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Review

Novel Therapies for Relapsed or Refractory Diffuse Large B-Cell Lymphoma

1
Oncology Division, Department of Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38103, USA
2
West Cancer Center & Research Institute, Memphis, TN 38103, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(22), 8553; https://doi.org/10.3390/ijms21228553
Received: 29 September 2020 / Revised: 2 November 2020 / Accepted: 10 November 2020 / Published: 13 November 2020
(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

Abstract

:
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).

2. Tafasitamab

Tafasitamab (MOR208) is an Fc-enhanced, humanized, anti-CD19 monoclonal antibody that has shown preclinical and single-agent activity in patients with relapsed or refractory B-cell malignancies [23]. It has been engineered to have better antibody directed cellular cytotoxicity (ADCC) than a native antibody LEN enhances natural killer cell-meditated, antibody-dependent cellular cytotoxicity with tafasitamab in vitro [24]. A recently published analysis confirmed synergistic effects of combining tafasitamab with LEN by comparing the L-MIND study (combination) to RE-MIND (LEN monotherapy) [25]. L-MIND is an open-label, single-arm, phase II clinical trial of tafasitamab plus lenalidomide in patients with relapsed or refractory DLBCL who were ineligible for high-dose chemotherapy with autologous stem-cell transplantation due to factors such as advanced age, refusal, or comorbidities [22]. Double-hit (simultaneous detection of MYC with BCL2 or BCL6 translocation) and primary refractory patients who relapsed within 6 months of anti-CD20 therapy were excluded (in the first 6 months of recruitment the exclusion was only 3 months to be primary refractory). Of the 80 patients who received the dual therapy, 43% experienced complete responses and 18% exhibited partial responses, and the median duration of these responses was 21.7 months, which is in contrast to LEN monotherapy in similar patients, where only 13.2% experienced complete response [25], and in contrast to the R2 regimen of LEN and Rituximab for R/R DLBCL, where only 13.3% experienced complete response [26]. All Tafasitamab+LEN patients experienced treatment-emergent adverse events, with neutropenia being the most common adverse event. Nonhematologic adverse events were most often grade 1 or 2 and included diarrhea and rash [22]. Notably, 12% of patients discontinued study treatment because of adverse events, and four patients died of treatment-emergent adverse events, although none of these deaths were deemed by the investigators to be due to the study treatment [27]. However, cytopenias are likely related to LEN use. Now in a phase 1b study, MOR 208 is being studied in combination with R-CHOP and lenalidomide for frontline DLBCL treatment.

3. Polatuzumab Vedotin

Polatuzumab vedotin is an antibody–drug conjugate (ADC) consisting of a humanized anti-CD79b monoclonal antibody and the anti-mitotic agent, mono-methyl auristatin E (MMAE) [28]. This Polatuzumab vedotin’s antibody recognizes the CD79b protein that is associated with the B-cell receptor. After the antibody binds to CD79b, the ADC’s toxic payload (MMAE) enters the B cell and then kills it by preventing tubulin polymerization. Targeting the pan-B marker CD79b is ideal since it will not select for resistance to CD19 regimens for patients who may later require CAR T cell therapy directed against CD19 [29]. Given as a parenteral triplet, polatuzumab-vedotin plus bendamustine and rituximab is approved for third-line therapy use after demonstrating a median overall survival of 12.4 months compared with 4.7 months for patients receiving a current standard salvage regimen of bendamustine and ritixumab [20]. Patients were excluded if they had a history of grade ≥2 peripheral neuropathy or prior HSCT. Primary-refractory nor double/triple-hit lymphomas were excluded. Adverse reactions led to dose reduction in 18%, dose interruption in 51%, and permanent discontinuation of all treatment in 31%. The most common adverse reactions leading to treatment discontinuation were thrombocytopenia and/or neutropenia [30]. In early phase studies and clinical practice, experts suggest Polatuzumab has significant single agent activity and it can be given without bendamustine. The POLARGO study is a currently enrolling a multicenter phase III randomized controlled trial of pola-R-GemOx vs. R-GemOx alone in R/R DLBCL [31]. In patients with relapsed disease who need a bridge to either CAR-T or ASCT, polatuzumab has proven to be an active regimen used in this situation. Since polatuzumab has been effective and well tolerated, there is a currently ongoing trial, POLARIX, using it in upfront therapy with RCHOP.

