Dynamics of epigenetic regulator gene BCOR mutation and response predictive value for hypomethylating agents in patients with myelodysplastic syndrome

Abstract Background BCOR (BCL6 corepressor) is an epigenetic regulator gene involved in the specification of cell differentiation and body structure development. Recurrent somatic BCOR mutations have been identified in myelodysplastic syndrome (MDS). However, the clinical impact of BCOR mutations on MDS prognosis is controversial and the response of hypomethylating agents in MDS with BCOR mutations (BCORMUT) remains unknown. Results Among 676 MDS patients, 43 patients (6.4%) harbored BCOR mutations. A higher frequency of BCOR mutations (8.7%) was investigated in patients with normal chromosome, compared to 4.2% in patients with abnormal karyotype (p = 0.040). Compared to the BCORWT patients, the BCORMUT patients showed a higher ratio of refractory anemia with excess blasts subset (p = 0.008). The most common comutations with BCOR genes were ASXL1 (p = 0.002), DNMT3A (p = 0.114) and TET2 (p = 0.148). When the hierarchy of somatic mutations was analyzed, BCOR mutations were below the known initial mutations (ASXL1 or TET2) but were above U2AF1 mutations. Transformation-free survival was significantly shorter in BCORMUT patients than that in BCORWT patients (16 vs. 35 months; p = 0.035). RNA-sequencing was performed in bone marrow mononuclear cells from BCORMUT and BCORWT patients and revealed 2030 upregulated and 772 downregulated genes. Importantly, HOXA6, HOXB7, and HOXB9 were significantly over-expressed in BCORMUT patients, compared to BCORWT patients. Eight of 14 BCORMUT patients (57.1%) achieved complete remission (CR) with decitabine treatment, which was much higher than that in BCORWT patients (28.7%, p = 0.036). Paired sequencing results (before and after decitabine) showed three of 6 CR patients lost the mutated BCOR. The median survival of CR patients with a BCORMUT was 40 months, which was significantly longer than that in patients with BCORWT (20 months, p = 0.036). Notably, prolonged survival was observed in three BCORMUT CR patients even without any subsequent therapies. Conclusions BCOR mutations occur more frequently in CN MDS patients, predicting higher risk of leukemia transformation. BCORMUT patients showed a better response to decitabine and achieved longer post-CR survival.

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Cytogenetic Features and Prognosis In Argentinean Patients with Myelodysplastic Syndrome: a Multicenter Study

Blood ◽

10.1182/blood.v116.21.1888.1888 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1888-1888

Author(s):

Carolina Belli ◽

Raquel Bengió ◽

Pedro Negri Aranguren ◽

Francisco Sakamoto ◽

María Gabriela Flores ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Cumulative Risk ◽

