Time-Limited Regimens Gain Notice, Offering a Break for Patients With Blood Cancer and Savings for Payers

The 67th American Society of Hematology (ASH) Annual Meeting & Exposition started with a bang: On the first day of the meeting in Orlando, Florida, news spread of long-awaited trial data comparing 2 treatment approaches in chronic lymphocytic leukemia (CLL): continuous therapy with a Bruton tyrosine kinase (BTK) inhibitor vs a fixed-duration combination.^1,2

So important it was designated Abstract 1, the CLL17 trial (NCT04608318) found that continuous treatment with the first-generation BTK inhibitor, ibrutinib (Imbruvica; Janssen), was noninferior to fixed-duration combinations of ibrutinib with the BCL2 inhibitor venetoclax (Venclexta; AbbVie) or venetoclax with the anti-CD20 monoclonal antibody obinutuzumab (Gazyva; Genentech).^1,2

But the trial was important not only to patients with CLL; these head-to-head results were also a key milestone in the shift away from continuous to fixed-duration or time-limited regimens, which promise potential savings to health systems. Fixed-duration regimens are approved across different types of lymphoma, and the use of testing to guide treatment has been studied across several blood cancers, including multiple myeloma. Authors of CLL17 wrote in the New England Journal of Medicine that “Fixed-duration treatment offers several potential advantages, such as treatment-free intervals and lower rates of treatment-related toxic effects in the long term,” and noted that unfit patients may benefit the most.²

Interest in fixed-duration therapy in blood cancers has increased as therapeutic advances allow patients to live longer. In CLL, for example, the positive benefit of BTK inhibitors is offset by the possible effects of taking the drug for multiple years. Ira Zackon, MD, of Ontada, presented real-world data at ASH on discontinuation rates of covalent BTK inhibitors among patients with CLL or small lymphocytic lymphoma.³ The data show discontinuation rates are higher than those seen in clinical trials and are “largely driven by toxicities,” while also associated with comorbidities, cytogenic abnormalities, and worsened performance status.

“There’s a good rationale, or potential advantages, to time-limited approaches,” Zackon said in an interview with The American Journal of Managed Care^®. “The patients will be on therapy for a shorter time overall; that means they’re going to achieve, hopefully, some treatment-free interval, which is valuable in terms of quality of life. Also, from a cost perspective, it’s going to be a lower cost burden on patients to be able to come off therapy, as well as for payers who are paying for expensive drugs, so that the overall cost of care can be lower with a fixed-duration treatment.”

This year, ASH produced a bounty of evidence on the clinical and quality-of-life benefits of fixed-duration therapy, as well as some data on savings to health systems. So far, CLL17 stands apart in offering a direct comparison of continuous vs fixed-duration treatment approaches.

Promising Results With MRD-Guided Treatment

In some cases, limited-duration treatment approaches are guided by measurable residual disease (MRD) testing. Here, treatment is not given until disease progression or unacceptable toxicity; instead, patients are monitored through sensitive bone marrow testing for the presence of cancer, with the potential to stop or adjust treatment, depending on individual responses.⁴ In CLL, the most important example is the phase 3 NCRI FLAIR trial (ISRCTN01844152); investigators published data at the European Hematology Association in June 2025⁵ and presented subgroup results at ASH in Orlando.⁶

FLAIR investigators compared ibrutinib plus venetoclax with ibrutinib monotherapy and with a combination of fludarabine, cyclophosphamide, and rituximab, or FCR.⁵ Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute, said during an ASH preview call that the MRD-guided approach led to improved progression-free survival (PFS) and overall survival (OS) compared with continuous ibrutinib.

“So that’s the first evidence that we have that a time-limited therapy actually improves outcomes, rather than is not inferior to them, compared with continuous therapy,” Brown said. At ASH, investigators showed how this MRD-guided approachproduced exceptional results for patients with baseline gene aberrations.⁶

Benjamin A. Derman, MD, of the University of Chicago, explored treatment strategy in multiple myeloma during a session with an accompanying paper titled, “Can I Stop My Treatment, Doctor? Is MRD-Guided Therapy Ready for Prime Time?” He highlighted evidence that stopping treatment can offer clinical, financial, and quality of life benefits for patients, while acknowledging the challenges.⁷

“Guidelines still recommend maintenance therapy until toxicity, progression, or death. But in addition to improvements in quality of life and reducing financial toxicity, less maintenance therapy may come with other benefits,” Derman wrote. “In the DETERMINATION trial (NCT01208662), which employed lenalidomide maintenance until progression, the incidence of second hematologic cancers was 2.5% among patients with no prior ASCT [autologous stem cell transplant] and 3.5% in those who received ASCT. Second primary malignancies overall may be reduced with a shorter duration of therapy.”⁷

