Diffuse Large B-Cell Lymphoma (DLBCL)


Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma (NHL), is an aggressive and biologically heterogeneous disorder. Risk stratification and treatments in DLBCL differ on the basis of disease stage and bulk, as well as other clinical and biological variables: the International Prognostic Index score, cell of origin, and molecular subset. The current standard-of-care treatment, R-CHOP, which provides Rituxan® (rituximab) combined with cyclophosphamide, hydroxydaunorubicin (sold as Lipodox® or Doxil®), Oncovin® (vincristine), and prednisone, is used to treat more than 60% of patients. 

With positive preliminary results, ongoing trials are currently investigating frontline therapy that incorporates novel agents, such as various small molecules, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies.1 

ZUMA-1

ZUMA-1 (NCT02348216) is a phase 1/2 multicenter study evaluating the safety and efficacy of Yescarta® (axicabtagene ciloleucel) in adults with refractory aggressive NHL.2 In this trial, patients treated with Yescarta had an objective response rate of 72%, and the median time to response was 0.9 month.3,4 Overall survival data updated after 3 years (median follow-up of 39.1 months) indicated that after a single infusion of Yescarta, approximately half of the patients with refractory large B-cell lymphoma in the pivotal phase 2 cohorts were alive, with a median overall survival of 25.8 months. 

Preliminary results of the safety management study (cohort 4) in ZUMA-1 indicate that early steroid intervention can decrease the incidence of the severe cytokine release syndrome (CRS) and neurologic events associated with Yescarta without decreasing the high response rates achieved in patients with relapsed/refractory large B-cell lymphoma.5,6 ZUMA-1 is estimated to conclude in July 2023. More information can be found at https://clinicaltrials.gov/ct2/show/NCT02348216.2 

Read more about Yescarta

ZUMA-14

ZUMA-14 (NCT04002401) is a multicenter study currently underway to evaluate the safety and efficacy of Yescarta in combination with rituximab in participants with refractory large B-cell lymphoma. Patients will receive rituximab plus fludarabine and cyclophosphamide conditioning chemotherapy, followed by Yescarta and additional rituximab. The study is estimated to be completed in December 2022.7 More information on this study can be found at https://clinicaltrials.gov/ct2/show/NCT04002401.7 

frontMIND

The frontMIND trial (NCT04824092) is a randomized, double-blind, placebo-controlled phase 3 trial structured to compare the safety and efficacy of the humanized monoclonal anti-CD19 antibody Monjuvi® (tafasitamab) in combination with Revlimid® (lenalidomide) and R-CHOP vs that of R-CHOP alone in patients with newly diagnosed, previously untreated, high-intermediate-risk or high-risk DLBCL. Patients in this study will receive tafasitamab, lenalidomide, and R-CHOP for six 21-day cycles. The primary outcome measure of the study is progression-free survival as assessed by the investigator according to the Lugano response criteria for malignant lymphoma.8 This study is estimated to conclude in May 2026. More information on the eligibility criteria for this study can be found at https://www.clinicaltrials.gov/ct2/show/NCT04824092.8 

Read more about Monjuvi

ALPHA2

ALPHA2 (NCT04416984) is a phase 1/2 study evaluating the safety, efficacy, and cell kinetics of ALLO-501A, an anti-CD19 allogeneic CAR T-cell therapy, and ALLO-647, an anti-CD52 monoclonal antibody, in participants with relapsed/refractory large B-cell lymphoma after a lymphodepletion regimen consisting of fludarabine, cyclophosphamide, and ALLO-647. Primary outcome measures include dose-limiting toxicity with ALLO-510A, characterized by protocol-defined adverse events with onset within 28 days following infusion, and dose-limiting toxicity with ALLO-647, characterized by protocol-defined adverse events with onset within 33 days following first infusion.9 The proposed completion date of this study is December 2022. More information on the eligibility criteria for this study can be found at https://clinicaltrials.gov/ct2/show/NCT04416984.9 

