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Meet the Expert: Prof. Alessandro Isidori

         

Meet the Expert

Prof. Alessandro Isidori (San Salvatore Hospital, Italy)

 

 

 

Prof. Isidori on comprehensive management of FLT3-ITD–positive AML

“Many more patients can now achieve MRD negativity and live longer. Acute myeloid leukaemia (AML) with a FLT3 internal tandem duplication (FLT3-ITD) mutation is generally associated with a poor prognosis. Comprehensive management can significantly prolong overall survival (OS). Prof. Alessandro Isidori (San Salvatore Hospital, Italy) explains the rationale and implementation of this treatment approach, including the use of a FLT3 inhibitor from induction through maintenance, in combination with chemotherapy, potentially followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), and guided by minimal residual disease (MRD) monitoring.

Advances in AML treatment enable more tailored therapeutic approaches [1–3]. Approximately one-third of newly diagnosed patients carry a FLT3 mutation. The 2 main types are FLT3-ITD and FLT3 tyrosine kinase domain (FLT3-TKD) mutations, with FLT3-ITD accounting for about 80% of all FLT3 mutations [4]. These mutations are associated with an increased risk of relapse and reduced OS [2]. For treatment-eligible patients with newly diagnosed FLT3-ITD–positive AML, quizartinib is currently the only approved FLT3 inhibitor that can be used across induction through maintenance therapy. As Prof. Isidori notes, it offers “a full package strategy applied from the very start through to maintenance and potentially cure.”

Key prognostic factors

Patients with FLT3-positive AML face a high risk of relapse, according to Prof. Isidori [5]. Prognostic factors include FLT3 mutation type (ITD vs TKD), ITD insertion site, allelic burden, and co-mutation(s) like DNMT3A and NPM1, which are commonly co-mutated with FLT3. Prof. Isidori explains: “Patients with an NPM1 mutation generally have a more favourable prognosis and do not necessarily need an allo-HSCT. In contrast, patients without NPM1 mutations, especially those with additional adverse mutations such as DNMT3A, tend to have worse outcomes and higher relapse risk.”

However, MRD status is considered the most important prognosis determinant, Prof. Isidori adds, particularly before and after allo-HSCT [5]. “We now have highly sensitive methods to monitor MRD. Before transplant, MRD assessment can help select eligible patients for allo-HSCT; after transplant, continued MRD monitoring is also recommended [5]. MRD negativity is consistently associated with improved outcomes, whereas MRD positivity indicates a higher likelihood of relapse. Importantly, MRD status is dynamic and can change during treatment, making continuous monitoring essential. Achieving deep MRD negativity—at very low detection thresholds—may be associated with long-term remission or even cure.”

These findings are supported by further analyses of the QuANTUM-First trial, showing that quizartinib induces deeper remissions and increases MRD negativity rates compared with placebo [7].

Treatment from induction to maintenance

Possible treatments for FLT3-ITD–positive AML include intensive induction chemotherapy combined with a FLT3 inhibitor (e.g. midostaurin or quizartinib), followed by consolidation and maintenance therapy, with or without preceding allo-HSCT [5].

Quizartinib is the first FLT3 inhibitor to demonstrate an improvement in OS compared with chemotherapy in patients with relapsed or refractory AML with FLT3-ITD mutations. It can be administered during induction, consolidation, and as maintenance therapy. Prof. Isidori notes: “No specific drug was approved as maintenance therapy after allo-HSCT before quizartinib. Our FLT3-positive patients, therefore, experienced high rates of relapse. That has changed after the QuANTUM-First study of quizartinib.”

In the phase 3 QuANTUM-First trial (NCT02668653), quizartinib, in combination with chemotherapy, followed by continuation therapy, significantly improved OS compared with placebo in patients with newly diagnosed FLT3-ITD–positive AML. Median OS was 31.9 months with quizartinib versus 15.1 months with placebo (HR 0.78, 95% CI 0.62–0.98, P=0.032) [7]. Toxicity was manageable. “The bottom line is that a higher proportion of patients achieved MRD negativity with quizartinib and could undergo allo-HSCT,” Prof. Isidori states [7]. “If, for whatever reason, a transplant is not an option, you can still administer maintenance therapy and achieve complete remission.”

