Bone Marrow Blast Percentage Research Articles

Characteristics and Outcomes for Adult Patients with T-Lymphoblastic Leukemia/Lymphoma (T-ALL/LBL): A Retrospective Study

Introduction T-lymphoblastic leukemia/lymphomas (T-ALL/LBL) are immature T-lymphoid neoplasms localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. T-ALL/LBL accounts for 10 - 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. Historically, the outcome of adult patients with newly diagnosed T-ALL/LBL) has been poor. Various studies reported low complete remission (CR) rates and short median overall survival (OS) ranging from 11 to 17 months. Here we present real-world data on outcomes and characteristics of an ethnically diverse adult population with T-ALL/LBL treated in a large academic center. Methods A retrospective chart review was performed of all patients with pathologic diagnosis of T-ALL/LBL at Los Angeles County + University of Southern California Medical Center and Norris Comprehensive Cancer Center. We identified thirty-one patients between January 1st, 2011 and January 1st, 2020. Demographic, clinical, and pathologic data were extracted from the medical record. Data analysis software SAS (9.4) was used to assess overall survival (OS). Results In our cohort, 61% were male and 55% were Hispanic. Median age at diagnosis was 32 (13 - 66) years (table 1). Median white blood cell count (WBC) at presentation was 81,000 (1,800 - 526,000) 109/L. Median peripheral blast percentage at presentation was 35% (0% - 91%), with 23% (7/31) having no peripheral blasts. Median bone marrow blast percentage at diagnosis was 68% (0% - 97%), with 30% (9/30) having <20% blasts. Extramedullary disease was present in 76% (22/29) at diagnosis, with 59% (17/29) presenting with bulky mediastinal disease and 3% (1/31) with central-nervous-system (CNS) disease. Early T-cell precursor phenotype was noted in 16% (5/31) and complex cytogenetics in 18% (5/28). The most common regimen was the pediatric-inspired USC-ALL regimen (based on CCG-1882), 68% (21/31), and the next most common was hyper-CVAD regimen, 23% (7/31). Two patients received alternative regimens and one patient did not receive therapy. 90% achieved CR using the definition of bone marrow blasts <5% and resolution of extramedullary disease. Seven patients (23%) relapsed after achieving CR. Median follow-up for our cohort was 26.5 months, with 71% followed at 1-year, and 58% followed at 2-years. At the time of the study, 17 patients (55%) were known to be alive, and 8 patients (26%) were deceased. Hematopoietic stem cell transplantation (HSCT) was performed in 48% (15/31). The OS was 76% at 1-year and 66% at 5-years. Conclusions According to MD Anderson group, a CR rate of 91% and 5-year OS rate of 67% were reported with hyper-CVAD in T-ALL/LBL patients. Similar results were reported with Berlin-Frankfurt-Munster and the UK ALL XII/ECOG 2993 protocols. Our data reflects a comparable outcome in this predominantly Hispanic adult T-ALL population. Increased utilization of allogeneic HSCT might have been attributed to improvement in survival. Currently, very limited data is available exploring diverse racial and ethnic groups in this disease and we hope our cohort is an addition to the process of better understanding the social and phenotypic differences in T-ALL characteristics and outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TP53 Mutation Status Defines a Distinct Clinicopathological Entity of Therapy-Related Myeloid Neoplasm, Characterized By Genomic Instability and Extremely Poor Outcome

