to 2 lines of therapy 30% 77% NR ORR 83%
    CR 58%
    mOS 24 mos
    Lisocabtagene maraleucel   Flu/Cy LD R/R DLBCL refractory to 2 lines of therapy NR 44% 13% ORR 73%
    CR 53%
    mOS >12 mos
    Tisagenlecleucel a 2018 Flu/Cy LD
    or Benda-Flu LD
    R/R DLBCL refractory to 2 lines of therapy NR 40% 27% ORR 52
    CR 40%
    mOS 12 mos
    Polatuzumab vedotin [20] 2019 Pola + BR R/R DLBCL
    Ineligible for ASCT
    53% 75% 0% CMR 40%
    mOS 12.4 mos
    Selinexor [21] 2020 Selinexor 60 mg po on days 1 and 3 of each week R/R DLBCL 33%
    §§
    72% 4% ORR 28%
    CR 12%
    mOS 9.1 mos
    Tafasitamab [22] 2020 Tafa + LEN 25 mg R/R DLBCL
    Ineligible for ASCT
    19%
    §
    44% 0% ORR 58%
    CR 33%
    mOS 22 mos

    FDA: United States Food and Drug Administration; Flu/Cy: Fludarabine/Cyclophosphamide; LD: lymphodepletion; Benda/Flu: Bendamustin/Cyclophosphamide; Pola: Polatuzumab vedotin; BR: Bendamustin and Rituximab; Ritux: Rituximab; LEN: Lenalidomide; Tafa: Tafasitamab; dx: diagnosis; DHL: Double Hit Lymphoma; THL: Triple Hit Lymphoma; R/R DLBCL: Relapsed or Refractory Diffuse Large B Cell Lymphoma; ORR: Overall Response Rate; CR: Complete Response; mOS: Median Overall Survival; mos: months; CMR: Complete Metabolic Response; po: by mouth; NR: Not Reported. a: investigational agent with pending Food and Drug Administration approval. § Excluded if received anti-CD20 therapy within 6 months. §§ Excluded if not in PR or CR and received therapy within 14 weeks.

    2. Sequencing Therapy

    With recent new drug approvals, treatment options for patients with R/R DLBCL have expanded. However, this poses a challenge in sequencing and treatment selection for patients. At this time, the sequencing of therapy is individualized based on the efficacy and side effect profile of treatment. In patients with R/R DLBCL, the treatment should be divided among transplant eligible and ineligible patients. If they are transplant ineligible or progress after ASCT, they have all the above approved regimens available as option. ASCT ineligible patients should be evaluated for CAR-T therapy as it offers the best ORR among therapies mentioned in Table 1. However, CAR-T can be challenging in terms of accessibility, the patient’s functional status, disease burden and other factors. Polatuxumab Vedotin in combination with bendamustine and rituximab is another option and can be used as a bridge to CAR-T as well. Polatuzumab Veodtin in combination with BR had 40% of CRR and manageable toxicities [20]. If patients respond well, Bendamustine can be dropped to allow cell collection for CAR-T. However, it is a three drug regimen and it carries risk of grade 3 or 4 cytopenias and peripheral neuropathy. In patients that are not candidates for CAR-T and goal is palliation, Tafasitamab with lenalidomide is a great option with limited toxicities. Based on the L-Mind study, Tafasitamab + Len had ORR of 60% and CRR of 42.5% and main side effects were cytopenias managed by dose adjustment of lenalidomide [22]. Tafasitamab prior to CAR-T may alter efficacy of CAR-T therapy since they both are CD-19 targeted therapy; however, more data are needed to support this. Selinexor is another option for ASCT ineligible patients with ORR of 28%; relatively lower than other agents. Selinexor also has a significant side effect profile for GI toxicity, hyponatremia and cytopenia, hence would reserve this as a last option.

