Correlation of New Method for Measuring Plasma Myeloperoxidase with Clinical Behavior in Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Abstract We previously reported that levels of myeloperoxidase (MPO) enzyme in plasma of patients with acute myeloid leukemia (AML) may correlate with aggressive disease. However, we found poor reproducibility and significant variability from lot to lot when commercially available kits are used. We developed a cytometric beads assay (CBA) for measuring plasma MPO that shows high reproducibility (CV<10%) with no significant variability with time. More importantly, MPO levels as measured using this CBA assay showed better correlation with clinical behavior in AML and myelodysplastic syndrome (MDS). Based on studying plasma levels of MPO in 98 patients with AML and 50 patients with advanced stage MDS, we found no significant difference in plasma MPO between AML and MDS patients. As expected MPO levels were significantly lower in patients with ALL (N=48) than in AML patient (P=0.04) and MDS (P=0.02). While MPO levels were significantly higher in patients with good cytogenetic abnormalities (P=0.004) in AML patients, MPO levels did not differ between intermediate and poor cytogenetic groups in patients with AML or MDS. Unexpectedly we found a difference between AML and MDS in their correlation with MPO levels and clinical outcome. Patients with advanced stage MDS and high levels of MPO (<300 ng/ml) had significantly longer survival than patients with lower levels (P=0.01). Multivariate analysis showed that this correlation with better survival in this group of MDS patients was independent of cytogenetic grouping. In contrast in AML, higher levels of MPO (>70 ng/ml) correlated with shorter survival (P=0.04). Similarly, patients with acute lymphoblastic leukemia (ALL) and high levels of MPO (>70 ng/ml) had shorter survival (P=0.05). Despite there was a correlation between the commercially available kit for measuring MPO and our CBA method (r=0.71, P<0.0001), the commercial kit did not provide robust data for clinical correlation. This data confirms that confirms that plasma levels of MPO play a role in the biology of the leukemia. Further studies are needed to establish if this role is a reflection of an inflammatory process or a reflection of disease load, although the finding of clinical relevance in ALL suggests that it is more likely reflecting an inflammatory process. Figure Figure

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Clinical Significance of Free Circulating CD33 in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v108.11.4502.4502 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4502-4502 ◽

Cited By ~ 1

Author(s):

Menna Hodge ◽

Francis Giles ◽

Adam Abdool ◽

Susan O’Brien ◽

Michael Keating ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Gemtuzumab Ozogamicin ◽

Leukemic Cells ◽

Clinical Behavior ◽

Cytogenetic Abnormalities ◽

Cytotoxic Compound ◽

Wbc Count ◽

Acute Myeloid

Abstract CD33, a 67-kDa sialoglycoprotein expressed on the cell surface of monocytic/myeloid lineage and early hematopoietic progenitor cells, is frequently expressed in patients with acute myeloid leukemia (AML). Gemtuzumab ozogamicin (GO), an immunoconjugate consisting of a humanized anti-CD33 antibody and a cytotoxic compound (N-acetyl-γ-calicheamicin dimethylhydrazine), targets CD33 and has shown promising results in patients with AML. No evidence of a relationship between the levels of CD33-positive leukemic cells and clinical response has been found. We investigated the possibility that cell-free circulating CD33 (cCD33) might be useful as a marker of clinical behavior. We used a newly developed bead-based immunoassay to measure cCD33 in the plasma of patients with AML (n = 97) or myelodysplastic syndrome (MDS; n = 44). All patients were treated with standard therapy including idarubicin and ara-C. cCD33 levels were significantly higher in patients with MDS (median, 1600 U/μL; range, 102–791,350 U/μL) than in those with AML (median, 2709 U/μL; range: 62–263,349 U/μL) (P = 0.004). High-risk cytogenetic abnormalities were associated with higher cCD33 levels in patients with MDS (P = 0.04) but not in patients with AML (P = 0.72). cCD33 levels correlated with WBC count and % monocytes in patients with AML (R >0.35) but not in patients with MDS. cCD33 levels correlated with clinical behavior only among AML patients with intermediate-risk cytogenetic abnormalities (n = 56); those with cCD33 levels above the median had longer survival (P = 0.04). These data confirm the presence of cCD33 in AML and MDS and also suggest that cCD33 can be used as a tumor marker in patients with AML. Although further study is needed for confirmation, cCD33 appears to result from turnover of leukemic cells, may play a role in patients being treated with GO, and should be considered in the pharmacokinetic and pharmacodynamic studies of such therapy. cCD33 in AML patient with intermediate cytogenetic abnormalities cCD33 in AML patient with intermediate cytogenetic abnormalities

