At this year’s American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando, we had the opportunity to navigate both manned and unmanned traffic, contend with temperamental weather, and count our steps as we took in the most consequential developments in hematologic oncology.
GUEST EDITOR
Matthew Lunning, DO, FACP
Dr. Lunning is Professor and James O. Armitage, MD, Chair of Hematologic Malignancies and Interim Chief of Hematology at the University of Nebraska Medical Center, Omaha. His clinical and research focus encompasses non-Hodgkin lymphoma, Hodgkin disease, cellular immunotherapies including CAR T-cell therapy, and benign hematologic disorders.
After catching my breath, I embarked on the time-honored, yet exhausting, mental exercise of synthesizing everything I’d learned: mulling over the application to my daily practice of time-limited targeted therapy in chronic lymphocytic leukemia (CLL), pondering if the spirit of Walt Disney had a hand in the fantasy-to-reality of the first-in-human in vivo chimeric antigen receptor (CAR) T-cell therapy, and discerning which phase III trials had the potential to be practice-changing in the community setting.
Below, I will navigate through some of the highlights of the meeting, providing a green-to-red-light summary to help readers determine which advances could be immediately applicable to their practice—and which require a slow roll.
Fixed-Duration vs Continuous Treatment in CLL
In the CLL space, Othman Al-Sawaf, MD, PhD, and colleagues presented findings from the phase III CLL17 trial, demonstrating that previously untreated patients who received fixed-duration venetoclax/obinutuzumab or venetoclax/ibrutinib had noninferior progression-free survival compared with those who received continuous treatment.1
Green Light: The study reframes discussions around the efficacy, tolerability, patient preference, and value of continuous BTK inhibition in untreated CLL.
Red Light: Although the trial provides a global perspective, many oncologists have moved on from ibrutinib and may choose to ignore ibrutinib-based studies.
Pirtobrutinib in Untreated CLL
The BRUIN CLL-313 trial, presented by Wojciech Jurczak, MD, PhD, and colleagues, showed a significant improvement in progression-free survival with the noncovalent BTK inhibitor pirtobrutinib compared with bendamustine plus rituximab in patients with treatment-naive CLL.2 This is one of the largest treatment effects ever observed for a single-agent BTK inhibitor against this comparator.
Green Light: Noncovalent BTK inhibition is now advancing into the front-line setting, reinforcing that chemotherapy is rapidly becoming a historical comparator in CLL.
Red Light: Sequencing between covalent and noncovalent BTK inhibitors remains a hotly debated topic. We shall see whether fixed-duration noncovalent BTK inhibition has any effect on the returning clone.
MajesTEC-3 in Relapsed Multiple Myeloma
In the phase III MajesTEC-3 trial, María-Victoria Mateos, MD, PhD, and colleagues reported an 83% reduction in the risk of death for patients with relapsed multiple myeloma who received the BCMA-directed CD3 T-cell engager teclistamab-cqyv plus daratumumab and hyaluronidase-fihj compared with the investigator’s choice of daratumumab regimen.3
Green Light: MajesTEC-3 demonstrates the power of teclistamab plus daratumumab vs established daratumumab-based triplets, supporting earlier integration of BCMA-directed bispecific antibodies.
Red Light: The bottom line is whether health system administrators will accept the burden of delivering this combination.
In Vivo CAR T-Cell Therapy
Preliminary results from the phase I inMMyCAR study, presented by Phoebe Joy Ho, MBBS, DPhil, FRACP, FRCPA, FFSc(RCPA), and colleagues, showed that all three patients treated with an off-the-shelf in vivo CAR T-cell platform (KLN-1010) achieved a measurable residual disease (MRD)-negative response by month 1, with manageable toxicities.4
Green Light: KLN-1010—the first-in-human in vivo CAR-T platform—generates anti-BCMA CAR T cells without ex vivo manufacturing and produces early MRD-undetectable responses.
Red Light: We will need master-class investigators to manage the explosion of in vivo products entering early-phase clinical research, both in hematologic malignancies and autoimmune diseases, so we don’t unintentionally become disorganized by envy—which could move the field into reverse.
Epcoritamab Plus R2 in Relapsed Follicular Lymphoma
Lorenzo Falchi, MD, and colleagues presented results from the phase III EPCORE FL-1 trial, demonstrating that the addition of the CD20 x CD3 bispecific antibody epcoritamab-bysp to rituximab and lenalidomide (R2) improves disease control in relapsed or refractory follicular lymphoma.5
Green Light: These improvements in overall response rate, complete response rate, and progression-free survival underscore the additive benefit of bispecific antibodies in relapsed follicular lymphoma—at a crucial crossroads in care.
Red Light: The risk of infection with additive vs sequential approaches must be discussed, especially with the prospect of tafasitamab-cxix plus R2 offering a smoother ride.