Allo-HSCT and maintenance therapy

Eligibility for allo-HSCT remains a subject of debate, according to Prof. Isidori. “Patients must, of course, be fit enough. Beyond that, the decision to perform allo-HSCT should mainly be based on MRD status and NPM1 co-mutation. About 70% of patients carry an NPM1 co-mutation and should be considered for allo-HSCT, as it remains the only curative. For the remaining 30% of patients who are NPM1-negative, current guidelines do not recommend allo-HSCT if the patient is MRD negative after induction and consolidation, but instead advise continued MRD monitoring.” He adds: “In my opinion, NPM1-negative patients should also be considered for allo-HSCT.”

Prof. Isidori thinks there is no discussion about the importance of maintenance therapy for MRD-positive patients, before or after transplant. “It may reduce relapse risk and contribute to the graft-versus-leukaemia effect.” This is less clear in MRD-negative patients, he says. “I would suggest giving them maintenance therapy too, especially if they are not NPM1 positive. In the QuANTUM-First trial, the number of patients on maintenance therapy was not high enough to demonstrate a statistically significant effect, but there was a numerical superiority” [6].

In MRD-positive patients following transplant, maintenance therapy should be initiated early. “Preferably between 30 and 60 days post-transplant. If you postpone maintenance in MRD-negative patients, and they become MRD positive after, for example, 6 months, you cannot start maintenance, which is a shame. You must then give another tyrosine kinase inhibitor instead,” Prof. Isidori cautions.

The optimal duration of maintenance therapy also remains a matter of debate. “In the  QuANTUM-First trial, the duration was 3 years. This is what the label says and what we try with quizartinib. After a transplant, this is not always easy for the patient. I think 1 year is definitely too short, but depending on the MRD status, 2 years may suffice for some patients.”

“Driving a Ferrari”

Prof. Isidori is enthusiastic about quizartinib as an option for FLT3-ITD–positive AML patients, but it should be used with caution. “Like driving a Ferrari, you do not master it right away. Clinicians must consider important factors like mutation status, patient selection, available dosages, transplant-related risks, MRD monitoring, and concomitant use of a strong CYP3A inducer increasing exposure of quizartinib.” He concludes: “The full package strategy that we can apply with quizartinib is a big opportunity for our patients with FLT3-ITD–positive AML. It opens up a path to longer survival and even a cure for more patients than ever before.”

Quizartinib is indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation chemotherapy, followed by quizartinib single-agent maintenance therapy for adult patients with newly diagnosed FLT3-ITD-positive AML [8].

References

1 Daver, N, et al. Blood Cancer J. 2020;10:107.

2 Kennedy VE, et al. Front. Oncol. 2020;10:612880.

3 Bhansali RS et al. J Hematol Oncol. 2023;16(1):29.

4 Patel PJ, et al. N Engl J Med. 2012;366(12):1079–1089.

5 Döhner H, et al. Blood. 2022;140(12):1345–1377.

7 Levis MJ, et al. Blood Adv. 2026;10(3):917–928.

6 Erba HP, et al. Lancet. 2023;401(10388):1571–1583.

8 Vanflyta (quizartinib) EMA product information (SmPC), current EMA version.

 

Copyrights Medicom Education B.V. 2026

Written by Dr Michiel Tent

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IL15-activated CIK cells post-HCT show broad efficacy

Donor-derived allogeneic interleukin-15–activated cytokine-induced killer (IL15-CIK) cell therapy was feasible, safe, and effective in high-risk patients with a broad spectrum of haematological malignancies. IL15-CIK demonstrated durable relapse-preventive activity following allogeneic haematopoietic stem cell transplantation (HCT).

“There is an urgent need for novel treatments, especially in the paediatric setting, for acute leukaemia relapsing within 6 months after allogeneic HCT,” said Dr Eva Rettinger (University Cancer Center Frankfurt, Germany). She presented the first in-human, disease burden–guided study (EudraCT 2013-005446-11) evaluating donor-derived IL15–activated CIK cells, which combine T-cell and natural killer cell properties. This prospective, multicentre phase 1/2 trial included 56 adult and paediatric patients with haematological malignancies who required urgent intervention due to imminent relapse following human leukocyte antigen (HLA)-matched or HLA-mismatched transplantation (n=28 each).

