Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of ...300 serial samples from 100 CML patients; 37 patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified 5 distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persisted despite successful TKI response (pattern 1), providing indirect evidence that these mutations also originated from preleukemic mutations, whereas patients exhibiting mutation clearance (pattern 3) showed mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution.
•Mutation clearance in CML does not directly result in successful treatment in CML.•Clinical implications of patterns of mutation acquisition, persistence, and clearance in CML should be interpreted with caution.
Traditional severity criteria of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were determined retrospectively but found inappropriate for therapeutic decisions. Data of 203 ...patients with SOS/VOD were collected according to the modified Seattle diagnostic criteria and were analyzed for validation of the revised severity criteria recently proposed from European Society for Blood and Marrow Transplantation (EBMT). According to the traditional severity criteria, none of the patients were mild grade, while 63.1% were moderate and 36.9% were severe grade. However, according to the revised EBMT criteria, the majority of patients (63.1%) were very severe, 18.2% were severe, 12.8% were moderate, and 5.9% were mild grade. The 100-day overall survival (OS) of mild, moderate, severe and very severe groups was 83.3, 84.3, 94.6, and 58.6%, respectively. Very severe SOS/VOD showed a significantly lower OS than the others (58.6 vs. 89.3%, p < 0.0001). The 100-day transplantation-related mortality was 25.2% in the entire cohort; 8.3% in mild, 8.0% in moderate, 2.7% in severe, and 36.7% in very severe SOS/VOD (p < 0.0001). The very severe grade newly classified by the revised EBMT criteria accounted for the majority of SOS/VOD associated with worse 100-day OS. Therefore, intervention should be applied at the latest for moderate to severe SOS/VOD before deterioration.
Recently, the endothelial Activation and Stress Index (EASIX) score has been reported to predict overall survival (OS) after allogeneic stem cell transplantation. This study evaluated the prognostic ...role of EASIX score in patients with newly diagnosed multiple myeloma (MM).
This retrospective study analyzed the records of 1177 patients with newly diagnosed MM between February 2003 and December 2017 from three institutions in the Republic of Korea. Serum lactate dehydrogenase (LDH), creatinine, and platelet count at diagnosis were measured in all included patients. EASIX scores were calculated using the formula-LDH (U/L) × Creatinine (mg/dL) / platelet count (10
/L) and were evaluated based on log2 transformed values.
The median age of patients was 63 years (range, 22-92), and 495 patients (42.1%) underwent autologous stem cell transplantation (ASCT). The median log2 EASIX score at diagnosis was 1.1 (IQR 0.3-2.3). Using maximally selected log-rank statistics, the optimal EASIX cutoff value for OS was 1.87 on the log2 scale (95% CI 0.562-0.619, p < 0.001). After median follow-up for 50.0 months (range, 0.3-184.1), the median OS was 58.2 months (95% CI 53.644-62.674). Overall, 372 patients (31.6%) showed high EASIX scores at diagnosis, and had significantly inferior OS compared to those with low EASIX (log2 EASIX ≤1.87) (39.1 months vs. 67.2 months, p < 0.001). In multivariate Cox analysis, high EASIX was significantly associated with poor OS (HR 1.444, 95% CI 1.170-1.780, p = 0.001). In the subgroup analysis of patients who underwent ASCT, patients with high EASIX showed significantly inferior OS compared to those with low EASIX (52.8 months vs. 87.0 months, p < 0.001). In addition, in each group of ISS I, II, and III, high EASIX was associated with significantly inferior OS (ISS 1, 45.2 months vs. 76.0 months, p = 0.001; ISS 2, 42.3 months vs. 66.5 months, p = 0.002; ISS 3, 36.8 months vs. 55.1 months, p = 0.001).
EASIX score at diagnosis is a simple and strong predictor for OS in patients with newly diagnosed MM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Next-generation sequencing (NGS) has been applied to define clinically relevant somatic mutations and classify subtypes in acute myeloid leukemia (AML). Persistent allelic burden after chemotherapy ...is associated with higher relapse incidence, but presence of allelic burden in AML patients after receiving allogeneic hematopoietic cell transplantation (HCT) has not been examined longitudinally. As such, we aimed to assess the feasibility of NGS in monitoring AML patients receiving HCT. Using a targeted gene panel, we performed NGS in 104 AML patients receiving HCT using samples collected at diagnosis, pre-HCT, and post-HCT at day 21 (post-HCTD21). NGS detected 256 mutations in 90 of 104 patients at diagnosis, which showed stepwise clearances after chemotherapy and HCT. In a subset of patients, mutations were still detectable pre-HCT and post-HCT. Most post-HCT mutations originate from mutations initially detected at diagnosis. Post-HCTD21 allelic burdens in relapsed patients were higher than in nonrelapsed patients. Post-HCTD21 mutations in relapsed patients all expanded at relapse. Assessment of variant allele frequency (VAF) revealed that overall VAF post-HCTD21 (VAF0.2%-post-HCTD21) is associated with an increased risk of relapse (56.2% vs 16.0% at 3 years; P < .001) and worse overall survival (OS; 36.5% vs 67.0% at 3 years; P = .006). Multivariate analyses confirmed that VAF0.2%-post-HCTD21 is an adverse prognostic factor for OS (hazard ratio HR, 3.07; P = .003) and relapse incidence (HR, 4.75; P < .001), independent of the revised European LeukemiaNet risk groups. Overall, current study demonstrates that NGS-based posttransplant monitoring in AML patients is feasible and can distinguish high-risk patients for relapse.
