Latest news with #targetedTherapy
Medscape
09-07-2025
- Health
- Medscape
CLL: Hematologists Face Off on Best Long-Term Strategy
In the age of targeted therapy, what's the best long-term strategy to treat chronic lymphocytic leukemia (CLL), the most common leukemia in Western countries? Should treatment be continuous to achieve deep remissions or time-limited to allow patients to take breaks? At the 18th International Conference on Malignant Lymphoma (ICML) 2025 in Lugano, Switzerland, a pair of hematologists set aside their friendship for a few moments and took opposite sides in a debate over off-and-on BCL2 targeting vs continuous treatment with Bruton's tyrosine kinaseinhibitors (BTKis). Here's a summary of their discussion — and insight from another specialist who provided perspective to Medscape Medical News. Team Venetoclax: It's the 'Most Potent' Therapy Hematologist John F. Seymour, MBBS, PhD, of the Royal Melbourne Hospital, Parkville, and the Peter MacCallum Cancer Center, Melbourne, both in Australia, supported on-and-off BLC2 targeting via therapy with venetoclax, which he called 'the most potent known anti-CLL therapy.' He highlighted its early record of rapid improvement in patients and asked, 'Why would we not want to use a drug that potent?' He cited data from the 2023 CLL13 study, which he said showed that venetoclax combinations have 'an astonishing and unprecedented ability to achieve incredibly deep remissions, as measured by undetectable MRD [measurable or minimal residual disease] rates in the peripheral blood above 90% with short term time-limited treatment.' The study authors reported that 'venetoclax-obinutuzumab [VO] with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL.' Seymour also noted phase 3 data from several studies demonstrating that time-limited therapy of 12-14 months achieved 4-year progression-free survival (PFS) rates between 75% and 85%, similar to continuous BTKi therapy outcomes. 'So in terms of PFS, both are equivalent,' he said. Team BTKi: The Evidence Is in Hematologist Stephan Stilgenbauer, MD, of Ulm University, Ulm, Germany, countered by emphasizing the extensive evidence base supporting continuous BTKi therapy, noting data from 'almost 2000 patients on nine clinical trials' with nearly 5 years of aggregate follow-up. He added that 'we have a median follow-up time that is close to 50 years in aggregate, and even more importantly, seven of these nine trial arms involved the relevant CLL patient population — namely, patients of a median age of about 70 years.' He contrasted this with more limited data for venetoclax combinations, stating that VO had evidence from only two trials, the CLL13 and CLL14 trials, with 'only a single arm' addressing the relevant older patient population. And the aggregated median follow-up time, he said, is just over 10 years. Regarding efficacy, Stilgenbauer presented cross-trial comparisons showing 48-month PFS rates in older patients, with aggregate data showing 72% for BCL-2 inhibitors and 79% for '79% BTKis.' 'It is quite clear efficacy is better with [BTKis],' he said. Team Venetoclax: Listen to Guidelines and Patients Seymour highlighted European Society For Medical Oncology (ESMO) recommendations regarding therapy. ESMO's 2024 interim guideline update says that in front-line therapy, 'first-line treatment in patients with CLL regardless of IGHV [immunoglobulin heavy chain variable region status] but without a TP53 mutation or del(17p), preference should be given to time-limited therapies and to therapies and/or combinations with longer follow-up data, if efficacy is similar.' However, the 2021 ESMO guidelines offer these cautions about time-limited therapies: 'side-effect profile (renal impairment and risk of TLS [tumor lysis syndrome] vs atrial fibrillation and bleeding risk), application mode (intravenous [IV] application with combination therapy due to the antibody infusion vs oral medication only), intensity of controls (5-week ramp-up period with the combination), and shorter follow-up have to be taken into consideration.' Seymour also noted patient preference data showing that 'the most dominant factor for patients' preference with given equivalent efficacy was shorter duration of treatment.' As for adverse effects, Seymour argued that current protocols have minimized this risk for TLS. 'Interventions are very uncommonly needed. When analyzing aggregate data, TLS is in less than 1 in 200 patients,' he said. He contrasted this with the risks of continuous therapy, noting that 'continuous accumulation of risk of adverse events is seen, and some of those, and the most troublesome among those are cardiovascular. That can be atrial fibrillation or flutter. While second-generation drugs have a lower rate, they still occur, and they still increase with time.' Most devastatingly, 'the risk of sudden cardiac death is increased with ibrutinib across a number of these studies. And that risk continues to accumulate with time.' Team BTKi: Safety Matters Stilgenbauer challenged safety perceptions about BTKis, highlighting the CLL12 placebo-controlled trial. 'When you look at the adverse event table from this trial, you see that all of these so-called treatment-emergent adverse events that occurred with ibrutinib also occurred with placebo,' he said. 'These adverse events occur due to the disease and not due to the treatment.' He also noted safety data showing higher rates of severe neutropenia in venetoclax combinations. 