IL15-CIK was administered as monotherapy, without lymphodepletion or graft-versus-host disease (GvHD) prophylaxis. Most patients had either B-cell acute lymphoblastic leukaemia (B-ALL; 34%) or acute myeloid leukaemia (AML; 42%). At the time of the first infusion, disease status was complete molecular remission (n=7), complete remission with impending relapse (n=34), or overt relapse (n=15). Patients at continued risk of relapse were eligible to receive additional IL15-CIK infusions, with a total of 169 infusions administered.

Centralised, on-demand manufacturing of IL15-CIK and their shipment to the 5 participating centres in Germany was feasible. Therapy-related adverse events were infrequent and predominantly mild. Acute GvHD of grades 1–2 and grade 3 occurred in 27% and 4% of patients, respectively.

“After a median follow-up of 7.3 years, response rates were excellent,” Dr Rettinger reported. Five-year overall survival was 71% (95% CI 26–92) in the consolidation cohort, 61% (95% CI 41–75) in the pre-emptive cohort, and 20% (95% CI 5–42) in the salvage cohort. At 700 days, the cumulative incidence of complete molecular remission was 74% in the pre-emptive cohort and 13% in the salvage cohort.

Dr Rettinger concluded that the efficacy of IL15-CIK was primarily determined by disease burden at the time of intervention, while prior serotherapy appeared to modulate the risk of post-HCT relapse.

  1. Rettinger E, et al. First-in-human trial of IL15-activated CIK cell therapy post-HCT: durable remission and serotherapy-associated immune reconstitution in high-risk hematologic malignancies. OS08-08, EBMT congress 2026, 22–25 March, Madrid, Spain.

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High 3-year efficacy and favourable safety of liso-cel in 3L+ FL

After 3 years of follow-up, results from the TRANSCEND FL study confirm the high efficacy and sustained favourable safety profile of lisocabtagene maraleucel (liso-cel) in patients with third-line or later relapsed/refractory follicular lymphoma (3L+ R/R FL). A single infusion resulted in high rates of deep and durable responses, as well as favourable survival outcomes, regardless of early progression after first-line chemoimmunotherapy (POD24) or prior exposure to bendamustine [1].

Liso-cel is a CD19-directed CAR T-cell therapy that has demonstrated favourable efficacy with a manageable safety profile across B-cell malignancies. In the primary analysis of the open-label phase 2 TRANSCEND FL study (NCT04245839), liso-cel achieved an overall response rate (ORR) of 97% with a favourable safety profile in patients with R/R FL [2]. Prof. Alejandro Martín García-Sancho (University of Salamanca, Spain) presented 3-year follow-up results for patients with 3L+ FL from the TRANSCEND FL trial [1].

In total, 107 patients were evaluable for safety and 103 for efficacy. The median age was 62 years (range 23–80); 95 patients (89%) had Ann Arbor stage III/IV disease, and 61 (57%) had high-risk disease per FL International Prognostic Index.

Three-year response rates were consistent with the primary analysis, as noted by Prof. García-Sancho. The ORR was 97% (95% CI 92–99%); the complete response rate (CRR) was 94% (95% CI 88–98%). The median duration of response was not reached; 70% of patients (95% CI, 60–78%) remained in response at 3 years.

Subgroup analyses demonstrated an ORR exceeding 95% in patients with high-risk features, including POD24, bulky disease, and double-refractory disease. Patients who received bendamustine ≥12 months prior to leukapheresis showed durable responses and high 3-year progression-free survival rates, comparable to the overall population.

Long-term safety analyses confirmed a favourable long-term safety profile for liso-cel, with no new signals identified. Grade ≥3 neutropenia and hypogammaglobulinaemia decreased over time, and the rate of severe infection remained low. These findings support the feasibility of outpatient management and suggest a potential for reduced healthcare resource utilisation with liso-cel in clinical practice.

  1. Dreyling M, et al. Three-year efficacy and longitudinal safety of lisocabtagene maraleucel (liso-cel) in patients with third-line or later (3l+) follicular lymphoma (fl) from TRANSCEND FL. OS02-02, EBMT congress 2026, 22–25 March, Madrid, Spain.
  2. Morschhauser F, et al. Nat Med. 2024;30(8):2199-2207.

