Study on Methylation of p15INK4B Gene and Its Mechanisms in Patients with Myelodysplastic Syndrome and Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3441-3441
Author(s):  
Hongyan Tong ◽  
Maofang Ling ◽  
Jie Jin
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Low Risk ◽  
Blast Phase ◽  
Genetic Event

Abstract The expression and methylation of p15INK4B gene and the expression of DNA methyltransferase genes (DNMTs) in the mononuclear cells (MNCs) from bone marrow of 54 cases with hematopoietic malignances were detected by using RT-PCR, Western blot, and methylation-specific PCR. Of the 54 patients, 10 cases were low-risk MDS, 10 cases were high-risk MDS, 10 cases were acute myeloid leukemia (AML), 10 cases were acute lymphocytic leukemia (ALL), 10 cases were chronic myeloid leukemia in chronic phase (CML-CP), and 4 cases were CML in blast phase (CML-BP). 10 normal persons were studied as nective controls. The results showed that the incidence of p15INK4B methylation in cells of high-risk MDS was higher than that in low-risk MDS (6/10 VS 1/10, P=0.003), and the p15INK4B methylation was found to be associated with the down-regulation of the expressions of p15INK4B gene on both mRNA (r=−0.734, p<0.001) and protein (r=−0.664, p=0.001)levels, which indicated that the silencing of p15INK4B gene was in conjunction with hypermethylation in MDS. The expressions of p15INK4B on mRNA level and protein levels were almost detected in the MNCs from bone marrow of normal persons without the p15INK4B methylation. We also found the expression of DNMT3A and DNMT3B in high-risk MDS (densitometry readings respectively: 0.624±0.146, 0.577±0.344) were higher than in low-risk MDS (densitometry readings respectively: 0.487±0.300, 0.338±0.290) (P<0.05). The expression of DNMT1 was higher in the groups of low-risk MDS, high-risk MDS, AL and CML-CP( densitometry readings respectively: 0.487±0.218, 0.697±0.243, 0.706±0.463 and 0.867±0.375) than in normal control (densitometry reading: 0.181±0.312)(P<0.05, figure listed bellow), which indicated that up-regulated DNMTS might contribute to the hypermethylation of p15INK4B, and the higher expressions of de novo methyltransferases DNMT3A and DNMT3B may be related to the disease progression of MDS. The methylation of p15INK4B was also detected in 9/20 of AL cases accompanied by over-expressions of DNMT1, DNMT3A, and DNMT3B (densitometry readings respectively: 0.706±0.463, 1.066±0.547, and 0.530±0.428). The methylation of p15INK4B was detected in 1 of 10 cases of CML-CP patients, but all be detected in 4 case of CML-BP patients. These results indicated that the hypermethylation of p15INK4B gene may be one of the most common genetic event in pathogenesis of high-risk MDS, acute leukemia, and blast phase of CML. Furthermore, DNMT3A and DNMT3B were substantially over-expressed in the bone marrow cells of these patients. which might play an important role in the transformation from MDS to acute leukemia. Figure Figure

scholarly journals Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1382-1388 ◽  
Author(s):  
PJ Tutschka ◽  
EA Copelan ◽  
JP Klein
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Marrow Transplantation ◽  
Risk Group ◽  
Chronic Phase ◽  
Length Of Hospital Stay ◽  
High Risk Group ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Standard Risk

Abstract Busulfan 16 mg/kg and cyclophosphamide 120 mg/kg were used as conditioning prior to allogeneic marrow transplantation in 50 adult patients with acute nonlymphocytic leukemia (ANLL), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML). A standard risk group of 20 patients included those with acute leukemia in remission and CML in chronic phase. A high-risk group of 30 patients included individuals with refractory acute leukemia, acute leukemia in relapse, acute leukemia following preleukemia, and CML in accelerated and blastic phase. Complete remission and sustained complete engraftment were achieved in all evaluable patients. The duration of aplasia was remarkably short (median of 8 days), resulting in a low infection rate during the period of neutropenia, a reduced need for blood product support, and a short length of hospital stay. Three-year actuarial relapse-free survival in both standard-risk (88.9% +/- 10.5%) and high- risk (50.5% +/- 9.6%) groups compares favorably with that reported with total body irradiation (TBI) containing regimens.

Phase I clinical and laboratory evaluation of topotecan and cytarabine in patients with acute leukemia.

