Validation and comparison of 5th edition World Health Organization classification (WHO 2022) and International Consensus Classification proposals for MDS-SFB31.

The criteria of myelodysplastic syndromes (MDS) with mutated SFB31 (MDS-SFB31) proposed by the 5th edition of the WHO classification (WHO 2022) and the International Consensus Classification (ICC) need validation. We analysed 125 consecutive MDS cases with SFB31 mutation or ring sideroblasts (RS) ≥15% without excess blasts. We found that SFB31-negative MDS with RS had significantly different clinical features and worse prognosis. According to WHO 2022, the detection of ≥15% RS may substitute for SF3B1 mutation and our analyses support this proposal for similar prognosis of two groups after excluding high-risk genetic features referred by WHO 2022. Patients with variant allele frequency (VAF) <10% SFB31 tend to have briefer survival, supporting the VAF 10% threshold of ICC. Patients with multilineage dysplasia (MLD) had significantly shorter OS than those with single lineage dysplasia. MLD is still a powerful morphological marker of worse outcome in WHO 2022 and ICC-defined MDS-SF3B1.

Impact of the International Consensus Classification of myelodysplastic syndromes.

The impact of the 2022 International Consensus Classification (ICC) of myelodysplastic syndromes (MDS) needs study. We analysed data from 989 MDS subjects classified using the 2016 World Health Organization (WHO) criteria to determine the impact of the new proposal. Our analyses suggested the ICC criteria of MDS-SF3B1 identifies a more homogenous disease entity than the WHO 2016 criteria of myelodysplastic syndromes with ring sideroblasts (MDS-RS). MDS, not otherwise specified with single lineage dysplasia (MDS, NOS-SLD) patients had a better prognosis than MDS, NOS with multilineage dysplasia (MDS, NOS-MLD) patients. MDS with mutated TP53 and MDS/acute myeloid leukaemia with mutated TP53 patients had the briefest survivals. These data support the ICC of MDS, which allows more accurate diagnoses and risk stratification.

Is race important in genomic classification of hematological neoplasms?

In recent years, genome-based classifications for hematological neoplasms have been proposed successively and proved to be more accurate than histologic classifications. However, some previous studies have reported the racial differences of genetic landscape in persons with hematological neoplasms including myelodysplastic syndromes (MDS), which may cause a genomic classification based on a particular ethnic group does not operate in other races. To determine whether race plays an important role in the genomic-based classification, we validated a newly proposed genomic classification of MDS (J Clin Oncol.2021; JCO2001659), which was based on a large European database, in Chinese patients from our center. Our results showed significant differences between Chinese and European patients including proportion of each group to overall cohort when applying this novel genomic classification. Our data indicate that a genomic classification of hematological neoplasms probably should be revised according to specific genetic features in different races.

Comparison of Levitt's CO breath test and the 15 N-glycine labeling technique for measuring the lifespan of human red blood cells.

The red blood cell (RBC) lifespan is an important physiological indicator of clear significance in clinical research, used for the differential diagnosis of various diseases such as anemia, compensatory phase hemolysis, and polycythemia. The 15 N-glycine labeling technique is the gold standard method for determining RBC lifespans. However, the usefulness of this technique in clinical settings is seriously hindered by the several weeks required to complete the analyses. Levitt's CO breath test is another reliable technique for determining RBC lifespans, with a simpler protocol giving much faster results, making it more useful in clinical applications. We compared the CO breath test and 15 N-glycine labeling technique for measuring the human RBC lifespan. We investigated human RBC lifespans where each subject undertook both the 15 N-glycine labeling technique and the CO breath test. The correlation between the results from these two methods was analyzed. Eight of the ten subjects successfully completed the study. The RBC lifespan values obtained by Levitt's CO breath test were lower than those obtained by the 15 N-glycine labeling technique. The RBC lifespan values determined from the 15 N-glycine labeling technique and the CO breath test were significantly correlated, with a Pearson correlation coefficient of R = 0.98 (p < 0.05), while the R2 of the linear regression equation was 0.96. The CO breath test exhibits as good performance as the 15 N-glycine labelling technique in distinguishing healthy subjects from subjects with hemolysis. The result suggests that the CO breath test is a reliable method for quickly determining human RBC lifespans in clinical applications.