World Health ◽

Red Blood Cell Transfusion ◽

Refractory Anemia ◽

Published Data ◽

Abnormal Karyotype ◽

Transfusion Requirements ◽

Cytogenetic Profile ◽

The Impact

Abstract Abstract 1888 Myelodysplastic Syndrome (MDS) comprises a group of heterogeneous hematological disorders with variable risk of leukemic evolution (LE) and short survival (SV). Around 40–50% of patients show abnormal karyotype at diagnosis and cytogenetic findings are an independent prognostic factor in MDS. Although the International Prognostic Scoring System (IPSS) differentiated 3 cytogenetic categories of risk (CCR), the Intermediate one is heterogeneous. The aim of this study was to characterize the cytogenetic profile, to test its prognostic value and to evaluate cytogenetic groups of risk in the Argentinean MDS population. Also, we tried to ascertain whether some abnormalities could be segregated from their respective CCR. This is a multicenter retrospective analysis of 488 primary Argentinean patients with MDS evaluated from 1984 to 2008 (including 183 patients from the Pilot Study for MDS Registry organized by the Argentinean Society of Hematology). Patients' distribution according to French-American-British classification (FAB) was: 235 Refractory Anemia (RA), 50 RA with Ringed Sideroblasts (RARS), 121 RA with excess of Blast (RAEB), 27 RAEB in transformation (RAEBt) and 55 Chronic Myelomonocytic Leukemia (CMML). The median age was 69 (17-92) years with a gender ratio (M/F) of 1.3. During the follow-up (mean: 25 months (m), range: 1–266 m), 110 (22.5%) underwent LE and 217 (44.5%) patients died. Age, sex, percentage of bone marrow blast, hemoglobin level, platelets count, number of cytopenias, LDH level and red blood cell transfusion requirements were significant predictive variables for prognosis (Kaplan-Meier and Long-Rank test, p<0.05). FAB and World Health Organization (WHO) classifications and scoring systems (Lille, Lausanne-Bournemouth, IPSS, GCECGH and WPSS) allowed us to differentiate groups of risk for SV and LE. Cytogenetic results were available in 421 patients and 176 (42%) showed abnormal karyotype. Cytogenetic profile showed that all chromosomes were involved and different cytogenetic alterations were found (total or partial chromosome losses were predominant). The most common cytogenetic aberrations were: -5/5q- (20% among cases with abnormal karyotype), -7/7q- (16%), +8 (20%), 20q- (9%) and –Y (8%). No particular aberration was associated to any FAB subtype though the frequency of abnormal karyotypes increased from 36% for RA, 39% RARS, 50% RAEB to 74% RAEBt and 39% for LMMC. Karyotypes were further divided according to IPSS CCR into 68% Good, 21% Intermediate and 12% Poor with median SV of 48, 34 and 17m and a LE cumulative risk to 1-year: 13%, 25% and 38%, respectively, p<0.0001. CCR were also predictive in the WHO classified population (p<0.0001 for SV and p=0.0021 for LE). Patients with normal karyotype had better outcome than those with cytogenetic alterations (median SV of 51 vs. 21 m, p=0.0012, and LE cumulative risk to 1-year: 13% vs. 26%, p=0.0047). When we tried to ascertain whether some alterations could be segregated from their respective Good and Poor CCR, no significant differences were observed both for SV and for LE. However, the outcome of the Intermediate CCR was heterogeneous ranging between patients with 12p- (median SV: 65 m and a LE cumulative risk to 1-year: 0%) and those with rearrangements 3q/ del(17p)/ +19/ t(11)(q23) (median SV: 15 m and a LE cumulative risk to 1-year: 48%, p=0.0220). Cytogenetic findings had a clear impact on SV and LE in our population and results in the present series, the largest in Latin America, are coincident with published data. However, the wide spectrum of low frequency aberrations stresses the importance of large study groups where the impact of such aberrations could be statistically evaluated to properly segregate them from their original CCR. Disclosures: No relevant conflicts of interest to declare.

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Decreased Megakaryocytepoiesis and No Excess of Platelet Destruction in Myelodysplastic Syndrome Patients.

Blood ◽

10.1182/blood.v110.11.4616.4616 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4616-4616

Author(s):

