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Developments in chronic lymphocytic leukemia (CLL) this year included the first CAR T-cell therapy approval for the chronic blood cancer, potential treatments for Richter transformation, and investigations into triplet regimens.

First CAR-T Approved for CLL

In March, the FDA granted accelerated approval to lisocabtagene maraleucel (liso-cel, Breyanzi) for pretreated CLL or small lymphocytic lymphoma (SLL).

A CD19-directed cellular therapy, liso-cel is the first CAR-T product specifically for CLL/SLL; the one-time infusion is indicated for patients with relapsed or refractory disease following two or more prior therapies, including both a BCL-2 inhibitor such as venetoclax (Venclexta) and a Bruton's tyrosine kinase (BTK) inhibitor such as ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa).

Findings from the phase I/II TRANSCEND CLL 004 study supported liso-cel's approval. Among patients with relapsed or refractory CLL/ SLL in the single-arm, open-label trial, 45% responded to treatment, including complete responses in 20%. The median duration of response reached 35.3 months overall and was not reached among complete responders, a group that had high rates of minimal residual disease (MRD) negativity in the blood (100%) and bone marrow (92.3%).

As with other CAR-T drugs, liso-cel includes a boxed warning about the risk for secondary T-cell malignancies, cytokine release syndrome, and neurologic toxicities.

Moving the Needle in Richter Transformation

New studies evaluated treatment options for Richter transformation, a rare complication of CLL/SLL where the leukemia turns into an aggressive lymphoma.

In a subgroup analysis of the BRUIN study -- which led to last year's approval of pirtobrutinib (Jaypirca) in CLL/SLL -- half of patients with Richter transformation responded to the oral non-covalent BTK inhibitor.

Of the 82 patients with Richter transformation in the phase I/II study, 13% achieved complete responses and 37% had partial responses. Almost half of the responses lasted a year or longer. Eight patients discontinued pirtobrutinib while still in response to undergo stem-cell transplantation. A majority of patients had grade ≥3 adverse events (AEs), but relatively few patients discontinued treatment because of AEs.

"For a disease with few treatment options, pirtobrutinib offered single-agent activity and, as is often the goal for some patients, a bridge to a potentially curative treatment option," William Wierda, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues concluded in .

"This subgroup with Richter transformation included many heavily pretreated patients, who historically have a poor expected overall survival [OS]," the researchers pointed out. For example, the study population had received a median of two prior therapies for Richter transformation, and three-fourths had prior treatment with a covalent BTK inhibitor.

In the phase II MOLTO study, a three-drug regimen involving a PD-L1 inhibitor and two targeted agents was active and safe for treating the diffuse large B-cell lymphoma variant of Richter transformation.

Among 28 patients previously untreated for their Richter transformation, the overall response rate reached 68% following six cycles of atezolizumab (Tecentriq) plus venetoclax and obinutuzumab (Gazyva), including complete responses in 29%. One-year rates of progression-free survival (PFS) and OS landed at 43% and 64%, respectively.

"The clinical activity of this chemotherapy-free regimen translated into durable remissions and a prolonged survival benefit, making the venetoclax, atezolizumab, and obinutuzumab triplet a potential first-line standard treatment for patients with Richter transformation," Alessandra Tedeschi, MD, of the Niguarda Cancer Center in Milan, and co-authors wrote in .

New Data on Triplets for CLL

A fixed-duration, three-drug regimen for CLL achieved deep and durable remissions lasting for up to 7 years, according to updated results from a prospective study.

Median PFS with ibrutinib, venetoclax, and obinutuzumab exceeded 80 months in patients with untreated or relapsed/refractory CLL. Almost 60% of patients with untreated disease had undetectable MRD (uMRD) status, as did 44% of the relapsed/refractory cohort. Overall response rate at the end of treatment was 88% in patients with previously treated CLL, and 84% and 96% for two untreated cohorts. The study involved 75 patients with CLL.

Interestingly, uMRD status had no association with PFS, reported Kerry Rogers, MD, of the Ohio State University in Columbus, at the 2024 European Hematology Association meeting in Madrid.

"Additional studies are needed to determine the relative benefit of either three- versus two-drug regimens, particularly the inclusion of an anti-CD20 monoclonal antibody, as well as mechanisms of resistance and sensitivity, and, of course, the optimal sequence of treatments over the lifespan of patients with CLL," she said.

