HemaSphere最新文献

I read with interest the recent article from Johnstone et al., which eloquently set out the case for changing the diagnostic approach to chronic lymphocytic leukemia (CLL).¹ The first-hand account from co-author Peter Allen, a person living with CLL, is powerful and resonated strongly with me. Although the article is centered on just one person's story, the literature suggests that Peter's experience is representative.

Medical decision-making can often be distilled to the careful balancing of benefits and risks. In this context, there is a rationale for identifying individuals with CLL, both to monitor for disease progression and because of the significant risk of infection.²

However, our skill as clinicians is to tailor our counseling and advice to the person in front of us. Several years ago, when starting out as a hematology trainee in the laboratory, I would frequently intercept and send off the blood of patients with isolated, persistent lymphocytosis for flow cytometry. This was with the best of intentions—knowing that if I did so and asked for the patient to be referred to the hematology clinic, we could save some time and effort. I do not know how common this practice is, but from recent discussions, I suspect that it is not unusual. Nowadays, I am much more circumspect about my ability to harm people, to effectively ruin their lives with a flick of my pen.

What right do I have to perform these kinds of investigations without consent? What right do I have to diagnose someone with leukemia without affording them a careful explanation of the risks and benefits? Moreover, in what world is it okay for a person to come to hospital, meet a hematologist for the first time, and walk out with the label of “leukemia patient”?

The same is true of monoclonal gammopathy of undetermined significance (MGUS), another diagnosis that medicalizes normal aging, and one that also has a profound impact on quality of life.^{3, 4} How many of the people we see with MGUS have given true, informed consent for a test that could ruin their lives? Of course, it is not possible to ask patients to consent for every single test, but the bar for consent should be high.

My plea is that we all think long and hard about the harm that we can do and make sure that we give the people for whom we care an informed choice.

Richard J. Buka: Conceptualization; writing—original draft; writing—review and editing.

The author was a named applicant on a grant from AstraZeneca UK Limited, which was for work unrelated to this subject area.

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with hypomethylating agents (HMAs) has improved treatment outcomes for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy and is increasingly used in the relapsed/refractory setting. However, primary resistance remains a significant challenge, affecting 20%–35% of treatment-naïve and around 50% of previously treated AML patients. To investigate the mechanisms driving primary resistance to VEN–HMA therapy, we analyzed genetic, transcriptomic, BCL-2 family protein expression, and ex vivo drug sensitivity data from 101 AML patients and correlated these profiles with clinical outcomes to VEN–HMA. Our study found that blasts from refractory patients exhibit an elevated BCL-XL/BCL-2 protein expression ratio, an immature CD34⁺CD38⁻ phenotype, and frequent TP53 mutations. Consistent with the high ratio of BCL-XL/BCL-2, resistant samples showed increased ex vivo sensitivity to the dual BCL-2/BCL-XL inhibitor navitoclax. In addition, SMAC mimetics were effective in refractory blasts, which correlated with high TNF gene expression in these cells. Ex vivo treatment with the combination of navitoclax and SMAC mimetics further enhanced the eradication of VEN–HMA refractory blasts, although toxicity was also observed in healthy CD34⁺ cells. In conclusion, our integrative analysis identifies molecular signatures associated with primary VEN–HMA resistance and highlights BCL-2/BCL-XL inhibition and SMAC mimetics as therapeutic strategies to target resistance.

Administration of memantine, an antagonist of the N-methyl-d-aspartate receptor, prevents Ca²⁺ overload and dehydration of red blood cells (RBCs) in patients with sickle cell disease (SCD). The objectives of the 1-year dose-escalation Phase IIa/IIb Memantine trial (MeMAGEN – NCT 03247218) with 17 SCD patients who were under stable hydroxycarbamide therapy were to test the drug's safety and tolerability. Daily memantine doses ranged from 5 to 15 mg for children/adolescents and from 5 to 20 mg for adults. Clinical and laboratory analysis showed that memantine was well tolerated. In children, a decrease in days spent in the hospital was observed. Safety was confirmed by laboratory tests, which were not, or were only minimally, altered during memantine therapy. In a subgroup of six patients whose RBCs presented with elevated K⁺ leakage before treatment, memantine therapy at its lowest dosage reduced this K⁺ loss and increased hemoglobin concentration. This study shows that memantine is safe and well tolerated by SCD patients, including children. Memantine has the potential to become a supportive and low-cost therapy in conjunction with hydroxycarbamide.

Chronic red blood cell (RBC) transfusion sustains patients with diverse hematologic disorders, but repeated transfusion leads to iron overload and alloimmunization. Reducing transfusion burden requires identifying donor units that circulate more effectively after storage, yet determinants of this variability remain incompletely defined. Here, we integrate forward genetics in mice, multi-omics analyses of over 13,000 human donors, and studies of two families with hereditary ATP11c mutations to reveal a central role for this phospholipid flippase in transfusion efficacy. We show that common ATP11C variants, including the missense SNP V972M, and rare familial loss-of-function alleles impair RBC survival by disrupting membrane lipid remodeling and cytoskeletal stability—a mechanism distinct from oxidative damage pathways. Together, these findings establish ATP11c as a novel determinant of transfusion outcomes across species and genetic contexts, and highlight opportunities for donor stratification and improved storage technologies to advance precision transfusion medicine.