Kazunori Murai ◽

Tatsuo Oyake ◽

Shugo Kowata ◽

Mamiko Ishiguro ◽

Shigeki Ito ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndrome ◽

Mononuclear Cells ◽

Flow Cytometric Analysis ◽

Annexin V ◽

Refractory Anemia ◽

Double Positive ◽

Platelet Destruction ◽

Color Flow ◽

Normal Controls

Abstract Myelodysplastic syndrome (MDS) is a malignant disorder of hematopoietic progenitor cells and characterize by peripheral blood cytopenias with normo- to hyper-cellular bone marrow (BM) and morphologically dysplastic changes. Thrombocytopenia is observed in approximately 50% of MDS. The underlying pathophysiology is not fully understood. We analyzed the megakaryocytopoiesis and thrombocytopoiesis state by several parameters, including % reticulated platelet (%RP), which indicated platelet production state, glycoalicine index (GCI), which indicated platelet destruction state, and serum thromopoietin (TPO) levels in 47 refractory anemia in myelodysplastic syndrome (MDS-RCMD) patients with platelet counts less than 100 x 109/L. Furthermore, apoptosis frequency of megakaryocyte progenitors was analyzed in several patients. In all patients, dysmegakaryocytopoiesis findings such as hypolobulated micromegakaryocyte, non-lobulated nuclei in all sizes, and multiple, widely-separated nuclei were observed. The megakaryocytes in BM was normal to decreased in number in 32 patients (70%). Plasma TPO levels were significantly higher (718.7±746.0 pg/ml, n=50) in MDS-RCMD, while they were less than 205.0 pg/ml in normal volunteers (68.3 ±65.3 pg/ml, n=32)(p< 0.01). The %RPs in MDS-RCMD and normal controls were similar (MDS-RCMD 1.7±0.9% vs control 1.2±0.6%), indicating that increased thrombocytopoiesis was not observed in MDS-RCMD, regardless of high TPO levels. GCI was similar to normal controls (MDS-RCMD, 1.5±1.3% vs controls, 1.6±0.3%), indicating no excess of platelet destruction. There was no correlation between %RP and GCI. These data strongly suggested that platelet life span be not shortend in MDS-RCMD. We have reported that excessive apoptosis of CD34(+) cells was observed in MDS patients in the previous ASH meetings. The three-color flow cytometric analysis of bone marrow mononuclear cells using PE labeled Annexin V, PerCP labeled anti-CD34 antibody and FITC labeled anti-CD41 antibody were carried out in 17 MDS-RCMD patients. Much higher frequency of apoptosis was observed in double positive cells for CD34 and CD41 (48.1%:13.4∼78.4%, median: range) in MDS-RCMD, compared to that in normal controls (7.7%: 4.4∼17.2%, median: range) (P<0.05). The frequency of apoptosis was not increased significantly in CD34(−)CD41(+) cells in MDS-RCMD patients (median: 6.9% ; 1.3∼21.5%), n=12), compared to those in normal controls (3.3%: 1.5∼8.1%, n=10). These data strongly suggested that the main cause of thrombocytopenia in MDS-RCMD should be apoptosis in megakaryocytes progenitors, followed by the decreased megakaryocytopoiesis.

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The Direct Medical Costs of Treatment Discontinuation Among Higher-Risk Myelodysplastic Syndrome Patients Receiving Hypomethylating Agents