Different Therapies, Different Disease States

The dozens of abstracts for fixed-duration or MRD-guided regimens presented during ASH covered a variety of diseases, therapies, and combinations, including the following:

Follow-up to AMPLIFY. In the wake of the CLL17 results, data from the phase 3 AMPLIFY trial (NCT03836261),⁸ presented at ASH in December 2024, gain greater relevance. That trial, led by Brown, found that fixed-duration regimens with the second-generation BTK inhibitor acalabrutinib (Calquence; AstraZeneca), combined with either venetoclax (AV) or venetoclax and obinutuzumab (AVO) in fit, treatment-naive patients, produced longer PFS than chemoimmunotherapy. An exploratory analysis presented at ASH 2025 examined the relationship between prognostic genetic aberrations and clinical outcomes in AMPLIFY.⁹ The analysis showed an association between the presence of mutations and unmutated IGHV status. Similar benefits in PFS and the time to next treatment with the AV/AVO arms vs chemoimmunotherapy were seen across these mutations. In the AVO arm, ATM, SF3B1, and NOTCH1 mutations were not associated with poorer outcomes; in the AV arm, patients in unmutated IGHV without NOTCH1 had better outcomes vs patients with unmutated IGHV with NOTCH1.⁹

Carlos Doti, MD, vice president and head of medical affairs, US Oncology Business Unit, AstraZeneca, said in an interview during ASH that more data will be forthcoming from AMPLIFY, and there are investigator-initiated studies underway. An important study to watch, he said, is the AstraZeneca-supported MAJIC trial (NCT05057494), a phase 3, open-label randomized study offering a head-to-head PFS evaluation of MRD-guided AV vs MRD-guided VO in a noninferiority design.¹⁰

This study, Doti said, “will try to answer, what is the best option—or are they equally good? And then, it’s a patient decision, because AV has the benefit in that it’s an all-oral [regimen] and because of the ramp-up that we have in AMPLIFY that we included in the MAJIC trial.” This ramp-up is a 5-week dose escalation of venetoclax to prevent tumor lysis syndrome.

Subcutaneous mosunetuzumab. The intravenous version of mosunetuzumab (Lunsumio; Roche), a CD3 x CD20 bispecific antibody, is FDA approved in relapsed/refractory follicular lymphoma (FL) after at least 2 prior lines of systemic therapy. Interim results of the phase 2 MorningSun study (NCT05207670) had shown promising efficacy and safety results for a subcutaneous formulation in patients with previously untreated FL with high tumor burden. In follow-up data presented at ASH, which included patients receiving optional maintenance, an exploratory analysis of circulating tumor DNA in a subset of patients showed MRD negativity in 86.4%, which investigators say supports fixed-duration use in an outpatient setting.¹¹ Two weeks after ASH, the FDA approved Lunsumio VELO, a fixed-duration subcutaneous treatment for relapsed/refractory FL for patients who have received at least 2 lines of therapy. In a statement, Roche officials said the subcutaneous formulation replaces a 2- to 4-hour infusion with a 1-minute injection.¹²

Epcoritamab in first-line FL. While the fixed-duration combination of the CD3 x CD20 bispecific antibody epcoritamab (Epkinly; AbbVie/Genmab) with rituximab and lenalidomide made headlines, both at ASH and with an FDA approval for use after an initial relapse,^13,14 investigators are already looking at fixed-duration regimens in first-line care. Results reported at ASH from the EPCORE NHL-2 trial (NCT04663347) included those from an arm that combined epcoritamab with bendamustine plus rituximab for first-line treatment of FL.¹⁵ Patients received 6 cycles (28 days) of the triplet followed by epcoritamab monotherapy (given subcutaneously) for a total of up to 2 years. The primary end point was overall response rate (ORR). At data cutoff, 25 patients had received the triplet, 11 completed the protocol, and 14 had discontinued. Nine patients stopped treatment due to adverse events (AEs), of which 7 were COVID-19–related, after at least 8 cycles. In the monotherapy phase, 14 cycles of epcoritamab were given. With a median follow-up of 41.3 months, the best ORR and complete response rate were both 96%. Median time to response and complete response were both 1.5 months; median duration of response, PFS, and OS were not reached. Three-year estimates were as follows: DOR, 87%; duration of complete response, 87%; PFS, 83%; and OS, 96%. PFS remained high in both low- and high-risk subgroups. No new safety signals were reported.