BACKGROUND: The prognostic and therapeutic impact of TP53-mutated (TP53mut) myeloid neoplasm (MN) is an area of intense interest, with the 5th edition of the World Health Organization, the International Consensus Classification, and the European LeukemiaNet guidelines, all recommending major changes MN classification based on TP53mut. However, studies driving these changes predominantly included de novo MDS (Bernard et al. Nat Med 2020), AML and high risk MDS treated with intensive chemotherapy (Grob et al. Blood 2022), or MN with complex karyotype (CK, Weinberg et al. Blood Adv 2022). Therefore, the significance of these findings as they relate to t-MN is not known. METHODS: We analyzed therapy-related myeloid neoplasm (t-MN) (n=377) patients evaluated at Mayo Clinic, Rochester and South Australian MDS Registry with clinical, integrated genomic profiling, and long-term follow-up to characterize the genomic profile and outcome of TP53mut t-MN. RESULTS: Our cohort of 377 t-MN included t-MDS (n=245, 65%) and t-AML (n=132, 35%), with a median age at t-MN diagnosis being 65.7 years. 184 TP53mut at variant allele frequency (VAF) ≥2% were detected in 131 (34.74%) patients. Median overall survival (OS) of TP53mut VAF <10% (n=14) was similar to wild-type TP53 (TP53wt), hence further analysis was restricted to TP53mut with VAF >10% (n=111). TP53mut patients without VAF (n=6) were not included for further analysis. Genomic instability was highly evident in TP53mut t-MN compared to TP53wt t-MN. CK, monosomal karyotype (MK), chromosome 5q deletion, and marker chromosomes were enriched in TP53mut t-MN. In contrast, driver oncogenic gene mutations such as IDH2, SRSF2, RAS, and TET2 were less frequent in TP53mut. TP53mut also dictated the clinical presentation, longer latency (interval between primary cancer and t-MN diagnosis), and inferior OS compared to TP53wt (8.2 vs. 19.4 months; P <0.001). On multivariate Cox regression analyses, TP53mut was associated with inferior OS (HR 1.43 95% CI 1.01-2; P =0.03) independent of CK and bone marrow blast %. A significantly higher proportion of CK patients had TP53mut compared to non-CK patients (74.4% vs. 5.4%, P <0.001). Even within the CK cohort, TP53mut was associated with structural genomic instability, with a higher proportion of TP53mut harbouring MK (P =0.013), marker chromosome (P =0.033), deletion 5q (P <0.001), abnormal chromosome 17 (P =0.001), and other structural chromosomal aberrancies compared to TP53wt-CK. In contrast to the predominance of structural chromosomal aberrancies in the TP53mut-CK cohort, mutations driving MN were sparse in TP53mut-CK compared to TP53wt-CK. Finally, TP53mut-CK was associated with significantly poor survival compared to the TP53wt-CK (8.2 vs. 17 months; P <0.001). Though bone marrow (BM) % predicted poor outcome in the whole t-MN cohort, it failed to predict outcome in TP53mut t-MN patients. We compared the clinical and molecular profiling of TP53mut t-MDS (<5%, 5-9%, 10-19% blasts) and t-AML (≥20% blasts) at t-MN diagnosis. Genomic instability, TP53mut allelic status, number of TP53mut, and the clone size were similar across all four cohorts. Remarkably, the survival of TP53mut patients were equally dismal irrespective of blast percentage (P=0.2, Figure 1A). Together, these findings suggest that TP53mut t-MN represent a homogenous group irrespective of BM blast percentage. Integrating the mutation, conventional cytogenetic, copy number variation, FISH, and SNP array analysis, TP53mut were classified as single- or multi-hit (Grob et al. Blood 2022). In total, 31 (25.2%) of the 123 patients with TP53mut (n=111) and/or loss of TP53 (n=12) locus were considered single-hit, and 92 (74.8%) were considered as multi-hit. In contrast to prior reports, we did not observe enrichment of genomic instability, or differences in degree of cytopenia, bone marrow blast % and t-MN phenotype in multi- vs single-hit TP53mut patients. Importantly, no OS differences were observed when TP53mut were stratified by type of TP53mut (truncation vs. missense), site of missense mutation (hot- vs. non-hot spot) and single- vs multi-hit (Figure 1B). CONCLUSION: The classification of t-MN based on TP53mut status is clinically and biological relevant, irrespective of blast % or single- or multiple-hit status. TP53mut t-MN is a molecularly defined unique group enriched for genetic instability and is associated with extremely poor outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk factors for leukemia transformation in patients with myelodysplastic syndromes

Objective: To explore the risk factors in leukemia transformation (LT) in those with myelodysplastic syndromes (MDS) . Methods: From January 2012 to December 2020,data on 320 patients with newly diagnosed primary MDS were gathered from the MDS center. The clinical features and molecular characteristics are explored. Additionally, a retrospective analysis of risk factors for the development of acute leukemia from MDS was done. Results: The median follow-up was13.6 (0.4-107.3) months. 23.4% (75/320) of the MDS patients had LT group. Significant differences between the LT group and non-LT group can be seen in age (P<0.001) , bone marrow blast percentage (P<0.001) , bone marrow fibrosis (P=0.046) , WHO classification (P<0.001) , IPSS-R (P<0.001) and IPSS-R karyotype group (P=0.001) . The median number of mutation of LT group was 1 (1, 3) , that in non-LT group was 1 (0, 2) ,which had a statistical difference (P=0.003) .At the time of the initial diagnosis of MDS, the LT group had higher rates of the TP53 mutation (P=0.034) , DNMT3A mutation (P=0.026) , NRAS mutation (P=0.027) and NPM1 mutation (P=0.017) . Compared with the mutations at first diagnosis and LT of six patients, the number of mutations increased and the variant allele frequencies (VAF) increased significantly in LT patients. Higher bone marrow blast percentage (Refer to <5% , 5% -10% : HR=4.587, 95% CI 2.214 to 9.504, P<0.001, >10% : HR=9.352, 95% CI 4.049 to 21.600, P<0.001) , IPSS-R cytogenetic risk groups (HR=2.603, 95% CI 1.229-5.511, P=0.012) , DNMT3A mutation (HR=4.507, 95% CI 1.889-10.753, P=0.001) , and NPM1 mutation (HR=3.341, 95% CI 1.164-9.591, P=0.025) were all independently associated with LT in MDS patients, according to results of multivariate Cox regression. Conclusion: Bone marrow blast percentage, IPSS-R cytogenetic risk groups, DNMT3A mutation, and NPM1 mutation are independent risk factors in LT for MDS patients.

