Haematologica

Therapy for acute myeloid leukemia in older and unfit adults

Mark Forsberg — 2024-12-01

New precision medicine weapons for targeted treatment of high-risk B-cell precursor acute lymphoblastic leukemia

Sinisa Dovat — 2024-07-11

A new frontier in the battle against infant acute lymphoblastic leukemia

Daisuke Tomizawa — 2024-07-18

A nu mouse model of diffuse large B-cell lymphoma in constitutional Atm loss

Laura K. Hilton — 2024-08-08

Entities versus diseases: Myers et al. propose distinct aspects of adult T-cell lymphoma/leukemia

Stefano A. Pileri — 2024-08-29

AURKA targeting: a NEAT approach to halt myeloma

Antonio Giovanni Solimando — 2024-08-29

Introduction to the Review Series on venous thromboembolism: emerging issues in pathophysiology and management

Paolo Prandoni — 2024-11-19

Multimorbidity, comorbidity, frailty, and venous thromboembolism

Bengt Zöller — 2024-11-19

Multimorbidity, i.e., the presence of two or more long-term health conditions, is challenging for healthcare systems worldwide. A related term is comorbidity. This denotes any condition that has existed or may occur during the clinical course of a patient who has the index disease under study. Moreover, frailty is also inter-related with multimorbidity but represents a distinct clinical concept. Few studies have explored how multimorbidity and frailty are related to venous thromboembolism (VTE), though many studies have looked at how different comorbidities, especially cancer, affect the outcome of VTE. Recently, a graded association between multimorbidity and VTE has been described. Several multimorbidity disease clusters, such as cardiometabolic and psychiatric disorders, have been associated with VTE. The comorbidity burden, i.e., Charlson Comorbidity Index (CCI), has also been related to short-term mortality after VTE. VTE patients without comorbidities, i.e., CCI = 0, have less than 1% three months mortality. Frailty and CCI have been associated with postoperative risk of VTE. In this review, drivers of multimorbidity and VTE risk, disease networks, and disease trajectories will also be discussed. Further studies including multimorbidity and frailty as predictors for VTE in situations of risk could be of clinical importance. Moreover, it will also be important to determine which diseases should be included in a multimorbidity risk score for VTE.

Minor trauma and venous thromboembolism: the threshold for antithrombotic prophylaxis

Alexandre Tran — 2024-11-19

Trauma is an established risk factor for venous thromboembolism (VTE). Whether minor trauma is linked to greater risk of VTE remains unclear given that many studies evaluating trauma and VTE risk have not differentiated risk by trauma severity. Furthermore, the underlying risk of VTE is not uniform across all injured patients. While it is generally accepted that severely and moderately injured patients requiring prolonged hospitalization benefit from early and consistent administration of thromboprophylaxis, the threshold for its initiation following minor injury or in patients managed in an ambulatory setting is less clear. This review will describe how trauma is classified, summarize the evidence of the risk of VTE in patients with minor trauma, and guide clinicians through an approach to individualize these treatment decisions based on contemporary evidence. Guidance will be provided for both injured patients requiring hospitalization (who may have severe, moderate or minor trauma), and those suitable to be managed in an ambulatory setting (minor trauma).

