Diffuse Large B-Cell Lymphoma (DLBCL)


Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), which is the most common hematological cancer. DLBCL is an aggressive malignancy for which the standard treatment is chemoimmunotherapy.1 Since many patients (45% to 50%) relapse following treatment, other therapeutic options have been explored and developed, including monoclonal antibodies and drugs targeting specific molecular pathways.2

Chemotherapy and Autologous Stem Cell Transplant

The first-line treatment of DLBCL consists of a combination of the monoclonal antibody rituximab and anthracycline derivatives known as R-CHOP, which stands for Rituxan® (rituximab) combined with cyclophosphamide, hydroxydaunorubicin (sold as Lipodox® or Doxil®), Oncovin® (vincristine), and prednisone.3 Patients may receive this R-CHOP chemoimmunotherapy with or without radiation therapy, depending on the disease stage and risk factors.1 Rituximab was first approved by the US Food and Drug Administration (FDA) for combined use with CHOP in patients with DLBCL in 2006.2

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For patients with stage III or IV disease and a higher risk of recurrence in the brain and spinal cord, the chemotherapy agents may be injected directly into the cerebrospinal fluid, known as intrathecal chemotherapy.3

Patients with disease progression after R-CHOP treatment may receive combination salvage chemotherapy with alternate regimens such as R-ICE, R-DHAP, R-GDP, R-GemOx, O-DHAP, O-ICE, and DR-ICE.4 

Salvage chemotherapy with autologous stem cell transplant (ASCT) consolidation is a current standard treatment for transplant-eligible patients who respond to chemotherapy.1 In ASCT, the patient’s stem cells are collected and stored before receiving high-dose chemotherapy with or without radiation. After chemotherapy treatment, these cells are reintroduced into the patient.5

Radiotherapy

Radiotherapy may be indicated before chemoimmunotherapy or in scenarios where palliative care is required, such as with spinal cord compression and pathologic bone fractures. Radiotherapy may also be used after systemic therapy, in patients presenting with bulky disease, or in those who do not show a complete response after 2 to 4 initial cycles of chemotherapy. It can also be combined with salvage chemotherapy in localized relapsed or refractory DLBCL.6

CAR T-Cell Therapy

Chimeric antigen receptors (CARs) are autologous genetically modified T cells produced by the combination of the antigen-binding site of an antibody with the intracellular domain of a T-cell activation receptor. The introduction of the CAR gene into the T-cell genome is achieved using a gammaretroviral or lentiviral vector. The T-cell receptor’s intracellular domain is directly stimulated when it contacts the surface antigen of interest expressed in the target cell.1

At present, 3 CAR T-cell therapies have been approved by the FDA for DLBCL: Yescarta® (axicabtagene ciloleucel, approved in October 2017), Kymriah® (tisagenlecleucel, approved in May 2018), and Breyanzi® (lisocabtagene maraleucel, approved in February 2021).1,2,7 All 3 therapies are approved for the treatment of relapsed or refractory DLBCL after at least 2 lines of systemic therapy have been administered.1 

Read more about Yescarta

The approval of Yescarta occurred following the ZUMA-1 clinical trial (NCT02348216),8 which reported an overall response rate (ORR) of 83% and a complete response rate (CR) of 54%.2,9 The approval of Kymriah followed the JULIET clinical trial (NCT02445248),10 in which an ORR of 52% and a CR of 40% were observed.2,11 Breyanzi was approved following the TRANSCEND-NHL-001 trial (NCT02631044),12 with a reported ORR of 73% and CR of 54%.7,13

Read more about Kymriah

CAR T-cell therapy is often well tolerated, and recent data point to durable responses in about 30% to 40% of patients.1 Toxicities associated with these therapies include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.1