Variables associated with hematological remission and survival in patients with acute myeloid leukemia after induction failure and relapse

Objective: This study aimed to explore variables associated with remission rate and survival in patients with acute myeloid leukemia (AML) after induction failure and relapse. Methods: Data of 373 consecutive patients with AML were analyzed after induction failure and relapse. Binary logistics and the Cox model regression were used to identify variables associated with remission rate and outcomes. Results: In patients with AML after induction failure and relapse, the total CR+CRi rates were 50.6% and 40.3%, respectively; among those who achieved CR/CRi, the 3-year RFS rates were 34.4% and 30.4%, respectively, and the 3-year overall survival rates were 40.1% and 31.6%, respectively. In the multivariate analyses, using CLAG or FLAG regimen as a re-induction chemotherapy regimen, age <39 years and SWOG low-risk were significantly associated with higher remission rates in patients with induction failure. Male, secondary AML, SWOG high-risk, the interval from the first remission to relapse within 12 months, and bone marrow blasts ≥20% at the time of relapse were significantly associated with lower remission rates in relapsed patients. Transplantation was significantly associated with prolonged relapse-free survival and overall survival in patients achieving hematologic remission; the SWOG low-risk group was significantly associated with longer overall survival in those with induction failure; and achieving CR (not CRi) or having female gender was associated with longer RFS or overall survival in relapsed patients. Conclusion: Reinduction chemotherapy regimen, age, gender, SWOG risk, secondary AML, the interval from the first remission to relapse, and bone marrow blast percentage at the time of relapse were significantly associated with remission rates in the patients with AML after induction failure and relapse. Transplantation, SWOG low-risk, achieving CR, or female gender were associated with longer survivals in those achieving remission.

Azacitidine and donor lymphocyte infusion for patients with relapsed acute myeloid leukemia and myelodysplastic syndromes after allogeneic hematopoietic stem cell transplantation: A meta-analysis.

BackgroundFor patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), azacitidine with donor lymphocyte infusion (DLI) is a feasible option to perform a preemptive or salvage treatment. However, its efficacy lacked comprehensive analysis, and this study aimed to fill this gap.MethodsWe searched potential studies in PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials. Thirteen studies involving 811 patients were analyzed. The inverse variance method was used to calculate the pooled proportion and 95% confidence interval (CI). Subgroup analysis was performed to explore the source of heterogeneity.ResultsThe rate of pooled complete remission + partial remission (CR + PR), CR, and 2-year overall survival (OS) were 30% (95% CI: 22%–39%), 21% (95% CI: 16%–28%), and 31% (95% CI: 27%–35%), respectively. The pooled acute graft-versus-host disease (GvHD) and chronic GvHD rates were 15% (95% CI: 9%–23%) and 14% (95% CI: 8%–23%), respectively. Adverse cytogenetics and a higher percentage of bone marrow (BM) blasts at relapse were correlated with worse CR + PR and CR (interaction p < 0.05). Higher 2-year OS was found in patients with lower BM blasts at relapse or a longer time from allo-HSCT to relapse (interaction p < 0.05). Furthermore, the preemptive treatment for molecular relapse/minimal residual disease positivity resulted in much better outcomes than that for hematological relapse, both in terms of CR and 2-year OS (interaction p < 0.001).ConclusionThe regimen of azacitidine and DLI could safely improve the outcomes of relapsed AML/MDS after allo-HSCT, especially in those with signs of early relapse. The administration of targeted medicines in azacitidine-based therapies may further improve the outcomes of relapsed AML/MDS.

Hypomethylating agents combined with low-dose chemotherapy for elderly patients with acute myeloid leukaemia unfit for intensive chemotherapy: a real-world clinical experience

This study aimed to assess the efficacy and safety of hypomethylating agent (HMA)-based regimens in the treatment of older adult patients with acute myeloid leukaemia (AML), unfit for standard induction chemotherapy. Treatment outcomes and prognostic factors of 140 older adult patients with AML who were unfit for intensive chemotherapy and were treated with HMA-based therapies were retrospectively analysed. The median age of the group was 70 years, and poor-risk cytogenetics and secondary/treatment-related AML (s/t-AML) accounted for 45.6% and 34.3% of these patients, respectively. The overall response rate was 48.6%, and 40.1% for patients who achieved complete remission (CR) or CR with incomplete blood count recovery. The median overall survival (OS) was 10.4 months, and the 1-, 2-, and 5-year OS rates were 42.6%, 19.9%, and 4.9%, respectively. Early mortality accounted for 4.3% of all cases, and infection occurred in 87.1% of all patients during induction therapy. Patients who received HMA and low-dose chemotherapy presented with significantly superior response and long-term survival rates compared to those who received HMA alone. They also showed comparable outcomes to those treated with the azacitidine plus venetoclax protocol. Low-dose chemotherapy in combination with decitabine or azacitidine showed a similar response rate and prognosis. Age ≥ 75years and a white blood cell (WBC) count ≥ 10 × 109 cells/L were identified as independent adverse prognostic factors for OS, while poor-risk cytogenetics, percentage of bone marrow blasts, and s/tAML had no significant impact on OS when patients were treated with HMA-based regimens. In conclusion, HMA combined with low-dose chemotherapy was effective and safe in older adults with AML who were unfit for intensive chemotherapy, and no difference was observed between decitabine and azacitidine.