Targeted anti-cancer agents and risk of venous thromboembolism

Melina Verso — 2024-11-19

The incidence of one-year venous thromboembolism (VTE) after cancer diagnosis is reported to be increasing for several types of cancer. The introduction of targeted anti-cancer therapies and immunotherapy into the therapeutic armamentarium of medical oncologists contributed to the significantly improved response rates and survival times of cancer patients. In recent years, a potential prothrombotic effect of several targeted anti-cancer agents and immunotherapy drugs has been suggested; however, the methodological limitations of clinical trials evaluating the possible role of these classes of drugs on the VTE risk often make the interpretation of their results difficult. It is still not clear whether the increased risk of VTE is more closely correlated to the expression of specific oncogenic profiles than to the administration of specific therapies against these mutations. Furthermore, the increased survival rates observed with these agents could influence the prevalence of VTE events in cancer patients by the competing risk mortality on the risk of VTE. To date, the available data have suggested that the risk of VTE varies among different categories of targeted therapy, being most reported for anti-vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), monoclonal antibodies and immune checkpoint inhibitors, and less reported for tyrosine kinase inhibitors (TKI). The risk of VTE seems to significantly increase when targeted therapy is administered in combination with traditional anti-cancer agents. Considering the uncertainties in estimating the rate of thrombotic complications associated with targeted therapy, the need for antithrombotic prophylaxis in cancer patients receiving targeted therapies still needs to be specifically assessed. In this review, we examine available evidence of the literature and the methodological limitations of clinical trials, and we discuss the potential future perspectives.

Next-generation strategies to improve safety and efficacy of adeno-associated virus-based gene therapy for hemophilia: lessons from clinical trials in other gene therapies

Giovanni Di Minno — 2024-03-07

Three major directions for the global progress of adeno-associated virus (AAV) vectors for gene therapies (GT) are analyzed: 1) engineering vectors to increase transgene expression; 2) aligning interests of the health system with costs and challenges for the pharmaceutical industry; and 3) refining patient eligibility criteria and endpoint definition. Currently employed AAV vectors may cause toxicity and adverse events. Furthermore, studies in animals do not fully predict risks and clinical benefits of AAV-based GT, and animal models reflecting the heterogeneity of certain clinical settings (e.g., congestive heart failure) are not widely available for improving AAV-based GT. Finally, antisense and gene editing approaches will soon complement gene augmentation strategies for the stable solution of unsolved issues of AAV-based GT. While minimizing toxicity, next-generation AAV vectors should decrease the viral load needed to achieve therapeutic efficacy, be functional in a restricted cellular subset, avoid transgene expression in unwanted cells (e.g., hepatocytes), and escape immune oversight in AAV-based GT. The role of stress-induced apoptosis in the loss of transgene expression in GT should also be explored. Aligning the interests and obligations of the pharmaceutical industry with those of the health system is critical for the success of AAV-based GT. Costs and challenges for the pharmaceutical industry include: a) removing impurities from AAV; b) validating tests to measure treatment efficacy; c) promoting training programs to standardize vector genome delivery; d) collecting long-term follow-up data; and e) maintaining sustainability and cost-effectiveness of AAV-based GT. In rare disorders with small patient numbers (e.g., hemophilia), clear-cut outcomes are mandatory as endpoints of unequivocal efficacy data.

Approaches for bridging therapy prior to chimeric antigen receptor T cells for relapsed/refractory acute lymphoblastic B-lineage leukemia in children and young adults

Tobias Feuchtinger — 2024-02-15

The ongoing development of immunotherapies, including chimeric antigen receptor (CAR) T cells, has revolutionized cancer treatment. In pediatric relapsed/refractory B-lineage acute leukemia antiCD19-CAR induce impressive initial response rates, with event-free survival plateauing at 30-50% according to long-term follow-up data. During the interval between diagnosis of relapse or refractoriness and CAR T-cell infusion, patients require a bridging therapy. To date, this therapy has consisted of highly variable approaches based on local experience. Here, in an European collaborative effort of pediatric and adult hematologists, we summarize current knowledge with the aim of establishing guidance for bridging therapy. We discuss treatment strategies for different subgroups of patients, the advantages and disadvantages of low- and high-intensity regimens, and the potential impact of bridging therapy on outcomes after CAR T-cell infusion. This guidance is a step towards cross-institutional harmonization of bridging therapy, including personalized approaches. This will allow better comparability of clinical data and increase the level of evidence for the treatment of children and young adults with relapsed/ refractory B-lineage acute leukemia until they can receive CAR T-cell infusion.