Allo-HSCT compared with immunosuppressive therapy for acquired aplastic anemia: a system review and meta-analysis.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and immunosuppressive therapy (IST) are two major competing treatment strategies for acquired aplastic anemia (AA). Whether allo-HSCT is superior to IST as a front-line treatment for patients with AA has been a subject of debate. To compare the efficacy and safety of allo-HSCT with that of IST as a front-line treatment for patients with AA, we performed a meta-analysis of available studies that examined the impact of the two major competing treatment strategies for AA. RESULTS: Fifteen studies including a total of 5336 patients were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival (OS) was 0.4 (95% CI 0.074-0.733, P = 0.016, I2 = 58.8%) and the pooled HR for failure-free survival (FFS) was 1.962 (95% CI 1.43-2.493, P = 0.000, I2 = 0%). The pooled relative risk (RR) for overall response rate (ORR) was 1.691 (95% CI 1.433-1.996, P = 0.000, I2 = 11.6%). CONCLUSION: Although survival was significantly longer among AA patients undergoing first-line allo-HSCT compared to those undergoing first-line IST, the selection of initial treatment for patients with newly diagnosed AA still requires comprehensive evaluation of donor availability, patient age, expected quality of life, risk of disease relapse or clonal evolution after IST, and potential use of adjunctive eltrombopag.

Effects of post-remission chemotherapy before allo-HSCT for acute myeloid leukemia during first complete remission: a meta-analysis.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is most frequently used to treat acute myeloid leukemia (AML). Whether patients should routinely receive consolidation chemotherapy before proceeding to transplant after achieving first complete remission (CR1) has been a subject of debate. We performed a systematic review and meta-analysis of studies examining the impact of post-remission chemotherapy before allo-HSCT in patients with AML in CR1. Six studies including 1659 patients were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival was 0.9 (95% confidence interval [CI] 0.77-1.05, P = 0.182), and the pooled HR for leukemia-free survival was 0.87 (95% CI 0.75-1.0, P = 0.07). No survival advantage was observed for post-remission chemotherapy before reduced-intensity conditioning or myeloablative conditioning (MAC) allo-HSCT for AML in CR1. The pooled relative risk for relapse incidence (RI) was 1.02 (95% CI 0.82-1.28, P = 0.834). Post-remission chemotherapy before allo-HSCT did not significantly affect the RI in patients with AML in CR1. The analyses revealed no significant benefit of post-remission consolidation chemotherapy in patients who received allo-HSCT. We recommend proceeding to allo-HSCT as soon as CR1 is attained.

Combination therapy with venetoclax and azacitidine for the treatment of myelodysplastic syndromes with DDX41 mutations.

Myelodysplastic syndromes (MDS) patients with DEAD-box helicase 41 (DDX41) mutations have been reported to be treated effectively with lenalidomide; however, there are no randomized studies to prove it. Venetoclax and azacitidine are safe and effective in high-risk MDS/AML. In this study, we evaluated the efficacy of venetoclax and azacitidine combination therapy in eight consecutive MDS patients with DDX41 mutations at our centre from March 2021 to November 2023. We retrospectively analyzed the genetic features and clinical characteristics of these patients. Our findings suggest that MDS patients with DDX41 mutation may benefit from the therapy, for six subjects received this regimen as initial therapy and five of the six subjects achieved complete remission.

Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis.

We investigated data from 180 consecutive patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) who were diagnosed according to the 2022 World Health Organization (WHO) classification of myeloid neoplasms to identify covariates associated with survival. At a median follow-up of 48 months (95% confidence interval [CI] 35-61 months), the median survival was 69 months (95% CI 59-79 months). Patients with bone marrow ring sideroblasts (RS) < 15% had shorter median overall survival (OS) than did those with bone marrow RS ≥ 15% (41 months [95% CI 32-50 months] versus 76 months [95% CI 59-93 months]; P < 0.001). According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.

Case of cryptic TNIP1::PDGFRB rearrangement presenting with myelodysplastic syndrome achieved hematologic and cytogenetic remission with low-dose imatinib plus decitabine therapy.

For a long time, FIP1L1::PDGFRA fusion seems to be the only cryptic rearrangement of myeloid/lymphoid neoplasm with tyrosine kinase gene fusions. Recently, with the wide application of RNA sequencing, more cryptic rearrangements of other TK genes have been identified, especially the PDGFRB. Here we report a case of myelodysplastic syndrome with severe thrombocytopenia. Conventional karyotype analysis revealed a t (5;19) (q33; p13.2) but no PDGFRB rearrangement was detected by the PDGFRB break-apart probe. The TNIP1::PDGFRB fusion was eventually found by RNA sequencing, leading us to treat with low-dose imatinib plus decitabine, and the patient achieved hematologic improvement and cytogenetic remission.

