Blinatumomab in MRD-negative B-ALL: E1910

A 45-year-old teacher finishes induction and intensification for Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL). The bone marrow aspirate shows complete remission, and flow cytometry finds no leukemic cells: measurable residual disease (MRD) negative. The family celebrates. At the team meeting, someone asks whether it is still worth adding blinatumomab to consolidation, since the disease no longer appears. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The topic is blinatumomab in consolidation for B-ALL in adults, based on the E1910 trial, which tested the drug precisely in patients with negative MRD. The question Dr. Alexei proposed for the series is this: why does a negative MRD not mean the treatment is over? The text does not replace your country's guideline or your service's protocol. If you play the case of the day on NEXO, you know that a normal test can be the most misleading clue.

Key points

• Many adults with B-ALL relapse even after achieving remission with negative MRD.
• In E1910, adding blinatumomab to consolidation in patients aged 30 to 70 with negative MRD improved overall survival.
• Overall survival at 3 years was 85 in 100 with blinatumomab versus 68 with chemotherapy alone.
• Blinatumomab is given as a continuous infusion for 4 weeks, followed by 2 weeks without treatment.
• Neurological events are the main effect to watch, and severe cytokine release syndrome is rare in consolidation.
• The sensitivity of the MRD test matters: a negative result on flow cytometry may be positive on a more sensitive method.

Why this is a reasoning scenario

Adult ALL is a disease in which remission is achieved in most patients, but cure is not. Juluri and colleagues recall that overall survival at 5 years is over 90 in 100 in children, but stays below 20 in 100 in older adults (Juluri and colleagues, 2022). In the classic comparison between adolescents and young adults treated in the CCG and CALGB groups, complete remission was 90 in 100 in both groups, but event-free survival at 7 years was 63 versus 34 in 100. The gap between remission and cure is made of relapses.

MRD, measured at the end of induction, came to separate those at higher risk of relapse from those at lower risk. The natural reasoning would be: negative MRD, low risk, standard treatment is enough. E1910 challenged that reasoning. The main paper opens with a sentence that sums up the problem: many older adults with B-ALL relapse despite remission with negative MRD after combination chemotherapy (Litzow and colleagues, 2024).

The organization of the team that cares for acute leukemias is the topic of the post on how the leukemia team is organized. Here the focus is the consolidation decision.

The patient in the scene is 45 years old, within the E1910 age range. She also has a whole life ahead of her, a profession and a family that has just heard the word remission. The conversation about 4 more cycles of a new drug, with continuous infusion and risk of neurological effects, must start from the numbers: the survival gain observed in the study was large enough to change regulatory approval, and severe cytokine release syndrome was rare in consolidation. Weighing benefit and risk with these numbers, and not with the feeling that the disease has disappeared, is the heart of the reasoning.

What makes this error easy to make

A negative MRD is a great result, and the temptation is to treat it as a guarantee. But it is only the absence of detectable disease below a threshold. If the test has a sensitivity of 1 cell in 10,000, a patient can have thousands of leukemic cells in the body and still be called negative. The error is confusing not detected with absent.

What MRD measures and what it does not measure

Saygin and colleagues describe MRD as the strongest independent predictor of relapse and survival in adults and children with ALL (Saygin and colleagues, 2022). There are three main ways to measure it:

• multicolor flow cytometry;
• quantitative PCR of fusion transcripts or of immunoglobulin and T-cell receptor rearrangements;
• high-sensitivity high-throughput sequencing (NGS).

The same authors note that the clinical meaning of very low MRD levels, below 1 in 10,000, is still not fully defined. Each method has a different limit of detection, and the report must state which one was used.

When negative is not negative

NGS identifies and tracks the immunoglobulin rearrangement sequences specific to the leukemic clone. Ching and colleagues validated the analytical performance of the clonoSEQ assay with DNA from 66 patients with multiple myeloma, ALL or chronic lymphocytic leukemia and from cell lines, and concluded that it is a very sensitive and accurate method for quantifying MRD in the marrow of patients with ALL (Ching and colleagues, 2020). The calculated limit of quantification reached the order of 1 leukemic cell in about 570,000 cells, with a large amount of DNA in the sample. Therefore, a negative result by flow cytometry does not equal a negative result by NGS.