    3. Future of DLBCL and Immunotherapy

    MT-3724 is a novel Engineered Toxic Body (ETB) comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to an antibody-like binding domain that binds CD20. ETBs work though a novel mechanism of action whereby the internalization of the fragment when bound to CD20 delivers the toxin intracellularly where ribosomal inactivation leads to targeted cell death [23][24]. MT-3724 is currently being studied in three ongoing Phase 2 studies for relapsed and refractory DLBCL. Loncastuximab tesirine, ADCT-402 is an antibody-drug conjugate composed of a humanized monoclonal antibody against CD19 and conjugated to a pyrrolobenzodiazepine dimer cytotoxin. In phase 2 trials, ADCT-402, 145 pts with relapsed or refractory DLBCL were enrolled and ORR was 45%. The common side effects were cytopenias requiring dose adjustments, which were otherwise well tolerated. Hu5F9-G4, a humanized monoclonal antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. A phase 1B study, 22 pts with relapsed NHL were treated with Hu5F9-G4 in combination with rituximab. The ORR in DLBCL subset was 40% with CR of 33%. The most common AEs were infusion reaction, fever and chills. Immune checkpoint inhibitors have gained recognition in multiple solid tumors and demonstrated durable responses. PD-1 and PDL-1 are expressed in many hematologic malignancies and have recently been approved for second line HL. In a phase 1 trial of relapsed DLBCL patients, nivolumab showed an ORR of 36%, but these responses were not durable. There are a few trials in DLBCL being completed with immune checkpoint inhibitors in combination with anti-CD-20 antibodies (NCT03401853) and immunomodulators and targeted agents such as LEN (NCT03015896) and Copanlisib (NCT03484819). Table 1 includes a list early clinical trials involving immunotherapy for treatment of relapsed/refractory DLBCL.

    Table 2 - Novel Regimens Under Investigation for Relapsed or Refractory Diffuse Large B Cell Lymphoma

    Bispecific Abs

     

    Epcoritamab (CD3/CD20)

    Flat dose

    Subcutaneous weekly

    Escalation study

    Hutchings, et al41

    NCT03625037

     

    Phase 1/2

    R/R DLBCL

    N= 41

    Enrolling

    Median f/u 4.7 mo

    ORR 56%

    CR 44%

    No dose limiting toxicities

     

    Odronextamab

    REGN1979

    (CD3/CD20)

    18 -320mg doses

    Bannerji, et al42

    NCT03888105

    Phase 1

    R/R DLBCL

    N=19

    Enrolling phase 2

    ORR 58%

    CR 37%

     

     

    Monsenetuzumab

    (CD3/CD20)

    Schuster, et al43

    NCT03677154

    Phase 1/2

    R/R DLBCL including p CAR-T

    N=119

    Enrolling phase 3

    ORR 34.7%

    CR 18.6%

     

    Glofitamab

    RG6026

    (CD3/CD20

    Morschhauser, et al44

    NCT03075696

     

    Phase 1/Ib

    R/R aggressive NHL

    +/- Obinituzumab

    N=21

    Enrolling Phase 1

    ORR 38%

    CR 31%

    Monoclonal Abs

     

    Tafasitamab (anti-CD19)

    (Fc-enhanced, humanized)

    + Lenolidomide

    Nowakowski, et al25

    Maddocks, et al45

    NCT02399085

    Phase 1/2

    R/R DLBCL

    Ineligible for ASCT

    Excluded double-hit

    N=81

    Enrolling phase 3

    ORR 58%

    CR 33%

    Median OS 22 mos (95% CI: 18.6 – NR)

     

    Magrolimab (5F9)

    (anti-CD47, promote phagocytosis)

    +Rituximab

    Advani, et al46

    NCT02953509

    Phase 1b/2

    R/R DLBCL

    N=15

    Enrolling, Preliminary results

    ORR 40%

    CR 27%

    On-target anemia primarily 1st dose

    Anti-PD-L1 Containing Regimens

     

    Atezolizumab (anti-PDL1)

    +Obinituzumab (anti-CD20)

    +Venetoclax (BCL2 inhibitor)

    Herbaux, et al47

    NCT03276468

    Phase 2

    R/R DLBCL

    N=58

    Interim Results

    ORR 23.6%

    CMR 18%

     

    Mogamulizumab (anti-CCR4)

    + Pembrolizumab

    Joffe, et al

    NCT03309878

    Phase 1b/2

    R/R DLBCL

    Ineligible for ASCT

     

    Enrolling

     

    Avelumab  (anti-PD-L1)

    +/- Utomilumab (4-1BB agonist)

    +/- Rituximab

    +/- Bendamustine or Azacitidine

    Chen, et al48

    NCT02951156

    Phase 1b/3

    R/R DLBCL

    Ineligible for ASCT

    ECOG<1

     