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Variations in Proteasome Enzymatic Activities in Plasma of Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome and Their Value in Predicting Clinical Behavior.

Blood ◽

10.1182/blood.v108.11.4497.4497 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4497-4497 ◽

Cited By ~ 1

Author(s):

Wanlong Ma ◽

Francis Giles ◽

Susan O’Brien ◽

Iman Jilani ◽

Xi Zhang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Performance Status ◽

Proteasome Inhibitors ◽

Leukemic Cells ◽

Clinical Behavior ◽

Cytogenetic Abnormalities ◽

Significant Difference ◽

And Performance ◽

Acute Myeloid

Abstract The ubiquitin-proteasome pathway is responsible for multiple pathways in cancer cells; proteasome inhibition causes rapid apoptosis of tumor cells. Three different types of peptidase activities have been reported for proteasomes: chymotrypsin-like (Ch-L), trypsin-like (Tr-L), and caspase-like (Cas-L) (postglutamyl peptide hydrolytic-like). Various proteasome inhibitors affect each of the 3 activities differently and at different concentrations. For example, NPI-0052 inhibits Ch-L and Tr-L activities at lower concentrations than does bortezomib, while bortezomib inhibits Cas-L at lower concentrations than does NPI-0052. These enzymatic activities are usually measured in normal or tumor cells to monitor therapy with proteasome inhibitors. Because rapidly proliferating leukemic cells pour their proteins, DNA, and RNA into the circulation, we developed fluorogenic kinetic assays using peripheral blood plasma. The assays used peptide-AMC (7-amino 4-methylcoumoran) substrates to measure Ch-L, Tr-L, and Cas-L activities. We measured proteasome activities in plasma from 188 patients with acute myeloid leukemia (AML) and 58 patients with myelodysplastic syndrome (MDS) and assessed their correlations with clinical behavior. Significantly (P < 0.001) higher Ch-L, Tr-L, and Cas-L activities were seen in AML patients (medians: 1.39, 1.51, and 2.40 pmol AMC/sec/mL, respectively) and MDS patients (medians: 1.16, 1.40, and 1.67 pmol AMC/sec/mL, respectively) than in healthy volunteers (n=42) (medians: 0.80, 0.74, and 0.81 pmol AMC/sec/mL, respectively). The difference in Cas-L activity between AML and MDS was significant (P <0.001). While there was no significant difference between Ch-L and Cas-L activities in healthy controls, there was a significant difference between the 2 activities in both AML and MDS. Cas-L and Ch-L, but not Tr-L, correlated with WBC count and lactic dehydrogenase in AML and MDS patients. In AML patients, higher levels of Ch-L and Cas-L were associated with poor response to a variety of therapies (P = 0.004 and P = 0.001, respectively). Cas-L correlated strongly with survival in AML patients when used as an activity-dependent variable (P <0.001) or when the median was used as a cut-off (P = 0.004). This was independent of cytogenetic abnormalities, age, and performance status. Patients with intermediate-risk cytogenetic abnormalities and Cas-L activity >3 pmol AMC/sec/mL had significantly shorter survival (P = 0.04). Ch-L activity was also predictive of survival in AML independent of age and cytogenetic and performance status, but not independent of Cas-L. In MDS, higher levels of Cas-L, but not Ch-L, correlated with shorter survival and this was independent of cytogenetic abnormalities. The increased cell-free circulating proteasome activities most likely reflect the leukemic cells and may be a marker not only for disease, but also potentially for monitoring therapy. These data also suggest that patients with AML may benefit differentially from proteasome inhibitors depending on the specific therapeutic effect of the inhibitor.