These data help to understand E1910. Some of the patients called MRD negative by flow cytometry still had disease, invisible to the method, and that is where an effective consolidation therapy can make a difference.

How blinatumomab works

Blinatumomab is a bispecific antibody that binds at the same time to CD3 on T lymphocytes and to CD19 on B cells. Portell and colleagues explain that, by physically bringing T lymphocytes close to malignant B cells, the drug boosts the destruction of these cells by T lymphocytes (Portell and colleagues, 2013). The elimination half-life is short, about 1.25 hours, which explains the need for continuous infusion.

The same authors report that, in a phase 2 study with patients with B-ALL and persistent or relapsed MRD, 80 in 100 achieved complete molecular remission. It was this activity against minimal disease that led to the idea of using blinatumomab earlier, in the first line.

Dose in consolidation

The FDA approval summary describes the recommended dose in consolidation: 28 micrograms per day by continuous intravenous infusion for 4 weeks, followed by 2 weeks without treatment, for patients weighing 45 kg or more; below 45 kg, the dose is 15 micrograms/m² per day (Rabik and colleagues, 2025). Continuous infusion requires a portable pump and central venous access, and many services start the cycle in hospital. Always check the package insert for your country.

What E1910 tested

E1910 was a phase 3 study by the American group ECOG-ACRIN. It included patients aged 30 to 70 years with B-ALL without BCR::ABL1. Those who achieved remission with negative MRD, defined as fewer than 1 leukemic cell in 10,000 in the marrow by flow cytometry, after induction and intensification, were randomized to receive 4 cycles of blinatumomab added to 4 cycles of consolidation chemotherapy, or only the 4 cycles of chemotherapy (Litzow and colleagues, 2024). The primary endpoint was overall survival.

The choice of endpoint matters. Many oncology studies use progression-free survival, which can be improved without patients living longer. E1910 chose the more demanding endpoint.

What E1910 showed

Of the 488 patients included, 395 achieved complete remission, 81 in 100. Of the 224 with negative MRD, 112 went to each group. With a median follow-up of 43 months, 3-year overall survival was 85 in 100 with blinatumomab versus 68 with chemotherapy alone, with a hazard ratio for death of 0.41 (Litzow and colleagues, 2024). Three-year relapse-free survival was 80 versus 64 in 100. Neuropsychiatric events were more frequent in the blinatumomab group.

Based on E1910, the FDA approved blinatumomab in June 2024 for consolidation of CD19-positive B-precursor ALL without the Philadelphia chromosome (Rabik and colleagues, 2025). Jabbour and colleagues note that the chemotherapy regimens used worldwide for Philadelphia-negative ALL are similar, and that adding blinatumomab to them will probably have an effect similar to that seen in E1910 (Jabbour and colleagues, 2024).

Study	Population	Strategy	Main result
E1910	30 to 70 years, MRD negative	Blinatumomab added to consolidation	3-year overall survival of 85 versus 68 per 100
Alliance A041703	60 years or older, no prior treatment	Inotuzumab followed by blinatumomab	1-year event-free survival of 75 per 100
Niyongere series	5 patients over 70 years	Blinatumomab alone in the first line	All in complete remission after cycle 1
Russian pediatric study	177 children	Blinatumomab in place of consolidation blocks	Deep MRD with reduced chemotherapy

Toxicity: what to watch for

The two typical effects of blinatumomab are cytokine release syndrome and neurologic events. Portell and colleagues describe seizures and encephalopathy as reversible toxicities (Portell and colleagues, 2013). In the FDA review of the consolidation studies, grade 3 or higher cytokine release syndrome was low in all studies, from 0 to 4 per 100, and encephalopathy was reported in 0 to 4 per 100; but neurotoxicity of any grade was high, from 37 to 63 per 100 (Rabik and colleagues, 2025).

The FDA review details the differences between the E1910 arms during consolidation. Among the effects that were more frequent with blinatumomab than without it are (Rabik and colleagues, 2025):

• tremor, in 23 versus 3 per 100;
• cytokine release syndrome, in 16 versus 0 per 100;
• aphasia, in 10 versus 0 per 100, with 8 per 100 of grade 3 or higher;
• headache, in 41 versus 30 per 100;
• fever, in 15 versus 5 per 100;
• grade 3 or higher infection, in 31 versus 21 per 100.