    Enrolling

    Bispecific CAR T Cell Therapies

     

    AUTO3 (CD19/CD22)

    Dual targeted

    + Pembrolizumab

    Osborne, et al

    NCT03287817

    Phase 1/2

    R/R DLBCL

    N=11

     

    ORR 64%

    CRR 55%

     

     

    LV20.19CAR (CD19/CD20)

    Dual targeted

    Lentiviral

    Shah, et al49

    NCT03019055

    Phase 1

    R/R NHL

    45% DLBCL

     

    Enrolling in expansion phase

    ORR 82%

    CR 54.5%

    No grade 3-4 CRS or NTX in first 11 pts.

    Antibody-Drug Conjugates

     

    Polatuzumab vedotin

    (anti-CD79b/MMAE) added to BR

    Sehn et al20

    Lu et al28

    NCT02257567

    Phase 2

    R/R DLBCL

    Ineligible for ASCT

    N=80

    CMR 40%

    Median OS 12.4 mos

     

    Polatuzumab vedotin

    (anti-CD79b/MMAE) added to GemOx

    Haioun, et al31

    NCT04182204

    Phase 3

    R/R DLBCL

     

    Enrolling

    Engineered Toxin Bodies

     

    MT-3724 (CD20 / SLT-I A1)

     

    Fanale, et al50

    Duque, et al51

    NCT02361346

    Phase 1

    Relapsed B-NHL after anti-CD20 and CT

    N=100

    Safety and efficacy assessment of 50 mcg/kg/dose ongoing.

    PI3K Inhibitor

     

    Parsaclisib 20 mg po daily

    Coleman, et al52, 53

    NCT02998476

    Phase 2

    R/R DLBCL

    N=60

    Interim Results

    ORR 25%

    CMR 12.5%

     

    Buparlisib 80 mg po daily

    + Ibrutinib

    Batlevi, et al54

    NCT02756247

    Phase 1/2

    R/R DLBCL, Mantle Cell, Follicular

    N=37

    Interim Results

    ORR 31%

    CMR 23%

    BTK Inhibitors

     

    Acalabrutinib 100mg po BID

    +Pembrolizumab

    Witzig, et al55

    NCT02362035

    Phase 1/2

    R/R DLBCL

    N=61

    ORR 26%

    CR 7%

     

    Zanubrutinib 160mg po BID

    Yang, et al56

     NCT03145064

    Phase 2

    R/R Non-GBC DLBCL

    Ineligible for ASCT

    N=41

    ORR 29.3%

    CR 17.1%

    Median OS 8.4 mos

    Immunomodulators

     

    R2-GDP

    Lenalidomide 10mg po d1-14 + R-GDP

    Merino, et al57

    EudraCT 2014-001620-29

    Phase 2

    R/R DLBCL

    Ineligible for ASCT

    N=79

    Enrolling

    ORR 59%

    CR 32%

    Median OS 12 mos

     

    R2-ICE

    Lenalidomide 20mg po d1-14 + RICE

    Guerra-Bauman, et al58

    NCT02628405

    Phase 1/2

    R/R DLBCL

    Candidates for ASCT

     

    Enrolling

    mAb = Monoclonal Antibody; PO = by mouth; BID = twice daily; Mo(s) = month(s); ORR = Overall Response Rate; CR=Complete Response; CMR=Complete Metabolic Response by Positron Emission Testing (PET); Dur.= Duration; CT = Chemotherapy; ATE+OBI+VEN (Atezulizumab+Obinituzumab+Venetoclax); BR = Bendamustin/Rituximab; Gem-Ox = Gemcitabine/Oxaliplatin; AE Trmt DC Ac/Pem =Adverse Events causing Treatment Discontinuation due to Acalabrutinib/Pembrolizumab; SLT-I A1=Shiga-like toxin-I A1; R2-GDP (Lenalidomide, Rituximab, Gemcitabine, Dexamethasone, Cisplatin); R2-IMED (Lenalidomide, Rituximab, Methotrexate, Etoposide, and Dexamethasone); R2-ICE (Lenalidomide, Rituximab, Ifosfamide, Carboplatin, Etoposide)

    The entry is from 10.3390/ijms21228553

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