Read more about Breyanzi

Monoclonal Antibodies and Antibody-Drug Conjugates

Various monoclonal antibodies targeting different cell surface antigens have been developed and studied both in unconjugated and conjugated forms with cytotoxic payloads, also known as antibody-drug conjugates (ADC).1,2 ADCs allow the selective delivery of cytotoxic agents into tumor cells by using targeted antibodies.14

CD20-Directed Agents

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody that binds to the CD20 antigen expressed on the surfaces of pre-B lymphocytes and mature B lymphocytes targeting tumor cells through antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and apoptosis induction.15 Rituximab was approved by the FDA in November 1997 for the treatment of relapsed or refractory, CD20-positive, B-cell, low-grade or follicular NHL.16 In June 2017, a subcutaneous formulation of rituximab containing recombinant human hyaluronidase to increase tissue permeability and decrease administration time, Rituxan Hycela®, was approved.17

Read more about Rituxan Hycela

CD19-Directed Agents

In July 2020, Monjuvi® (tafasitamab-cxix) was approved by the FDA in combination with Revlimid® (lenalidomide) for the treatment of relapsed or refractory DLBCL.2 Tafasitamab-cixi is an Fc-engineered anti-CD19 immunoglobulin G (IgG) 1/IgG2 monoclonal antibody that has been developed to exhibit increased ADCC and phagocytosis.1,4 The approval of this medication was granted based on the findings of the L-MIND study (NCT02399085).18,19 Updated results in November 2020 showed an ORR of 58.8% and a CR of 41.3%.20

Read more about Monjuvi

Zynlonta® (loncastuximab tesirine) is an ADC formed by a humanized anti-CD19 monoclonal antibody conjugated with the cytotoxic payload pyrrolobenzodiazepine dimer (PBD) toxin.1 The approval of loncastuximab tesirine by the FDA occurred in April 2021 based on findings from the LOTIS-2 clinical trial (NCT03589469),21 which reported an ORR of 48.3% and a CR of 24.1%.22

Read more about Zynlonta

CD79b-Directed Agents

Polivy® (polatuzumab vedotin) is an ADC formed by a humanized anti-CD79b monoclonal antibody and the cytotoxic payload mono-methyl auristatin E (MMAE), an antimitotic agent.4 Polatuzumab vedotin targets the CD79b protein of the B-cell receptor, which has a role in chronic-active B-cell receptor signaling and the canonical nuclear factor (NF)-κB signaling pathway of DLBCL survival.2 Once MMAE is internalized, it affects tubulin polymerization, leading to cell death.4 

This ADC was approved by the FDA in June 2019 in combination with bendamustine (sold as Treanda® or Bendeka®) and rituximab for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, after at least 2 prior therapies.23 Approval was based on Study GO29365 (NCT02257567),24 which reported a CR of 40% at the end of the therapy.23 Therapeutic approaches targeting CD79b will not promote resistance to CD19 regimens, which may be of relevance in patients who require CAR T-cell therapy.4

Read more about Polivy

Molecular Pathway Inhibitors

Xpovio® (selinexor) is an oral selective inhibitor of the nuclear export protein XPO1 that was approved by the FDA in June 2020 for the treatment of patients with relapsed or refractory DLBCL after at least 2 prior systemic therapies.2 The inhibition induced by this drug leads to nuclear accumulation and the activation of tumor suppressor proteins while reducing the levels of the oncoproteins Bcl2, Bcl-XL, and Myc.1,14 The efficacy of selinexor was reported in the SADAL trial (NCT02227251),25 which reported an ORR of 28% and a CR of 12%.26

Read more about Xpovio

References

1. Susanibar-Adaniya S, Barta SK. 2021 Update on diffuse large B cell lymphoma: a review of current data and potential applications on risk stratification and management. Am J Hematol. 2021;96(5):617-629. doi:10.1002/ajh.26151

2. Wang L, Li LR, Young KH. New agents and regimens for diffuse large B cell lymphoma. J Hematol Oncol. 2020;13(1):175. doi:10.1186/s13045-020-01011-z

3. Treating B-cell non-Hodgkin lymphoma. American Cancer Society. Updated April 5, 2022. Accessed August 10, 2022.

4. Harris LJ, Patel K, Martin M. Novel therapies for relapsed or refractory diffuse large B-cell lymphoma. Int J Mol Sci. 2020;21(22):8553. doi:10.3390/ijms21228553

5. High-dose chemotherapy and stem cell transplant for non-Hodgkin lymphoma. American Cancer Society. Updated August 1, 2018. Accessed August 10, 2022.

