Chimeric antigen receptor T-cell (CAR-T) therapy is a revolutionary treatment for CLL and other B-cell malignancies. At the American Society of Hematology’s (ASH) 2020 conference, Dr. Brian Koffman, Chief Medical Officer and Executive Vice President of the CLL Society, interviewed Hematologist/Oncologist Dr. Tanya Siddiqi, a lead investigator of the TRANSCEND CLL 004 trial at City of Hope National Medical Center in Duarte, California.
The TRANSCEND CLL 004 trial is focused on an investigational CAR-T therapy in CLL patients known as JCAR017 (lisocabtagene maraleucel) or Lisocel® and its use with or without ibrutinib. The trial is still recruiting patients, and more information can be found here. To be eligible, patients had to have failed at least two prior treatments, including at least one Bruton’s tyrosine kinase inhibitor (BTKi), such as ibrutinib (Imbruvica®) or acalabrutinib (Calquence®).
Lisocel® is a type of CAR-T therapy that targets B lymphocytes in various lymphomas. It specifically targets CD-19, a protein expressed during B-cell development of both healthy and malignant B-cells. This is a one-time treatment using the patient’s own genetically modified T-cells to kill malignant B-cells. The procedure involves removing healthy T-cells from the patient, preparing and freezing them at the collection site, and then sending the T-cells back to the laboratory of the manufacturer. In the laboratory, scientists genetically modify the patient’s own T-cells so that they can recognize and target malignant B-cells when they are infused back into the patient.
Last year at ASH 2019, Drs. Siddiqi and Koffman discussed the results from the first arm of the trial in which patients received Lisocel® alone as a monotherapy.
Dr. Siddiqi provided a brief update to the 2019 interview:
- Several of the patients have arrived at their two-year mark and have maintained a response of undetectable measurable residual disease (uMRD) without requiring any further treatment.
- A total of 23 patients were studied who had previously been treated for CLL, all of whom had relapsed after being treated with ibrutinib. At least half of the patients studied had also already been treated with venetoclax and progressed.
- A small subset of seven patients did not remain in remission:
- Two patients relapsed after achieving remission.
- Five progressed due to Richter’s transformation.
- All the patients who did not remain in remission were part of a subgroup that had previously failed both venetoclax and ibrutinib (meaning they had a more aggressive form of the disease).
- By and large the patients are still doing well after two years, which is amazing considering these are patients who had previously failed at least two previous lines of therapy.
Dr. Siddiqi then reviewed the results of the second arm of the trial, in which patients received a combination therapy of ibrutinib in addition to Lisocel®.
Takeaways:
- In the second arm of the trial, 19 patients received combination therapy with both ibrutinib and Lisocel®:
- Only 2 people experienced cytokine release syndrome (CRS).
- Five patients had grade 3-4 neurotoxicity with significant neurological problems. Fortunately, the neurotoxicity was transient and resolved in all the patients.
- The great news was at the 30-day follow-up point after receiving CAR-T, 85% had achieved a positive response to treatment.
- 75% achieved a response of undetectable minimal residual disease response (uMRD) in their bone marrow or blood.
- The uMRD response has been maintained over time.
- So far, there have been fewer toxicities and responses have been better in the short-term (patients have been followed for at least six months now), but patients need to be followed for a longer period of time.
- Outcomes are better with CAR-T therapy when those who receive it are not severely ill. Ideally, CAR-T should be considered before CLL has become progressive (especially after being on a BTKi and one other novel therapy like venetoclax) and should not be considered as a last resort.
- For those who have failed previous lines of therapy multiple times, it can become concerning as to what treatment options remain. The use of Lisocel® in this particular group of patients looks promising.
Conclusions:
This trial adds yet another potential treatment option for heavily pretreated CLL patients who have poor prognoses. Although Lisocel® works well by itself in R/R CLL patients who have previously failed previous lines of therapy, when ibrutinib is added the response rate might be even better and result in fewer toxicities.
Dr. Wierda presented the results from that combination cohort that studied the combination of Lisocel® with ibrutinib. To learn more, see ASH 2020: Dr. Bill Wierda on CAR-T Lisocel® Combined with Ibrutinib for Chronic Lymphocytic Leukemia (CLL).
Dr. Brian Koffman has been the beneficiary of CAR-T treatment, and he chronicled his experience in a blog that can be accessed here. He received CAR-T therapy after progressing on ibrutinib, but he had not yet tried venetoclax.
Please enjoy this interview between Dr. Brian Koffman and Dr. Tanya Siddiqi on Lisocel® monotherapy in CLL:
Visit https://ash.confex.com/ash/2020/webprogram/Paper140622.html to read the ASH abstract on the TRANSCEND trial and study the details.
The future with CAR-T looks bright! Patients now have a strong experimental option when all the oral therapies stop working. Should CAR-T be considered even earlier on in the CLL journey? Maybe. But first, CAR-T needs to be approved for CLL. Today it is available only in clinical trials.
For more resources about this exciting therapy, please visit the CAR-T section of the CLL Society’s website.
Keep learning, be kind, and stay well!
Robyn Brumble, MSN, RN
Director of Scientific Affairs
CLL Society
