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IACH NEWS OF THE WEEK

November 2, 2025
Prepared by Dr Edwin Uriel Suárez 

Measurable residual disease-guided interventions in patients with acute myeloid leukaemia undergoing allogeneic haematopoietic cell transplantation: best practice recommendations from the European Society for Blood and Marrow Transplantation Practice Harmonisation and Guidelines Committee

Key points: 

See Panel 1 in paper for recommendations for measurable residual disease (MRD) evaluation techniques.


●      Molecular markers:

○      Molecular MRD assessment by reverse transcription quantitative PCR (RT-qPCR) is recommended for patients with NPM1 mutations or RUNX1::RUNX1T1, CBFB::MYH11, or PML::RARA rearrangements.

○      For patients with mutated FLT3-ITD and the absence of the molecular markers, ultrahigh-sensitivity next-generation sequencing should be used as an alternative to multiparameter flow cytometry (MFC), when available. Current data indicate that this technique provides powerful prognostic information immediately before or after transplantation, and can guide maintenance therapy. Data on the utility of this technique for sequential monitoring are still being collected.

○      Additional techniques such as digital droplet PCR reaction and RT-qPCR for other fusion genes have been technically validated but need further prospective clinical evaluation in terms of thresholds and informative timepoints. However, these techniques are for stable disease-specific markers and are suitable for sequential post-hematopoietic cell transplant (HCT) monitoring for the early detection of relapse.

●      Flow cytometry: 

○      Recommended for patients with acute myeloid leukaemia (AML) outside the aforementioned molecularly defined subgroups.

○      For clinical decision making, MRD assessment should be performed with a qualified assay according to the guidelines for rare events in MFC:

■       Minimum eight colour panel.

■      Acquisition of at least 500 000–1 000 000 CD45- expressing relevant events. 

■       Adequate limit of detection or limit of quantification of the assay.

●      Chimerism: 

○      Chimerism analysis is not recommended as a reliable tool for MRD monitoring in patients with AML.

○      In the absence of available flow or molecular MRD techniques, chimerism analysis can provide prognostic information for predicting individual relapse risk.

 

See Panel 2 in paper for summary of MRD-guided modification of transplant procedure and post-transplantation therapy.

●      HCT procedure:

○      A myeloablative conditioning regimen can overcome some of the poor prognostic implications of pre-HCT MRD.

○      Insufficient data exist to guide graft-versus-host disease (GVHD) prophylaxis or donor selection according to MRD.

●      Immunotherapy:

○      Antileukaemic efficacy can be modulated with immunological interventions, by reducing exposure to immunosuppressants and by use of donor lymphocyte infusion, to enhance the graft-versus-leukemia (GVL) effect.

○      These interventions are commonly used in clinical practice as prophylactic or pre-emptive strategies in patients who have MRD positivity, especially in the absence of other alternatives, but evidence of efficacy is weak. 

○      The risk of side-effects, especially GVHD, needs to be carefully considered.

●      Post-transplantation pharmacological interventions.

○      With the growing availability of new, targeted pharmacological agents, pharmacological intervention after allogeneic HCT is an increasingly appealing option.

○      In addition to administration as maintenance to all patients, pharmacological intervention can be guided by MRD to both restrict prophylaxis in a selected higher-risk population who have MRD positivity pre-HCT and to guide pre-emptive therapy for those with MRD persistence or relapse. 

○      Post-HCT FLT3 inhibitors are safe and effective in patients with FLT3-mutated AML. Sorafenib has been shown to reduce relapse independently from MRD, and gilteritinib has been shown to decrease relapse in patients with detectable MRD before or after-HCT.