Early activation of inflammatory pathways in UBA1-mutated hematopoietic stem and progenitor cells in VEXAS.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a pleiotropic, severe autoinflammatory disease caused by somatic mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. To elucidate VEXAS pathophysiology, we performed transcriptome sequencing of single bone marrow mononuclear cells and hematopoietic stem and progenitor cells (HSPCs) from VEXAS patients. HSPCs are biased toward myeloid (granulocytic) differentiation, and against lymphoid differentiation in VEXAS. Activation of multiple inflammatory pathways (interferons and tumor necrosis factor alpha) occurs ontogenically early in primitive hematopoietic cells and particularly in the myeloid lineage in VEXAS, and inflammation is prominent in UBA1-mutated cells. Dysregulation in protein degradation likely leads to higher stress response in VEXAS HSPCs, which positively correlates with inflammation. TCR usage is restricted and there are increased cytotoxicity and IFN-γ signaling in T cells. In VEXAS syndrome, both aberrant inflammation and myeloid predominance appear intrinsic to hematopoietic stem cells mutated in UBA1.

IPSS-M has greater survival predictive accuracy compared with IPSS-R in persons ≥ 60 years with myelodysplastic syndromes.

There are considerable new data on mutation topography in persons with myelodysplastic syndromes (MDS). These data have been used to update conventional risk models such as the Revised International Prognostic Scoring System (IPSS-R). Whether the molecular IPSS (IPSS-M) which includes these data improves survival prediction accuracy is untested. To answer this question, we compared survival prediction accuracies of the IPSS-R and IPSS-M in 852 consecutive subjects with de novo MDS. Concordance statistics (C-statistics) of the IPSS-R and IPSS-M in the entire cohort were similar, 0.67 (95% Confidence Interval [CI] 0.64, 0.71) and 0.68 (0.64, 0.71). Average numbers of mutations and of IPSS-M related mutations were greater in persons ≥ 60 years (2.0 [Interquartile Range [IQR], 1, 3] vs. 1.6 [0, 2], P = 0.003; 1.6 [0, 2] vs. 1.3 [0, 2], P = 0.006). Subjects ≥ 60 years had a higher incidence of mutations in RUNX1, TP53, TET2, SRSF2, DNMT3A, STAG2, EZH2 and DDX41. In contrast, mutations in U2AF1 were more common in persons < 60 years. Next we tested survival prediction accuracy based on age < or ≥ 60 years. C-statistics of the IPSS-R and IPSS-M in subjects ≥ 60 years were 0.66 (0.61, 0.71) and 0.69 (0.64, 0.73) whereas in subjects < 60 years they were 0.67 (0.61, 0.72) and 0.65 (0.59, 0.71). These data indicate an advantage for the IPSS-M over the IPSS-R in subjects ≥ 60 years but not in those < 60 years probably because of a great frequency of mutations correlated with survival in those ≥ 60 years.

Comparison of the revised 4th (2016) and 5th (2022) editions of the World Health Organization classification of myelodysplastic neoplasms.

We used data from 852 consecutive subjects with myelodysplastic neoplasms (MDS) diagnosed according to the 2016 (revised 4th) World Health Organization (WHO) criteria to evaluate the 2022 (5th) edition WHO classification of MDS. 30 subjects previously classified as MDS with an NPM1 mutation were re-classified as acute myeloid leukaemia (AML). 9 subjects previously classified as MDS-U were re-classified to clonal cytopenia of undetermined significance (CCUS). The remaining 813 subjects were diagnosed as: MDS-5q (N = 11 [1%]), MDS-SF3B1 (N = 70 [9%]), MDS-biTP53 (N = 53 [7%]), MDS-LB (N = 293 [36%]), MDS-h (N = 80 [10%]), MDS-IB1 (N = 161 [20%]), MDS-IB2 (N = 103 [13%]) and MDS-f (N = 42 [5%]) and MDS-biTP53 (N = 53 [7%]). 34 of these subjects came from the 53 (64%) MDS-biTP53 previously diagnosed as MDS-EB. Median survival of subjects classified as MDS using the WHO 2022 criteria was 45 months (95% Confidence Interval [CI], 34, 56 months). Subjects re-classified as MDS-biTP53 and MDS-f had significantly briefer median survivals compared with other MDS sub-types (10 months, [8, 12 months] and 15 months [8, 23 months]). In conclusion, our analyses support the refinements made in the WHO 2022 proposal.