MicroRNA-125b Accelerates and Promotes PML-RARa-driven Murine Acute Promyelocytic Leukemia

ObjectiveMost acute promyelocytic leukemia cases are characterized by the PML-RARa fusion oncogene and low white cell counts in peripheral blood. MethodsBased on the frequent overexpression of miR-125-family miRNAs in acute promyelocytic leukemia, we examined the consequence of this phenomenon by using an inducible mouse model overexpressing human miR-125b. ResultsMiR-125b expression significantly accelerates PML-RARa-induced leukemogenesis, with the resultant induced leukemia being partially dependent on continued miR-125b overexpression. Interestingly, miR-125b expression led to low peripheral white cell counts to bone marrow blast percentage ratio, confirming the clinical observation in acute promyelocytic leukemia patients. ConclusionThis study suggests that dysregulated miR-125b expression is actively involved in disease progression and pathophysiology of acute promyelocytic leukemia, indicating that targeting miR-125b may represent a new therapeutic option for acute promyelocytic leukemia.

P782: IMMUNOPHENOTYPIC AND MOLECULAR GENETIC MARKERS OF UNFAVORABLE PROGNOSIS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME

Background: Therapy is selected based on risk, need for transfusion of blood components, percentage of bone marrow blasts, and cytogenetic profile. In low-risk groups, the goal of treatment is to reduce the need for replacement therapy and prevent transformation to higher-risk or AML. In higher risk groups, the goal is to prolong survival. Currently, there are no approved criteria for selecting therapy for patients with MDS based on the classifications and prognostic scales used, treatment regimens for progression of MDS or its refractory forms. Aims: The aim of the study was to identify unfavorable prognostic immunophenotic and molecular genetic markers of blast cells in patients with high-risk myelodysplastic syndrome Methods: The prospective cohort study included 68 patients with newly diagnosed MDS in the period from January 2017 to December 2021. The patients underwent a primary diagnostic complex of MDS, including immunophenotyping and molecular genetic research of bone marrow aspirate. The age of patients is 25-82 years, the median age is 64 years. According to the IPSS classification included: high risk (10 pats), intermediate-2 (26 pats), intermediate-1 (26 pats), low risk (6 pats). According to the IPSS-R classification included: very high risk (23 pats), high risk (17 pats), intermediate (14 pats), low risk (12 pats), very low risk (2 pats). The following molecular genetic markers were found: complex aberrations >3 (10 pats), trisomy 8 chromosome (8 pats), absence of molecular genetic disorders (27 pats), isolated 5q chromosome (13 pats), any changes of the 7 chromosome (8 pats), deletion of the 20 chromosome (3 pats), deletion of the 11 chromosome (1 pats), TP53 (2 pats). To explore immunophenotic and molecular genetic markers we use three state “illness-death” model. We consider the following states: diagnosis, transformation into leukemia; death. Results: We identified high-risk immunophenotypic and molecular genetic markers - · for transition “diagnosis-death”: - CD38 <50% HR 3.7 (1.2-11.5 CI; p = 0.022), - CD13> 50% HR 8.7 (1.1-67.8 CI; p = 0.04), - complex aberrations >3 HR 5.8 (1.4-24.6 CI; p=0,015); - · for transition “diagnosis-transformation”: - CD71 ≥65% HR 4.1 (1.35-12.4 CI; p = 0.013); - CD13> 75% HR 2.8 (1.1-7.1 CI; p = 0.034), - complex aberrations >3 HR 2.8 (0,86-9,0 CI; p=0,087); - · for transition “transformation-death“: - CD25 <5% HR 6.3 (1.4-28 / 4 CI; p = 0.017), - CD 33 <50% HR 6.6 (1.3-34.7 CI; p = 0.026)), - complex aberrations >3 HR 0,22 (0,06-0,84 CI; p=0,027), - trisomy 8 chromosome HR 7.9 (0.71-88 CI; р=0,093). Figure 1 – The probability of various conditions depending on the time since the diagnosis. State 1 - estimation of the probability of being in the state «diagnosis-transformation» State 2 - estimation of the probability of being in the state «transformation-death» State 3 - estimation of the probability of being in the state «diagnosis-death» Image:Summary/Conclusion: The selection of groups of patients with identified immunophenotypic and molecular genetic markers of a high risk of transformation into acute leukemia and a high risk of death (“diagnosis-death”: CD38<50%, CD13>50%, complex aberrations>3; “diagnosis-transformation”: CD71≥65%, CD13>75%, complex aberrations>3; “transformation-death“: CD25<5%, CD33<50%, complex aberrations>3, trisomy 8 chromosomes) requires consideration of a new approach to therapy.

