Novel targeted therapies and cellular immunotherapies are fundamentally reshaping treatment approaches for B-cell malignancies, with chemotherapy-free regimens gaining prominence in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), according to insights from the inaugural Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Conference.
The findings, published in Clinical Lymphoma, Myeloma & Leukemia, highlight how BTK inhibitors and CAR-T cell therapies are addressing longstanding treatment challenges in hematologic malignancies, particularly for high-risk patient populations.
Chemotherapy-Free Approaches Gain Ground in Mantle Cell Lymphoma
Chemotherapy-free regimens have begun to shift the treatment paradigm in patients with MCL, moving away from the long-established standard of chemoimmunotherapy and autologous stem cell transplant (ASCT). This transition builds on evidence from the phase 3 TRIANGLE study and cooperative group studies demonstrating good efficacy of chemoimmunotherapy-free regimens while questioning the role of ASCT.
"Building on recent advances such as the phase 3 TRIANGLE study, cooperative group studies, as well as smaller studies—which demonstrate good efficacy of chemoimmunotherapy-free regimens and also question the role of ASCT—there has been a slow but steady shift in favor of these therapies," explained Dr. Alexey Danilov, the Marianne and Gerhard Pinkus Professor of Early Clinical Therapeutics at City of Hope.
The phase 3 ENRICH trial demonstrated potential superiority of ibrutinib-based therapy over chemoimmunotherapy, though this was primarily limited to R-CHOP in the control arm rather than bendamustine plus rituximab, which showed less significant differences.
High-Risk MCL Requires Specialized Approaches
For high-risk MCL patients, particularly those with TP53 mutations who do not respond well to chemotherapy, BTK inhibitor-based regimens are increasingly used in frontline therapy. Pirtobrutinib has been listed in NCCN guidelines for such patients, reflecting increased clinical adoption.
However, BTK inhibitors alone are not a complete solution for high-risk MCL patients. "I strongly believe that these patients should not receive chemoimmunotherapy, even though bendamustine plus rituximab still remains an option listed in NCCN Guidelines," Danilov noted. "I do believe that a clinical trial is the best option for those patients."
The BOVen regimen of zanubrutinib plus venetoclax and obinutuzumab has demonstrated efficacy in high-risk patients, though confirmation in larger patient populations is needed. Clinical trials are evaluating combinations such as ibrutinib, venetoclax, and lenalidomide with obinutuzumab pretreatment specifically for high-risk MCL patients.
BTK Inhibitor Selection Evolves in CLL
In CLL, chemoimmunotherapy has been essentially eliminated from the treatment armamentarium, with very rare exceptions. Frontline treatment now typically involves choosing between time-limited regimens such as venetoclax and obinutuzumab, or single-agent BTK inhibitors.
Three BTK inhibitors are currently approved: ibrutinib, acalabrutinib, and zanubrutinib. However, ibrutinib use has declined based on randomized study data demonstrating better efficacy of zanubrutinib. Selective BTK inhibition with zanubrutinib or acalabrutinib has become the preferred approach, though no clear consensus exists on superiority between these two agents.
Combination Regimens Show Promise
The phase 3 AMPLIFY study has introduced exciting data on the combination of acalabrutinib and venetoclax, and the triplet of acalabrutinib, venetoclax, and obinutuzumab in frontline CLL therapy. While not yet approved, these regimens are being included in guidelines and have shown successful results in clinical trials.
Emerging data also support combinations of zanubrutinib with venetoclax and zanubrutinib with sonrotoclax, an alternative BCL2 inhibitor, expanding the future armamentarium for CLL treatment.
CAR-T Therapy Addresses Double-Refractory CLL
The FDA approval of lisocabtagene maraleucel (liso-cel) for double-refractory CLL represents a significant development for patients who are refractory to both BTK inhibitors and BCL2 inhibitors like venetoclax. This approval addresses a critical unmet medical need in a patient population with limited treatment options.
Currently, pirtobrutinib, a non-covalent BTK inhibitor, is often used while considering CAR-T cell therapy with liso-cel. However, time to next therapy in patients with double-refractory disease on pirtobrutinib is typically less than two years, indicating the need for more durable treatment options.
Optimizing CAR-T Outcomes
The TRANSCEND CLL 004 study that led to liso-cel's FDA approval was conducted when all patients had previously received chemoimmunotherapy, with many receiving up to a dozen therapies. This severe immune compromise may have negatively affected both efficacy and increased toxicities, including infectious complications.
Future strategies to improve liso-cel efficacy and safety include prophylactic measures for cytokine release syndrome and combination studies with BTK inhibitors, which early data suggests may demonstrate increased efficacy and improved toxicity profiles.
Future Directions
The conference proceedings indicate that novel immunotherapy agents, such as bispecific antibodies, are being evaluated in frontline MCL therapy to determine optimal treatment approaches. The meeting is expected to reconvene in 2025 to further develop best practices and consensus recommendations for ongoing areas of debate in B-cell malignancy management.
These advances represent a fundamental shift toward more targeted, less toxic treatment approaches that address the specific molecular characteristics of different B-cell malignancies while improving patient outcomes and quality of life.