Febrile neutropenia was slightly less frequent in the blinatumomab arm, 19 versus 25 per 100. The same review lists among the most common effects in the blinatumomab arm neutropenia, in 81 per 100, thrombocytopenia, in 74, and anemia, in 58, which mainly reflect the chemotherapy that accompanies the antibody.

In older patients, the profile was similar. Jabbour and colleagues report, in a study with blinatumomab and low-intensity chemotherapy, that grade 3 cytokine release syndrome occurred in a single patient, 3 per 100, and resolved within 24 hours, while 47 per 100 had some neurologic event related to blinatumomab (Jabbour and colleagues, 2024). The same authors cite febrile neutropenia in 82 per 100, transaminase elevation in 26 and hyperglycemia in 21, effects that come largely from the associated chemotherapy. These numbers show that the neurologic risk is frequent, but it is usually manageable when the team is prepared to recognize it early.

How the team prepares

Since tremor and aphasia are among the effects that most distinguish blinatumomab, it makes sense for the team and the family to watch the patient's speech and writing during the infusion, and to know that confusion or altered speech calls for immediate contact. In the Alliance A041703 study, patients not in remission were hospitalized for the first 9 days of the course and for at least 2 days at any restart after an interruption of 4 hours or more, while patients in remission could start as inpatients or outpatients (Wieduwilt and colleagues, 2025). In the Niyongere and colleagues series with patients over 70 years, cytokine release syndrome was treated with dexamethasone or tocilizumab, and neurotoxicity with dexamethasone, without interrupting blinatumomab (Niyongere and colleagues, 2020).

Since the infusion pump stays with the patient at home, training to handle alarms and the catheter is part of the care. An interruption of the infusion, even a short one, may require a restart in a monitored setting, according to the service protocol.

The burden of the chemotherapy that remains

Blinatumomab does not replace chemotherapy in E1910; it is added to it. Jabbour and colleagues recall the risks of intensive chemotherapy for ALL: high doses of anthracyclines, cytarabine, mercaptopurine, methotrexate, cyclophosphamide and corticosteroids can cause febrile neutropenia and infection requiring hospitalization and life-threatening risk (Jabbour and colleagues, 2024). Asparaginase can cause liver dysfunction, venous sinus thrombosis, pancreatitis and hypersensitivity reactions, and anthracyclines can cause cardiac damage.

Juluri and colleagues note that asparaginase is a central part of pediatric protocols and that lack of familiarity with managing its specific toxicities can lead to decisions that worsen outcomes in adults (Juluri and colleagues, 2022). In the DFCI 01-175 study, summarized in the review, with adults aged 18 to 50 treated with a pediatric-based protocol, liver toxicity appeared in 53 out of every 100 patients, thrombosis in 17 and pancreatitis in 11. That is why the idea of using immunotherapy to reduce chemotherapy, and not only to add to it, gained strength.

Older adults and regimens with less chemotherapy

Older adults are the group in which ALL kills the most. Pourhassan and colleagues recall that, historically, older adults with Philadelphia-negative ALL treated with chemotherapy had 5-year overall survival of 10 to 20 out of every 100, due to less favorable genetics and poorer tolerance of chemotherapy, and that even dose-reduced regimens have high early mortality (Pourhassan and colleagues, 2023).

The Alliance A041703 study tested in 33 patients aged 60 or older, with no prior treatment, a sequence of up to 2 cycles of inotuzumab ozogamicin followed by 4 or 5 cycles of blinatumomab, with no maintenance chemotherapy (Wieduwilt and colleagues, 2025). The median age was 71 years. Composite complete remission reached 97 out of every 100 at the end of 2 cycles of blinatumomab. With a median follow-up of 30 months, 1-year event-free survival was 75 out of every 100 and overall survival was 85. The authors propose the regimen as a standard option in this population.