4. Selinexor

Selinexor, an oral selective inhibitor of XPO1-mediated nuclear export (SINE), has a broad potential mechanism of action. It induces the expected nuclear accumulation and activation of tumor suppressor proteins and reduces Bcl2, Bcl-XL, and c-Myc oncoprotein concentrations [21]. It received accelerated FDA approval in 2019 for relapsed or refractory DLBCL after 2 lines of systemic therapy in addition to approval for relapsed Multiple Myeloma [32]. In the multicenter, open-label, phase 2b SADAL study, 127 patients with DLBCL who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were given selinexor orally at the fixed dose of 60 mg on day 1 and day 3 weekly, until disease progression or manifested unacceptable toxicity [33]. The primary endpoint of overall response rate was 28% (36/127) with median duration of response 23 months. Complete response was achieved in 12% with a median duration of 23.0 months. In the subgroup analysis of those with low c-myc expression by immunohistochemistry, the overall response rate was 42% [21]. Selinexor caused adverse events that were reversible with standard supportive care and dose modification to 40 mg dosing. Without apparent cumulative toxicity, there is currently no maximum duration of treatment; the longest duration of treatment in the SADAL study with selinexor is > 3.5 years [21]. Two experimental studies (NCT02303392 and NCT03955783) in aggressive lymphoma, testing the combinations of selinexor with ibrutinib or venetoclax are active and recruiting. Results of the studies might clarify if a totally oral and chemotherapy free treatment should be an option for patients with relapsed or refractory DLBCL.

5. CAR T Cells

Anti-CD19 CAR T cell therapy has transformed the approach to multiple-relapsed/refractory aggressive B-cell lymphomas. Three anti-CD19 CAR T cell products have demonstrated efficacy in relapsed DLBCL with a remarkably long duration of effect in patients who achieve a complete response. Second generation receptors, dual target CD19/CD22, novel dose escalation protocols, and addition of PD-1 blockade are in ongoing studies for improved efficacy and/or reduced toxicity [34]. The indications for use may expand in the future as the collection and manufacturing process becomes more streamlined and more centers develop experience managing its toxicities [9,35,36,37]. Currently, axicabtagene ciloleucel (axi-cel) and Tisagenlecleucel (tisa-cel) are approved by the US Food and Drug Administration in adults with relapsed or refractory DLBCL after two or more lines of systemic therapy. The ZUMA study (n = 101) of axi-cel reported a 58% CR and 24 month survival rate of 50.5%. The cohort of patients age ≥ 65 years (n = 81) had a 44% rate of grade ≥3 neurologic toxicity. The JULIET study (n = 93) of tisagenlecleucel had a 40% CR and 12 month overall survival rate of 49%. The TRANSCEND study (n = 344) of lisocabtagene maraleucel reported CR 53% and estimated 12 month overall survival rate 58%, and only 1% experienced grade 3 or higher neurologic toxicity of confusional state during therapy [38]. Multiple randomized trials are currently enrolling patients with primary refractory or early relapsed aggressive B-cell lymphomas comparing anti-CD19 CAR T cell therapy with traditional salvage therapy and ASCT (TRANSFORM, NCT03575351; BELINDA, NCT03570892; and ZUMA-7, NCT03391466) [39]. A key limitation of CAR-T therapies is limitations in access and the time that lapses between collecting and infusing cells that ranged 17 to 54 days during phase 2 clinical trials [40].

6. 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.

7. Future of DLBCL and Immunotherapy

There are many other immunotherapy based regimens under early clinical trials aside from those mentioned above (Table 2).
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 [50,51]. 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.

8. Conclusions

Novel agents are changing treatment strategies in relapsed or refractory DLBCL after the failure of cytotoxic chemoimmunotherapy. Harnessing the surveillance of the patient’s T cell immunity has produced prolonged responses in studies of heavily pre-treated patients. The inclusion of immunotherapies such as CAR T cells, bispecific antibodies, ADCs, and other immunomodulatory drugs to the treatment algorithms for DLBCL is filling the unmet need for agents with activity in the multiply relapsed setting. A recurring theme in the development of noncytotoxic regimens is that chemotherapy free does not equal toxicity-free [39]. Distinct adverse effects seen with immunotherapies are part of these treatment decisions, and ongoing studies are informing the physical toxicities expected in broader populations. Learning which patients reap the most benefit from these agents enables more accurate calculations of financial toxicities.