IKZF1 gene deletions drive resistance to cytarabine in B-cell precursor acute lymphoblastic leukemia

Britt M. T. Vervoort — 2024-06-06

IKZF1 deletions occur in 10-15% of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and predict a poor outcome. However, the impact of IKZF1 loss on sensitivity to drugs used in contemporary treatment protocols has remained underexplored. Here we show in experimental models and in patients that loss of IKZF1 promotes resistance to cytarabine (AraC), a key component of both upfront and relapsed treatment protocols. We attribute this resistance, in part, to diminished import and incorporation of AraC due to reduced expression of the solute carrier hENT1. Moreover, we found elevated mRNA expression of Evi1, a known driver of therapy resistance in myeloid malignancies. Finally, a kinase directed CRISPR/Cas9-screen identified that inhibition of either mediator kinases CDK8/19 or casein kinase 2 can restore response to AraC. We conclude that this high-risk group of patients could benefit from alternative antimetabolites, or targeted therapies that re-sensitize leukemic cells to AraC.

Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children’s Oncology Group trial AALL15P1

Erin M. Guest — 2024-06-13

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of failure to achieve remission, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children’s Oncology Group trial AALL15P1 tested the safety and tolerability of 5 days of azacitidine treatment immediately prior to the start of chemotherapy on day 6, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was well-tolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells demonstrated decreased DNA methylation in 87% of samples tested following 5 days of azacitidine treatment. Event-free survival was similar to that in prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of peripheral blood mononuclear cells in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.

Blockade of the CD47/SIRPα checkpoint axis potentiates the macrophage-mediated antitumor efficacy of tafasitamab

Alexander Biedermann — 2024-06-27

Macrophages are one of the key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD19 antibody tafasitamab, approved in combination with lenalidomide for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, antibody-dependent cellular phagocytosis (ADCP) in the tumor microenvironment can be counteracted by increased expression of the inhibitory receptor SIRPα on macrophages and its ligand, the immune checkpoint molecule CD47, on tumor cells. The aim of this study was to investigate the impact of the CD47-SIRPα axis on tafasitamab- mediated phagocytosis and explore the potential of anti-CD47 blockade to enhance its antitumor activity. Elevated expression of both SIRPα and CD47 was observed in DLBCL patient-derived lymph node biopsies compared to healthy control lymph nodes. CRISPR-mediated CD47 overexpression affected tafasitamab-mediated ADCP in vitro and increased expression of SIRPα on macrophages correlated with decreased ADCP activity of tafasitamab against DLBCL cell lines. A combination of tafasitamab and an anti-CD47 blocking antibody enhanced ADCP activity of in vitro-generated macrophages. Importantly, tafasitamab-mediated phagocytosis was elevated in combination with CD47 blockade using primary DLBCL cells and patient-derived lymphoma-associated macrophages in an autologous setting. Furthermore, lymphoma cells with low CD19 expression were efficiently eliminated by the combination treatment. Finally, combined treatment of tafasitamab and an anti-CD47 antibody resulted in enhanced tumor volume reduction and survival benefit in lymphoma xenograft mouse models. These findings provide evidence that CD47 blockade can enhance the phagocytic potential of tumor-targeting immunotherapies such as tafasitamab and suggest that there is value in exploring the combination in the clinic.

Umbilical cord blood T cells can be isolated and enriched by CD62L selection for use in ‘off the shelf’ chimeric antigen receptor T-cell therapies to widen transplant options

Christos Georgiadis — 2024-07-11

Umbilical cord blood (UCB) T cells exhibit distinct naïve ontogenetic profiles and may be an attractive source of starting cells for the production of chimeric antigen receptor (CAR) T cells. Pre-selection of UCB-T cells on the basis of CD62L expression was investigated as part of a machine-based manufacturing process, incorporating lentiviral transduction, CRISPR- Cas9 editing, T-cell expansion, and depletion of residual TCRαβ T cells. This provided stringent mitigation against the risk of graft-versus-host disease (GvHD), and was combined with simultaneous knockout of CD52 to enable persistence of edited T cells in combination with preparative lymphodepletion using alemtuzumab. Under compliant manufacturing conditions, two cell banks were generated with high levels of CAR19 expression and minimal carriage of TCRαβ T cells. Sufficient cells were cryopreserved in dose-banded aliquots at the end of each campaign to treat dozens of potential recipients. Molecular characterization captured vector integration sites and CRISPR editing signatures, and functional studies, including in vivo potency studies in humanized mice, confirmed anti-leukemic activity comparable to peripheral blood-derived universal CAR19 T cells. Machine manufactured UCB-derived T-cell banks offer an alternative to autologous cell therapies and could help widen access to CAR T cells.