○      At present, insufficient data exist on the safety and efficacy of other post-transplant therapies, such as IDH (isocitrate dehydrogenase) inhibitors, menin inhibitors, or non-directed regimens including both venetoclax and azacitidine, to support their routine use since they remain under investigation in clinical trials. Their use might be considered in some patients who have MRD-positivity post-HCT and are showing signs of impending relapse, particularly when no alternative therapeutic options are available. 
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35 years of academic trials focusing on high-dose therapy and autologous stem cell transplantation: the Intergroupe Francophone du Myélome (IFM) experience [Review]

Key points:

●      In the late 1980s, oral melphalan plus prednisone (MP) was the standard of care (SoC) for patients with multiple myeloma (MM), and the addition of anthracyclines and/or vincristine to MP did not significantly increase efficacy.

●      In 1984, the concept of high-dose melphalan (HDM) was introduced by McElwain and Powles, first in the relapse setting, but subsequently as frontline therapy. The severe myelosuppression with HDM alone was counterbalanced by concurrent use of stem cell support, which was evaluated in different Phase 2 trials in Europe and the United States (US).

●      At the time of initiation of the IFM90 trial, the median overall survival (OS) with conventional chemotherapy (CC) was 3 years, and there was a true skepticism regarding the superiority of autologous stem cell transplant (ASCT) regarding OS.

●      The IFM90 study was the first to show the superiority of ASCT compared to CC in terms of response rate, event-free survival, and OS. These results were confirmed seven years later by the British Medical Research Council. Consequently, ASCT became the SoC for frontline therapy,  at least in younger patients (≤65 years) with normal renal function, and remains in 2025 the SoC recommended by international guidelines.

●      Lenalidomide maintenance until progression is also recommended per international guidelines.

●      Daratumumab was approved in 2015 for advanced MM patients. This allowed its development at earlier lines of therapy, especially in the frontline setting, in combination with SoC regimens.

●      Following CASSIOPEIA, induction therapy with a quadruplet regimen became SoC in 2020, an approach further supported by findings from the GRIFFIN, PERSEUS, and GMMG-HD7 trials.

●      The prognostic value of measurable residual disease negativity in predicting favorable progression-free survival was confirmed, not only before maintenance but also after induction and prior to ASCT (MIDAS study).  Nevertheless, it is currently impossible to drive definite conclusions on the need to keep ASCT as a SoC or not, due not only to the lack of long-term results, but also to the impossibility of having isatuximab, carfilzomib, lenalidomide, and

dexamethasone (Isa-KRD) as the induction regimen in the real-life setting.

●      The Intergroupe Francophone du Myélome has developed in the last 35 years in newly diagnosed MM patients eligible for ASCT, 13 academic clinical trials (See Table 1 in original paper) to establish new SoCs over time.

●      With these therapeutic advances, the OS for patients with MM has increased from 5 years in the 1990s, to over 15 years at present.  
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Remission of TP53-Mutant AML After Transplantation With Trem-Cel, a CRISPR/Cas9 Gene-Edited Allograft Lacking CD33, Followed by a Donor-Derived Anti-CD33 Chimeric Antigen Receptor T (VCAR33) [Case report]

Highlights:

●      Relapse is the leading cause of death for patients receiving allogeneic HCT (alloHCT) for acute myeloid leukemia (AML). Biallelic TP53-mutated AML with complex cytogenetics is associated with particularly dismal survival. Maintenance therapy post-HCT to decrease relapse risk is a desirable, but an unproven strategy often limited by hematotoxicities.

●      CD33, widely expressed on AML cells, has been challenging as a target because of its expression on normal myeloid cells.  Use of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, has been limited by on-target, off-tumor toxicity resulting in severe cytopenias.

●      Tremtelectogene empogeditemcel (trem-cel) is a hematopoietic stem and progenitor cell product manufactured from purified CD34+ cells of human leukocyte antigen–matched donors that have been CRISPR/Cas9 gene-edited to delete CD33.

●      CD33neg hematopoiesis enables exclusive targeting of residual CD33+ AML by CD33-targeted therapies post-HCT.