6. Wright CM, Koroulakis AI, Baron JA, et al. Palliative radiotherapy for diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2021;21(10):650-658. doi:10.1016/j.clml.2021.05.007

7. FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. US Food and Drug Administration (FDA). February 5, 2021. Accessed August 10, 2022.

8. Study evaluating the safety and efficacy of KTE-C19 in adult participants with refractory aggressive non-Hodgkin lymphoma (ZUMA-1). ClinicalTrials.gov. January 28, 2015. Updated May 23, 2022. Accessed August 10, 2022.

9. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447

10. Study of efficacy and safety of CTL019 in adult DLBCL patients (JULIET). ClinicalTrials.gov. May 15, 2015. Updated June 3, 2022. Accessed August 10, 2022.

11. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980

12. Study evaluating the safety and pharmacokinetics of JCAR017 in B-cell non-Hodgkin lymphoma (TRANSCEND-NHL-001). ClinicalTrials.gov. December 15, 2015. Updated August 2, 2022. Accessed August 10, 2022.

13. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0

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

15. Davies A, Berge C, Boehnke A, et al. Subcutaneous rituximab for the treatment of B-cell hematologic malignancies: a review of the scientific rationale and clinical development. Adv Ther. 2017;34(10):2210-2231. doi:10.1007/s12325-017-0610-z

16. Grillo-López AJ, White CA, Dallaire BK, et al. Rituximab: the first monoclonal antibody approved for the treatment of lymphoma. Curr Pharm Biotechnol. 2000;1(1):1-9. doi:10.2174/1389201003379059

17. FDA approves rituximab plus hyaluronidase combination for treatment of FL, DLBCL and CLL. US Food and Drug Administration (FDA). June 22, 2017. Accessed August 10, 2022.

18. A study to evaluate the safety and efficacy of lenalidomide with MOR00208 in patients with R-R DLBCL (L-MIND). ClinicalTrials.gov. March 26, 2015. Updated September 29, 2021. Accessed August 10, 2022.

19. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. US Food and Drug Administration (FDA). August 3, 2020. Accessed August 10, 2022.

20. Cheson BD, Nowakowski G, Salles G. Diffuse large B-cell lymphoma: new targets and novel therapies. Blood Cancer J. 2021;11(4):68. doi:10.1038/s41408-021-00456-w

21. Study to evaluate the efficacy and safety of loncastuximab tesirine in patients with relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2). ClinicalTrials.gov. July 18, 2018. Updated June 1, 2022. Accessed August 10, 2022.

22. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. US Food and Drug Administration (FDA). April 23, 2021. Accessed August 10, 2022.

23. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. US Food and Drug Administration (FDA). June 10, 2019. Accessed August 10, 2022.

24. A study of polatuzumab vedotin (DCDS4501A) in combination with rituximab or obinutuzumab plus bendamustine in participants with relapsed or refractory follicular or diffuse large B-cell lymphoma. ClinicalTrials.gov. October 6, 2014. Updated December 1, 2021. Accessed August 10, 2022.

25. Selinexor (KPT-330) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). ClinicalTrials.gov. August 28, 2014. Updated June 6, 2022. Accessed August 10, 2022.

26. Kalakonda N, Maerevoet M, Cavallo F, 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(7):e511-e522. doi:10.1016/S2352-3026(20)30120-4

Reviewed by Kyle Habet, MD, on 8/18/2022.

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