A Phenogenetic Axis that Modulates Clinical Manifestation and Predicts Treatment Outcome in Primary Myeloid Neoplasms.

Although the concept of "myeloid neoplasm continuum" has long been proposed, few comparative genomics studies directly tested this hypothesis. Here we report a multi-modal data analysis of 730 consecutive newly diagnosed patients with primary myeloid neoplasm, along with 462 lymphoid neoplasm cases serving as the outgroup. Our study identified a "Pan-Myeloid Axis" along which patients, genes, and phenotypic features were all aligned in sequential order. Utilizing relational information of gene mutations along the Pan-Myeloid Axis improved prognostic accuracy for complete remission and overall survival in adult patients of de novo acute myeloid leukemia and for complete remission in adult patients of myelodysplastic syndromes with excess blasts. We submit that better understanding of the myeloid neoplasm continuum might shed light on how treatment should be tailored to individual diseases. Significance: The current criteria for disease diagnosis treat myeloid neoplasms as a group of distinct, separate diseases. This work provides genomics evidence for a "myeloid neoplasm continuum" and suggests that boundaries between myeloid neoplastic diseases are much more blurred than previously thought.

Clinical features and treatment outcomes in patients with T-cell large granular lymphocytic leukemia: A single-institution experience.

AIM: Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder associated with failure of hematopoiesis and autoimmune diseases. This study describes the clinical features and treatment responses of 108 patients with T-cell large granular lymphocyte leukemia (T-LGLL). METHODS: Clinical data were collected from T-LGLL patients treated at an anemia treatment center within the hematology and blood diseases unit of a single hospital from January 2009 to April 2019. RESULTS: The majority of patients (78 %) were symptomatic at the time of presentation. Splenomegaly was observed in 41 % of cases, while hepatomegaly and lymphadenopathy were rare (6 % and 7 %, respectively). Cyclosporine (CsA) monotherapy was used as first-line therapy for 16 patients, with an overall response rate (ORR) of 56 %. CsA in combination with steroids was administered in 83 patients, with an ORR of 48 %. Among patients experiencing relapse or resistance to first-line therapy, 10 received antithymocyte globulin (ATG) therapy, with an ORR of 50 %; an additional 9 patients received a modified regimen of high-dose cyclophosphamide (CTX) therapy, yielding an ORR of 78 %. CONCLUSIONS: This study provides new information regarding the clinical features and therapeutic strategies for T-LGLL, which can be used to improve clinical decision making for T-LGLL patients. The data presented here indicate the CsA is an effective option for the treatment of T-LGLL, while modified regimens of high-dose CTX or ATG are safe and effective choices for patients with CsA refractory disease.

Eltrombopag, oral immunosuppressant and androgen combination therapy in twelve patients with refractory severe aplastic anemia.

Objective: Eltrombopag monotherapy or eltrombopag combined with immunosuppressant has achieved robust hematologic responses in severe aplastic anemia (SAA). In patients with refractory SAA, for whom hematopoietic stem cell transplantation is unavailable, we attempted to combine eltrombopag with oral immunosuppressant and androgen, to further improve hematologic response. Methods: We collected and analyzed data retrospectively from twelve refractory SAA cases who had received combination therapy of eltrombopag, oral immunosuppressant and androgen. All these patients had received intensive immunosuppressive treatment (IST) for more than 6 months and were evaluated as nonresponders. Results: A total of 12 SAA patients were treated with a combination of eltrombopag, an oral immunosuppressant (cyclosporine, N = 9; tacrolimus, N = 3) and androgen. The median maximum dose of eltrombopag was 75 mg/day (range, 75-150). After a median follow-up of 8.5 months (7-23), the overall response rate (ORR) was 42% (5/12, including trilineage, N = 4; hemoglobin + platelet, N = 1). Two of 5 responders reached normal blood counts. Optimal hematological response rates were reached at 6 months. The median increase in neutrophil, hemoglobin and platelet count were 1.64 × 109 /L (0.71-2.66), 53 g/L (25-66.5) and 25 × 109 /L (14-230), respectively. In general, the combination therapy was well tolerated; however, two patients suffered from non-lethal upper extremity venous thrombosis when they were platelet transfusion-dependent. Conclusion: Eltrombopag, oral immunosuppressant and androgen combination therapy in patients with IST-refractory SAA is feasible and could restore multi-lineage hematopoiesis. Thrombosis risk of eltrombopag still needs to be monitored.