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Dr. Tatyana Feldman

2yr
CAR T cell therapy for CLL

The TRANSCEND CLL004 trial, published in The Lancet in 2023, presents compelling evidence for the use of lisocabtagene maraleucel (liso-cel) in chronic lymphocytic leukemia (CLL), particularly in patients who have exhausted other treatment options. Among a heavily pretreated group of trial participants, 88% were refractory to BTK inhibitors and 76% to Venetoclax, with a median of 5 prior lines of therapy.

The data suggest that liso-cel is highly effective in this difficult-to-treat patient population, with a complete response rate (CRR) of 18% and an overall response rate (ORR) of 43%. Notably, high-risk patients (i.e., those with TP53 deletion/mutation or unmutated IGHV)—who generally have poorer outcomes—achieved a CRR of 23% and ORR of 47%.

A further testament to liso-cel's efficacy is the MRD negativity rate of 63% in peripheral blood, suggesting deep responses.

The durability of the responses is impressive, with a median duration of response (mDOR) of 35.3 months and a median progression-free survival (mPFS) of 26.2 months in MRD-negative patients. Median duration of CR was not reached.

Toxicity is manageable and predictable, and no new safety signals different from DLBCL trials were seen. Importantly, most deaths during the trial were due to disease progression, not treatment-related toxicity.

Despite the drug’s efficacy, there is a clear need to streamline the production of liso-cel. The 36-day wait from leukaphereses to infusion is particularly problematic for CLL patients at this stage of the disease. In total, the 15% drop off between leukaphereses and infusion is very telling; the company should focus on shortening this timeline to improve patient outcomes.

Based on the TRANSCEND CLL004 trial data, liso-cel offers a new treatment avenue for CLL patients who have exhausted other options. It is effective, provides durable responses, and has manageable toxicity, thus justifying its use in this difficult-to-treat population.

What are the benefits and challenges of using liso-cel in your practice? How does liso-cel compare with other newer treatments?

  • 2yr
    Biggest challenges are insurance issues, performance status, distance issues, social support, and most importantly, the lack of patients who are candidates for CAR-T
  • 2yr
    In CLL there are limited options, CD20, BTK and BCL2, and then nothing really, so the addition of CAR-T as effective therapy is meeting a huge gap in necessary options. There are still problems getting slots, but that has improved in other cancer types; I expect with new demand in CLL, there will be shortages, however and I am hopeful that will resolve quickly to meet the need
  • 2yr
    Very good data, very promising for pts if they can receive it. Problem is the time interval to get it arranged, travel issues, caregiver support issues, cost issues limit the number of pts who can feasibly receive it.
  • 2yr
    Great addition to treatment regimens for refractory CLL. Issue of travel, availability and side effects are there. But I will definitely refer to tertiary care for this option. I’ve had great successes with CARt in other lymphomas
  • 2yr
    As others have said, this is a welcome option for our patients but production issues have severely limited its use. This is the main reason to choose other therapies.
  • 2yr
    the challenges are more logistic than anything . i practice in a rural area so closest center is over 300 miles away so patients lack support in the area. the cost is an issue as well. the wait to get in for these therapies can be long so unfortunately some patients die while waiting. i do believe it's superior therapy to many other drugs that we have and it's wonderfully effective however these are the challenges i have. many of my patients are older so their fitness would also disqualify them from these drugs. if i have an appropriate patient, yes, i would definitely send to get treatment with this drug
  • 2yr
    I am concerned that the patient population I deal with is going to be different from the patient population studied. Most of my patients are elderly, with several different comorbid conditions, usually cardiac, renal, peripheral vascular, or diabetic related. By the time my patients are through several lines of therapy, the clinical condition is going to be impaired, and it may not be candidates for CAR-T based therapies. It would be interesting to see the demographics of the patient studied. The comment that toxicities were manageable, is a bit in the eye of the holder. Frequently patients and research physicians disagree on the severity and impact of toxicity. We have a CAR-T center that is only a few miles away, but we draw from a population area over 100 miles in diameter, and travel distance, housing, and cost of living, not to mention being away from home and job for several weeks at a time, may put a significant financial burden on patient family members. For the highly selected, young, motivated patient without significant comorbidities, this might be a reasonable choice, but I do not think my patient population is going to have a significant number of eligible patients.
  • 2yr
    Grear option for pts with relapsed and refractory ds but it is only available to few pts due to limited availability and pt lack of social support
  • 2yr
    This is a great option for patients with relapsed / refractory DLBCL. However, today this treatment has issues with logistics and slot availability. I do refer my patients for evaluation at tertiary centers.
  • 2yr
    The data from the Transcend trial are interesting, lysis provides a salvage option for previously heavily pretreated, refractory patients. MRD negativity of 63% with peripheral blood is impressive. Median duration of response and median PFS appear to be very good, especially off treatment, after initial CAR-T therapy. The complete response rate of 18% and overall response rate of 43% is somewhat underwhelming. However these were generally refractory patients. May be CAR-T cell therapy directed against other Antigens may be useful.
  • 2yr
    an option for healthy pts who are willing to travel and have the resources to obtain therapy
    specially for high risk pts who have progressed on BTK and bcl2 inhibitors
    with newer agents noncovalent binders will need to see if car t with its toxicity remians wothwhile
  • 2yr
    I think to have a salvage treatment such as CART on reserve for the very resistant patients is fine, but not early on use
  • 2yr
    We use liso-cel per label for B-cell lymphoma. I think one of the most appealing aspect of this product for lymphoma is the low incidence of high grade CRS and ICANS while preserving a decent efficacy profile.
    In terms of CLL, here are my points regarding the TRANSCEND CLL004 trial:
    Pros: durable response in responders (CR/CRi, PR/nPR), impressive PFS in CR patients (and in PR), median OS not reached for patients in CR or PR, undetectable MRD in a small subset of patients.
    Cons: Only 18% of CRR, higher incidence and severity of CRS and ICANS than what was reported in LBCL. This study was a single arm design. High dropout rate of 15%. Short duration of follow-up.
    Having said that, overall I think that liso-cel is a promising treatment for heavily treated CLL patients refractory to conventional treatments.

  • 2yr
    So I think this is a great therapy for the right patient. Challenge in our area is that the closest car T cell center is 2 hours away so if a patient cannot travel it’s tough to get therapy. Also some patients won’t have the performance status to get this therapy.
  • 2yr
    It is a great option for multi-refractory CLL patients. Fortunately those patients are extremely rare in my practice. If I have a patient that is refractory to both BTKi and Bcl2 inhibitors , I will certainly refer for CAR-T
  • 2yr
    Unfortunately, CAR-T therapy is plagued by lack of enough slots or timely initiation of therapy and associated side effects. Financial toxicity in the need to travel to another center far away from home and stay locally. Although this is promising data, particularly those are finance or leader, it may still be utilized in patients are fit at the line of therapy and can afford it and covered insurance . I will wait-and-see.
  • 2yr
    1. Patient preferences to be treated in the community rather than traveling 100 miles for a car-t cell center
    2. Lack of social support around the post car-t cell time
    3. Heavily pretreated patient population and compromised organ function reserve might disqualify them from such aggressive form of therapy.

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