Ph-Positive ALL Without Chemotherapy
The phase III GIMEMA ALL2820 trial, presented by Sabina Chiaretti, MD, PhD, and colleagues, found that the targeted immunotherapeutic approach of ponatinib plus blinatumomab led to higher response rates, fewer deaths, and improved event-free survival compared with chemotherapy plus imatinib in patients with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL).6
Green Light: The trial supports chemotherapy-free induction using ponatinib and blinatumomab, redefining treatment paradigms in Ph-positive ALL.
Red Light: Will the MRD-detectable and -undetectable goalpost continue to move, or will we be content with its current position to defer a consolidative allogeneic transplant?
Mutant CALR in Myelofibrosis
John O. Mascarenhas, MD, and colleagues reported the preliminary results of two global phase I trials evaluating INCA033989, a first-in-class mutant calreticulin (CALR)-specific monoclonal antibody, alone or in combination with ruxolitinib in patients with myelofibrosis.7 The therapy was well tolerated and resulted in spleen and anemia responses, as well as symptom improvements.
Green Light: INCA033989 introduces mutation-specific CALR immunotherapy in myelofibrosis, marking a shift toward disease-modifying precision approaches.
Red Light: As we move forward with combination therapies in myelofibrosis, knowing which drug is not playing nicely in the sandbox won’t be solved by algorithms alone; it will require careful effort, well-designed trials, biologic correlates, and experienced clinicians.
Conclusion
Taken together, the traffic patterns at this year’s ASH make one thing crystal clear: precision medicine is no longer aspirational, but operational. Crucially, although hematologic oncology is accelerating, not every therapeutic development lane should be pursued at full speed. So, as we merge back into the grand prix of daily practice, we must acknowledge that data blind spots exist, and our task is not simply to change lanes haphazardly. While the green lights are many—whether they are time-limited therapy, a chemotherapy-free induction upgrade, or an automatic start of combinations that include bispecific antibodies—each checkpoint in care brings its own yellow and red lights that demand a clinical deceleration rather than a fast pass straight to the electronic medical treatment template. Slowing down is OK; we don’t want to fly off course with our patient as our passenger.
DISCLOSURE: Dr. Lunning has served as a consultant or advisor for AbbVie, AstraZeneca, Bristol Myers Squibb, Fate Therapeutics, Genentech, Incyte, Ipsen, Kite Pharma, Loxo, Pfizer, Recordati, and ViTToria; and has received research funding from Curis and Fate Therapeutics.
REFERENCES
1. Al-Sawaf O, Stumpf J, Zhang C, et al: Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: Results from the randomized CLL17 trial. 2025 ASH Annual Meeting & Exposition. Abstract 1. Presented December 6, 2025.
2. Jurczak W, Kwiatek M, Czyz J, et al: Pirtobrutinib vs bendamustine plus rituximab (BR) in patients with CLL/SLL: First results from a randomized phase III study examining a non-covalent BTK inhibitor in untreated patients. 2025 ASH Annual Meeting & Exposition. Abstract LBA3. Presented December 9, 2025.
3. Mateos M-V, Bahlis N, Perrot A, et al: Phase 3 randomized study of teclistamab plus daratumumab versus investigator’s choice of daratumumab and dexamethasone with either pomalidomide or bortezomib in patients with relapsed refractory multiple myeloma: Results of MajesTEC-3. 2025 ASH Annual Meeting & Exposition. Abstract LBA6. Presented December 8, 2025.
4. Harrison S, Ho PJ, Lim SL, et al: Minimal residual disease (MRD)-negative outcomes following a novel, in vivo gene therapy generating anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cells in patients with relapsed and refractory multiple myeloma (RRMM): Preliminary results from inMMyCAR, the first-in-human phase 1 study of KLN-1010. 2025 ASH Annual Meeting & Exposition. Abstract LBA1. Presented December 9, 2025.
5. Falchi L, Nijland M, Huang H, et al: Primary phase 3 results from the epcore FL-1 trial of epcoritamab with rituximab and lenalidomide (R2) versus R2 for relapsed or refractory follicular lymphoma. 2025 ASH Annual Meeting & Exposition. Abstract 466. Presented December 7, 2025.
6. Chiaretti S, Di Trani M, Skert C, et al: First results of the Phase III GIMEMA ALL2820 trial comparing ponatinib plus blinatumomab to imatinib and chemotherapy for newly diagnosed adult ph+ acute lymphoblastic leukemia patients. 2025 ASH Annual Meeting & Exposition. Abstract 439. Presented December 7, 2025.
7. Mascarenhas JO, Al-Ali HK, Gupta V, et al: Safety and efficacy of the mutant calreticulin-specific monoclonal antibody INCA033989 as monotherapy or in combination with ruxolitinib in patients with myelofibrosis: Preliminary results from dose escalation of two global phase 1 studies. 2025 ASH Annual Meeting & Exposition. Abstract 484. Presented December 7, 2025.