Author Contributions

Conceptualization, K.P. and M.M.; Writing—Original draft preparation, L.J.H.; Writing—Review and editing, L.J.H., K.P., M.M.; supervision, M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Swerdlow, S.H.; Campo, E.; Pileri, S.A.; Harris, N.L.; Stein, H.; Siebert, R.; Advani, R.; Ghielmini, M.; Salles, G.A.; Zelenetz, A.D.; et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016, 127, 2375–2390. [Google Scholar] [CrossRef] [PubMed][Green Version]
  2. Tkacz, J.; Garcia, J.; Gitlin, M.; McMorrow, D.; Snyder, S.; Bonafede, M.; Chung, K.C.; Maziarz, R.T. The economic burden to payers of patients with diffuse large B-cell lymphoma during the treatment period by line of therapy. Leuk. Lymphoma 2020, 61, 1601–1609. [Google Scholar] [CrossRef] [PubMed]
  3. Grimm, K.E.; O’Malley, D.P. Aggressive B cell lymphomas in the 2017 revised WHO classification of tumors of hematopoietic and lymphoid tissues. Ann. Diagn. Pathol. 2019, 38, 6–10. [Google Scholar] [CrossRef] [PubMed]
  4. Hu, S.; Xu-Monette, Z.Y.; Tzankov, A.; Green, T.; Wu, L.; Balasubramanyam, A.; Liu, W.M.; Visco, C.; Li, Y.; Miranda, R.N.; et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: A report from The International DLBCL Rituximab-CHOP Consortium Program. Blood 2013, 121, 4021–4031. [Google Scholar] [CrossRef][Green Version]
  5. Dunleavy, K.; Fanale, M.A.; Abramson, J.S.; Noy, A.; Caimi, P.F.; Pittaluga, S.; Parekh, S.; Lacasce, A.; Hayslip, J.W.; Jagadeesh, D.; 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, e609–e617. [Google Scholar] [CrossRef]
  6. Ziepert, M.; Hasenclever, D.; Kuhnt, E.; Glass, B.; Schmitz, N.; Pfreundschuh, M.; Loeffler, M. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J. Clin. Oncol. 2010, 28, 2373–2380. [Google Scholar] [CrossRef]
  7. Chapuy, B.; Stewart, C.; Dunford, A.J.; Kim, J.; Kamburov, A.; Redd, R.A.; Lawrence, M.S.; Roemer, M.G.M.; Li, A.J.; Ziepert, M.; et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat. Med. 2018, 24, 679–690. [Google Scholar] [CrossRef]
  8. Van Den Neste, E.; Schmitz, N.; Mounier, N.; Gill, D.; Linch, D.; Trneny, M.; Milpied, N.; Radford, J.; Ketterer, N.; Shpilberg, O.; et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transpl. 2016, 51, 51–57. [Google Scholar] [CrossRef][Green Version]
  9. Schuster, S.J.; Bishop, M.R.; Tam, C.S.; Waller, E.K.; Borchmann, P.; McGuirk, J.P.; Jager, U.; Jaglowski, S.; Andreadis, C.; Westin, J.R.; et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N. Engl. J. Med. 2019, 380, 45–56. [Google Scholar] [CrossRef]
  10. Gisselbrecht, C.; Glass, B.; Mounier, N.; Singh Gill, D.; Linch, D.C.; Trneny, M.; Bosly, A.; Ketterer, N.; Shpilberg, O.; Hagberg, H.; et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J. Clin. Oncol. 2010, 28, 4184–4190. [Google Scholar] [CrossRef][Green Version]
  11. Crump, M. Management of Relapsed Diffuse Large B-cell Lymphoma. Hematol. Oncol. Clin. N. Am. 2016, 30, 1195–1213. [Google Scholar] [CrossRef] [PubMed]
  12. Crump, M.; Kuruvilla, J.; Couban, S.; MacDonald, D.A.; Kukreti, V.; Kouroukis, C.T.; Rubinger, M.; Buckstein, R.; Imrie, K.R.; Federico, M.; et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J. Clin. Oncol. 2014, 32, 3490–3496. [Google Scholar] [CrossRef] [PubMed][Green Version]
  13. Ionescu-Ittu, R.; Shang, A.; Velde, N.V.; Guerin, A.; Lin, Y.; Shi, L.; Shi, S.; Qayum, N. Second-line rituximab-bendamustine versus rituximab-gemcitabine-oxaliplatin in diffuse large B-cell lymphoma in the real world. J. Comp. Eff. Res. 2019, 8, 1067–1075. [Google Scholar] [CrossRef] [PubMed]