'You have a high-grade neutropenia in more than 55% of patients. You have thrombocytopenia, anemia, you have febrile neutropenia and pneumonia,' Stilgenbauer said, comparing this to single-digit percentages with BTKis. The Outside Expert: Focus on Patient Characteristics Medscape Medical News contacted Hematologist Seema Ali Bhat, MD, of The Ohio State University in Columbus, Ohio, and asked her for her perspective. Here are excerpts from our conversation: What do you think regarding time-limited venetoclax-based therapy vs continuous BTKi therapy? Both regimens are highly effective options for CLL, and the choice between them should be individualized. Time-limited venetoclax combinations (with obinutuzumab or acalabrutinib +/- obinutuzumab) offer the advantage of finite therapy, with potential for deep remissions, MRD negativity, and treatment-free intervals. On the other hand, BTKis have shown sustained efficacy with long-term data, even in high-risk groups. In fact, a pooled analysis of three trials showed that first-line treatment with ibrutinib provides long-term overall survival benefits, with estimates similar to those of an age-matched adult population. What should hematologists be thinking about when they make decisions regarding treatment in these patients? Several factors should guide treatment selection: •Patient-specific factors: age, fitness, cardiovascular comorbidities (atrial fibrillation, hypertension, congestive heart failure, etc.), renal function, medication adherence, and treatment goals. BTKis are known to have cardiac adverse effects, so patients with underlying uncontrolled cardiac condition like atrial fibrillation or hypertension may not be suitable for this kind of therapy. On the other hand, patients with renal dysfunction may be prone to worsening renal function due to risk for TLS with venetoclax. •Patient preferences: If a patient does not want to come in for frequent laboratory monitoring during venetoclax ramp-up, a BTKi is preferred. Similarly, if coming for IV infusions for 6 months is burdensome, it is better to avoid a VO regimen. If there is a patient who wants fixed duration therapy but prefers not to have IV treatments, the acalabrutinib plus venetoclax (AV) regimen will be ideal in this case. The consideration of patient preferences is important. Some patients value time off treatment and the concept of deep remissions while others may prioritize fewer visits or simpler oral treatments. •Disease characteristics: We take disease biology into consideration, especially IGHV mutation status and TP53 disruption. In the CLL14 study, it was very clear that in patients with TP53 disruptions, the responses were not as durable as in patients without these abnormalities. Studies with BTKis have consistently shown similar outcomes in patients with or without TP53 disruption. •Drug interactions: Due to an increased risk for bleeding, it is advised to be cautious when combining BTKis with blood thinners. In a patient who is at an increased risk for bleeding, venetoclax-based therapy may be preferred. •Access and cost: Time-limited therapy may be more cost-effective, but access to obinutuzumab and logistical complexity of venetoclax ramp-up can be barriers. Shared decision-making is essential, especially as both options — time-limited or continuous offer excellent outcomes in many patients. Is there anything else you'd like to add about this topic? Head-to-head comparisons between these different types of treatments are ongoing — for example, trials like FLAIR and CLL17— so we are eagerly awaiting those results which may help further refine this field. Also, the oral doublets have so far been compared with chemoimmunotherapy, it will be important to see how AV compares to VO in the MAJIC trial or how zanubrutinib plus sonrotoclax, a new BCL2 inhibitor, compares to VO in the CELESTIAL trial. Until we have definitive long-term comparative data, clinicians should avoid rigid treatment algorithms.
Medscape
12-05-2025
- Health
- Medscape
Multigene Testing in Pancreatic Cancer: NCCN Impact
This transcript has been edited for clarity. Hello. I'm Dr Maurie Markman, from City of Hope. I'd like to present a very interesting analysis. I think it's open to interpretation, and follow up of what I'm going to discuss is necessary, but I think it makes a number of important points relative to the question of optimal utilization o f multi-panel molecular testing as we move forward in this very exciting world of targeted therapy. The paper is entitled, 'Utilization and outcomes of multigene panel testing in patients with pancreatic ductal adenocarcinoma.' This analysis was looking specifically at pancreas cancer and data that come from a Mayo Clinic analysis, from Mayo Clinic in Rochester, Arizona, and Florida. They were looking at the utilization of multi-panel testing in a population of 533 patients with pancreas cancer before and after guideline recommendations from NCCN (National Comprehensive Cancer Network) that suggested such testing. One of the advantages of the Mayo Clinic system is that the groups work very closely have a really robust database. One would not know if the information in this report is comparable to other organizations, but I think it's very provocative to look at and for organizations that ask themselves, 'How are we doing with such testing?' Of these 533 patients, 60% (321 patients) that they looked at in terms of the question of testing were before the NCCN recommendations, and 40% (212 patients) they looked at whether the testing was performed or whether a discussion was held with the patients and then testing performed. Again, they were looking at the electronic medical record after the recommendations. Here's what they found: Prior to the NCCN recommendations — where doctors made their decisions based upon their knowledge of t he field, what they had read, meeting information, and CME programs — 34% of the patients had had a documented discussion regarding this testing. Of these, 81% — that's 81% of the population that had the discussion — had the test actually performed. Post NCCN recommendations for the testing, that number increased minimally to 39%, of whom 75% of that population had the testing. WithNCCN recommendations, still only 40% of the patients had a discussion of the testing at the Mayo Clinic. They noted that among the patients who did have testing, 17% had pathologic variants identified, of whom 11%, so 1 out of 10, had documented prostate cancer-related abnormalities that are potentially quite relevant for their treatment and also for discussions with their family. This is a very important paper. It's a very important baseline, you might say. One must ask, how are we doing today? The implications of such testing are only greater compared to a year or two ago , both in terms of therapy and of course discussions with the family. It's an interesting analysis and an important can conclude that this is not so bad, considering it's new. You could say that we wished it would've been higher. I'd love to see a follow-up from Mayo Clinic. Where are they in 2024 or 2025? Th ank you for your attention.