 

The authors report a 65-year-old male patient with biallelic TP53-mutant AML who was transplanted with trem-cel and experienced CD33+ AML relapse 2 months post-HCT. The patient subsequently received VCAR33, an allogeneic CD33-directed chimeric antigen receptor-T cell product manufactured from the original stem cell donor’s lymphocytes. Treatment with VCAR33 led to sustained complete remission with return of CD33neg hematopoiesis. 
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Thirty Years of Hydroxyurea for Sickle Cell Anemia — Scientific Progress, Global Health Gaps [Perspective]

Key takeaways:

●      Anecdotal accounts of patients treated with hydroxyurea in whom decreased hemolysis and fewer pain crises were associated with increased F cells, began to appear in the 1980s.

●      Hydroxyurea, which impairs DNA synthesis by inhibiting deoxyribo-nucleotide reductase, has a chemical structure closely related to that of both urea and cyanate, a breakdown product of urea.

●      In 1995, the New England Journal of Medicine published results from the Multicenter Study of Hydroxyurea (MSH) in sickle cell anemia (SCA), a double-blind, randomized, placebo-controlled trial supported by the National Institutes of Health and other funders.          

●      The trial, which involved 299 patients with SCA at 21 clinics in North America, represented a key advance: it was the first to provide evidence that hydroxyurea is a disease-modifying drug, revealing that it reduces rates of vasoocclusive crises. Hydroxyurea was approved for SCA by the Food and Drug Administration in 1998 as the first drug authorized for patients with the disease. Additional follow-up research involving patients in the MSH trial found that, after 9 years, hydroxyurea was associated with reduced mortality.

●      SCA is a global challenge.

●      Whereas the MSH trial was conducted in North America — and many other hydroxyurea trials have been conducted in the United States, Brazil, and Europe — most patients with SCA live in sub-Saharan Africa or parts of India.

●      In sub-Saharan Africa, it’s estimated that only 1 to 13% of people with SCA receive hydroxyurea regularly. The price of 1 g of hydroxyurea (the average daily dose for an adult) is less than $1 in most countries, but many people can’t afford the lifelong treatment required; correcting this inequity should be a global health priority.

●      Although cures are better than noncurative treatments, a safe and effective noncurative treatment is far preferable to allowing patients to suffer without any treatment beyond supportive care.
Click for the full article

Monitoring ctDNA in aggressive B-cell lymphoma: a prospective correlative study of ctDNA kinetics and PET-CT metrics [Prospective, single-center study]

Highlights:

●      Positron emission tomography–computed tomography (PET-CT) is recommended for response evaluation in aggressive large B-cell lymphoma (LBCL) but cannot detect minimal residual disease (MRD). Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for real-time disease monitoring.

●      ctDNA levels correlated with PET-CT-based total metabolic tumor volume (TMTV) and may enable earlier relapse detection than imaging alone.

●      This study demonstrates ctDNA-based MRD monitoring in LBCL using a fixed targeted assay with an analytical sensitivity of at least 10 −3.

 

This study evaluated longitudinal ctDNA monitoring as an MRD marker in LBCL.  In this single-center study, 14 newly diagnosed patients with LBCL receiving first-line immunochemotherapy underwent frequent longitudinal blood sampling. A 53-gene targeted sequencing panel quantified ctDNA and evaluated its kinetics, correlating it with clinical parameters and PET-CT, including TMTV calculated using artificial intelligence (AI)–based analysis via RECOMIA (AI-calculated TMTV was not compared to manual segmentation in this study). Baseline ctDNA was detected in 11 of 14 patients (79%) with a median variant allele frequency of 6.88% (IQR, 1.19%-10.20%). ctDNA levels correlated significantly with TMTV (P<0.0001) and lactate dehydrogenase. ctDNA kinetics, including after 1 treatment cycle, mirrored PET-CT metabolic changes and identified relapsing or refractory patients. Limitations were the small patient cohort which limited the ability to perform meaningful survival analyses and detect significant associations. The proportion of patients without detectable ctDNA (~20%) may also pose a limitation. 
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