  14. Vosuri, V.; Kaisreddy, R.; Bandi, S. Comparison of salvage therapies for relapsed or refractory diffuse large B-cell lymphoma (DLBCL): Network meta-analysis. J. Clin. Oncol. 2019, 37. [Google Scholar] [CrossRef]
  15. Nabhan, C.; Klink, A.; Lee, C.H.; Laney, J.R.; Yang, Y.; Purdum, A.G. Overall survival (OS) and transplantation (ASCT) utilization in real-world patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). J. Clin. Oncol. 2018, 36. [Google Scholar] [CrossRef]
  16. Crump, M.; Neelapu, S.S.; Farooq, U.; Van Den Neste, E.; Kuruvilla, J.; Westin, J.; Link, B.K.; Hay, A.; Cerhan, J.R.; Zhu, L.; et al. Outcomes in refractory diffuse large B-cell lymphoma: Results from the international SCHOLAR-1 study. Blood 2017, 130, 1800–1808. [Google Scholar] [CrossRef]
  17. Coyle, L.; Morley, N.J.; Rambaldi, A.; Mason, K.D.; Verhoef, G.; Furness, C.L.; Zhang, A.; Jung, A.S.; Cohan, D.; Franklin, J.L. Open-Label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Leuk. Lymphoma 2020, 1–10. [Google Scholar] [CrossRef]
  18. Purdum, A.; Tieu, R.; Reddy, S.R.; Broder, M.S. Direct Costs Associated with Relapsed Diffuse Large B-Cell Lymphoma Therapies. Oncologist 2019, 24, 1229–1236. [Google Scholar] [CrossRef][Green Version]
  19. Patel, K.K.; Isufi, I.; Kothari, S.; Foss, F.; Huntington, S. Cost-effectiveness of polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. Leuk. Lymphoma 2020, 1–8. [Google Scholar] [CrossRef]
  20. Sehn, L.H.; Herrera, A.F.; Flowers, C.R.; Kamdar, M.K.; McMillan, A.; Hertzberg, M.; Assouline, S.; Kim, T.M.; Kim, W.S.; Ozcan, M.; et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J. Clin. Oncol. 2020, 38, 155–165. [Google Scholar] [CrossRef]
  21. Kalakonda, N.; Maerevoet, M.; Cavallo, F.; Follows, G.; Goy, A.; Vermaat, J.S.P.; Casasnovas, O.; Hamad, N.; Zijlstra, J.M.; Bakhshi, S.; et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): A single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020, 7, e511–e522. [Google Scholar] [CrossRef]
  22. Salles, G.; Duell, J.; Gonzalez Barca, E.; Tournilhac, O.; Jurczak, W.; Liberati, A.M.; Nagy, Z.; Obr, A.; Gaidano, G.; Andre, M.; et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): A multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020, 21, 978–988. [Google Scholar] [CrossRef]
  23. Jurczak, W.; Zinzani, P.L.; Hess, G.; Gaidano, G.; Provencio, M.; Nagy, Z.; Robak, T.; Maddocks, K.J.; Buske, C.; Ambarkhane, S.; et al. A Phase IIa, Open-Label, Multicenter Study of Single-Agent Tafasitamab (MOR208), an Fc-Optimized Anti-CD19 Antibody, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphoma: Long-Term Follow-up, Final Analysis. Blood 2019, 134, 4078. [Google Scholar] [CrossRef]
  24. Gribben, J.G.; Fowler, N.; Morschhauser, F. Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma. J. Clin. Oncol. 2015, 33, 2803–2811. [Google Scholar] [CrossRef] [PubMed][Green Version]
  25. Nowakowski, G.S.; Rodgers, T.D.; Marino, D.; Frezzato, M.; Barbui, A.M.; Castellino, C.; Meli, E.; Fowler, N.H.; Feinberg, B.A.; Tillmann, S.; et al. RE-MIND study: A propensity score-based 1:1 matched comparison of tafasitamab + lenalidomide (L-MIND) versus lenalidomide monotherapy (real-world data) in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