•Higher allelic burden at day 21 of post-HCT is associated with higher risk of relapse and mortality.•Longitudinal tracking of AML patients receiving HCT is feasible and provides clinically relevant information.
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FMS-like tyrosine kinase 3 (
) mutations, the most frequently detected genetic aberrations in patients with acute myeloid leukemia (AML), are identified in approximately 30% of patients with newly ...diagnosed AML and are more common in patients with normal karyotypes. Since the discovery of
mutations in AML, clinical trials have been actively conducted in patients with
mutated AML, and
inhibitors have been introduced into clinical practice. The current standard treatment for patients with newly diagnosed
-mutated AML is 7+3 induction chemotherapy combined with midostaurin. Additionally, gilteritinib is more effective than salvage chemotherapy for relapsed or refractory
-mutated AML. Ongoing trials are expected to provide additional treatment options depending on the disease state and patient vulnerability. This review summarizes information on clinically available
inhibitors for the management of AML with
mutations.
The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector ...functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγ
(NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.
Despite the current effective treatments for acute promyelocytic leukemia (APL), early mortality (EM), defined as death within 30 days of presentation, is a major hurdle to long-term survival.
We ...performed a multicenter retrospective study to evaluate the incidence and clinical characteristics of EM in patients with newly diagnosed APL and to develop a risk stratification model to predict EM.
We identified 313 eligible patients diagnosed between 2000 and 2021 from five academic hospitals. The median age was 50 years (range 19-94), and 250 (79.9%) patients were <65 years. Most patients (n=274, 87.5%) received their first dose of all-trans retinoic acid (ATRA) within 24 hours of presentation. EM occurred in 41 patients, with a cumulative incidence of 13.1%. The most common cause of EM was intracranial hemorrhage (n=22, 53.6%), and most EMs (31/41, 75.6%) occurred within the first seven days of APL presentation. In a multivariable analysis, we identified three independent factors predicting EM: age ≥65 years (HR, 2.56), white blood cell count ≥8.0 x 10
/L (HR, 3.30), and ATRA administration >24 hours of presentation (HR, 2.95). Based on these factors, patients were stratified into three categories with a significantly increasing risk of EM: 4.1% for low risk (54.3%; no risk factors; HR 1), 18.5% for intermediate risk (34.5%; 1 factor; HR 4.81), and 40.5% for high risk (11.2%; 2-3 factors; HR 13.16).
The risk of EM is still not negligible in this era of ATRA-based therapies. Our risk model serves as a clinically useful tool to identify high-risk patients for EM who may be candidates for novel treatments and aggressive supportive strategies.
This study aimed to validate the 2022 European LeukemiaNet (ELN) risk stratification for acute myeloid leukemia (AML). A total of 624 newly diagnosed AML patients from 1998 to 2014 were included in ...the analysis. Genetic profiling was conducted using targeted deep sequencing of 45 genes based on recurrent driver mutations. In total, 134 (21.5%) patients had their risk classification reassessed according to the 2022 ELN risk stratification. Among those initially classified as having a favorable risk in 2017 (n = 218), 31 and 3 patients were reclassified as having intermediate risk or adverse risk, respectively. Among the three subgroups, the 2022 ELN favorable-risk group showed significantly longer survival outcomes than the other groups. Within the 2017 ELN intermediate-risk group (n = 298), 21 and 46 patients were reclassified as having favorable risk or adverse risk, respectively, and each group showed significant stratifications in survival outcomes. Some patients initially classified as having adverse risk in 2017 were reclassified into the intermediate-risk group (33 of 108 patients), but no prognostic improvements were observed in this group. A multivariable analysis identified the 2022 ELN risk stratification, age, and receiving allogeneic hematopoietic cell transplantation as significant prognostic factors for survival. The 2022 ELN risk stratification enables more precise decisions for proceeding with allogeneic hematopoietic cell transplantation for AML patients.
BCR-ABL-independent drug resistance is a barrier to curative treatment of chronic myeloid leukemia (CML). However, the molecular pathways underlying BCR-ABL-independent tyrosine kinase inhibitor ...(TKI) resistance remain unclear.
In silico bioinformatic analysis was performed to identify the most active transcription factor and its inducer that contribute to BCR-ABL-independent TKI resistance. Tandem mass spectrometry analysis was performed to identify the receptor for the noncanonical NF-κB activator FAM167A. In vitro and in vivo mouse experiments revealed detailed molecular insights into the functional role of the FAM167A-desmoglein-1 (DSG1) axis in BCL-ABL-independent TKI resistance. CML cells derived from CML patients were analyzed using quantitative reverse transcription PCR and flow cytometry.
We found that NF-κB had the greatest effect on differential gene expression of BCR-ABL-independent TKI-resistant CML cells. Moreover, we found that the previously uncharacterized protein FAM167A activates the noncanonical NF-κB pathway and induces BCR-ABL-independent TKI resistance. Molecular analyses revealed that FAM167A activates the noncanonical NF-κB pathway by binding to the cell adhesion protein DSG1 to upregulate NF-κB-inducing kinase (NIK) by blocking its ubiquitination. Neutralization of FAM167A in a mouse tumor model reduced noncanonical NF-κB activity and restored sensitivity of cells to TKIs. Furthermore, FAM167A and surface DSG1 levels were highly upregulated in CD34
CML cells from patients with BCR-ABL-independent TKI-resistant disease.
These results reveal that FAM167A acts as an essential factor for BCR-ABL-independent TKI resistance in CML by activating the noncanonical NF-κB pathway. In addition, FAM167A may serve as an important target and biomarker for BCR-ABL-independent TKI resistance.
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