1997 ◽  
Vol 15 (1) ◽  
pp. 44-51 ◽  
Author(s):  
K Seiter ◽  
E J Feldman ◽  
H D Halicka ◽  
F Traganos ◽  
Z Darzynkiewicz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Acute Leukemia ◽  
S Phase ◽  
Low Risk ◽  
Myelogenous Leukemia ◽  
Laboratory Evaluation ◽  
Apoptotic Cells ◽  
High Risk Patients ◽  
Risk Patients

PURPOSE To determine the maximal-tolerated dose (MTD) of topotecan with cytarabine in acute leukemia patients, and to evaluate leukemia cell apoptosis in these patients. PATIENTS AND METHODS Fifty-three patients with acute leukemia not responsive to standard therapy were treated at eight dose levels of topotecan (2.5 mg/m2/d to 7.75 mg/m2/d). Topotecan was given as a 30-minute infusion daily with cytarabine 1 g/m2/d, both for 5 days. Using a flow-cytometric technique, the percent apoptotic cells in blood and bone marrow samples was determined, and the cell cycle distribution of the leukemic cells studied. RESULTS Oropharyngeal mucositis was dose-limiting. The MTD of topotecan was 4.75 mg/m2/d for 5 days in high-risk patients and 7.0 mg/m2/d for 5 days in low-risk patients. The mean percent apoptotic cells in the peripheral blood reached a peak of 18.8%, a median of 48 hours following the first dose of topotecan. Patients with higher S-phase fractions, either before treatment or following cytarabine, were more likely to achieve bone marrow aplasia than those with lower S-phase fractions (P = .01 and P < .05, respectively). Clinical responses were seen in four of 39 patients with acute myelogenous leukemia (AML; of whom 32 had received prior high-dose cytarabine), three of six with acute lymphoblastic leukemia (ALL), and one of eight with chronic myelogenous leukemia in blast phase (CML-BP). CONCLUSION The recommended phase II dose of topotecan with intermediate-dose cytarabine is 4.75 mg/m2/d for high-risk patients and 7.0 mg/m2/d for low-risk patients. The percentage of cells in S phase was important in determining response to treatment.

scholarly journals Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1382-1388 ◽  
Author(s):  
PJ Tutschka ◽  
EA Copelan ◽  
JP Klein
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Marrow Transplantation ◽  
Risk Group ◽  
Chronic Phase ◽  
Length Of Hospital Stay ◽  
High Risk Group ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Standard Risk

Busulfan 16 mg/kg and cyclophosphamide 120 mg/kg were used as conditioning prior to allogeneic marrow transplantation in 50 adult patients with acute nonlymphocytic leukemia (ANLL), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML). A standard risk group of 20 patients included those with acute leukemia in remission and CML in chronic phase. A high-risk group of 30 patients included individuals with refractory acute leukemia, acute leukemia in relapse, acute leukemia following preleukemia, and CML in accelerated and blastic phase. Complete remission and sustained complete engraftment were achieved in all evaluable patients. The duration of aplasia was remarkably short (median of 8 days), resulting in a low infection rate during the period of neutropenia, a reduced need for blood product support, and a short length of hospital stay. Three-year actuarial relapse-free survival in both standard-risk (88.9% +/- 10.5%) and high- risk (50.5% +/- 9.6%) groups compares favorably with that reported with total body irradiation (TBI) containing regimens.

The EUTOS Score Is Highly Predictive for Clinical Outcome and Survival in Asian Patients with Early Chronic Phase Chronic Myeloid Leukemia Treated with Imatinib

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3758-3758 ◽  
Author(s):  
Hein Than ◽  
Lingyee Kuan ◽  
Chiu Hong Seow ◽  
Wenyun Li ◽  
John C Allen ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Risk Group ◽  
Low Risk ◽  
Free Survival ◽  
Asian Patients ◽  
Eutos Score