Evaluating bispecifics in frail patients with MM. Frail patients often have inferior outcomes to others newly diagnosed with multiple myeloma (MM), as many cannot withstand the toxicity of anti-CD38–based triple-class regimens. The bispecific antibodies teclistamab (Tecvayli; Johnson & Johnson) and talquetamab (Talvey; Johnson & Johnson) have been shown to be efficacious in late-line therapy, and preliminary data on frail patients who are newly diagnosed with MM have shown that this could offer a new approach, allowing a treatment-free interval.¹⁶ On the heels of the landmark results seen at ASH with teclistamab and daratumumab in relapsed/refractory MM,¹⁷ Johnson & Johnson will support the phase 2 EMN37 FITFIX study (NCT07107529) through the European Myeloma Network. The study will evaluate 2 cohorts of frail patients with newly diagnosed MM: The first will be treated with teclistamab and daratumumab, and the second with talquetamab and daratumumab. Patients will be randomly assigned 1:1 to receive 18 cycles of the combinations; following a treatment-free interval of at least 6 months, patients who progress may restart with the doublet until progression or until treatment is no longer tolerated. The primary end point will be PFS at 18 months; secondary end points will include safety and efficacy, including MRD negativity and OS, of each combination. Prophylactic tocilizumab and intravenous immunoglobulin supplementation are permitted.

Long-Term Results Are Encouraging

Of course, the important question is: Can fixed- or limited-duration therapy offer patients long-term survival? This year’s ASH meeting offered good news. A French study, the ICLL-07 FILO trial (NCT02666898), provided results from 8 years of follow-up on fit patients with CLL who had received a 15-month immunochemotherapy regimen with 9 months of ibrutinib plus obinutuzumab induction. Patients in complete remission (CR) with MRD less than 0.01% continued on ibrutinib alone for 6 months, while all other patients received 4 cycles of fludarabine, cyclophosphamide, and obinutuzumab plus ibrutinib consolidation. At 16 months, 62.2% patients had achieved CR with MRD less than 0.01%.¹⁸ At this year’s meeting, results from 97 months of follow-up reported PFS and OS rates of 87% and 93%, respectively, with 72% of the 128 evaluable patients still alive. Eight were in partial response, 1 was in stable disease, 14 were progressing, and 4 were receiving treatment. Twelve patients had died, including 2 from cardiotoxicity attributable to ibrutinib. Four additional deaths were from infections, 1 death was from sarcoma, and 1 patient died from acute myeloid leukemia.¹⁹

Does Fixed-Duration Therapy Bring Savings?

Shifting from continuous to fixed-duration treatment in CLL offers trade-offs, say authors of an abstract that demonstrated long-term savings from the latter approach. Led by Farrukh Awan, MD, hematologist/oncologist at UT Southwestern Medical Center in Dallas, Texas, and supported by AstraZeneca, the authors state that useof targeted BTK inhibitors to progression can offer oral dosing with minimum monitoring; a fixed-duration combination of BTK and BCL2 inhibitors, by contrast, requires “intensive” early monitoring but offers patients “the possibility of treatment-free intervals possibly lasting multiple years.”²⁰ The authors say research shows patients prefer these periods without therapy, assuming the regimens work equally well. They developed a budget impact model for a US payer for the use of AV over the years 2025 through 2029, based on data from the AMPLIFY trial.⁸ The model included standard of care for first-line CLL, including single-agent BTK inhibitors used in a treat-to-progression approach (ibrutinib, acalabrutinib, zanubrutinib), as well as AO, VO, and chemoimmunotherapy regimens. The analysis evaluated the introduction of AV at both the individual patient level and at the health plan level. Comparisons included the following:

• 100% use of AV vs 100% use of treat-to-progression BTK inhibitor for an individual patient, and
• changes in CLL cost for a health plan across all indicated treatments, assuming a gradual uptake of AV over time.²⁰

The model estimated the annual number of patients in the plan with previously untreated CLL eligible to start treatment, based on US epidemiological data. Clinical inputs included treatment duration, AE rates, and dosing and treatment schedules, based on clinical trials. Cost of care inputs included drug acquisition and administration costs, monitoring of tumor lysis syndrome, and AE management, based on 2025 US dollars.

For an individual patient with CLL, a shift to AV from a BTK inhibitor would save $618,849 per patient over 5 years; the first-year increase of $160,757 would be offset by $184,254 in savings in year 2, as the patient completes the 12.9-month fixed-duration regimen. Cost savings in years 3 to 5 were $198,451 annually. In a typical US health plan with 1 million members, 37 patients would be expected to have CLL and require treatment in 2025; with gradual AV uptake, there would be a cumulative cost reduction of $19,539 per incident diagnosed patient in the health plan across the 5 years, corresponding to a decrease in monthly cost to the health plan of $0.06 per health plan member per month and $722,943 lower total cumulative cost for plan, the authors found.²⁰

“This evidence on the economic impact of AV—alongside its clinical profile—can inform clinical decision-making and help payers and providers optimize treatment strategies for CLL,” the authors wrote. ²⁰

Pearl Steinzor contributed to this report.