P762: NONLINIEAR IMPACT OF CLINICAL FEATURES ON THE SURVIVAL OUTCOME OF MYELODYSPLASTIC SYNDROMES PATIENTS

Background: Myelodysplastic syndromes (MDS) are a group of hematopoietic stem-cell disorders with heterogenous prognosis. The revised international prognostic scoring system (IPSS-R) (Greenberg et al., Blood, 2012) is the most widely used score for prognostication. However, the allocation of IPSS-R risk categories remains imprecise for some patients leading to unsatisfactory therapy decisions. Newer molecular prognostic models (Nazha et al., JCO, 2021 and Bernard et al., ASH, 2021) have added mutation data to improve survival predictions for MDS patients. Aims: Our aims were to investigate the nonlinear association of normalized clinical data in combination with molecular and cytogenetic data and to improve the prognostication potential of IPSS-R for patients with MDS. Methods: A multivariable fractional polynomials (MFP) algorithm was applied on clinical data of 943 MDS patients and nonlinear associations between continuous covariates and survival outcomes were efficiently modeled within Cox regression. Selected transformed variables were picked and the potential overfit was avoided by a closed test procedure for function selection (Royston et al., John Wiley & Sons, 2008). The performance of the model was evaluated in an independent set of 436 MDS patients and the accuracy was assessed using a concordance (c)index and the area under the Receiver Operating Characteristic curve (AUC) at each time point. Mutation data was obtained in a subset of 695 patients using next-generation sequencing, evaluating a panel of 81 genes at the time of diagnosis. Results: An MFP-model consisting of cytogenetics per IPSS-R and WHO subtypes, continuous forms of age and hemoglobin, and non-linear transformations of platelets and bone marrow blast percentage yielded a c-index performance of 0.82 vs 0.78 for IPSS-R and a significant AUC upgrade at all time points in the training set (Figure a). In comparison with the IPSS-R, absolute neutrophil count was not identified as an independent prognostic covariate and common features were treated in a non-linear fashion. Validation of the model in an independent set of 438 patients yielded a higher c-index (0.72 vs 0.68) with an improved AUC over time compared to the IPSS-R (Figure b). Based on MFP risk score, patients were then clustered into 5 different risk categories and compared with IPSS-R classifications. Our data showed no significant difference in time to death between IPSS-R groups for very low risk and low risk or between low risk and intermediate risk (Figure c); however, MFP classification showed 5 significantly different subgroups in predicting time to death for MDS patients (Figure d). We further investigated the effect of molecular data on disease prognostics in a subset of 695 patients sequenced using an 81 gene panel. In addition to the selected clinical covariates, occurrence of TP53, SRSF2, and ZRSR2 mutations were independently associated with lower survival, while the presence of TET2 mutation showed a depression effect on TP53 mutation towards a better outcome. As SF3B1 was not selected in the final model, we further evaluated its potential interactions and identified its correlation with cytogenetics and platelets, which predominated in the MFP model. This might be due to heterogeneity within the data set (e.g., 25% co-occurrence of SF3B1 with TP53 mutation) and needs to be investigated in larger cohorts. Image:Summary/Conclusion: We have established a nonlinear model that yields improved risk assessment compared to IPSS-R criteria.

Event-free Survival in Patients with Chronic Myeloid Leukemia Receiving Front-line Imatinib Mesylate

Objective: Chronic myeloid leukemia (CML) prognostication at the time of diagnosis is critical to determine the intensity of initial treatment. Event-free survival (EFS) has become a prominent concept of prognosis in the patients with chronic phase CML (CML-CP). The aim of this study is to assess the prognostic impact of bone marrow (BM) and peripheral blood (PB) cellular components, in correlation with the clinical parameters. Materials and Methods: One hundred forty-three patients with CML-CP on the front-line imatinib mesylate therapy were recruited into this study. Clinical and laboratory characteristics, therapeutic responses were recorded. Sokal, Euro/Hasford, The EUropean Treatment Outcome Study (EUTOS) and The EUTOS long-term survival (ELTS) scores were calculated for the studied patients. Results: Median follow-up time was 84 (IQR: 54-125) and median front-line therapeutic duration was 56 (IQR:23-89) months. Five-year EFS rate was 62.3% (95% CI: 53.9-70.7). The blast percentage in the BM, EUTOS scores, and basophil percentage in PB were related with the poor therapeutic outcomes in frontline therapy (p=0.002, p=0.002 and p=0.042, respectively). Although Sokal risk classification showed that the intermediate class had a higher event risk compared to the low-risk class (p=0.001), the predictive association disappeared in high-risk classes. Conclusion: EUTOS score system has better predictive capability for front-line imatinib therapy comparing with other indices. Higher blast percentage in BM and increased basophil percentage in PB are independent risk factors, adversely related with EFS in patients with CML.

Hyperfibrinogenemia as a Poor Prognostic Indicator in Myelodysplastic Syndrome.

BackgroundMyelodysplastic syndrome (MDS) is a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells. It has been demonstrated that fibrinogen (FIB) is associated with disease risk in several cancer types. Coagulation and fibrinolysis problems are widespread in MDS patients. Therefore, FIB might be one of these indicators. We thus examined the role of FIB levels in the prognosis of MDS.MethodsA cohort of 198 MDS patients were retrospectively analyzed to explore the prognostic value of the plasma FIB levels at diagnosis. Patients were divided into the high FIB group and low FIB group. The prognostic significance of FIB was determined by univariate and multivariate Cox hazard models.ResultsIn our cohort, the FIB levels in 198 MDS patients were higher than those in 100 healthy donors (3.9 g/L vs 2.9 g/L, P < 0.0001). MDS patients with high FIB levels had significantly shorter overall survival (OS; P = 0.001) and decreased leukemia-free survival (LFS; P = 0.036). Multivariate cox proportional hazards regression analysis indicated that, in addition to older age, gender, lower HB, poorer karyotype for OS, lower NE, and higher bone marrow blast percentage for OS and LFS, elevated FIB level was also an independent adverse prognostic factor for OS (P = 0.045) but not for LFS (P = 0.188).ConclusionElevated FIB levels may be associated with mortality risk among MDS patients and could predict disease progress and patient prognosis. Thus, assessment of FIB levels may promote the determination of the prognosis of MDS patients.