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Risks and causes of non-relapse mortality after CAR T-cell therapy

A retrospective registry study by the European Society for Blood and Marrow Transplant (EBMT) evaluated the risk and causes of non-relapse mortality (NRM) associated with CAR T-cell therapy, as well as differences by disease indication and therapeutic product [1]. NRM remains a clinically relevant concern, with infectious complications representing a leading cause. Other causes of NRM included CAR T-cell therapy-related toxicities (32.8%) and secondary malignancies (9.5%).

“Approval studies of CAR T-cell products demonstrated low mortality due to small patient numbers and relatively short follow-up. Early real-world data showed higher NRM, which may reflect treatment of more advanced patients later in the disease course,” noted Dr Charlotte Graham (King’s College London, UK). A recent meta-analysis reported an NRM of 5–10% following CAR T-cell therapy for haematological malignancies [2]. The study presented by Dr Graham was conducted by the EBMT Transplant Complications Working Party, using real-world registry data to assess NRM risk across disease types and CAR T-cell products.

A total of 6,928 adult patients who received a licensed CAR T-cell therapy between 2019 and 2023 for a haematological malignancy were included. Of these, 5,573 patients were treated for B-cell lymphoma (BCL), 583 for multiple myeloma (MM), 514 for mantle cell lymphoma (MCL), and 258 for B-cell acute lymphoblastic leukaemia (B-ALL). There were 2,887 deaths overall; 2,214 (76.7%) were attributed to disease progression or relapse. NRM accounted for 673 deaths (23.3%).

The 1-year post-infusion incidence of NRM by disease indication was:

  • MCL: 13.3% (95% CI 10.5–16.5);
  • B-ALL: 9.8% (95% CI 6.5–14.0);
  • BCL: 6.9% (95% CI 6.2–7.6);
  • MM: 5.3% (95% CI 3.6–7.5).

The highest 1-year NRM was observed in patients with MCL treated with brexucabtagene-autoleucel (brexu-cel) (13.3%), followed by patients with B-ALL treated with brexu-cel (11.4%). The lowest 1-year NRM was seen in patients with BCL treated with lisocabtagene maraleucel (liso-cel) (4.0%).

The leading causes of NRM were infection (n=191, 35.4%), CAR T-cell therapy-related toxicities (n=177, 32.8%), and secondary malignancies (n=51, 9.5%). “Our results allow us to create strategies focused on infection prophylaxis, surveillance and management, which could enhance CAR T-cell outcomes,” concluded Dr Graham.

  1. Graham C, et al. Non-relapse mortality following CAR-T cell therapy: a study by the EBMT Transplant Complications Working Party. GS2-6, EBMT congress 2026, 22–25 March, Madrid, Spain.
  2. Cordas Dos Santos DM, et al. Nat Med. 2024;30(9):2667-2678.

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Recent advances in gene therapy for inborn errors of immunity

Prof. Claire Booth (University College London, UK) discussed recent advances in gene therapy for inborn errors of immunity, including regulatory innovation for rare diseases [1]. She noted that this field remains one of the foundational test beds for the broader gene therapy landscape.

Inborn errors of immunity encompass more than 500 rare disorders that affect the development and function of the immune system. Many are treatable with allogeneic haematopoietic stem cell transplantation (HSCT), while some can be amenable to gene therapy, Prof. Booth explained. Some advantages of gene therapy include avoiding graft-versus-host disease, reducing conditioning requirements compared with HSCT, and avoiding long-term immunosuppression. Over the past 5 years, clinical outcomes have improved due to several process innovations, including the use of mobilised peripheral blood stem cells collected by apheresis, lentiviral (LV) transduction enhancers, and cryopreservation.

Prof. Booth presented recent clinical data demonstrating the durable efficacy and safety of LV-based gene therapy. One example is a cross-border trial (NCT03538899), in which low-exposure busulfan conditioning followed by infusion of lentiviral gene-corrected autologous CD34+ cells resulted in the generation of genetically corrected, functional T- and B-cells in infants with newly diagnosed Artemis-deficient severe combined immunodeficiency (ART-SCID) [2].