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Long-Term Outcomes of Treosulfan- vs. Busulfan-Based Conditioning Regimen for Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia Before Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis

Frontiers in Oncology ◽

10.3389/fonc.2020.591363 ◽

2020 ◽

Vol 10 ◽

Author(s):

Sheng Zhu ◽

Gang Liu ◽

Jing Liu ◽

Qiuying Chen ◽

Zhiqiang Wang

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Hematopoietic Cell Transplantation ◽

Meta Analysis ◽

Graft Versus Host ◽

Significant Difference ◽

Conditioning Regimens ◽

Acute Myeloid

BackgroundMany studies aimed to evaluate the efficacy and safety of treosulfan-based conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT) compared with other regimens, but different outcomes were reported across studies.AimTo determine the long-term survival outcomes of treosulfan-based vs. busulfan-based conditioning regimens in myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) patients.MethodsPubMed, Embase, and Cochrane library were searched for studies published prior to December 6, 2019. The fixed-effects model was applied for overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM), acute and chronic graft versus host disease (GvHD). Relapse incidence (RI) was pooled by the use of the random-effects model.ResultsSix studies were included (3,982 patients; range, 57–1,956). The pooled HR for OS favored treosulfan (HR=0.80, 95%CI: 0.71–0.90). There was no significant difference in NRM between the two regimens (HR=0.84, 95%CI=0.71–1.01). There was no significant difference in LFS between the two regimens (HR=0.98, 95%CI=0.87–1.12). Treosulfan-based regimens showed a lower risk of aGvHD (HR=0.70, 95%CI=0.59–0.82), but there was no difference for cGvHD (HR=0.94, 95%CI=0.81–1.09). There was no significant difference in RI between the two regimens (HR=0.96, 95%CI=0.71–1.31). There was no publication bias among these studies.ConclusionThe current meta-analysis determined that treosulfan-based conditioning regimens could improve the OS in patients with MDS and AML, with lower acute graft-versus-host disease incidence, compared with busulfan-based regimens.

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Monitoring of Post-Transplant MLL-PTD as Minimal Residual Disease Can Predict Relapse After Allogeneic HSCT in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndrome

10.21203/rs.3.rs-601950/v1 ◽

2021 ◽

Author(s):

Jun Kong ◽

Meng-Ge Gao ◽

Ya-Zhen Qin ◽

Yu Wang ◽

Chen-Hua Yan ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Minimal Residual Disease ◽

Myeloid Leukemia ◽

Residual Disease ◽

Hematopoietic Stem ◽

Post Transplant ◽

Significant Difference ◽

Minimal Residual ◽

Acute Myeloid

Abstract Background: MLL-PTD is a special MLL rearrangement gene that occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, including AML and MDS, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation.Methods: We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People’s Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL>0.08% was defined as MLL-PTD positive in this study.Results: The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7%±5.2%, 67.8%±6.9%, 68.1%±6.8% and 20.3%±6.1%, respectively. ROC curve showed that post-transplant MLL-PTD≥1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD≥1.0% and MLL-PTD<1.0% groups (3-year CIR: 75%±15.3% vs. 0%, P<0.001; 3-year OS: 25.0±15.3% vs. 80.7%±6.6%, P<0.001; 3-year DFS: 25.0±15.3% vs. 80.7%±6.6%, P<0.001; 3-year TRM: 0 vs. 19.3±6.6%, P=0.277). However, whether MLL-PTD≥1% or MLL-PTD<1% before transplantation has no significant difference on the prognosis. Conclusions: Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.