Read more about DLBCL experimental therapies

JULIET

This study (NCT02445248) aims to evaluate the efficacy and safety of CTL019, or Kymriah® (tisagenlecleucel), in adult patients with relapsed/refractory DLBCL.10 The primary outcome measure is the overall response rate (ORR), in addition to numerous secondary outcome measures: incidence and severity of adverse events (AEs), time to response (TTR), duration of overall response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), in vivo cellular pharmacokinetic (PK) profile, incidence of immunogenicity, number of participants with exposure to replication-competent lentivirus (RCL) as assessed by quantitative polymerase chain reaction (qPCR), and prevalence of immunogenicity. The estimated study completion date is February 2023. More information on this study can be found at https://clinicaltrials.gov/ct2/show/study/NCT02445248.10 

Read more about Kymriah

Other Clinical Trials 

NCT02628405

A phase 1/2 trial (NCT02628405) is studying the side effects and dose of lenalidomide when used in combination with rituximab-ifosfamide-carboplatin-etoposide (R-ICE) and evaluating its efficacy in patients with relapsed/refractory DLBCL. Chemotherapy drugs such as rituximab, ifosfamide, carboplatin, etoposide, and lenalidomide function in various ways to inhibit the growth of cancer cells—by killing cells, preventing them from multiplying, or preventing them from spreading. Patients with DLBCL may receive additional benefit if they receive lenalidomide together with R-ICE.11 The expected completion date is December 2025. More information for this study can be found at https://clinicaltrials.gov/ct2/show/NCT02628405.11 

NCT02443077

A randomized phase 3 study (NCT02443077) is comparing the efficacy of Imbruvica® (ibrutinib) vs that of placebo when administered before and after stem cell transplant to patients with relapsed/refractory DLBCL. It is not yet known whether the addition of ibrutinib to chemotherapy before and after stem cell transplant can increase the effectiveness of transplant in such cases.12 The primary outcome measure of the study is 24-month PFS as assessed with the Lugano criteria. The proposed completion date is October 2022. More information on this study can be found at https://clinicaltrials.gov/ct2/show/NCT02443077.12 

References

  1. Spinner MA, Advani RH. Current frontline treatment of diffuse large B-cell lymphoma. Oncology (Williston Park). 2022;36(1):51-58. doi:10.46883/2022.25920940 
  2. Study evaluating the safety and efficacy of KTE-C19 in adult participants with refractory aggressive non-Hodgkin Lymphoma (ZUMA-1). ClinicalTrials.gov. April 21, 2015. Updated May 23, 2022. Accessed August 29, 2022.
  3. Yescarta (axicabtagene ciloleucel) for the treatment of large B-cell lymphoma. Clinical Trials Arena. March 25, 2019. Accessed August 29, 2022.
  4. Yescarta (axicabtagene ciloleucel). wcg CenterWatch. October 1, 2017. Accessed August 29, 2022.
  5. Kite announces new Yescarta® data from ZUMA-1. News release. Business Wire; June 3, 2019.
  6. Kite’s Yescarta yields positive results in ZUMA-1 trial in refractory large B-cell lymphoma. News release. Pharmaceutical Business Review; December 9, 2019.
  7. Safety and efficacy of axicabtagene ciloleucel in combination with rituximab in participants with refractory large B-cell lymphoma (ZUMA-14). ClinicalTrials.gov. November 5, 2019. Updated August 26, 2022. Accessed August 29, 2022.
  8. Tafasitamab + lenalidomide + R-CHOP versus R-CHOP in newly diagnosed high-intermediate and high risk DLBCL patients (frontMIND). ClinicalTrials.gov. May 11, 2021. Updated August 24, 2022. Accessed August 29, 2022.
  9. Safety and efficacy of ALLO-501 anti-CD19 allogeneic CAR T cells in adults with relapsed/refractory large B cell lymphoma (ALPHA2). ClinicalTrials.gov. May 21, 2020. Updated April 8, 2022. Accessed August 29, 2022.
  10. Study of efficacy and safety of CTL019 in adult DLBCL patients (JULIET). ClinicalTrials.gov. July 29, 2015. Updated June 3, 2022. Accessed August 29, 2022.
  11. R-ICE and lenalidomide in treating patients with first-relapse/primary refractory diffuse large B-cell lymphoma. ClinicalTrials.gov. May 20, 2016. Updated March 11, 2022. Accessed August 29, 2022.
  12. Ibrutinib before and after stem cell transplant in treating patients with relapsed or refractory diffuse large B-cell lymphoma. ClinicalTrials.gov. July 6, 2016. Updated August 22, 2022. Accessed August 29, 2022. 

Reviewed by Hasan Avcu, MD, on 8/31/2022.

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