Clinical impact of clonal hematopoiesis in hematopoietic cell transplantation: a review, meta-analysis, and call to action

Nancy Gillis — 2024-06-20

Hematopoietic cell transplantation (HCT) is the only potentially curative treatment option for many patients with hematologic malignancies. While HCT outcomes have improved drastically over the years, patients and clinicians continue to face numerous survivorship challenges, such as relapse, graft-versus-host disease, and secondary malignancies. Recent literature suggests that clonal hematopoiesis (CH), the presence of a recurrent somatic mutation in hematopoietic cells, in HCT patients or donors may be associated with outcomes in autologous and allogeneic HCT. Herein, we perform a review of the literature and summarize reported associations between CH and clinical outcomes in HCT. For commonly reported outcomes, we used meta-analysis methods to provide estimates of effect sizes when combining results. A total of 32 articles with relevant and independent contributions were included, covering both autologous (N=19) and allogeneic (N=13) HCT. The articles report variable risk for developing outcomes according to CH characteristics, patient disease status, and method of HCT. Using meta-analysis of available results, HCT outcomes with statistically significant effects by CH status include therapy-related myeloid neoplasms (odds ratio =3.65; 95% confidence interval [CI]: 2.18-6.10) and overall survival (hazard ratio [HR]=1.38; 95% CI: 1.20-1.58) in autologous HCT and relapse (HR=0.80; 95% CI: 0.68-0.94) in allogeneic HCT. However, heterogeneity, biases, and limitations in the literature provide challenges for informing the translation of CH to clinical decision- making. We conclude with a call to action and discussion of next steps to build upon the current literature and provide granularity to the true clinical impact of CH in the setting of HCT.

Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia

Yunfan Yang — 2024-06-27

The aim of this study was to evaluate the efficacy and safety of flumatinib in later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia ((CP-CML) previously treated with tyrosine kinase inhibitors (TKI). Patients with CML-CP were evaluated for probabilities of responses, including complete hematologic response (CHR), cytogenetic response, and molecular response (MR), and adverse events after the later-line flumatinib therapy. Of 336 enrolled patients with a median age 50 years, the median duration of treatment with flumatinib was 11.04 months (range, 2-25.23). Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR) or 2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% of patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR were achieved in 86.4%, 52.7%, 49.6%, and 23.5% of patients, respectively, who lacked the respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as a second-line TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR rates. The adverse events observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who were resistant or intolerant to other TKI. In particular, second-line flumatinib treatment induced high response rates and was more beneficial to patients without previous second-generation TKI resistance, thus serving as a probable treatment option for these patients.

LSD1/KDM1A and GFI1B repress endothelial fate and induce hematopoietic fate in induced pluripotent stem cell-derived hemogenic endothelium