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Classification of Acute Myeloid Leukemia and Myelodysplastic Syndrome Based on Molecular Profiling

Blood ◽

10.1182/blood.v126.23.3836.3836 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3836-3836

Author(s):

Sally Agersborg ◽

Maya Thangavelu ◽

Wanlong Ma ◽

Steven Brodie ◽

Christopher Mixon ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

P Value ◽

Molecular Abnormalities ◽

Significant Difference ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is currently distinguished from myelodysplastic syndrome (MDS) based on the presence of 20% blasts in bone marrow, an arbitrary cut-off adopted by the WHO classification and replacing the 30% cut-off required by the older FAB (French, American and British) classification. Patients with t(15;17), t(8;21), or inversion 16 cytogenetic abnormalities are classified as having AML irrespective of the percentage of blasts. We explored the possibility that currently defined molecular abnormalities can distinguish AML from MDS without relying on an arbitrary percentage of blasts in the bone marrow. We compared the molecular profiles obtained by next generation sequencing (NGS) from consecutive patients with a clinical diagnosis of AML or MDS by WHO criteria. Methods: NGS data from 251 patients with the diagnosis of AML and 294 patients with the diagnosis of MDS was studied. All samples were analyzed using a panel of 25 genes including FLT3, NPM1 SF3B1, CBL, DNMT3A, ASXL1, BRAF, CEBPA, CSFR3, ETV6, EZH2, IDH1, IDH2, JAK2, c-KIT, KRAS, NRAS, PHF6, PTPN11, RUNX1, SETBP1, TET2, TP53, WT1, and ZRSR2. We compared the frequency of mutations in each gene between AML and MDS patients. Results: Mutations in FLT3 and NPM1 were uniquely and commonly detected in AML (27% and 22%, respectively). In contrast, mutations in SF3B1 gene were uniquely dominant (22%) in MDS and FLT3 and NPM1 mutations were rare (2% and 3%, respectively). SF3B1 mutations were extremely rare in AML (1%). Overall, 102 (41%) of all AML patients had mutations in either FLT3 or NPM1 and 8% of AML patients had mutations in both FLT3 and NPM1. In addition, WT1 gene was mutated in 8% of AML cases, but none of the MDS cases showed WT1 mutation. TET2 gene was commonly mutated in both AML and MDS (25% and 36%, respectively), but the frequency was significantly higher in MDS (P=0.003). IDH1, IDH2, NRAS, and PTPN11 were mutated slightly more often in AML than in MDS, while ASXL1, EZH2, and ZRSR2 were more frequently mutated in MDS than in AML. There was no statistically significant difference in mutation frequency between AML and MDS for the other genes analyzed. Conclusion: Mutations in FLT3, NPM1 and WT1 are molecular abnormalities characteristically detected in patients with AML and can be used as objective criteria for the classification of AML rather than blast count in bone marrow. These mutations are detected in 49% of AML patients. This suggests that approximately half of AML patients can be diagnosed based on the detection of molecular abnormalities, irrespective of bone marrow morphology. The presence of mutation in SF3B1 gene is also a characteristic molecular finding for MDS. Table. AML (No=251) MDS (No=294) P-Value No % No % FLT3 68 27 5 2 0.00001 NPM1 55 22 8 3 0.0001 SF3B1 3 1 66 22 0.00006 CBL 4 2 10 3 NS DNMT3A 51 20 51 17 0.07 ASXL1 44 18 75 26 0.01 BRAF 3 1 1 0 NS CEBPA 38 15 51 17 NS CSFR3 11 4 11 4 NS ETV6 3 1 6 2 NS EZH2 8 3 25 9 0.03 IDH1 20 8 7 2 0.03 IDH2 17 7 7 2 0.04 JAK2 4 2 10 3 NS KIT 2 1 0 0 NS KRAS 11 4 6 2 NS NRAS 34 14 18 6 0.01 PHF6 5 2 2 1 NS PTPN11 26 10 6 2 0.01 RUNX1 31 12 33 11 NS SETBP1 5 2 9 3 NS TET2 64 25 105 36 0.003 TP53 61 24 75 26 NS WT1 19 8 0 0 0.01 ZRSR2 7 3 30 10 0.02 Disclosures No relevant conflicts of interest to declare.

