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ASH 2023: Lymphomas and CLL

CE / CME

Key Studies in Lymphomas and CLL: Independent Coverage of ASH 2023

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurses: 1.00 Nursing contact hour

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Pharmacists: 1.00 contact hour (0.1 CEUs)

Released: March 06, 2024

Expiration: March 05, 2025

Ian Flinn
Ian Flinn, MD, PhD
CME/CE Information

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ELEVATE-TN 6-Year Update: Study Design

I will now switch gears again to discuss a couple of studies in the setting of CLL. At ASH 2023, we saw a  longer follow-up (median 74.5 months) of the phase III ELEVATE-TN trial, which randomized patients with untreated CLL to either acalabrutinib plus obinutuzumab (n = 179); acalabrutinib (n = 179); or obinutuzumab plus chlorambucil (n = 177).27,28 Acalabrutinib 100 mg PO BID was continued until disease progression or unacceptable toxicity. Obinutuzumab and chlorambucil were administered for 6 cycles.

We have known for some time now that the arms containing acalabrutinib demonstrate superior PFS compared to obinutuzumab plus chlorambucil.28

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ELEVATE-TN 6-Year Update: PFS

Median PFS was not reached with acalabrutinib plus obinutuzumab or acalabrutinib alone, but their respective 6-year PFS rates were significantly different (78% vs 62%; HR: 0.14; 95% CI: 0.10-0.20; P <.0001).27 Furthermore, among patients who received acalabrutinib, PFS was longer in those who achieved CR/complete remission with incomplete count recovery (CRi) vs those who did not (HR: 0.23; 95% CI: 0.12-0.42; P <.0001).

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ELEVATE-TN 6-Year Update: OS

Median OS also was not reached with acalabrutinib plus obinutuzumab or acalabrutinib alone, and their respective 6-year OS rates were not significantly different at the time of this analysis (87% vs 79%; HR: 0.69; 95% CI: 0.44-1.09; P = .1220).

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ELEVATE-TN 6-Year Update: Most Common AEs

The toxicity profile was not drastically changed with the addition of obinutuzumab to acalabrutinib. As expected, there was an increase in the incidence of cytopenias. Grade 3 or higher neutropenia was increased with the addition of obinutuzumab to acalabrutinib compared to acalabrutinib monotherapy (30.9% vs 11.7%, respectively). There was also a marginal increase in any-grade COVID-19 with acalabrutinib plus obinutuzumab compared with acalabrutinib (24.7% vs 21.2%, respectively). Otherwise, given their nonoverlapping mechanisms of action, we would not anticipate any other AEs to be increased with the combination.

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ELEVATE-TN 6-Year Update: AEs of Clinical Interest

This holds up when looking at AEs of clinical interest. Adding obinutuzumab to acalabrutinib did not significantly increase the rate of hypertension (11.2% in both arms).27

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ELEVATE-TN 6-Year Update: Clinical Implications

In my opinion, the biggest debate to emerge from this ongoing study is whether it is worthwhile to add obinutuzumab to acalabrutinib in the first-line setting for CLL. Clearly, the addition improves PFS and yet there is no difference in OS; however, looking at the OS curves, which are starting to separate more and more with each updated analysis, I wonder if an OS advantage may ultimately emerge over time.

Even so, most clinicians I talk to do not plan on using this combination. One of the benefits of giving acalabrutinib, an oral medication, is its ease of use compared to venetoclax plus obinutuzumab (VO), which requires patients to come to clinic for ramp-up dosing. So, if obinutuzumab is added, requiring the patient to come in, why not just use VO, especially considering that VO is a limited treatment whereas acalabrutinib is lifelong, until progression or unacceptable toxicity. The addition of obinutuzumab also introduces a medication administered by IV, which gets away from the benefits of acalabrutinib being an oral regimen.

TRANSCEND CLL 004 Update: Study Design

Although CAR T-cell therapy has a role in most B-cell malignancies at this time, we do not have an agent approved in CLL, despite this disease being one of the earliest reports in the development of CAR T-cell therapy. TRANSCEND CLL 004 is an important study, because they were able to show efficacy of lisocabtagene maraleucel in untreated CLL.29

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TRANSCEND CLL 004 Update: Baseline Characteristics

TRANSCEND CLL 004 was composed of a very difficult-to-treat patient population. The median number of prior lines of therapy was 5 in both the full study population and in the subset of patients with disease progression on a BTK inhibitor and venetoclax failure. All patients had received a prior BTK inhibitor, and the majority (81%) had prior venetoclax.

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TRANSCEND CLL 004 Update: Efficacy at RPD2

In the full study population, lisocabtagene maraleucel achieved an ORR of 48% with a CR/CRi rate of 19% and undetectable MRD rates of 66% and 60% in the blood and marrow, respectively, which does not make much sense to me. I would assume that a CR would need to be achieved before undetectable MRD would be observed, but here we see the opposite. I suspect this discrepancy is a result of the definition of CR. Despite the disconnect between the rates of objective response, CR, and MRD undetectability, I find the rate of undetectable MRD in two thirds of patients to be most interesting and important.

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TRANSCEND CLL 004 Update: Time to Next Therapy at RPD2

Unfortunately, the median time to next treatment (TTNT) was suboptimal, at 18.4 months in the overall population.

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TRANSCEND CLL 004 Update: Clinical Outcomes by Best Overall Response at RPD2

The median PFS of 17.9 months was also relatively low, especially considering the administration, AEs, and cost associated with CAR T-cell therapy. On the other hand, these are patients who do not have many viable treatment options remaining at this point in their disease course, as they’ve already had BTK inhibitor and venetoclax-based therapy.

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TRANSCEND CLL 004 Update: TEAEs

Regarding safety, any-grade CRS occurred in 85% of patients, which was primarily low-grade, but with 8% experiencing a grade 3 or higher event.

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TRANSCEND CLL 004 Update: TEAEs of Special Interest

Although grade 3 or higher CRS in 8% is not too concerning, 18% with grade 3 or higher neurologic toxicity is. Considering these rates of CRS and neurologic toxicity and the relatively short gains in terms of PFS and TTNT, I feel that this therapy will only be useful in a very few selected patients. The AE profile, time to deliver the therapy, and cost with CAR T-cell therapy all must be considered.

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TRANSCEND CLL 004 Update: Clinical Implications

At present, I am unsure where lisocabtagene maraleucel falls into the treatment paradigm for patients with CLL. Most patients with CLL will never need this therapy, as we have so many good options in our armamentarium. In fact, part of the reason that it has taken so long to develop CAR T-cell therapy in CLL is that our other options, such as BTK inhibitors and venetoclax-based therapies, are so effective. Furthermore, pirtobrutinib was recently approved by the FDA for adults with CLL/SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor,30 which I would consider prior to CAR T-cell therapy. Bispecific antibodies are also being developed in the setting of R/R CLL, which I think will be exciting data to see.

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