Less chemotherapy in children

In children, Mikhailova and colleagues replaced three consolidation blocks with a 4-week course of blinatumomab. All 177 patients completed induction in remission, and MRD by flow cytometry at the end of induction was negative in 82 out of every 100 (Mikhailova and colleagues, 2024). The authors conclude that the replacement led to deep MRD response with reduced chemotherapy, but warn that it is still too early to assess the study's final results.

Canichella and colleagues summarize the trend: in Philadelphia-negative ALL, combining blinatumomab with intensive chemotherapy led to better MRD clearance and better long-term survival (Canichella and colleagues, 2025).

MRD and transplant

MRD also guides the transplant decision. In a large European registry, Pavlů and colleagues analyzed adults with ALL transplanted in first remission: 1,816 without detectable disease and 964 with positive MRD before transplant (Pavlů and colleagues, 2019). Positive MRD was an independent factor for worse overall survival and more relapse. Total body irradiation conditioning was associated with better survival, with no significant interaction with MRD status.

For the patient in the scene, negative MRD reduces the urgency of a transplant in first remission, but it does not reduce the importance of consolidation. On the contrary: E1910 shows that this is precisely where blinatumomab adds survival. The post about genetics and MRD in acute myeloid leukemia discusses the same logic in another leukemia.

Other studies with blinatumomab in the first line

E1910 is not alone. Pourhassan and colleagues describe the Italian GIMEMA LAL2317 study, with 146 patients aged 18 to 65, which intercalated two cycles of blinatumomab in early and late consolidation (Pourhassan and colleagues, 2023). Hematologic remission after induction was 90 in 100. After the first blinatumomab cycle, MRD negativity was reached in 96 in 100, with conversion from positive to negative MRD in 87 in 100. Overall survival at 12 months was 84 in 100.

In Philadelphia chromosome ALL, the logic is different. Canichella and colleagues recall that combinations of tyrosine kinase inhibitors, especially ponatinib, with blinatumomab are questioning the traditional role of allogeneic transplant in this disease (Canichella and colleagues, 2025). That is why the first question in the diagnosis of B-ALL is always the presence or absence of BCR::ABL1.

• B-ALL without Philadelphia and MRD negative: E1910 supports blinatumomab in consolidation.
• B-ALL without Philadelphia and MRD positive: blinatumomab was already approved in this setting, and transplant enters the discussion.
• B-ALL with Philadelphia: tyrosine kinase inhibitor is the backbone, with or without blinatumomab.
• Patient aged 60 or older: consider regimens with less chemotherapy, such as inotuzumab followed by blinatumomab.

Jabbour and colleagues summarize the common goal of first-line regimens: reduce the disease to undetectable levels and maintain durable remission. They recall that intensive regimens inspired by pediatrics are not tolerated by everyone and that high-risk patients still have inferior outcomes, which makes the design of more effective and less toxic strategies central (Jabbour and colleagues, 2024).

The role of new therapies

Saygin and colleagues recall that blinatumomab, inotuzumab ozogamicin and CAR-T cells showed efficacy in clearing MRD in B-ALL (Saygin and colleagues, 2022). In the INO-VATE study, reviewed by Short and colleagues, inotuzumab achieved complete remission, with or without hematologic recovery, in 80.7 versus 29.4 in 100 with salvage chemotherapy, and allowed 41 versus 11 in 100 to reach transplant (Short and colleagues, 2024). The post about relapse, transplant and CAR-T covers cell therapy in another context.

And when ALL has the Philadelphia chromosome?

E1910 left out B-ALL with the Philadelphia chromosome, Ph-positive ALL, which has the BCR::ABL1 transcript. In it, the backbone of treatment is a tyrosine kinase inhibitor from day one, and the question becomes what to combine it with: chemotherapy, blinatumomab or both, and who still needs allogeneic transplant.

The Italian GIMEMA LAL2116 study, called D-ALBA, tested an induction without systemic chemotherapy: dasatinib with corticosteroid, followed by at least 2 cycles of blinatumomab in consolidation, with no upper age limit. There were 63 adults, with a median age of 54. With a median follow-up of 53 months, disease-free survival was 75.8 in 100 and overall survival was 80.7 in 100 (Foà and colleagues, 2024). Twenty-nine patients never received chemotherapy or transplant and continued only with the inhibitor; 27 of them were in molecular response after dasatinib and blinatumomab. Transplant in first remission was done mainly in those who remained MRD positive, with transplant-related mortality of 12.5 in 100. Patients with the IKZF1 plus profile did worse, and four of the 9 relapses had IKZF1 plus and developed the T315I mutation; the authors point to ponatinib as the way to get around this mutation.