In certain primary immunodeficiencies, the T-cell compartment is predominantly affected, with clinical manifestations driven by T-cell dysfunction. In these cases, autologous gene-modified T-cell approaches may provide clinical benefit, explained Prof. Booth. Proof of concept has now been demonstrated for T-cell gene therapy in several conditions, such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), CD40 ligand deficiency, Munc13-4 deficiency (familial haemophagocytic lymphohistiocytosis type 3; FHL3), perforin deficiency (FHL2), and X-linked lymphoproliferative disease (XLP). “Advantages of this approach include ease of cell collection, high transduction or editing efficiency, less intensive conditioning, and a potentially lower genotoxic risk compared with stem cell-based approaches,” noted Prof. Booth.

The first trial for IPEX syndrome is underway: a phase 1 study (NCT05241444) evaluating autologous reengineered CD4LVFOXP3 regulatory T-cell (Treg-like) therapy. In patients with XLP-01, autologous T-cell gene therapy has been shown to correct SAP-dependent immune defects [3], including improvements in germinal centre formation, T-cell–dependent antibody responses, T follicular helper (TFH) cell function, in vitro cytotoxicity, and in vivo tumour clearance. These findings have paved the way for the upcoming XLP T01 clinical trial.

Prof. Booth concluded that while the benefit/risk profile is well established, challenges remain in health technology assessments to determine pricing and reimbursement at the country level, as well as in regulation through hospital exemption policies for gene and cell therapies [4]. Regulatory innovation for rare diseases is ongoing. The U.S. Food and Drug Administration (FDA) recently introduced the Rare Disease Evidence Principles (RDEP) to support accelerated evaluation of therapies for rare genetic diseases. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) has committed to major reforms in the regulation of advanced therapies [5], with a new framework for rare disease treatments expected in 2026.

  1. Booth C. Gene therapy for inborn errors of immunity. P02-5, EBMT congress 2026, 22–25 March, Madrid, Spain.
  2. Cowan MJ, et al. N Engl J Med. 2022;387(25):2344-2355.
  3. Panchal N, et al. J Allergy Clin Immunol. 2018;142(1):235–245.E6.
  4. https://op.europa.eu/o/opportal-service/PDF.
  5. www.gov.uk/government/publications/rare-therapies-and-uk-regulatory-considerations/rare-therapies-and-uk-regulatory-considerations. Accessed 21 April 2026

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Gene-edited autologous cell therapy in patients with TDT or SCD

Exagamglogene autotemcel (exa-cel) demonstrated durable clinical benefits with >6 years of follow-up in patients with transfusion-dependent β-thalassemia (TDT) or sickle cell disease (SCD). The safety profile was consistent with myeloablative busulfan conditioning and autologous transplantation, with no malignancies reported [1]. These data suggest that exa-cel has the potential to provide a one-time functional cure for TDT and SCD.

Exa-cel is a one-time, ex vivo CRISPR/Cas9 gene-edited autologous cell therapy approved for patients aged ≥12 years with TDT or SCD who have recurrent vaso-occlusive crises (VOCs). Prof. Franco Locatelli (University of Pavia, Italy) reported long-term efficacy and safety results from 3 phase 3 trials: CLIMB THAL-111 (NCT03655678), CLIMB-121 (NCT03745287), and the extension study CLIMB-131 (NCT04208529). Participants were aged between 12 and 35 years, with a mean age of approximately 21 years.

In CLIMB THAL-111, 56 participants with TDT received exa-cel. TDT was defined as a history of ≥100 mL/kg/year or ≥10 units/year of red blood cell (RBC) transfusions in the previous 2 years. The primary endpoint is transfusion independence (TI12), defined as maintaining a weighted average haemoglobin ≥9 g/dL without RBC transfusion for ≥12 consecutive months. In the combined CLIMB THAL-111 and CLIMB-131 analysis, 55 of 56 patients (98.2%) achieved TI12 after a median follow-up of 49.6 months. Transfusion independence was sustained for a median of 3.9 years. All participants achieved neutrophil and platelet engraftment.

In CLIMB-121, 46 participants with severe SCD and a history of ≥2 severe VOCs per year in the previous 2 years received exa-cel. The primary endpoint was the proportion of participants free of severe VOCs for ≥12 consecutive months (VF12). After a median follow-up of 44.7 months, all 46 evaluable participants achieved VF12 in CLIMB-121 and CLIMB-131 analysis. All participants also achieved neutrophil and platelet engraftment.