Abstract Abstract 3758 Background: The EUTOS score has been proposed by the European LeukemiaNet (ELN) as a new scoring system which is predictive for 18-month (mth) complete cytogenetic response (CCyR) and 5-year (yr) progression-free survival (PFS) in chronic phase (CP) chronic myeloid leukemia (CML) patients treated with first-line imatinib (IM) (Hasford et al, Blood 2011). The score is calculated using spleen size and basophil percentage and divides patients into low risk and high risk groups. However the EUTOS score was not validated in two studies, one which determined 8-yr overall survival (OS), PFS, CCyR and major molecular remission (MMR) (Marin et al, J Clin Oncol 2011); and in another which analysed 3-yr event-free survival, transformation-free survival and OS and overall CCyR and MMR (Kantarjian H et al, Blood 2012). Recent reports have suggested that Asian CML patients may have clinical and genetic differences compared to Causcasians, e.g. younger median age at presentation (Au et al, Int J Hem 2009) and genetic polymorphism leading to IM resistance (Pan et al, Nat Med 2012). Although a different disease, splenomegaly was also reported to be less frequent in Chinese patients with myelofibrosis (Xiao et al, Blood 2012). Given these differences, we sought to determine if the EUTOS score was predictive for clinical outcome and survival in Asian CP-CML patients treated with IM. Methods: A retrospective analysis was undertaken of CP-CML patients followed up in our institution from 2000–2012. All patients were treated with IM 400 mg within one year of diagnosis. The rates of 6-mth major cytogenetic response (MCyR), 12-mth CCyR, 18-mth CCyR, 12-mth MMR and 18-mth MMR were evaluated. MMR was defined as BCR-ABL transcript levels ≤ 0.1% by the International Scale. The probability of OS, PFS and failure-free survival (FFS) at 5 and 8 years was also determined. Progression was defined as transformation to accelerated or blast phase (AP/BP) or death from any reason. Failure was defined according to the 2009 ELN criteria or as an increase in dose of IM, change of therapy, transformation to AP/BP or death. Results: A total of 139 patients were included in the analysis. The median age at presentation of CML was 45 yrs (range 16–88) with 64% Chinese, 17% Malays and 8% Indians. There was 69% in the low risk EUTOS group. Cytogenetic responses were significantly better in the low risk group compared to the high risk group with 6-mth MCyR rates of 82% vs 48% (p<0.001), 12-mth CCyR rates of 68% vs 39% (p=0.008) and 18-mth CCyR rates of 73% vs 36% (p=0.003). MMR rates were also higher in the low risk group at 12 mth (42% vs 14%, p=0.026) and at 18 mth (56% vs 21%, p=0.009). The probability of PFS was significantly higher in the low risk group compared to the high risk group at 5 yrs (93% vs 83%, p=0.032) and at 8 yrs (92% vs 70%, p=0.032). The low risk group also had a significantly higher FFS at 5 yrs (64% vs 20%, p<0.001) and at 8 yrs (61% vs 20%, p<0.001). (Figure 1) There was a trend towards a better overall survival in the low risk group at 5 and 8 yrs but this did not reach statistical significance (95% vs 92% and 94% vs 83% respectively, p=0.084). Conclusion: Our analysis confirms that the EUTOS score is a valid tool in predicting 18-mth CCyR and 5-yr PFS in Asian patients with early CP-CML treated with IM. In addition, we have shown that the EUTOS score was highly predictive for cytogenetic and molecular responses at earlier time points and long-term PFS and FFS. Disclosures: Chuah: Novartis, Bristol Myers-Squibb: Honoraria.

scholarly journals Differences in Inducing Activity for Human Bone Marrow Colonies in Normal Serum and Serum From Patients With Leukemia

Blood ◽  
1973 ◽  
Vol 42 (3) ◽  
pp. 331-339 ◽  
Author(s):  
Uri Mintz ◽  
Leo Sachs
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Normal Activity ◽  
Normal Serum ◽  
Lymphocytic Leukemia ◽  
Human Bone ◽  
Human Bone Marrow ◽  
High Concentration

Abstract Normal serum and serums from patients with acute and chronic leukemia were assayed for granulocyte colony-inducing activity with human bone marrow cells. Serum from untreated acute leukemia, but not from the other patients, showed about normal inducing activity at low serum concentration and lower than normal activity at high concentration. This suggests that serum from patients with acute leukemia contained an inhibitor for colony formation. Serums from chronic myeloid leukemia were in about the same range as normal, whereas serums from chronic lymphocytic leukemia showed the highest colony-inducing activity.

BCR/ABL mRNA and the P210BCR/ABL Protein Are Downmodulated by Interferon- in Chronic Myeloid Leukemia Patients

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2200-2207 ◽  
Author(s):  
Fabrizio Pane ◽  
Ilaria Mostarda ◽  
Carmine Selleri ◽  
Rossella Salzano ◽  
Anna Maria Raiola ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Single Agent ◽  
Chronic Phase ◽  
Dependent Manner ◽  
Complete Hematologic Response ◽  
Ifn Treatment

The BCR/ABL hybrid gene plays a central role in the pathogenesis of the chronic phase of chronic myeloid leukemia (CML). We used a very sensitive quantitative reverse transcriptase-polymerase chain reaction to investigate the levels of hybrid BCR/ABL mRNA in bone marrow cells of 20 patients with Philadelphia positive (Ph+) CML treated with interferon- (IFN-) as a single agent. Bone marrow samples were collected at diagnosis and at hematologic remission induced by IFN-, or by hydroxyurea in case of resistance to IFN-. The mean levels of BCR/ABL transcripts in bone marrow mononuclear cells of patients who showed a complete hematologic response to IFN- were significantly reduced with respect to those at diagnosis (48 × 103v168 × 103; P &lt; .001), whereas no difference was detected between the values at diagnosis and at hematologic remission in patients resistant to IFN-. In cell culture experiments, IFN- priming significantly reduced the levels of BCR/ABL hybrid transcripts in a dose-dependent manner in Ph+ bone marrow precursors obtained at diagnosis from patients who subsequently responded to IFN- treatment (P &lt; .005). No downmodulation was observed in bone marrow precursors from patients who subsequently proved to be IFN-resistant. These results indicate that downmodulation of BCR/ABL gene expression could be one of the mechanisms involved in the response of CML patients to IFN- treatment.