The phase 3 PhALLCON study compared ponatinib with imatinib, both combined with reduced-intensity chemotherapy, in 245 adults randomized in a 2 to 1 ratio. The rate of complete remission with MRD negativity at the end of induction was 34.4 in 100 with ponatinib versus 16.7 in 100 with imatinib (Hanley and colleagues, 2025). The ponatinib dose studied was 30 mg once a day, reduced to 15 mg a day when the patient reaches complete remission with MRD negativity at the end of induction; the imatinib dose was 600 mg a day. The same analysis linked higher ponatinib exposures to more hypertension and more ALT increase. Always check the label in your country, because approval for this use does not yet exist everywhere.

In the review by Shanmuganathan and Grigg, MRD is the thread that ties all of this together (Shanmuganathan and Grigg, 2026). The practical points they highlight:

• an inhibitor combined with chemotherapy remains the standard in younger patients, because an inhibitor with a corticosteroid alone rarely gives a durable response;
• ponatinib seems to be the best first-line inhibitor, with dose reduction in those who respond;
• the combination of an inhibitor with blinatumomab may become the standard and may spare intensive chemotherapy and transplant in first remission;
• MRD is measured most practically by RT-qPCR of BCR::ABL1, and NGS may be more sensitive;
• IKZF1 plus, p210 transcript, monosomy 7 and white blood cells above 100 thousand per microliter are factors of worse prognosis;
• intrathecal central nervous system prophylaxis remains indicated whatever the systemic treatment.

The reasoning, therefore, is similar to that of E1910: negative MRD does not end the discussion, but persistent or rising MRD weighs in favor of allogeneic transplant, and testing for ABL1 mutations, such as T315I, guides the switch of inhibitor.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. ALL with negative MRD is a good exercise because a normal result invites you to stop early. The post on diagnostic pause shows how to avoid this early closure, and the post on clinical decision-making helps you understand the limit of each test.

Three exercises with cases

Change the method. Say what changes if the negative MRD on flow cytometry were positive on NGS.

Change the age. Say how you would think if the patient were 74 years old.

Change the toxicity. Say what you would do if, on the third day of infusion, she could not write her own name.

The post on differential diagnosis helps organize the clues, and the post on diagnostic uncertainty helps talk about residual risk. The limits of use of the game are described on the NEXO economy page. If you research teaching of clinical reasoning, the page for researchers explains how to get in touch. Professionals who write or review cases find information in curation and in creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

If MRD is negative, why treat more?

Because many adults relapse even with negative MRD, and in E1910 blinatumomab increased overall survival in this group (Litzow and colleagues, 2024).

What is the dose?

In consolidation, 28 micrograms per day by continuous infusion for 4 weeks, with a 2-week pause; 15 micrograms/m² per day below 45 kg (Rabik and colleagues, 2025).

Why is the infusion continuous?

Because the half-life of the drug is just over 1 hour (Portell and colleagues, 2013).

What is the most common adverse effect?

Neurological events of any grade, which were frequent, although severe ones were rare (Rabik and colleagues, 2025).

Is it suitable for older adults?

E1910 included patients up to 70 years. Above that, regimens with inotuzumab and blinatumomab have promising data (Wieduwilt and colleagues, 2025).

Does E1910 apply to Philadelphia chromosome-positive ALL?

No. E1910 included adults with B-ALL without the Philadelphia chromosome. In Philadelphia-positive disease, the basis of treatment is the tyrosine kinase inhibitor, and combinations with ponatinib and blinatumomab are being studied to reduce dependence on allogeneic transplant.

Final checklist

• I confirmed CD19-positive B-ALL and absence of BCR::ABL1.
• I recorded the method and sensitivity of MRD.
• I considered blinatumomab in consolidation even with negative MRD.
• I planned central venous access and an infusion pump.
• I advised the patient and family about neurological signs.
• I agreed on how to watch speech, writing and tremor during the infusion.
• I discussed the indication for transplant based on risk.
• I scheduled serial MRD during treatment.