Hematologic improvements with ivosidenib + azacitidine compared to placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia.

7042 Background: Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival and complete remission + partial hematologic recovery rates compared with placebo (PBO) + AZA, in patients (pts) with newly diagnosed IDH1-mutant acute myeloid leukemia (AML) in the Phase 3 AGILE trial (NCT03173248). Here we report blood count recovery results from the AGILE trial. Methods: Pts were randomized 1:1 to IVO 500 mg QD + AZA 75 mg/m2 SC or IV for 7 days in 28-day cycles (n = 72), or PBO+AZA (n = 74). Red blood cell (RBC)/platelet transfusion history were assessed at screening and follow-up. Bone marrow (BM) and peripheral blood samples were obtained at screening, and during weeks 9, 17, 25, 33, 41, 53, and every 24 weeks thereafter, and at end of treatment and during EFS follow up. Samples were analyzed at each local site according to ICSH guidelines. Results: In the IVO+AZA and PBO+AZA arms, 4.2% and 5.5% of pts, respectively, received concomitant granulocyte colony-stimulating factor. Hemoglobin levels steadily increased from baseline at a similar rate in both treatment arms. Mean platelet count recovered from baseline values in the IVO+AZA and PBO+AZA arms (71.0 and 92.6 x 109/L, respectively) as early as week 9 of treatment (171.1 and 155.1 x 109/L, respectively) and continued to steadily increase thereafter in the treated population. In pts receiving IVO+AZA, mean neutrophil counts rapidly increased from baseline (0.99 x 109/L) to week 2 (2.05 x 109/L) and week 5 (4.07 x 109/L), and then generally stabilized to within the normal range to study end (last available cycle value; ̃2.0 x 109/L). Mean neutrophil counts initially declined with PBO+AZA before slowly recovering to near-normal levels after 36-40 weeks. The increased blood counts were accompanied by a rapid decrease in the mean BM blast percentage from 54.8% at baseline to 12.0% and 7.2% at week 9 and 17, respectively, in IVO+AZA treated patients and were maintained for 149 weeks. The decline in BM blasts was slower in the PBO+AZA arm (53.7%, 34.6% and 19.6% at baseline, week 9 and week 17, respectively). Among patients who were RBC/platelet transfusion-dependent at baseline (̃54.0% in both groups), 46.2% in the IVO+AZA group achieved RBC/platelet transfusion independence compared with 17.5% in the PBO+AZA arm (1-sided p = 0.0032). Additionally, fewer adverse events of febrile neutropenia (28.2% vs 34.2%) and infections (28.2% vs 49.3%) were reported in the IVO+AZA arm compared to the PBO+AZA arm. Conclusions: IVO+AZA demonstrated a significant clinical benefit compared with PBO+AZA and this sub-analysis demonstrated a rapidly improved recovery of blood counts and a reduced dependence on RBC and/or platelet transfusion. Moreover, rates of febrile neutropenia and infections were reduced with IVO+AZA. Clinical trial information: NCT03173248.

Dynamic trajectory of platelet counts after the first cycle of induction chemotherapy in AML patients

BackgroundPlatelet counts varied over time after induction chemotherapy. We aimed to investigate the different trajectories of platelet counts after the first cycle of induction chemotherapy in patients newly diagnosed with acute myeloid leukemia.Methods and resultsIn total, 149 individuals were included in this study. We identified four distinct trajectories using a group-based trajectory model: low- stability group (n = 27, 18.12%), low-level decrease–medium elevation group (n = 42, 28.19%), low-level decrease–high elevation group (n = 60, 40.27%), and high-level decrease–medium elevation group (n = 20, 13.42%). The baseline characteristics of the high-level decrease–medium elevation group included higher platelet count, lower white blood cell count, lower percentage of bone marrow blasts, and lower rates of complete remission after the first cycle of induction chemotherapy. Compared with the low-stability group, the hazard ratios were 0.32 (95% confidence interval, 0.15–0.68) for the low-level decrease–medium elevation group, 0.31 (95% confidence interval, 0.15–0.63) for the low-level decrease–high elevation group, and 0.35 (95% confidence interval, 0.13–0.89) for the high-level decrease–medium elevation group after adjustment for age and gender by Cox proportional hazard regression. Compared with the low-stability group, the hazard ratios were 0.33 (95% confidence interval, 0.14–0.77) for the low-level decrease–medium elevation group and 0.31 (95% confidence interval, 0.14–0.67) for the low-level decrease–high elevation group after adjustment for age, gender, white blood cell count, and bone marrow blasts. These associations persisted after adjusting for age, gender, white blood cell count, bone marrow blasts, and platelet count.ConclusionThe dynamic trajectory of platelet counts after the first cycle of induction chemotherapy is a significant predictor of all-cause mortality in patients with acute myeloid leukemia. Timely intervention should be considered for the low-stability group. The low-level decrease–medium elevation and low-level decrease-high elevation groups were independent protective factors for all-cause mortality.