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. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Paper 1.
2. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med. Published online December 6, 2025. doi:10.1056/NEJMoa2515458
3. Zackon I. Real-world treatment patterns, factors associated with discontinuation and toxicity across covalent BTK inhibitors in first-line treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Paper 2111.
4. Munir T, Cairns DA, Bloor A, et al; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337. doi:10.1056/NEJMoa2310063
5. Munir T, Girvan S, Cairns D, et al. Ibrutinib plus venetoclax with MRD-guided duration of treatment is superior to both continuous ibrutinib monotherapy and FCR for previously untreated CLL: report of the phase 3 UK FLAIR Study. Presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S155.
6. Dalal S, Shingles J, Girvan S, et al. MRD-guided ibrutinib plus venetoclax improves outcomes in CLL patients with TP53, ATM, or NOTCH1 aberrations compared to ibrutinib and FCR: results from the phase III NCRI FLAIR trial. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 679.
7. Derman BA. Can I stop my treatment, doctor? is MRD-guided therapy ready for prime time? Hematology Am Soc Hematol Educ Program. 2025;2025(1):645-651. doi:10.1182/hematology.2025000761
8. Brown JR, Seymour JF, Jurczak W; AMPLIFY Investigators. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804
9. Ghia P, Eichhorst B, Wrobel T, et al. Impact of prognostic mutations on outcomes with fixed-duration acalabrutinib-venetoclax combinations versus chemoimmunotherapy: an exploratory analysis from AMPLIFY. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 3898.
10. Ryan CE, Davids MS, Hermann R, et al. MAJIC: a phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Future Oncol. 2022;18(33):3689-3699. doi:10.2217/fon-2022-0456
11. Burke JM, Sharman J, Anz B, et al. Fixed-duration subcutaneous (SC) mosunetuzumab, with maintenance therapy, in patients (pts) with previously untreated high-tumor burden follicular lymphoma (HTB FL): Longer follow-up and exploratory circulating tumor (ct)DNA analysis of the phase II MorningSun study. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 228.
12. FDA approves Roche’s Lunsumio VELO for subcutaneous use in relapsed or refractory follicular lymphoma. News release. Roche. December 21, 2025. Accessed December 22, 2025. https://www.roche.com/media/releases/med-cor-2025-12-22
13. Falci L, Nijland M, Huang H, et al; EPCORE FL-1 Investigators. Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial. Lancet. Published online December 7, 2025. doi:10.1016/S0140-6736(25)02360-8
14. Caffrey M. Epcoritamab with rituximab plus lenalidomide approved for R/R follicular lymphoma in second line. AJMC. November 18, 2025. Accessed December 7, 2025. https://www.ajmc.com/view/epcoritamab-with-rituximab-plus-lenalidomide-approved-for-r-r-follicular-lymphoma-in-second-line
15. Patah P, Altintas I, Marek J, et al. Fixed-duration epcoritamab in combination with bendamustine + rituximab (BR) for first-line (1L) treatment of follicular lymphoma (FL): 3-year results from EPCORE NHL-2 arm 3 demonstrate deep and durable responses with manageable safety. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 5357.
16. Zweegman S, Schjesvold F, Larocca A, et al. Fixed-duration teclistamab and talquetamab for frail patients with newly diagnosed multiple myeloma: the EMN37 FITFIX study. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 4064.
17. Costa LJ, Bahlis NJ, Perrott A, et al; MajesTEC-3 Trial Investigators. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. Published online December 9, 2025. doi:10.1056/NEJMoa2514663
18. Michallet AS, Dilhuydy MS, Subtil F, et al. Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease-driven strategy in patients with chronic lymphocytic leukaemia (ICLL07 FILO): a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2019;6(9):e470-e479. doi:10.1016/S2352-3026(19)30113-9
19. Michallet AS, Letestu R, Garff-Tavernier M, et al. A fixed-duration, chemo-sparing approach in CLL: 8-year results of the phase 2 ICLL-07 FILO trial. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 3833.
20. Awan F, Zawadzki N, Teschemaker A, et al. Budget impact of fixed duration acalabrutinib in combination with venetoclax in previously untreated chronic lymphocytic leukemia patients in the United States. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 2627.