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Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases

Blood ◽

10.1182/blood.v65.6.1364.bloodjournal6561364 ◽

1985 ◽

Vol 65 (6) ◽

pp. 1364-1372 ◽

Cited By ~ 213

Author(s):

SD Michels ◽

RW McKenna ◽

DC Arthur ◽

RD Brunning

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Median Survival ◽

Myeloid Leukemia ◽

De Novo ◽

Poor Response ◽

Significant Difference ◽

Multiple Cell ◽

De Novo Aml ◽

Acute Myeloid

Abstract This study consists of 65 patients (pts) who developed a myelodysplastic syndrome (MDS) (39 pts) or acute myeloid leukemia (AML) (26 pts) following chemotherapy and/or radiotherapy; the interval from the onset of therapy to bone marrow abnormality ranged from 11 to 192 months (median, 58). Thirty-three patients had been previously treated for lymphoproliferative diseases, 29 for carcinoma, and three for a nonneoplastic disorder. Approximately 30% of the cases presenting in the MDS phase evolved to AML in one to 12 months (median, 3.5). The AML in 49% of the cases was not readily classified according to French- American-British (FAB) criteria; the primary difficulty in classification related to the involvement of multiple cell lines. Among the cases that could be classified, all FAB types were represented except for M1; M2 was the most frequent type. Clonal chromosome abnormalities were found in marrow specimens from 22 of 24 (92%) patients studied with G banding; 11 had abnormalities of chromosomes 5 and/or 7. The median survival for all patients was four months with no significant difference between those treated and not treated with antileukemic therapy. The median survival was three months for the patients presenting with AML, six months for the patients with AML following an MDS, and four months for the patients with an MDS that did not evolve to AML. The findings in the present study suggest that there are three stages of therapy-related panmyelosis: (1) pancytopenia with associated myelodysplastic changes, (2) a frank MDS, and (3) overt AML. Many patients will present in the stage of overt AML that differs from de novo AML primarily by the high incidence of trilineage involvement, difficulty in classification, frequent cytogenetic abnormalities, and poor response to antileukemic therapy. The myelodysplastic phase, with or without evolution to acute leukemia, is a highly lethal disease with a median survival comparable to that of the patients who present with AML.

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Monitoring of post-transplant MLL-PTD as minimal residual disease can predict relapse after allogeneic HSCT in patients with acute myeloid leukemia and myelodysplastic syndrome

BMC Cancer ◽

10.1186/s12885-021-09051-5 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Jun Kong ◽

Meng-Ge Gao ◽

Ya-Zhen Qin ◽

Yu Wang ◽

Chen-Hua Yan ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Minimal Residual Disease ◽

Myeloid Leukemia ◽

Residual Disease ◽

Hematopoietic Stem ◽

Post Transplant ◽

Significant Difference ◽

Minimal Residual ◽

Acute Myeloid

Abstract Background The mixed-lineage leukemia (MLL) gene is located on chromosome 11q23. The MLL gene can be rearranged to generate partial tandem duplications (MLL-PTD), which occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation. Methods We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People’s Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL > 0.08% was defined as MLL-PTD positive in this study. Results The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7 ± 5.2, 67.8 ± 6.9, 68.1 ± 6.8 and 20.3% ± 6.1%, respectively. ROC curve showed that post-transplant MLL-PTD ≥ 1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD ≥ 1.0% and MLL-PTD < 1.0% groups (3-year CIR: 75% ± 15.3% vs. 0%, P < 0.001; 3-year OS: 25.0 ± 15.3% vs. 80.7% ± 6.6%, P < 0.001; 3-year DFS: 25.0 ± 15.3% vs. 80.7 ± 6.6%, P < 0.001; 3-year TRM: 0 vs. 19.3 ± 6.6%, P = 0.277). However, whether MLL-PTD ≥ 1% or MLL-PTD < 1% before transplantation has no significant difference on the prognosis. Conclusions Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.

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