The Prognostic Value of Pretherapy Peripheral Blood Inflammatory Indices in Myelodysplastic Syndromes.

BackgroundInflammation appears to have a critical role in carcinogenesis tumor growth according to emerging research. The platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and plasma C-reactive protein (CRP) are considered to reflect the systemic inflammatory response and clinical prognosis. The prognostic value of inflammatory indices in myelodysplastic syndrome (MDS) patients remains unclear.MethodsA total of 213 MDS patients were enrolled for the study. Univariate and multivariate analyses were performed to determine the prognostic significance of various indicators, including PLR, NLR, and CRP.ResultsMDS patients with higher PLR, NLR, and CRP levels had significantly shorter overall survival (OS). Based on univariate analysis, age (≥60 years), gender (men), lower hemoglobin level (<10 g/dl), higher bone marrow blast percentage (>5%), poorer karyotype, and higher Revised International Prognostic Scoring System (IPSS-R) score were significantly associated with shorter OS. Patients with higher CRP levels had shorter leukemia-free survival (LFS, P = 0.041). However, higher PLR and NLR had no significant influence on LFS (P > 0.05). Multivariate Cox proportional hazards regression analysis indicated that high PLR and CRP were also independent adverse prognostic factors for OS in MDS.ConclusionsElevated PLR and CRP predict poor prognosis independent of the IPSS-R and provide a novel evaluation factor for MDS patients.

Platelet to white blood cell ratio was an independent prognostic predictor in acute myeloid leukemia

ABSTRACT Background Recently, platelet to white blood cell ratio (PWR) was reported as an independent prognostic predictor in acute promyelocytic leukemia. Acute myeloid leukemia (AML) often presents with abnormal platelet counts and white blood cell counts (WBC) at disease diagnosis. However, the clinical impact of PWR on cytogenetically normal AML (CN-AML) is still unclear. Therefore, we evaluate its prognostic impact on CN-AML patients. Methods We recorded the clinical information at the time of disease diagnosis, and calculated the ratio of platelet counts to WBC in 338 patients with CN-AML. To assess the prognostic value of PWR, we divided patients into low, intermediate and high group based on the values of PWR. The independent prognostic value of PWR was investigated in the context of the well-established predictors including white blood cell counts, age, and genes of NPM1, FLT3-ITD, CEBPA, and DNMT3A mutations. Receiver operating characteristic (ROC) curve was used to assess the performance of its prognostic prediction. Results Higher PWR have the higher levels of platelet counts, but lower levels of white blood cell counts, percentage of bone marrow blasts, FLT3-ITD and NPM1 mutations. The performance of survival prediction was comparable between PWR alone and combined molecular biomarkers. Moreover, PWR had the additional prognostic information to the molecular biomarkers. Finally, PWR was associated with favorable overall survival and event free survival in CN-AML patients independent of genetic subtypes and clinical parameters. Conclusion We found PWR was an independent prognostic predictor in CN-AML.

Evaluation of flow cytometric expressions of CD96 and CD123 on leukemic stem cells in patients with adult acute myeloid leukemia and their utility as prognostic markers

Background Acute myeloid leukemia (AML) is a disease associated with a risk of relapse or refractoriness to the frontline agents. This is attributable to the quiescent leukemic stem cells (LSC). We aimed to determine the expression status of CD96 and CD123 on the surface of LSC in adult patients with AML and their relationship to prognosis. Patients and methods A total of 40 adult patients with de novo AML and 40 age-matched and sex-matched controls were recruited from Center ‘X,’ City ‘Y,’ Country ‘Y’ from June 2017 to February 2018, with 1-year follow-up. Bone marrow samples were collected for flow cytometric analysis using CD34, CD38, CD96, and CD123 monoclonal antibodies. For cases, samples were obtained at diagnosis and on day 28 after chemotherapy, whereas for controls, samples were taken once. Results CD96 and CD123 expressions are significantly higher in patients with AML as compared with controls. CD96 expression is associated with higher initial bone marrow and peripheral blood blast percentages. Day28 CD96 expression is positively correlated with its expression on day 0 and with CD123 expression at diagnosis, with P values of less than 0.001 and 0.034, respectively. Both markers were much more frequently expressed on LSCs in differentiated AML as compared with ill-differentiated subtypes (P&lt;0.05). Both markers are linked to poor therapy outcome, with inferior progression-free survival among CD96-positive and CD123-positive cases at day 28 (P=0.035 and 0.041, respectively). Conclusions CD96 and CD123 represent potential targetable markers for the future development of therapeutic armamentarium for AML.

Prognostic impacts of serum levels of C-reactive protein, albumin, and total cholesterol in patients with myelodysplastic syndromes.