  26. Wang, M.; Fowler, N.; Wagner-Bartak, N.; Feng, L.; Romaguera, J.; Neelapu, S.S.; Hagemeister, F.; Fanale, M.; Oki, Y.; Pro, B.; et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: A phase II clinical trial. Leukemia 2013, 27, 1902–1909. [Google Scholar] [CrossRef]
  27. Rose, S.C.; Catherine, C.; Lewis, D.L. Diffuse Large B-cell Lymphoma Responds to Tafasitamab plus Lenalidomide. Cancer Discov. 2020, 10, 1091. [Google Scholar] [CrossRef]
  28. Lu, T.; Gibiansky, L.; Li, X.; Li, C.; Shi, R.; Agarwal, P.; Hirata, J.; Miles, D.; Chanu, P.; Girish, S.; et al. Exposure-safety and exposure-efficacy analyses of polatuzumab vedotin in patients with relapsed or refractory diffuse large B-cell lymphoma. Leuk. Lymphoma 2020, 1–10. [Google Scholar] [CrossRef]
  29. Shingleton, J.R.; Dave, S.S. Polatuzumab Vedotin Approved for DLBCL. Cancer Discov. 2019, 9, OF2. [Google Scholar] [CrossRef][Green Version]
  30. Polavy FDA Prescriber Label. Available Online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761121s000lbl.pdf (accessed on 14 August 2020).
  31. Haioun, C.; Matasar, M.J.; Sancho, J.-M.; Viardot, A.; Hernandez, J.; Perretti, T.; McMillan, A. POLARGO: Randomized Phase III study of polatuzumab vedotin plus rituximab, gemcitabine, and oxaliplatin (R-GemOx) in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
  32. Jencks, S.F.; Williams, M.V.; Coleman, E.A. Rehospitalizations among Patients in the Medicare Fee-for-Service Program. N. Engl. J. Med. 2009, 360, 1418–1428. [Google Scholar] [CrossRef] [PubMed]
  33. Chiappella, A.; Corradini, P. Selective inhibitors of nuclear export in aggressive B-cell lymphomas. Lancet Haematol. 2020, 7, e500–e501. [Google Scholar] [CrossRef]
  34. Osborne, W.; Marzolini, M.; Tholouli, E.; Ramakrishnan, A.; Bachier, C.R.; McSweeney, P.A.; Irvine, D.; Zhang, M.; Al-Hajj, M.A.; Pule, M.; et al. Phase I Alexander study of AUTO3, the first CD19/22 dual targeting CAR T cell therapy, with pembrolizumab in patients with relapsed/refractory (r/r) DLBCL. J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
  35. Chavez, J.C.; Bachmeier, C.; Kharfan-Dabaja, M.A. CAR T-cell therapy for B-cell lymphomas: Clinical trial results of available products. Adv. Hematol. 2019, 10, 2040620719841581. [Google Scholar] [CrossRef] [PubMed][Green Version]
  36. Locke, F.L.; Ghobadi, A.; Jacobson, C.A.; Miklos, D.B.; Lekakis, L.J.; Oluwole, O.O.; Lin, Y.; Braunschweig, I.; Hill, B.T.; Timmerman, J.M.; et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019, 20, 31–42. [Google Scholar] [CrossRef]
  37. Fitzgerald, L.; Kittai, A.; Nastoupil, L.J.; Waller, A.; Jacobson, C.A.; Saucier, A.; Kamdar, M.K.; Spradley, J.; Denlinger, N.; Chipman, J.; et al. Real-world outcomes of elderly patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor T-cell (CAR-T) therapy. J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
  38. Roex, G.; Feys, T.; Beguin, Y.; Kerre, T.; Poire, X.; Lewalle, P.; Vandenberghe, P.; Bron, D.; Anguille, S. Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. Pharmaceutics 2020, 12, 194. [Google Scholar] [CrossRef][Green Version]
  39. Abramson, J.S.; Ghosh, N.; Smith, S.M. ADCs, BiTEs, CARs, and Small Molecules: A New Era of Targeted Therapy in Non-Hodgkin Lymphoma. Am. Soc. Clin. Oncol. Educ. Book 2020, 40, 302–313. [Google Scholar] [CrossRef]
  40. Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544. [Google Scholar] [CrossRef]