Huan Zhang — 2024-07-04

Differentiation of induced pluripotent stem cells (iPSC) into hematopoietic lineages offers great therapeutic potential. During embryogenesis, hemogenic endothelium (HE) gives rise to hematopoietic stem and progenitor cells through the endothelial- to-hematopoietic transition (EHT). Understanding this process using iPSC is key to generating functional hematopoietic stem cells (HSC), a currently unmet challenge. In this study, we examined the role of the transcriptional factor GFI1B and its co-factor LSD1/KDM1A in EHT. To this end, we employed patient-derived iPSC lines with a dominant-negative dysfunctional GFI1B Q287* and irreversible pharmacological LSD1/KDM1A inhibition in healthy iPSC lines. The formation of HE remained unaffected; however, hematopoietic output was severely reduced in both conditions. Single-cell RNA sequencing (scRNAseq) performed on the CD144+/CD31+ population derived from healthy iPSC revealed similar expression dynamics of genes associated with in vivo EHT. Interestingly, LSD1/KDM1A inhibition in healthy lines before EHT resulted in a complete absence of hematopoietic output. However, uncommitted HE cells did not display GFI1B expression, suggesting a timed transcriptional program. To test this hypothesis, we ectopically expressed GFI1B in uncommitted HE cells, leading to downregulation of endothelial genes and upregulation of hematopoietic genes, including GATA2, KIT, RUNX1, and SPI1. Thus, we demonstrate that LSD1/KDM1A and GFI1B can function at distinct temporal points in different cellular subsets during EHT. Although GFI1B is not detected in uncommitted HE cells, its ectopic expression allows for partial hematopoietic specification. These data indicate that precisely timed expression of specific transcriptional regulators during EHT is crucial to the eventual outcome of EHT.

Genome-scale clustered regularly interspaced short palindromic repeats screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma

Nicholas Davies — 2024-06-06

Diffuse large B-cell lymphoma (DLBCL) is the most common malignancy that develops in patients with ataxia-telangiectasia, a cancer-predisposing inherited syndrome characterized by inactivating germline ATM mutations. ATM is also frequently mutated in sporadic DLBCL. To investigate lymphomagenic mechanisms and lymphoma-specific dependencies underlying defective ATM, we applied RNA sequencing and genome-scale loss-of-function clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to systematically interrogate B-cell lymphomas arising in a novel murine model (Atm-/-nu-/-) with constitutional Atm loss, thymic aplasia but residual T-cell populations. Atm-/-nu-/- lymphomas, which phenotypically resemble either activated B-cell-like or germinal center B-cell-like DLBCL, harbor a complex karyotype, and are characterized by MYC pathway activation. In Atm-/-nu-/- lymphomas, we discovered nucleotide biosynthesis as a MYC-dependent cellular vulnerability that can be targeted through the synergistic nucleotide-depleting actions of mycophenolate mofetil (MMF) and the WEE1 inhibitor, adavosertib (AZD1775). The latter is mediated through a synthetically lethal interaction between RRM2 suppression and MYC dysregulation that results in replication stress overload in Atm-/-nu-/- lymphoma cells. Validation in cell line models of human DLBCL confirmed the broad applicability of nucleotide depletion as a therapeutic strategy for MYC-driven DLBCL independent of ATM mutation status. Our findings extend current understanding of lymphomagenic mechanisms underpinning ATM loss and highlight nucleotide metabolism as a targetable therapeutic vulnerability in MYC-driven DLBCL.

Core regions in immunoglobulin heavy chain enhancers essential for survival of non-Hodgkin lymphoma cells are identified by a CRISPR interference screen

Marta Elżbieta Kasprzyk — 2024-06-27

Chromosomal translocations in non-Hodgkin lymphoma (NHL) result in activation of oncogenes by placing them under the regulation of immunoglobulin heavy chain (IGH) super-enhancers. Aberrant expression of translocated oncogenes induced by enhancer activity can contribute to lymphomagenesis. The role of the IGH enhancers in normal B-cell development is well established, but knowledge regarding the precise mechanisms of their involvement in control of the translocated oncogenes is limited. The goal of this project was to define the critical regions in the IGH regulatory elements and identify enhancer RNA (eRNA). We designed a single guide RNA library densely covering the IGH enhancers and performed tiling CRISPR interference screens in three NHL cell lines. This revealed three regions crucial for NHL cell growth. With chromatin- enriched RNA sequencing we showed transcription from the core enhancer regions and subsequently validated expression of the eRNA in a panel of NHL cell lines and tissue samples. Inhibition of the essential IGH enhancer regions decreased expression of eRNA and translocated oncogenes in several NHL cell lines. The observed expression and growth patterns were consistent with the breakpoints in the IGH locus. Moreover, targeting the Eμ enhancer resulted in loss of B-cell receptor expression. In a Burkitt lymphoma cell line, MYC overexpression partially rescued the phenotype induced by IGH enhancer inhibition. Our results indicated the most critical regions in the IGH enhancers and provided new insights into the current understanding of the role of IGH enhancers in B-cell NHL. As such, this study forms a basis for development of potential therapeutic approaches.