Want to practice the reasoning with progressive clues? Play the case of the day.

References

1. Canichella M, De Fazio L, Molica M. Integrating Blinatumomab in the Frontline Treatment in B-Cell Acute Lymphoblastic Leukemia: A New Era in Therapeutic Management. J Clin Med. 2025. PMID 40142863.
2. Ching T, Duncan ME, Newman-Eerkes T, et al. Analytical evaluation of the clonoSEQ Assay for establishing measurable (minimal) residual disease in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. BMC Cancer. 2020. PMID 32605647.
3. Foà R, Bassan R, Elia L, et al. Long-Term Results of the Dasatinib-Blinatumomab Protocol for Adult Philadelphia-Positive ALL. J Clin Oncol. 2024. PMID 38127722.
4. Hanley MJ, Larson TR, Diderichsen PM, et al. Population Pharmacokinetic and Exposure-Response Analyses for Ponatinib in the Phase 3 PhALLCON Study. Clin Transl Sci. 2025. PMID 40025846.
5. Jabbour EJ, Kantarjian HM, Goekbuget N, et al. Frontline Ph-negative B-cell precursor acute lymphoblastic leukemia treatment and the emerging role of blinatumomab. Blood Cancer J. 2024. PMID 39562780.
6. Juluri KR, Siu C, Cassaday RD. Asparaginase in the Treatment of Acute Lymphoblastic Leukemia in Adults: Current Evidence and Place in Therapy. Blood Lymphat Cancer. 2022. PMID 35669980.
7. Litzow MR, Sun Z, Mattison RJ, et al. Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2024. PMID 39047240.
8. Mikhailova E, Popov A, Roumiantseva J, et al. Blinatumomab as postremission therapy replaces consolidation and substantial parts of maintenance chemotherapy and results in stable MRD negativity in children with newly diagnosed B-lineage ALL. J Immunother Cancer. 2024. PMID 38844406.
9. Niyongere S, Sanchez-Petitto G, Masur J, et al. Frontline Blinatumomab in Older Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia. Pharmaceuticals (Basel). 2020. PMID 32560218.
10. Pavlů J, Labopin M, Niittyvuopio R, et al. Measurable residual disease at myeloablative allogeneic transplantation in adults with acute lymphoblastic leukemia: a retrospective registry study on 2780 patients from the acute leukemia working party of the EBMT. J Hematol Oncol. 2019. PMID 31647022.
11. Portell CA, Wenzell CM, Advani AS. Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. Clin Pharmacol. 2013. PMID 23671399.
12. Pourhassan H, Agrawal V, Pullarkat V, et al. Positioning blinatumomab in the frontline of adult B-cell acute lymphoblastic leukemia treatment. Front Oncol. 2023. PMID 37664035.
13. Rabik CA, Wang S, Chadda R, et al. FDA Approval Summary: Blinatumomab for the Treatment of B-Cell Precursor Acute Lymphoblastic Leukemia in the Consolidation Phase of Multiphase Chemotherapy. Clin Cancer Res. 2025. PMID 40828516.
14. Saygin C, Cannova J, Stock W, et al. Measurable residual disease in acute lymphoblastic leukemia: methods and clinical context in adult patients. Haematologica. 2022. PMID 36453516.
15. Shanmuganathan N, Grigg A. A critical review of management of allogeneic transplant-eligible adults with Ph+ acute lymphoblastic leukaemia. Br J Haematol. 2026. PMID 39289867.
16. Short NJ, Jabbour E, Jain N, et al. Inotuzumab ozogamicin for the treatment of adult acute lymphoblastic leukemia: past progress, current research and future directions. J Hematol Oncol. 2024. PMID 38734670.
17. Wieduwilt MJ, Yin J, Kour O, et al. Inotuzumab Ozogamicin Then Blinatumomab for Older Adults With Newly Diagnosed B-Cell ALL: Alliance Study A041703 Cohort 1 Results. J Clin Oncol. 2025. PMID 41026957.