  41. Hutchings, M.; Lugtenburg, P.; Mous, R.; Clausen, M.R.; Chamuleau, M.; Linton, K.; Rule, S.; Lopez, J.S.; Oliveri, R.S.; DeMarco, D.; et al. Epcoritamab (GEN3013; DuoBody-CD3×CD20) to induce complete response in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL): Complete dose escalation data and efficacy results from a phase I/II trial. J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
  42. Bannerji, R.; Allan, J.N.; Arnason, J.E.; Brown, J.R.; Advani, R.H.; Barnes, J.A.; Ansell, S.M.; O’Brien, S.M.; Chavez, J.; Duell, J.; et al. Clinical Activity of REGN1979, a Bispecific Human, Anti-CD20 x Anti-CD3 Antibody, in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL). Blood 2019, 134, 762. [Google Scholar] [CrossRef]
  43. Schuster, S.J.; Bartlett, N.L.; Assouline, S.; Yoon, S.-S.; Bosch, F.; Sehn, L.H.; Cheah, C.Y.; Shadman, M.; Gregory, G.P.; Ku, M.; et al. Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines. Blood 2019, 134, 6. [Google Scholar] [CrossRef]
  44. Morschhauser, F.; Carlo-Stella, C.; Offner, F.; Salles, G.A.; Hutchings, M.; Iacoboni, G.; Sureda, A.; Crump, M.; Martinez-Lopez, J.; Thomas, D.; et al. Dual CD20-Targeted Therapy With Concurrent CD20-TCB and Obinutuzumab Shows Highly Promising Clinical Activity and Manageable Safety in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma: Preliminary Results From a Phase Ib Trial. Blood 2019, 134, 1584. [Google Scholar] [CrossRef]
  45. Maddocks, K.J.; Duell, J.; Barca, E.G.; Jurczak, W.; Liberati, A.M.; Nagy, Z.; Obr, A.; Gaidano, G.; André, M.; Kalakonda, N.; et al. Update of the single-arm phase II L-MIND study of MOR208 + lenalidomide (LEN) in relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL): Response rates in patient subgroups with poor prognosis. J. Clin. Oncol. 2019, 37. [Google Scholar] [CrossRef]
  46. Advani, R.H.; Flinn, I.; Popplewell, L.; Forero-Torres, A.; Bartlett, N.L.; Ghosh, N.; Kline, J.P.; Tran, T.; Lynn, J.; Chen, J.Y.; et al. Activity and tolerabilty of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/refractory non-Hodgkin lymphoma: Initial phase 1b/2 results. J. Clin. Oncol. 2018, 36. [Google Scholar] [CrossRef]
  47. Herbaux, C.; Casasnovas, O.; Feugier, P.; Damaj, G.; Bouabdallah, R.; Guidez, S.; Ysebaert, L.; Tilly, H.; Gouill, S.L.; Fornecker, L.; et al. Atezolizumab + obinutuzumab + venetoclax in patients with relapsed or refractory diffuse large B-cell Lymphomas (R/R DLBCL): Primary analysis of a phase II trial from LYSA. J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
  48. Chen, R.W.; Ansell, S.M.; Zinzani, P.L.; Vacirca, J.L.; Lopez-Guillermo, A.; Hutchings, M.; Jurczak, W.; Hess, G.; Gouill, S.L.; Offner, F.; et al. Phase 1b/3 study of avelumab-based combination regimens in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
  49. Shah, N.N.; Zhu, F.; Schneider, D.; Taylor, C.; Krueger, W.; Worden, A.; Longo, W.L.; Hamadani, M.; Fenske, T.; Johnson, B.; et al. Results of a phase I study of bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) modified T cells for relapsed, refractory, non-Hodgkin lymphoma. J. Clin. Oncol. 2019, 37. [Google Scholar] [CrossRef]
  50. Fanale, M.A.; Hamlin, P.A.; Park, S.I.; Persky, D.O.; Higgins, J.P.; Burnett, C.; Dabovic, K.; Poma, E.; Sarapa, N.; Younes, A. Safety and efficacy of anti-CD20 immunotoxin MT-3724 in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in a phase I study. J. Clin. Oncol. 2018, 36, 7580. [Google Scholar] [CrossRef]