The safety of exa-cel was consistent with that expected for myeloablative busulfan conditioning and autologous transplantation in both TDT and SCD. In CLIMB THAL-111, 16 patients (28.6%) experienced adverse events (AEs) related to exa-cel, and 55 (98.2%) experienced AEs related to busulfan. In CLIMB-121, 13 patients (28.3%) and 46 patients (100%) experienced AEs related to exa-cel and busulfan, respectively. No malignancies were reported during follow-up in CLIMB-131.

“Long-term follow-up continues to demonstrate that exa-cel has the potential to provide a one-time, durable treatment benefit for patients with SCD and TDT,” concluded Prof. Locatelli.

  1. Locatelli F, et al. Durable clinical benefits with exagamglogene autotemcel for greater than 6 years of follow-up in transfusion-dependent thalassemia and sickle cell disease with recurrent vaso-occlusive crises. GS2-5, EBMT congress 2026, 22–25 March, Madrid, Spain.

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AI is an important driver of innovation in haematology

Clinical information in haematology, such as real-world data, is often unstructured, noisy, predominantly longitudinal, and multimodal. Prof. Federico Alvarez (Universidad Politécnica de Madrid, Spain) explained that, despite these challenges, artificial intelligence (AI) can generate data of substantial value in haematology, for example, by accelerating clinical research [1].

AI refers to technologies that emulate human or beyond-human intelligence. Machine learning (ML) is a subset of AI that uses data to train models capable of making predictions or generating insights. A particularly transformative branch of ML, often compared in impact to electricity, is generative AI (GenAI). GenAI encompasses deep learning models that can learn from raw data to generate statistically plausible outputs when prompted. At a high level, these models encode a simplified representation of their training data and use this to produce new, similar (but not identical) outputs. In other words, they can autonomously generate content.

Generative models have long been used in statistics to analyse numerical data; however, advances in deep learning now enable the integration of complex data types such as images, speech, and multimodal clinical data, according to Prof. Alvarez. Applications such as AI-assisted radiology reporting and clinical decision support systems exemplify this capability.

GenAI has the potential to accelerate clinical trials across multiple stages, including trial design, data sharing, data augmentation, bias mitigation, model validation, digital twin development, single-arm controlled trial optimisation, health technology assessment, and regulatory processes. Prof. Alvarez highlighted that GenAI can support the setup of clinical trials by leveraging historical data, thereby reducing design time. It can also assist in defining key trial parameters (e.g. dosing, sample size, endpoints), improve patient stratification, predict patient adherence, and streamline the management of a large volume of case reports and regulatory documentation.

Importantly, GenAI may also contribute to faster clinical trial approvals. A recent study reported that the approval times in the UK decreased from an average of 91 days to 41 days following major reforms supported by new digital platforms at the Medicines and Healthcare products Regulatory Agency (MHRA) [2].

Prof. Alvarez is the coordinator of Genomed4All, a European initiative aimed at transforming the management of haematological diseases through AI. The project pools genomic and other omics data within a secure, federated learning infrastructure, he explained. Its goal is to create a large-scale, distributed repository of omics health data across Europe, enabling the integration of currently fragmented or non-standardised datasets.

In recent years, this initiative has enabled the application of AI in several haematological conditions:

  • Myelodysplastic syndromes: identification of at-risk individuals through genomic screening; omics-based personalised classification and prognosis; prediction of treatment response to support clinical decision-making; and identification of candidates for drug repurposing in specific myelodysplastic syndrome subgroups.
  • Multiple myeloma: improved understanding of the disease’s heterogeneity; characterisation of temporal disease evolution; risk stratification; and integration of radiomics and radiogenomics to predict treatment response and progression-free survival.
  • Sickle cell disease: identification of gene mutations associated with inflammatory pathways; AI-driven patient stratification; development of predictive models for clinical outcome; and creation of probability scores based on brain MRI analysis to predict silent cerebral infarctions in paediatric patients.

Prof. Alvarez pointed out that initiatives such as this represent a significant step toward advanced precision medicine.