In updated results of another prospective study, time-limited treatment with a similar triplet -- acalabrutinib, venetoclax, and obinutuzumab -- produced long-term uMRD in more than 90% of patients with relapsed/refractory CLL.

After a median follow-up of 36.3 months, 42 of 45 patients (93%) achieved uMRD in peripheral blood at any time point with the combination. The estimated 3-year OS rate was 94%. Subgroups with uMRD status exceeding 90% included patients previously treated with venetoclax and those with TP53 mutations.

At last follow-up, patients had been off treatment for a median of 21.9 months. COVID-19 was responsible for all three fatal AEs in the study, reported Moritz Fürstenau, MD, of the University of Cologne in Germany, and co-authors in .

Their report also showed that monitoring circulating tumor (ct)DNA in addition to flow cytometry at least doubled early detection of MRD recurrences.

Ibrutinib's Negotiated Medicare Price

In August, the Centers for Medicare & Medicaid Services (CMS) unveiled the negotiated prices for the 10 drugs selected under Medicare's drug-price negotiation program -- the first-generation BTK inhibitor ibrutinib among them.

Ibrutinib will drop from a list price of $14,934 to $9,319 under the negotiated terms, representing a 38% decrease. The new prices will take effect beginning in January 2026.

The price negotiation program was passed in 2022 as part of the Inflation Reduction Act. The measure lowers prescription drug costs for seniors by empowering Medicare to negotiate the cost of prescription drugs for the first time. The 10 drugs chosen for negotiation by CMS -- single-source brand-name drugs with no therapeutically equivalent generic or biosimilar competition -- were targeted for negotiation based on their total expenditures in the Medicare Part D program. These drugs are either costly, widely used, or both. Costs for ibrutinib in 2023 totalled $2.37 billion for the 17,000 enrollees who used the drug.

Other drugs on the list include blood thinners and therapeutics for diabetes, heart failure, chronic kidney disease, rheumatoid arthritis, inflammatory bowel disease, and psoriasis.

New Labeling for Fludarabine

In November, the FDA as part of its Project Renewal program, an initiative that aims to make sure the prescribing information for older oncology drugs remains clinically meaningful and up to date.

Fludarabine's now reflects that the chemotherapy can be used for adults with B-cell CLL in combination with cyclophosphamide and rituximab, and as monotherapy for those who have failed on a prior regimen containing an alkylating agent.

In addition, a previous boxed warning regarding central nervous system toxicity, hemolytic anemia, and pulmonary toxicity was removed and the information was moved to the label's "warnings and precautions" section.

Fixed-Duration Oral Doublet for Fit CLL Wins in Frontline Setting

At the American Society of Hematology (ASH) annual meeting, findings from a phase III study showed that a fixed-duration oral combination significantly improved PFS compared with chemoimmunotherapy in fit patients with previously untreated CLL.

In the AMPLIFY trial, the 3-year PFS rate reached 76.5% with acalabrutinib plus venetoclax, as compared with 66.5% with investigator's choice of standard chemoimmunotherapy options (HR 0.65, 95% CI 0.49-0.87, P=0.0038), reported Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

A third arm evaluating acalabrutinib-venetoclax plus intravenous obinutuzumab also topped chemoimmunotherapy when it came to PFS, with a 3-year rate of 83.1% (HR 0.42, 95% CI 0.30-0.59, P<0.0001).

OS was significantly prolonged with acalabrutinib-venetoclax versus chemoimmunotherapy -- either fludarabine, cyclophosphamide, and rituximab; or bendamustine plus rituximab. With the obinutuzumab regimen, however, OS was significantly improved only after censoring for COVID-19 deaths, said Brown.

Both investigational regimens had tolerable safety profiles, with a low incidence of the cardiac AEs typically associated with BTK inhibitors such as ibrutinib, including atrial fibrillation and hypertension.

Other CLL research reported at ASH included early but promising data on single-agent epcoritamab (Epkinly) in heavily pretreated patients and the confirmatory trial of pirtobrutinib in patients who failed on prior BTK inhibition.

Senior Editor Charles Bankhead and Washington Editor Joyce Frieden contributed to this report.

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