  51. Duque, A.E.D.; Perekhrestenko, T.; Musteata, V.; Zodelava, M.; Guthrie, T.H.; Strack, T.; Burnett, C.; Wilson, S.; Waltzman, R.J.; Baetz, T.D.; et al. A phase II study of MT-3724, a novel CD20-targeting engineered toxin body, to evaluate safety, pharmacodynamics, and efficacy in subjects with relapsed or refractory diffuse large B-cell lymphoma. J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
  52. Coleman, M.; Belada, D.; Casasnovas, R.-O.; Gressin, R.; Lee, H.-P.; Mehta, A.; Munoz, J.; Verhoef, G.; Corrado, C.; DeMarini, D.J.; et al. Phase 2 study of parsaclisib (INCB050465) for relapsed or refractory diffuse large b-cell lymphoma (DLBCL) (CITADEL-202). J. Clin. Oncol. 2019, 37, e19038. [Google Scholar] [CrossRef]
  53. Coleman, M.; Forero-Torres, A.; Ribrag, V.; Chau, I.; DeMarini, D.J.; Zinzani, P.L. Phase 2 study of the safety and efficacy of INCB050465 in patients with relapsed or refractory (R/R) diffuse large b-cell lymphoma (DLBCL) (CITADEL-202). J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
  54. Batlevi, C.L.; Frank, S.D.; Stewart, C.; Hamlin, P.A.; Matasar, M.J.; Gerecitano, J.F.; Moskowitz, A.J.; Hamilton, A.M.; Zelenetz, A.D.; Drullinsky, P.; et al. Phase I/II clinical trial of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma. J. Clin. Oncol. 2018, 36. [Google Scholar] [CrossRef]
  55. Witzig, T.E.; Vose, J.M.; Zinzani, P.L.; Reeder, C.B.; Buckstein, R.; Polikoff, J.A.; Bouabdallah, R.; Haioun, C.; Tilly, H.; Guo, P.; et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann. Oncol. 2011, 22, 1622–1627. [Google Scholar] [CrossRef] [PubMed]
  56. Yang, H.; Xiang, B.; Song, Y.; Zhang, H.; Zhao, W.; Zou, D.; Lv, F.; Bai, O.; Liu, A.; Li, C.; et al. Zanubrutinib monotherapy for patients with relapsed or refractory non-germinal center diffuse large B-cell lymphoma: Results from a phase II, single-arm, multicenter, study. J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
  57. de la Merino, L.C. Lenalidomide plus R-GDP (R2-GDP) in relapsed/refractory diffuse large B-cell lymphoma: Final results of the R2-GDP-GOTEL trial. J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
  58. Guerra-Bauman, F.; LaPlant, B.; Macon, W.R.; Witzig, T.E.; Farooq, U.; Nowakowski, G.S.; Feldman, T. Phase I/II study of R-ICE (rituximab-ifosfamide-carboplatin-etoposide) with lenalidomide (R2-ICE) in patients with first-relapse/primary refractory diffuse large B-cell lymphoma (DLBCL) in academic and community cancer research united (ACCRU) network. J. Clin. Oncol. 2020, 38. [Google Scholar] [CrossRef]
Table 1. Novel Regimens with FDA Approval.
Table 1. Novel Regimens with FDA Approval.
AgentYear of FDA ApprovalRegimenPopulationRelapse < 1 year of DLBCL DiagnosisRefractory to Last RegimenDHL/THLEfficacy Outcomes
Axicabtagene ciloleucel
(axi-cel)
2017Flu/Cy LDR/R DLBCL refractory to 2 lines of therapy30%77%NRORR 83%
CR 58%
mOS 24 mos
Lisocabtagene maraleucel Flu/Cy LDR/R DLBCL refractory to 2 lines of therapyNR44%13%ORR 73%
CR 53%
mOS >12 mos
Tisagenlecleucel a2018Flu/Cy LD
or Benda-Flu LD
R/R DLBCL refractory to 2 lines of therapyNR40%27%ORR 52
CR 40%
mOS 12 mos
Polatuzumab vedotin [20]2019Pola + BRR/R DLBCL
Ineligible for ASCT
53%75%0%CMR 40%
mOS 12.4 mos
Selinexor [21]2020Selinexor 60 mg po on days 1 and 3 of each weekR/R DLBCL33%
§§
72%4%ORR 28%
CR 12%
mOS 9.1 mos
Tafasitamab [22]2020Tafa + LEN 25 mgR/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.
Table 2. Novel Regimens under Investigation for Relapsed or Refractory Diffuse Large B Cell Lymphoma.
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 al. [41]
NCT03625037
Phase 1/2
R/R DLBCL
N = 41Enrolling
Median f/u 4.7 mo
ORR 56%