Various systems for predicting the prognosis of patients with myelodysplastic syndromes (MDS) have been developed. However, associations between performance status (PS) and prognosis of MDS require further investigation. To objectively assess the impact of PS on survival, we examined laboratory findings associated with PS, including serum levels of C-reactive protein (CRP), albumin (ALB), and total cholesterol (CHOL). Patients (n = 123; male 86, female 37; median age 74 yrs.) diagnosed with MDS or myelodysplastic/myeloproliferative neoplasms at Kanazawa Medical University Hospital between 2010 and 2020 were enrolled and grouped by cutoff values determined by receiver operating characteristic analysis: 0.44mg/dL for CRP, 4.0g/dL for ALB, and 120mg/dL for CHOL. The median follow-up period was 17.6months. Kaplan-Meier analysis revealed that overall survival (OS) in the high CRP, low ALB, and low CHOL groups was significantly shorter than in the low CRP, high ALB, and high CHOL groups, respectively. Multivariable analysis revealed that elevated serum CRP was an independent prognostic risk factor independent of gender, bone marrow blast percentage, and cytogenetics.

Decreased serum apolipoprotein A1 level predicts poor prognosis of patients with de novo myelodysplastic syndromes

BackgroundMyelodysplastic syndromes (MDS) is a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells. It has been demonstrated that apolipoproteins A1(ApoA1) are associated with disease risk in many cancer types. However, there still lacks evidence regarding the link between ApoA1 and MDS. This study was designed to investigate the prognostic value of pretreatment ApoA1 levels in MDS patients.MethodsWe retrospectively analyzed a cohort of 228 MDS patients to explore the prognostic value of the serum ApoA1 levels at diagnosis. Patients were divided into the high ApoA1 group and the low ApoA1 group. The prognostic significance was determined by univariate and multivariate Cox hazard models.ResultsMDS patients with low ApoA1 levels had significantly shorter overall survival (OS, P < 0.0001) along with a higher frequency of TP53 mutation (P = 0.002). Based on univariate analysis, age (≥ 60 years), gender (male), lower levels of hemoglobin (< 10 g/dl), HDL (≤0.91 mmol/L), higher bone marrow blast percentage (> 5%), higher IPSS-R scores and poorer karyotype were significantly associated with decreased OS. However, low ApoA1 level did not influence leukemia-free survival (LFS, P = 0.367). Multivariate Cox proportional hazards regression analysis indicated that low ApoA1 level (≤ 1.02 g/L) was also an independent adverse prognostic factor for OS in MDS (P = 0.034).ConclusionsDecreased ApoA1 level predicts a poor prognosis of MDS patients and thus provides a novel evaluation factor for them that is independent of the IPSS-R system.

BSG (CD147) Serum Level and Genetic Variants Are Associated with Overall Survival in Acute Myeloid Leukaemia

Basigin (BSG, CD147) is a multifunctional protein involved in cancer cell survival, mostly by controlling lactate transport through its interaction with monocarboxylate transporters (MCTs) such as MCT1. Previous studies have found that single nucleotide polymorphisms (SNPs) in the gene coding for BSG and MCT1, as well as levels of the soluble form of BSG (sBSG), are potential biomarkers in various diseases. The goal of this study was to confirm BSG and MCT1 RNA overexpression in AML cell lines, as well as to analyse soluble BSG levels and selected BSG/MCT1 genetic variants as potential biomarkers in AML patients. We found that BSG and MCT1 were overexpressed in most AML cell lines. Soluble BSG was increased in AML patients compared to healthy controls, and correlated with various clinical parameters. High soluble BSG was associated with worse overall survival, higher bone marrow blast percentage, and higher white blood cell count. BSG SNPs rs4919859 and rs4682, as well as MCT1 SNP rs1049434, were also associated with overall survival of AML patients. In conclusion, this study confirms the importance of BSG/MCT1 in AML, and suggests that soluble BSG and BSG/MCT1 genetic variants may act as potential AML biomarkers.

Plasmacytoma Variant Translocation-1 as Prognostic Markers in Pediatric Acute Lymphoblastic Leukemia

Introduction and Aim: Acute lymphoblastic leukemia (ALL) is the commonest form of childhood leukemia. Molecular studies can provide diagnostic and prognostic information with direct impact on the patient. Recent micro RNAs (miRNAs) studies showed that aberrant expression can be used as signatures of ALL with different subtypes and predict drug resistance. The present work aimed to evaluate the expression of Plasmacytoma Variant Translocation-1 (PVT1) in Childhood ALL patients.&#x0D; Methodology: The study included 55 children from 2 months to 15 years old; 45 patients with ALL before receiving any treatment, and 10 control children. Long non-coding RNA PVT1 expression in plasma cells was detected by reverse transcription quantitative polymerase chain reaction.&#x0D; Results: Lnc_PVT1 expression is upregulated by twelve-folds in ALL patients. At optimum cut-off value of 22.0, the biomarker has a sensitivity of 72% and 82% specificity to discriminate ALL patients from controls. Correlating the mean values of miR_1204gene fold expression with different subgroups concerning prognostic criteria, there was no statistical differences between age groups, gender, ALL phenotypes, cytogenetic abnormality, total leukocytes count, hemoglobin concentrations and platelet count. In contrast, statistical significance was detected with bone marrow blasts percentage, clinical response, and minimal residual disease.&#x0D; Conclusion: A higher expression of lnc-PVT1 was observed in ALL patients, and it had a diagnostic and prognostic potential. In addition, miR-1204 was down-regulated in pediatric ALL and associated with higher risk.