Blood ◽

10.1182/blood-2020-139642 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

Namita Joshi ◽

Hrishikesh P Kale ◽

Shelby Corman ◽

Kala Hill ◽

Tim Wert ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Research Funding ◽

Healthcare Spending ◽

Medical Costs ◽

Refractory Anemia ◽

Cell Transplant ◽

Hypomethylating Agents ◽

Publicly Traded ◽

Direct Medical Costs

Introduction: Non-persistence to treatment with hypomethylating agents (HMA) in higher-risk myelodysplastic syndrome (HR-MDS) patients can result in loss of response or ability to achieve a primary response. HMA treatment is recommended to be given to HR-MDS patients for least 4-6 treatment cycles to elicit a clinical response and premature termination is likely to result in poor outcomes and considerable healthcare spending. The study objective was to assess direct medical costs associated with HMA treatment non-persistence among HR-MDS patients. Methods: Using a retrospective cohort design, MDS patients with refractory anemia with excess blasts (RAEB) were analyzed using 2010-2016 Surveillance, Epidemiology and End Results-Medicare linked database. RAEB diagnosis is considered to substantially overlap with HR-MDS and has been used as a surrogate for HR-MDS. The study cohort included RAEB patients diagnosed between 01/2011 and 12/2015. Patients were included if they had ≥ 1 year of continuous Medicare enrollment prior to diagnosis and did not receive stem cell transplant or lenalidomide in the follow-up period. HR-MDS patients receiving HMAs were stratified into HMA persistent (receiving 4 or more HMA cycles without any gap of ≥90 days between cycles) and HMA non-persistent (receiving less than 4 cycles or a gap of ≥90 days between cycles) groups. Healthcare resource use (HCRU) and associated direct medical costs incurred during the follow-up period were described as per-patient-per-month (PPPM). To account for baseline differences between HMA persistent and non-persistent groups, propensity score-based inverse probability of treatment weights (IPTW) were calculated. Weighted HCRU and costs (PPPM) were further estimated using generalized linear models (GLMs). Costs were inflated to 2019 USD using medical component of consumer price index. Results: There were 664 patients identified with RAEB, of which 295 (44.4%) patients were classified in the HMA non-persistent group and 369 (55.6%) patients in the HMA persistent group. HMA persistent and non-persistent groups were similar in baseline demographic and clinical characteristics; however, non-persistent HMA users were older at diagnosis and a lower proportion of patients were married. Results from weighted GLM analysis indicated higher PPPM resource utilization in HMA non-persistent patients compared to HMA persistent patients specifically for hospitalizations (Incident rate ratio [IRR], 1.543, 95% Confidence interval [CI]: 1.181 - 2.018]), ER visits (IRR= 1.322, 95% CI: 1.146 - 1.524), SNF use (IRR = 2.158, 95% CI: 1.308 - 3.560), home health (IRR = 1.335, 95% CI: 1.039 - 1.714] and hospice care use (IRR = 2.555, 95% CI:1.972 - 3.309) (Table 1). Further, HMA non-persistent patients had significantly (P<0.05) higher total PPPM costs than HMA persistent patients ($18,039 vs. $13,893, p<0.05); particularly for hospitalizations ($3,375 vs. $2,131), and ER costs ($5,517 vs. $2,867) (Figure 1). Conclusions: A significant proportion of HR-MDS (RAEB) patients discontinue guideline-recommended HMA treatment. Non-persistence with HMA treatments was associated with substantial cost burden. The study findings call for closer care management by healthcare providers to ensure HMA treatment is completed as scheduled (unless directed otherwise by the provider) to manage outcomes and healthcare spending. Disclosures Joshi: Pharmerit International: Current Employment. Kale:Pharmerit International: Current Employment. Corman:Pharmerit International: Current Employment. Hill:Taiho Oncology: Current Employment, Current equity holder in publicly-traded company. Wert:Taiho Oncology: Current Employment, Current equity holder in publicly-traded company. Zeidan:Otsuka: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Astex: Research Funding; CCITLA: Other; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; MedImmune/Astrazeneca: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding.

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Complex, Not Monosomal, Karyotype Is the Cytogenetic Marker of Poorest Prognosis in Patients With Primary Myelodysplastic Syndrome

Journal of Clinical Oncology ◽

10.1200/jco.2012.41.6073 ◽

2013 ◽

Vol 31 (7) ◽

pp. 916-922 ◽

Cited By ~ 52

Author(s):

David Valcárcel ◽

Vera Ademà ◽

Francesc Solé ◽

Margarita Ortega ◽

Benet Nomdedeu ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Prognostic Value ◽