CR 44%
No dose limiting toxicities
Odronextamab
REGN1979
(CD3/CD20)
18–320 mg doses
Bannerji et al. [42]
NCT03888105
Phase 1
R/R DLBCL
N = 19Enrolling phase 2
ORR 58%
CR 37%
Monsenetuzumab
(CD3/CD20)
Schuster et al. [43]
NCT03677154
Phase 1/2
R/R DLBCL including
p CAR-T
N = 119Enrolling phase 3
ORR 34.7%
CR 18.6%
Glofitamab
RG6026
(CD3/CD20)
Morschhauser et al. [44]
NCT03075696
Phase 1/Ib
R/R aggressive NHL
+/− Obinituzumab
N = 21Enrolling Phase 1
ORR 38%
CR 31%
Monoclonal Abs
Tafasitamab (anti-CD19)
(Fc-enhanced, humanized)
+Lenolidomide
Nowakowski et al. [25]
Maddocks et al. [45]
NCT02399085
Phase 1/2
R/R DLBCL
Ineligible for ASCT
Excluded double-hit
N = 81Enrolling phase 3
ORR 58%
CR 33%
Median OS 22 mos
(95% CI: 18.6–NR)
Magrolimab (5F9)
(anti-CD47, promote phagocytosis)
+Rituximab
Advani et al. [46]
NCT02953509
Phase 1b/2
R/R DLBCL
N = 15Enrolling, 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 al. [47]
NCT03276468
Phase 2
R/R DLBCL
N = 58Interim 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 al. [48]
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 al. [49]
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 al. [20]
Lu et al. [28]
NCT02257567
Phase 2
R/R DLBCL
Ineligible for ASCT
N = 80CMR 40%
Median OS 12.4 mos
Polatuzumab vedotin
(anti-CD79b/MMAE) added to Gem-Ox
Haioun et al. [31]
NCT04182204
Phase 3
R/R DLBCL
Enrolling
Engineered Toxin Bodies
MT-3724 (CD20/
SLT-I A1)
Fanale et al. [50]
Duque et al. [51]
NCT02361346
Phase 1
Relapsed B-NHL after
anti-CD20 and CT
N = 100Safety and efficacy assessment of 50 mcg/kg/dose ongoing.
PI3K Inhibitor
Parsaclisib 20 mg
po daily
Coleman et al. [52,53]
NCT02998476
Phase 2
R/R DLBCL
N = 60Interim Results
ORR 25%
CMR 12.5%
Buparlisib 80 mg
po daily
+Ibrutinib
Batlevi et al. [54]
NCT02756247
Phase 1/2
R/R DLBCL, Mantle Cell, Follicular
N = 37Interim Results
ORR 31%
CMR 23%
BTK Inhibitors
Acalabrutinib 100 mg
po BID
+Pembrolizumab
Witzig et al. [55]
NCT02362035
Phase 1/2
R/R DLBCL
N = 61ORR 26%
CR 7%
Zanubrutinib 160 mg po BIDYang et al. [56]
NCT03145064
Phase 2
R/R Non-GBC DLBCL
Ineligible for ASCT
N = 41ORR 29.3%
CR 17.1%
Median OS 8.4 mos
Immunomodulators
R2-GDP
Lenalidomide 10 mg po d1-14 + R-GDP
Merino et al. [57]
EudraCT 2014-001620-29
Phase 2
R/R DLBCL
Ineligible for ASCT
N = 79Enrolling
ORR 59%
CR 32%
Median OS 12 mos
R2-ICE
Lenalidomide 20 mg po d1-14 + RICE
Guerra-Bauman et al. [58]
NCT02628405
Phase 1/2
R/R DLBCL
Candidates for ASCT
Enrolling
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); CT = Chemotherapy; 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-ICE (Lenalidomide, Rituximab, Ifosfamide, Carboplatin, Etoposide).
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Harris, L.J.; Patel, K.; Martin, M. Novel Therapies for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Int. J. Mol. Sci. 2020, 21, 8553. https://doi.org/10.3390/ijms21228553

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Harris LJ, Patel K, Martin M. Novel Therapies for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. International Journal of Molecular Sciences. 2020; 21(22):8553. https://doi.org/10.3390/ijms21228553

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Harris, Leonard Jeff, Kruti Patel, and Michael Martin. 2020. "Novel Therapies for Relapsed or Refractory Diffuse Large B-Cell Lymphoma" International Journal of Molecular Sciences 21, no. 22: 8553. https://doi.org/10.3390/ijms21228553

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