Distinctive genomic features of human T-lymphotropic virus type 1-related adult T-cell leukemia-lymphoma in Western populations

Caroline S. Myers — 2024-08-08

Adult T-cell leukemia-lymphoma (ATLL) is an aggressive malignancy driven by human T-cell leukemia virus type 1 (HTLV-1). Although patients from the Western hemisphere (Afro-Caribbean and South American) face worse prognoses, our understanding of ATLL molecular drivers derives mostly from Japanese studies. We performed multi-omic analyses to elucidate the genomic landscape of ATLL in Western cohorts. Recurrent deletions and/or damaging mutations involving FOXO3, ANKRD11, DGKZ, and PTPN6 implicate these genes as potential tumor suppressors. RNA-sequencing, published functional data and in vitro assays support the roles of ANKRD11 and FOXO3 as regulators of T-cell proliferation and apoptosis in ATLL, respectively. Survival data suggest that ANKRD11 mutation may confer a worse prognosis. Japanese and Western cohorts, in addition to acute and lymphomatous subtypes, demonstrated distinct molecular patterns. GATA3 deletion was associated with chronic cases with unfavorable outcomes. IRF4 and CARD11 mutations frequently emerged in relapses after interferon therapy. Our findings reveal novel putative ATLL driver genes and clinically relevant differences between Japanese and Western ATLL patients.

Combinatorial strategies targeting NEAT1 and AURKA as new potential therapeutic options for multiple myeloma

Noemi Puccio — 2024-07-11

Multiple myeloma (MM) is a dreadful disease, marked by the uncontrolled proliferation of clonal plasma cells within the bone marrow. It is characterized by a highly heterogeneous clinical and molecular background, supported by severe genomic alterations. Important de-regulation of long non-coding RNA (lncRNA) expression, which can influence progression and therapy resistance, has been reported in MM patients. NEAT1 is a lncRNA essential for nuclear paraspeckles and is involved in the regulation of gene expression. We showed that NEAT1 supports MM proliferation, making this lncRNA an attractive therapeutic candidate. Here, we used a combinatorial strategy integrating transcriptomic and computational approaches with functional high-throughput drug screening to identify compounds that synergize with NEAT1 inhibition in restraining MM cell growth. AURKA inhibitors were identified as top-scoring drugs in these analyses. We showed that the combination of NEAT1 silencing and AURKA inhibitors in MM profoundly impairs microtubule organization and mitotic spindle assembly, finally leading to cell death. Analysis of the large publicly available CoMMpass dataset showed that, in MM patients, AURKA expression is strongly associated with reduced progression-free survival (P<0.0001) and overall survival (P<0.0001) probabilities and patients with high levels of expression of both NEAT1 and AURKA have a worse clinical outcome. Finally, using RNA-sequencing data from NEAT1 knockdown MM cells, we identified the AURKA allosteric regulator TPX2 as a new NEAT1 target in MM and as a mediator of the interplay between AURKA and NEAT1, therefore providing a possible explanation for the synergistic activity observed upon their combinatorial inhibition.

Single-point and kinetics of peripheral residual disease by mass spectrometry to predict outcome in patients with high-risk smoldering multiple myeloma included in the GEM-CESAR trial