Chromosomal Abnormalities ◽

Strong Association ◽

Hemoglobin Level ◽

Abnormal Karyotype ◽

Free Survival ◽

Monosomal Karyotype ◽

Acute Myeloid

Purpose Complex karyotype (CK) is the poorest risk factor in patients with myelodysplastic syndrome (MDS). It has recently been reported that monosomal karyotype (MK) worsens the prognosis of patients with CK. Patients and Methods We analyzed 1,054 adult patients with MDS with an abnormal karyotype from the Spanish Registry of MDS. The aim of the study was to describe the incidence, characteristics, and prognosis of MK; the main end points were overall survival (OS) and leukemia-free survival. Results MK was identified in 172 patients (16%), most of whom (88%) presented with CK. Variables significantly associated with OS were age (hazard ratio [HR], 1.90; P < .001), bone marrow (BM) blast percentage (HR, 1.05; P < .001), hemoglobin level (HR, 1.71; P < .001), platelet count (HR, 1.41; P < .001), karyotype complexity (CK [three abnormalities]: HR, 1.81; P = .003; very CK [> three abnormalities]: HR, 2; P < .001), and abnormalities of chromosome 5 and/or 7 (HR, 1.89; P < .001). Variables significantly related to the risk of transformation to acute myeloid leukemia (AML) were higher BM blast percentage (HR, 1.12; P < .001) and karyotype complexity (CK: HR, 2.53; P = .002; very CK: HR, 2.77; P < .001). Conclusion After accounting for karyotype complexity, MK was not associated with OS or evolution to AML. In conclusion, these results demonstrate that the prognostic value of MK in MDS is not independent and is mainly the result of its strong association with number of chromosomal abnormalities.

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Maintenance Hypomethylating Therapy Post Allogeneic Stem Cell Transplantation Provides Favorable Progression Free Survival in High Risk Acute Myelogenous Leukemia or Non Responsive Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v120.21.4468.4468 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4468-4468

Author(s):

Connie A. Sizemore ◽

Xu Zhang ◽

Melissa Sanacore ◽

Asad Bashey ◽

Scott R. Solomon ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Complete Remission ◽

Myelodysplastic Syndrome ◽

Progression Free Survival ◽

Myelogenous Leukemia ◽

Hypomethylating Agents ◽

Free Survival ◽

Allogeneic Hsct ◽

Acute Myelogenous

Abstract Abstract 4468 Introduction Patients with acute myelogenous leukemia (AML) or non responsive myelodysplastic syndrome (MDS) who fail to achieve a complete remission, have unfavorable cytogenetics or are refractory to therapy have a poor prognosis. Allogeneic HSCT is frequently considered a salvage option for these patients although remissions are short-lived. New strategies are needed for maintaining remission in this extremely high risk patient group. We hypothesized hypomethylating agents post allogeneic HSCT would enable patients to remain in complete remission. Methods Eleven patients were treated. Patient characteristics: median age, 48 years (range, 18–70 years), PBSC (n=9) or bone marrow (n=2); Diagnoses AML= 10, Non- responsive MDS=1, CIBMTR disease risk category: High [n=8], Intermediate [n=1], Low [n=2]; 36% of the patients had primary induction failure, 54% had complex molecular abnormalities with 18% of the patients having deletion 11q 23 molecular abnormality. Donors were unrelated (36%) and related (64%). All but 1 donor-recipient pairs were fully matched. Preparative regimen- busulfan based (16mg/kg or equivalent) (82%), TBI ≥ 12 Gy (9%) based or reduced-intensity haplo-identical regimen (9%). The median number of prior chemotherapy regimens was 2.5 (range, 2–6). Azacitidine (n=10) or decitabine (n=1) was selected at physician discretion as a planned prophylactic regimen post allogeneic HSCT engraftment. Initial starting doses were based on hematological conditions at the time of therapy initiation. Results Ten patients received azacitidine subcutaneously daily for seven days for a median of 5 cycles (range, 1–10 cycles) and one patient received decitabine 20mg/m2 intravenously for 5 days for 3 cycles. Median initial Azacitidine dose of 50 mg/m2 (range, 25–75mg/m2) daily were given at a median of 40 days (range, 38–101 days) post HSCT engraftment. Azacitidine doses were increased based on counts to a maximum dose of 75mg/m2. With a median follow-up of 24 months (range, 1.7–49 months) 6 patients are alive in complete remission. Twenty-four month progression free survival is 51% with overall survival of 76%. Conclusion Given the dismal results of progression free survival and overall survival following allogeneic HSCT in high risk AML or non responsive MDS, hypomethylating agents given post transplantation provide a valuable approach to prolonging remission. Disclosures: No relevant conflicts of interest to declare.

