DLBCL,   CLL/SLL

Educational theme: chimeric antigen receptor (CAR) T-cell therapies in DLBCL and CLL

In recent years researchers have looked into ways of harnessing the power of the immune system to fight cancer in a more targeted way than traditional chemotherapy. These new approaches alongside monoclonal antibodies, bispecific antibodies, include antibody-drug conjugates, immune-checkpoint inhibitors, and CAR T-cell therapies. Initial clinical trials reported promising results of CAR T cells in indolent non-Hodgkin lymphoma (iNHL) and there are a number of trials still ongoing.  

To date, two different CAR T-cell therapies have received FDA and EMA approval for the treatment of diffuse large B-cell lymphoma (DLBCL) and CLL.

  • Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR T-cell therapy induced durable responses in patients with relapsed or refractory (R/R) DLBCL in the ZUMA-1 study, with a median overall survival of more than 2 years and a manageable long-term safety profile.1 Axi-cel is now approved for the treatment of adult patients with R/R DLBCL after two or more prior lines of systemic therapy. Axi-cel is currently being investigated as second-line therapy in the clinical study ZUMA-7.
  • Tisagenlecleucel, the anti-CD19 CAR T-cell therapy is approved for the treatment of adult patients with R/R DLBCL, high-grade B-cell lymphoma and transformed follicular lymphoma (tFL) and pediatric and young adult R/R acute lymphoblastic leukemia (ALL) based on the results from the ELIANA and JULIET clinical trials.

The topic of CAR Ts has been prominent at several hematology meetings, and so this month, through a series of articles, the Lymphoma Hub will take a closer look at CAR T-cell therapies in DLBCL and CLL. This educational theme will start by recapping some of the relevant articles and video interviews that we covered earlier this year.

CAR T-cell therapy with or without conditioning chemotherapy: Results from a phase I trial

In this single-center, non-blinded, phase I trial (NCT00466531), the investigators sought to evaluate the efficacy and toxicity of their CAR-T construct (CD28 co-stimulatory domain: 19−28z) with or without conditioning chemotherapy in patients with R/R CLL or indolent B-cell NHL. Conditioning chemotherapy (including Flu/Cy, and in combination with ibrutinib) and 19–28z CAR T cells were acceptably tolerated in heavily pretreated patients and a subgroup of patients achieved durable CR.

EBMT | Debate Session: How to treat R/R DLBCL in 2019? | Part 3. CAR T

A Keynote Debate Session on how to treat patients with R/R DLBCL took place during the 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE. During this Lymphoma Working Party session, Prof Marie José Kersten advocated for the use of CAR T-cell therapy in patients with R/R DLBCL who currently have poor outcomes with conventional therapies. She presented the three main multicenter CD19 CAR-T trials: ZUMA-1, JULIET and TRANSCEND, in aggressive NHL that is transplantation-ineligible, unresponsive to salvage chemotherapy or relapse after ASCT and/or allo-SCT.

EHA 2019 | Investigating liso-cel in R/R CLL and small lymphocytic lymphoma

At the 24th EHA congress, Tanya Siddiqi presented results of the ongoing phase I/II TRANSCEND CLL 004 study. The study assessed the safety, pharmacokinetics, and efficacy of lisocabtagene maraleucel (liso-cel, JCAR017), an anti-CD19 CAR T-cell product, administered as a defined composition of CD4+/CD8+ CAR T-cells. Dr. Siddiqi discussed the manageable toxicity associated with liso-cel and the promising clinical activity in patients who had been heavily pre-treated with ibrutinib and venetoclax. The follow-up of 9 months showed a high proportion of durable responses that improved over time. The majority of responses and undetected MRD were achieved by day 30, with a large proportion of patients remaining in CR at 6 months. A phase II study is currently enrolling patients at dose level 2, stemming from the results of this phase I trial. Patients in this trial will be treated with liso-cel in combination with ibrutinib.

CAR T-Cell Meeting 2019 | CAR T-cell therapy in lymphoma

During a session on the use of CAR T-cell therapy at the 1st European CAR T Cell Meeting, Paris, FR, a talk was presented by Prof Marie José Kersten, entitled ‘when to use CAR T in lymphoma’. She summarized how the treatment of B-cell malignancies has evolved in recent years and highlighted  CAR T cells as a rapidly growing therapeutic approach to treat patients with B-cell malignancies. She discussed the similarities and differences between the ZUMA-1, JULIET and  TRANSCEND studies. The ZUMA-7 study was highlighted, which will investigate axi-cel versus standard-of-care second-line treatment in patients with R/R DLBCL.

CD19 CAR T-cell immunotherapy plus ibrutinib results in durable responses in R/R CLL

In a pilot phase I/II study (NCT01865617) conducted by Jordan Gauthier, Fred Hutchinson Cancer Research Center, Seattle, US, and colleagues, the safety and efficacy of ibrutinib plus CD19 CAR T-cell infusion was evaluated in patients with R/R CLL, who had previously failed ibrutinib therapy. The primary goal of this trial was to investigate a potential synergistic association between ibrutinib and CAR T therapy, with the hope of improving outcomes for patients with R/R CLL. Results showed that ibrutinib may improve CAR T cell anti-tumor efficacy and could also reduce the risk of cytokine release syndrome (CRS).

EBMT 2019 | A consensus grading system for toxicities in CAR T trials

A new grading system for use CAR T-cell trials was presented during the 45th Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in Frankfurt, Germany, by Richard Maziarz, Oregon Health and Science University, Portland, US.

Relevant videos

EHA 2019 | Access and implementation of CAR T treatment in lymphoma

In this video interview from the 24th Congress of the European Hematology Association (EHA), Marie José Kersten from the Amsterdam UMC, Amsterdam, NL,  highlights issues surrounding access and implementation of CAR T treatment. She stated the need to increase access to these therapies in Europe. There are still challenges to be overcome in the implementation, such as appropriate training and education for centers, delivering the therapy to the patient, as well as managing the side effects.

ICML 2019: The rise of CAR T-cell therapy: where are we in the US and Europe?

During ICML 2019 in Lugano, Switzerland, the Lymphoma Hub was pleased to speak to Loretta Nastoupil, MD Anderson Cancer Center, Houston, US and Peter Borchmann, University of Cologne, Cologne, DE, who discussed the use of CAR T-cell therapy in the US compared with European countries. It was highlighted that Europe is still behind the US in its use of CAR T-cell therapy.

ICML 2019 | Have we improved the management of CAR T-cell toxicities?

During ICML 2019 in Lugano, Switzerland, the Lymphoma Hub was pleased to speak to Sattva Neelapu from MD Anderson Cancer Center, Houston, US, about whether we have improved the management of CAR T toxicities.

References
  1. Locke FL. 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 Jan;20(1):31-42. doi: 10.1016/S1470-2045(18)30864-7. DOI: 10.1016/S1470-2045(18)30864-7
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