  1. Alvarez F. AI-driven innovation in hematology – transforming transplantation and cellular therapy. P01-5, EBMT congress 2026, 22–25 March, Madrid, Spain.
  2. Manfrin A, et al. Br J Clin Pharmacol. 2026;92(3):822-829.

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Post-transplant MRD surveillance enables intervention before overt relapse

Standardised surveillance of measurable residual disease (MRD) after allogeneic haematopoietic stem cell transplantation (allo-HCT) may enable timely therapeutic intervention in patients with acute myeloid leukaemia (AML) before overt morphological relapse. This conclusion was drawn from a retrospective review including all adult AML patients who underwent allo-HCT at the Mayo Clinic, MN, USA, between 2018 and 2025.

AML remains associated with high relapse rates despite achievement of initial morphologic remission. MRD has emerged as an established prognostic tool, playing a pivotal role in detecting residual leukaemic cells beyond the limits of conventional morphologic assessment. However, it remains unclear whether relapse detected at the MRD level confers a different prognosis compared with overt morphological relapse.

To address this question, Dr Hassan Alkhateeb (Mayo Clinic, MN, USA) and colleagues evaluated treatment patterns and outcomes associated with morphological versus MRD relapse following allo-HCT [1]. The study cohort comprised 272 consecutive AML patients who underwent allo-HCT. After a median follow-up of 128 days (range 28–741), relapse occurred in 77 patients (28%): 50 patients (65%) experienced morphological relapse, while 27 patients (35%) had MRD relapse.

ELN-adverse risk disease was significantly more common among patients with morphological relapse compared with MRD relapse (77.5% vs 22.4%; P=0.006). Overall survival (OS) following morphological relapse was markedly inferior, likely reflecting a more aggressive disease biology. One- and 2-year OS rates after morphological relapse versus MRD relapse were 21% versus 44.5% and 12.6% versus 30.5%, respectively (P=0.0014). Adverse cytogenetic abnormalities were also more frequently observed in patients with morphological relapse (58% vs 14.8%; P<0.001).

Among the 50 patients with morphological relapse, 18 patients (36%) achieved remission, with a median time to response of 73 days (range 14–296). The median duration of response was 146 days, after which 10 patients (20%) experienced a subsequent relapse.

Of the 27 patients with MRD relapse, 18 patients (67%) progressed to morphological relapse during follow-up, with a median follow-up duration of 447 days. Among the 9 patients who remained free from morphological relapse, 8 achieved MRD negativity, with a median time to MRD clearance of 69.5 days.

MRD relapse detected by digital droplet polymerase chain reaction (MRDM) was associated with a numerically superior 1-year morphological relapse-free survival and OS compared with MRD relapse defined by multiparametric flow cytometry (MRDF) or cytogenetic abnormalities (MRDC).

  1. Alkhateeb HB, et al. Outcomes of morphological versus minimal residual disease (MRD) relapse after allogeneic transplantation (allo-HCT) for acute myeloid leukemia (AML). B300, EBMT congress 2026, 22-25 March, Madrid, Spain.

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The value of repeated molecular testing early after HCT highlighted

Findings from a retrospective, multicentre study underscore the importance of intensified molecular monitoring in patients with acute myeloid leukaemia (AML) early after allogeneic hematopoietic stem cell transplantation (allo-HCT). Early relapse emerged as the strongest predictor of poor prognosis, while increased mutational complexity was associated with a higher risk of early relapse [1].

Relapse following allo-HCT remains a major clinical challenge in AML and is associated with poor outcomes. To better characterise the mutational and clonal dynamics underlying relapse, 57 adult AML patients from 3 centres in Germany, Greece, and Canada who relapsed after allo-HCT were analysed. Study presenter, researcher Dr Kristina Maas-Bauer (University of Freiburg, Germany), explained that the molecular analyses performed may improve the prediction of early relapse (<6 months post-HCT) and help guide therapeutic decision-making.

Dr Maas-Bauer and colleagues performed paired next-generation sequencing (NGS) myeloid panels analyses (38–84 genes) at diagnosis/pre-HCT and again at relapse. The median patient age was 52.5 years (range 18-71). More than half of patients (54%) had adverse-risk AML according to ELN classification, while 25% had refractory disease prior to transplantation.