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Outcome Of Patients With Myelodysplastic Syndrome (MDS) With Bone Marrow Blasts Between 10-30% Treated With Hypomethylating Agents Versus Intensive Chemotherapy

Blood ◽

10.1182/blood.v122.21.2788.2788 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2788-2788 ◽

Cited By ~ 1

Author(s):

Aziz Nazha ◽

Hagop M. Kantarjian ◽

Elias Jabbour ◽

Courtney D. DiNardo ◽

Gautam Borthakur ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndrome ◽

Regression Model ◽

Conflicts Of Interest ◽

World Health ◽

Refractory Anemia ◽

Intensive Chemotherapy ◽

Hypomethylating Agents ◽

Specific Protocol ◽

Bone Marrow Blasts

Abstract Background In 2001, the World Health Organization modified the French-American-British (FAB) classification for myelodysplastic syndrome (MDS) by folding the refractory anemia with excess blasts in transformation (RAEB-t) category into acute myeloid leukemia (AML). Whether this group of patients (pts) should be treated with AML versus MDS therapy remains controversial. A subset analysis of the AZA-001 trial showed that azacitidine prolongs overall survival (OS) in elderly pts with low blasts AML (bone marrow blasts [BM] 20-30%). Aim To compare the clinical outcome and OS of patients with MDS or AML with BM blasts between 10-30%, treated with hypomethylating agents (HMA) vs intensive chemotherapy (IC). Patients and Methods We conducted a retrospective analysis of newly diagnosed pts with MDS (or AML by WHO) and BM blasts between 10-30% treated with either HMA (alone or in combination with investigational therapies) or IC on clinical trials. Eligibility was based on pt characteristics and specific protocol inclusion criteria. A univariate Cox proportional hazards regression model was used to evaluate the overall effects of treatments and outcome (remission duration (RD), and OS). Then a regression model with the interactions between treatments and baseline covariates were used for subgroup analysis. The final model was obtained by a stepwise selection using 0.05 as a cut off of significant values. Results 330 patients were included in the final analysis, with 93 (28%) HMA-treated pts and 237 (72%) pts treated with IC. Clinical characteristics at diagnosis are summarized in Table1. The overall response rate (ORR= CR+CR p) was 42% for the pts who treated with HMA and 60% for pts treated with IC (P = 0.01). The median RD was similar between the two groups (14.7 mos (m) vs. 14.7 mos, respectively, P = 0.74). Early induction mortality was also similar among the two groups (4-week mortality was 5% vs. 7%, respectively, and the 8-week mortality was 10% vs. 13 %, respectively). With median follow up of 37 mos (range, 1-94 mos), the median OS was 18.8 mos for pts who treated with HMA vs. 14.6 mos for pts treated with IC (P = 0.32). Moreover, the BM blasts percentage did not impact the overall outcome. In multivariate analysis, treatment with IC was associated with worse OS compared to HMA (HR 2.09, 95% CI 2.07-3.17, P = 0.003) but not for RD (HR 0.43, 95% CI 0.89-2.68, P = 0.13). Conclusion Although patients with MDS or AML with BM blasts between 10-30% initially achieve a higher ORR when treated with IC compared to HMA-based therapy, the OS was better for pts treated with HMA after accounting for all other covariates. Interestingly, BM blast percentages within this cohort did not impact overall outcome suggesting that pts with BM blasts 20-30% may achieve better outcome with MDS therapy. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age

Blood ◽

10.1182/blood.v95.4.1188.004k38_1188_1194 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1188-1194 ◽

Cited By ~ 141

Author(s):