Smoldering multiple myeloma (SMM) represents an intermediate clinical stage between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic multiple myeloma (MM). SMM carries a highly variable risk of progression to MM, requiring individualized risk stratification to guide management. Historically, risk models relied on static clinical markers reflective of tumor burden to predict progression. While useful, these models failed to capture the underlying biological heterogeneity of the disease. Recent advances have incorporated dynamic biomarkers, cytogenetics, and genomic profiling, providing a more nuanced understanding of disease trajectory. Immune dysregulation and subclonal evolution are now recognized as key drivers of progression, enabling the development of biologically informed risk models. Clinical trials have begun to challenge the traditional watch-and-wait approach by exploring early therapeutic interventions for high-risk SMM patients. However, uncertainty persists as clinicians balance the risks of overtreatment against therapeutic delay in the absence of clearly defined high-risk criteria. This review charts the evolution of SMM from a clinically defined entity to a biologically characterized precursor state, highlighting emerging tools and strategies aimed at improving risk prediction and patient outcomes. As personalized medicine continues to advance, integrating evolving molecular, immunologic, and clinical data will be pivotal in refining the management of SMM.

Novel therapies are needed for patients with multiple myeloma (MM) and extramedullary plasmacytomas. The prospective, Phase II EMN19 study assessed the efficacy and safety of daratumumab plus bortezomib, cyclophosphamide, and dexamethasone (DaraVCD) in 40 patients with newly diagnosed MM (NDMM; n = 29) or at first relapse (RMM; n = 11) and positron emission tomography or computed tomography (PET/CT)-confirmed extramedullary plasmacytomas (extraosseous [EMD] and/or paraosseous [PS]). DaraVCD was administered until disease progression or up to 3 years. The primary endpoint was hematological complete response (CR). Among patients, 22 (55.0%), 4 (10.0%), and 14 (35.0%) had EMD, EMD/PS, and PS plasmacytomas, respectively. Median patient age was 58.0 years, and 16 (40.0%), 12 (30.0%), and 10 (25.0%) patients were at International Staging System (ISS) Stages I, II, and III, respectively. Median circulating tumor cell (CTC) level was 0.002% (range, 0.000–0.353), significantly higher (P < 0.05) in patients with ISS Stage III and those with plasma cells > 60%. At a median follow-up of 30.0 months, all patients completed treatment (median duration: 19.8 months). The overall hematologic ≥CR rate was 47.5% (19/40; NDMM patients: 58.6% [17/29]; RMM patients: 18.2% [2/11]). Of patients with ≥CR, 80.0% (15/19) achieved minimal residual disease (MRD) negativity, and 68.4% (13/19) combined MRD negativity and complete metabolic response (CMR) on PET/CT. The overall median progression-free survival was 25.8 months, significantly longer in patients achieving hematologic ≥CR and/or CMR than others (not reached and 4.8 months, respectively; P < 0.001). DaraVCD showed encouraging efficacy in patients with MM and extramedullary plasmacytomas. Notably, this is the first report on CTC levels in EMD, and they were lower than previously reported NDMM thresholds.

Rapid and profound reduction of free light chains (FLCs) improves outcomes in AL amyloidosis; however, early FLC kinetics with daratumumab-based frontline therapy remain undefined. We retrospectively analyzed 315 patients treated with daratumumab–bortezomib–cyclophosphamide–dexamethasone (Dara–VCd) or Dara–Vd at eight centers. Involved FLC (iFLC), the difference between iFLC and uninvolved FLC (dFLC), and hematologic response (≥very good partial response [VGPR]) were assessed at baseline and at 1, 3, and 6 months, and correlated with light chain isotype, disease burden (bone-marrow plasma-cell percentage [%BMPC], baseline dFLC), and cytogenetics. Hematological ≥VGPR increased from 49.8% at 1 month to 66.0% at 3 months. The kappa isotype showed slower responses, with higher iFLC/dFLC and lower ≥VGPR at each time point compared to lambda. Higher %BMPC or baseline dFLC predicted persistently elevated iFLC/dFLC and reduced ≥VGPR. The t(11;14) translocation was associated with lower baseline FLC but similar subsequent kinetics. BMPC < 10% and dFLC < 18 mg/dL independently predicted early ≥VGPR (in ≤1 month). Early ≥VGPR conferred superior hematologic event-free survival (heme-EFS) and overall survival (OS) versus later responders (P < 0.001). At a 3-month landmark, achieving dFLC < 1 mg/dL further stratified prognosis, conferring longer heme-EFS and OS (P < 0.01). Frontline Dara-based therapy elicits rapid, deep responses in AL amyloidosis; early ≥VGPR (within 1 month) and dFLC < 1 mg/dL by 3 months predict durable EFS and OS, whereas higher baseline disease burden delays hematologic response.

Chimeric antigen receptor (CAR)-T-cell therapy has improved response rates in relapsed/refractory multiple myeloma (RRMM), yet long-term disease control remains limited, with only 20% of patients remaining progression-free at 5 years. Therefore, identifying early predictors of treatment success is critical. Here, we used next-generation flow cytometry to analyze T-cell populations in blood at leukapheresis, before infusion, and post-anti-BCMA CAR-T infusion, together with CAR-T-cell kinetics and phenotypes before, during, and after the expansion peak, in 53 RRMM patients. Anti-BCMA CAR-T cells peaked at Day +14 (72%), comprising >65 distinct populations, predominantly central memory (CM) T-helper (Th) 1 and Th1/2 CAR-TCD4⁺ and CM CAR-TCD8⁺ cells. Multivariate analyses revealed that higher frequencies of TCD4⁺ naive and Th22 transitional memory (TM) cells at leukapheresis, together with circulating tumor plasma cells (CTPCs) before infusion, but none of the specific CAR-T-cell populations, were predictors of progression-free survival (PFS). Based on these variables, we built a risk score that together with disease stage (International Staging System-Revised [ISS-R]) independently predicted, before CAR-T-cell infusion, which RRMM patients were most likely to benefit from anti-BCMA CAR-T therapy. These findings suggest that long-term PFS is primarily influenced by the patient's immune landscape and the tumor burden rather than anti-BCMA CAR-T-cell properties.