Noemí Puig — 2024-07-11

The value of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein is being investigated in patients with monoclonal gammopathies but no data are yet available in high-risk smoldering myeloma (HRsMM). We have, therefore, investigated QIP-MS to monitor peripheral residual disease (PRD) in 62 HRsMM patients enrolled in the GEM-CESAR trial. After 24 cycles of maintenance, detecting the M-protein by MS or clonal plasma cells by next-generation flow cytometry (NGF) identified cases with a significantly shorter median progression-free survival (mPFS) (MS: not reached vs. 1.4 years, P=0.001; NGF: not reached vs. 2 years, P=0.0002) but reaching complete response (CR) + stringent CR (sCR) did not discriminate between patients with different outcome. With NGF as a reference, the combined results of NGF and MS showed a high negative predictive value (NPV) of MS: 81% overall and 73% at treatment completion. When sequential results were considered, sustained negativity by MS or NGF was associated with a very favorable outcome with an mPFS not yet reached versus 1.66 years and 2.18 years in cases never attaining PRD or minimal residual disease (MRD) negativity, respectively. We can, thus, conclude that: 1) the standard response categories of the International Myeloma Working Group do not seem to be useful for monitoring treatment in HRsMM patients; 2) MS could be used as a valuable, non-invasive, clinical tool with the capacity of guiding timely bone marrow evaluations (based on its high NPV with NGF as a reference); and 3) similarly to NGF, sequential results of MS are able to identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (clinicaltrials.gov identifier: 02415413).

Co-shared genomic alterations within tumors from patients with both myeloproliferative neoplasms and lymphoma

Johanne M. Holst — 2024-07-25

Nucleotide sugars correlate with leukocyte telomere length as part of a dyskeratosis congenita metabolomic plasma signature

Yufeng Li — 2024-08-08

A multicenter, phase Ib study of subcutaneous administration of isatuximab in combination with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma

Hang Quach — 2024-08-15

A transgenic mouse model of Down syndrome acute lymphoblastic leukemia identifies targetable vulnerabilities

Jacob J. Junco — 2024-07-25

Minimal residual disease monitoring in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia: prognostic significance and correlation between multiparameter flow cytometry and real-time quantitative polymerase chain reaction

Jun Li — 2024-05-02

Ponatinib alone or with chemo-immunotherapy in heavily pre treated Philadelphia-like acute lymphoblastic leukemia: a CAMPUS ALL real-life study

Francesca Kaiser — 2024-08-01

Minimal residual disease assessment in transplant-eligible patients with multiple myeloma: real-world applications of multiparametric flow cytometry-DURAClone (CAREMM-2104)

Ari Ahn — 2024-07-18

A phase II study of post-remission therapy with pembrolizumab in older patients with acute myeloid leukemia

Kevin Quann — 2024-08-08

Infection by Helicobacter pylori cytotoxin-A-associated antigen-positive strains is associated with iron deficiency anemia in a longitudinal birth cohort in Brazil

Dulciene M. M. Queiroz — 2024-08-22

Maternal prolactin or estrogen signaling in hepatocytes does not regulate iron homeostasis during pregnancy

Vida Zhang — 2024-08-01

An important oversight in the World Health Organization diagnostic classification: chronic myeloid leukemia with the PML::RARA fusion clone

Jieyu Wang — 2024-08-08

Superior survival with allogeneic hematopoietic stem cell transplantation versus chemotherapy for high-risk adult acute lymphoblastic leukemia in a PDT-ALL-2016 pediatric-inspired cohort

Junjie Chen — 2024-08-01

Repurposing CD19-directed immunotherapies for pediatric t(8;21) acute myeloid leukemia

Farnaz Barneh — 2024-08-08

Mimicry of inherited red cell disorders: the result of somatic mutations in a clonal myeloid disease

Marshall A. Lichtman — 2024-07-18

Expanding the genetic landscape of congenital neutropenia: CXCR2 mutations in three families revealed through whole exome sequencing

Maksim Klimiankou — 2024-08-01

von Hippel-Lindau syndrome-related congenital polycythemia and response to belzutifan

Paulo Siqueira do Amaral — 2024-08-08

Have we truly uncovered the key to primary vitreoretinal lymphoma’s pathway to the central nervous system?

Liang Wang — 2024-07-11

Erratum to: Breast implant-associated Epstein-Barr virus-positive large B-cell lymphomas: a report of three cases

Socorro María Rodríguez-Pinilla — 2024-12-01