H. J. Deeg ◽

H. M. Shulman ◽

J. E. Anderson ◽

E. M. Bryant ◽

T. A. Gooley ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Plasma Levels ◽

Marrow Transplantation ◽

Disease Free Survival ◽

Inverse Correlation ◽

Myelogenous Leukemia ◽

Refractory Anemia ◽

International Prognostic Scoring System ◽

Free Survival ◽

Disease Free

We carried out bone marrow transplantation (BMT) in 50 patients with myelodysplastic syndrome (MDS) who were 55.3 to 66.2 years of age (median, 58.8 years). According to the criteria of the French-American-British (FAB) classification, 13 patients had refractory anemia (RA), 19 had RA with excess blasts (RAEB), 16 had RAEB in transformation or acute myelogenous leukemia (RAEB-T/AML), and 2 had chronic myelomonocytic leukemia (CMML). According to the recently established International Prognostic Scoring System (IPSS), available for 45 patients, 2 patients were considered low risk; 14, intermediate 1 risk; 19, intermediate 2 risk; and 10, high risk. Conditioning regimens were cyclophosphamide (CY) (120 mg/kg of body weight) plus 12-Gy fractionated total-body irradiation (FTBI) (n = 15), CY plus FTBI with lung and liver shielding (n = 4), busulfan (7 mg/kg) plus FTBI (n = 4), or busulfan (16 mg/kg) plus CY (n = 27). The busulfan-plus-CY group included 16 patients in whom busulfan was targeted to plasma levels of 600 to 900 ng/mL. In these 16 patients, steady-state levels of busulfan actually achieved were 714 to 961 ng/mL (mean ± SD, 845 ± 64 ng/mL; median, 838 ng/mL). The donors were HLA-identical siblings for 34 patients, HLA-nonidentical family members for 4, identical twins for 4, and unrelated volunteers for 6. All 46 patients surviving > 21 days had engraftment, and 22 patients (44%) are surviving 9 to 80 months after BMT. Specifically, among 13 patients with RA, 1 had relapse (cumulative incidence [CI] at 3 years, 8%) and 8 are surviving, for a Kaplan-Meier (KM) estimate of survival at 3 years of 59% (disease-free survival [DSF], 53%). Among 19 patients with RAEB, 3 had relapse (CI at 3 years, 16%), and 8 are surviving disease free (KM estimate at 3 years, 46%). Among 18 patients with RAEB-T/AML or CMML, 6 had relapse (CI at 3 years, 28%), and the KM estimate of DSF at 3 years is 33%. Relapse-free survival had an inverse correlation with cytogenetic risk classification and with the risk score according to the IPSS. Survival in all FAB categories was highest among patients enrolled in a protocol in which busulfan plasma levels were targeted to 600 to 900 ng/mL. These data indicate that BMT can be carried out successfully in patients with MDS who are older than 55 years of age.

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STUDY OF CXCL12, CCR4, EGFR GENE EXPRESSION IN MIGRATING MYELOMONOBLASTIC LEUKEMIA CELLS BEFORE AND AFTER CHEMOTHERAPY

Journal of microbiology epidemiology immunobiology ◽

10.36233/0372-9311-2019-1-100-104 ◽

2019 ◽

Vol 1 (1) ◽

pp. 100-104

Author(s):

A. B. Filina ◽

O. A. Svitich ◽

Yu. I. Ammur ◽

A. K. Golenkov ◽

E. F. Klinushkina ◽

...

Keyword(s):