AML relapse following allo-HCT demonstrated substantial genetic and clonal instability. Overall, 68% of patients showed acquisition or loss of mutations, predominantly involving FLT3-ITD, NRAS, and KRAS, highlighting recurrent activation of proliferative and survival signalling pathways. In contrast, founder mutations in DNMT3A and TP53 were frequently retained. Distinct relapse evolution patterns, including constant, linear, branching, and parallel evolution, were not predictive of relapse risk and did not influence overall survival  (OS) or progression-free survival (PFS).

By contrast, relapse occurring within the first 6 months after allo-HCT was identified as a strong independent predictor of poor OS (P=0.049). Furthermore, increased mutational burden at diagnosis independently predicted early relapse (OR 1.84; 95% CI 1.02–3.33; P=0.04), potentially reflecting rapid expansion of pre-existing dominant clones.

Dr Maas-Bauer noted that the unfavourable baseline characteristics of the study population may also have contributed to the poor survival outcomes, independent of clonal evolution or mutational patterns. Overall, these findings emphasise the importance of repeated molecular profiling, particularly during the first 6 months after transplantation. For measurable residual disease assessment, persistent mutations may represent the preferred molecular targets.

  1. Maas-Bauer C, et al. Mutational landscape changes of AML in patients relapsing after allogeneic hematopoietic cell transplantation. A342, EBMT congress 2026, 22-25 March, Madrid, Spain.

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Dual MRD assessment improves relapse prediction in AML

Combining multiparameter flow cytometry (FACS) and error-corrected next-generation sequencing (NGS) for measurable residual disease (MRD) assessment improved relapse prediction in patients with acute myeloid leukaemia (AML). This dual-assessment strategy may also help identify appropriate candidates for early intervention following allogeneic hematopoietic stem cell transplantation (allo-HCT).

Accurate MRD assessment is critical in AML management to guide treatment decisions before and after allo-HCT. FACS-MRD and NGS-MRD are considered complementary modalities. Study presenter Dr Evgeny Klyuchnikov (University Medical Centre Hamburg-Eppendorf, Germany) and colleagues aimed to find possible advantages of combining them in an observational, single-centre study [1].

The analysis included 107 adult patients with AML undergoing their first allo-HCT. FACS-MRD assessment was performed with a sensitivity of 10-4 to 10-5, and an MRD positivity cut-off of 0.1%. In parallel, error-free NGS-MRD analysis was conducted using the Oncomine Myeloid MRD (RUO) Assay, with a limit of detection of approximately 0.1 % variant allele frequency.

The results demonstrated that the combined FACS and NGS was approximately 10% more accurate at predicting relapse. Before transplant, MRD was detected by FACS in 37% of patients and by NGS in 45%, with moderate-to-substantial concordance between both methods (Cohen’s kappa 0.60). Notably, among patients classified as MRD-negative by FACS, error-corrected NGS identified additional subclonal variants, including FLT3-ITD mutations, in 26% of cases, indicating discordant findings between the 2 methods and suggesting that NGS may detect residual molecular disease missed by FACS alone.

MRD positivity by either FACS-MRD or NGS-MRD was significantly associated with an increased 5-year relapse risk and lower overall survival (OS). Using FACS, the 5-year OS was 39% (95% CI, 25–55%) in MRD-positive patients versus 79% (95% CI, 68–87%) in MRD-negative patients (P<0.001). Using NGS-MRD, the corresponding 5-year OS rates were 49% (95% CI, 39–63%) versus 76% (95% CI, 64–85%; P=0.006). Patients with discordant MRD findings demonstrated an intermediate-risk profile, whereas patients who were MRD-positive by both FACS and NGS had significantly higher relapse risk and lower OS (P<0.001). In multivariate analysis, dual MRD positivity remained the strongest independent predictor of relapse (HR 6.8; 95% CI 3.0–15.0; P<0.001) and inferior OS (HR 3.2; 95% CI 1.6–6.1; P=0.001).

Dr Klyuchnikov concluded that combined MRD assessment using FACS and NGS reduces the frequency of false positives and improves relapse prediction, although it does not significantly improve OS prediction.

  1. Klyuchnikov E, et al. Combined pre-transplant MRD detection by FACS and NGS may enhance relapse prediction in AML patients receiving allo-SCT in complete remission. B293, EBMT congress 2026, 22-25 March, Madrid, Spain.

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