Tumor Cells ◽

Mononuclear Cells ◽

Boyden Chamber ◽

External Stimulation ◽

Healthy Donors ◽

Genes Expression ◽

Before And After ◽

Chemokine Cxcl12 ◽

And Migration ◽

Cell Chemotaxis

Аim. A study of CXCL12 effect on the migration of mononuclear cells isolated from healthy patients, from patients with myelomonoblastic leukemia before and after chemotherapy and the study of CCR4, EGFR and CXCL12 genes expression after exposure to CXCL12. Materials and methods. The chemotaxis of mononuclear cells (MNCs) of healthy donors and patients with myelomonoblastic leukemia was studied in a Boyden chamber, followed by isolation of RNA, reverse transcription and PCR-RV. Results. A significant increase in myelomonoblasic cell chemotaxis towards CXCL12 after chemotherapy was demonstrated, as well as a decrease in the expression of this chemokine in tumor cells before chemotherapy after exposure to CXCL12. Сonclusion. Presumably, the tumor cells themselves produce CXCL12 in large amounts, which is necessary for the disturbance of intercellular interactions and further intravasation, whose production may decrease with external stimulation by the same chemokine. CXCL12 also helps to increase the expression level of EGFR and CCR4, which leads to increased tumor proliferation and migration of tumor cells.

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Clinical features and outcomes of combined hepatocellular carcinoma and cholangiocarcinoma versus hepatocellular carcinoma versus cholangiocarcinoma after surgical resection: a propensity score matching analysis

BMC Gastroenterology ◽

10.1186/s12876-020-01586-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chih-Wen Lin ◽

Tsung-Chin Wu ◽

Hung-Yu Lin ◽

Chao-Ming Hung ◽

Pei-Min Hsieh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Propensity Score ◽

Propensity Score Matching ◽

Surgical Resection ◽

Disease Free Survival ◽

Clinicopathological Features ◽

Free Survival ◽

Before And After ◽

Disease Free

Abstract Background Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an infrequent type of primary liver cancer that comprises hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). This study investigated the clinicopathological features and prognosis among cHCC-CC, HCC, and CC groups. Methods We prospectively collected the data of 608 patients who underwent surgical resection for liver cancer between 2011 and 2018 at E-Da Hospital, I-Shou University, Kaohsiung, Taiwan. Overall, 505 patients with cHCC-CC, HCC, and CC were included, and their clinicopathological features, overall survival (OS), and recurrence were recorded. OS and recurrence rates were analyzed using the Kaplan–Meier analysis. Results In the entire cohort, the median age was 61 years and 80% were men. Thirty-five (7.0%) had cHCC-CC, 419 (82.9%) had HCC, and 51 (10.1%) had CC. The clinicopathological features of the cHCC-CC group were more identical to those of the HCC group than the CC group. OS was significantly lower in the cHCC-CC group than in the HCC group but was not significantly higher in the cHCC-CC group than in the CC group. The median OS of cHCC-CC, HCC, and CC groups was 50.1 months [95% confidence interval (CI): 38.7–61.2], 62.3 months (CI: 42.1–72.9), and 36.2 months (CI: 15.4–56.5), respectively. Cumulative OS rates at 1, 3, and 5 years in cHCC-CC, HCC, and CC groups were 88.5%, 62.2%, and 44.0%; 91.2%, 76.1%, and 68.0%; and 72.0%, 48.1%, and 34.5%, respectively. After propensity score matching (PSM), OS in the cHCC-CC group was not significantly different from that in the HCC or CC group. However, OS was significantly higher in the HCC group than in the CC group before and after PSM. Furthermore, the disease-free survival was not significantly different among cHCC-CC, HCC, and CC groups before and after PSM. Conclusion The clinicopathological features of the cHCC-CC group were more identical to those of the HCC group than the CC group. The OS rate was significantly lower in the cHCC-CC group than the HCC group. However, after PSM, OS and disease-free survival in the cHCC-CC group were not significantly different from those in the HCC or CC group.

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TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

Cell Death and Disease ◽

10.1038/s41419-021-03734-4 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Sha Zhou ◽

Jianhong Peng ◽

Liuniu Xiao ◽

Caixia Zhou ◽

Yujing Fang ◽

...

Keyword(s):

Colorectal Cancer ◽

Disease Free Survival ◽

Free Survival ◽

Epigenetic Regulator ◽

Crc Management ◽

Disease Free ◽

Resistance To Chemotherapy

AbstractResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

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