Chronic myeloid leukemia and interferon-α: a study of complete cytogenetic responders

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 3074-3081 ◽  
Author(s):  
Francesca Bonifazi ◽  
Antonio de Vivo ◽  
Gianantonio Rosti ◽  
François Guilhot ◽  
Joëlle Guilhot ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Collaborative Study ◽  
Chronic Phase ◽  
Low Risk ◽  
Interferon Α ◽  
Term Survival ◽  
High Risk Patients ◽  
Risk Patients

Abstract Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CML) with interferon-α (IFN-α), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the collection of data on 317 patients who were first seen between 1983 and 1997 and achieved CCgRs with IFN-α alone or in combination with hydroxyurea. The median time to first CCgR was 19 months (95% CI, 17-21; range, 3-84 months). At last contact, 212 patients were still alive and in continuous CCgR; 105 patients had lost CCgR, but 53% of them were still alive and in chronic phase. IFN-α treatment was discontinued permanently in 23 cases for response loss, in 36 cases for chronic toxicity (15 are still in unmaintained continuous CCgR), and in 8 cases because it was believed that treatment was no longer necessary (7 of these 8 patients are still in unmaintained continuous CCgR). The 10-year survival rate from first CCgR is 72% (95% CI, 62%-82%) and is related to the risk profile. High-risk patients lost CCgR more frequently and more rapidly and none survived more than 10 years. Low-risk patients survived much longer (10-year survival probability 89% for Sokal low risk and 81% for Euro low risk). These data point out that a substantial long-term survival in CCgRs is restricted mainly to low-risk and possibly intermediate-risk patients and occurs significantly less often in high-risk patients.

BNIP3 Is Downregulated in Myelodysplastic Syndromes and Acute Myeloid Leukemia and Is a Potential Molecular Target for Decitabine

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1708-1708
Author(s):  
Mariana Lazarini ◽  
Joao Machado-Neto ◽  
Adriana S. S. Duarte ◽  
Fernando V Pericole ◽  
Patricia Favaro ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Marrow ◽  
High Risk ◽  
Colony Formation ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Low Risk ◽  
U937 Cells ◽  
Healthy Donors ◽  
Marrow Cells

Abstract Abstract 1708 In myelodysplastic syndromes (MDS), changes in the balance between pro- and anti-apoptotic proteins are associated with disease progression and evolution towards acute myeloid leukemia (AML). BNIP3 is a pro-apoptotic protein, member of the Bcl-2 superfamily, associated with the pathogenesis of many diseases, including cancer. More recently, BNIP3 was identified as a potent inducer of autophagy. In primary leukemia cells, BNIP3 expression has been shown to be reduced due to epigenetic modifications; however, there is a lack of studies of BNIP3 in MDS. The aim of this study was to characterize BNIP3 mRNA expression levels and DNA methylation status of its 5' CpG island in bone marrow cells from MDS and AML patients, healthy donors and in leukemia hematopoietic cell lines. We also investigated the effects of BNIP3 silencing upon decitabine (DAC) treatment in U937 cells regarding colony formation, apoptosis and autophagy. Bone marrow aspirates were obtained from 21 healthy donors, 55 patients with MDS and 44 patients with AML at diagnosis. MDS patients were grouped into low-risk and high-risk groups according to FAB (RA/RARS=30; RAEB/RAEBt=25), WHO (RCUD/RCMD/RARS/del5/=29; RAEB1/RAEB2=17) and IPSS (low/INT-1=38; INT2/high=16). The study was approved by the ethics committee and informed written consent was provided. Gene expression was evaluated by qPCR and DNA methylation was performed by Combined Bisulfite Restriction Analysis. BNIP3 knockdown was performed in U937 cells with specific shRNA-expressing lentiviral vector. ShRNA encoding no specific sequence was used as control. Colony formation was carried out in semisolid methylcellulose medium. Apoptosis and autophagy were accessed by flow cytometry. All assays were performed in lentiviral transduced cells treated or not with 5μM DAC for 72 hours. Mann-Whitney and Student's t-test were used for statistical analyses. We observed a significant decrease in BNIP3 mRNA expression in total bone marrow cells from AML and MDS compared to healthy donors (AML= 0.52 [5.27-0.00]; MDS=0.52 [5.25-0.02] versus healthy donors=1.09 [6.04-0.18]; P<0.05). BNIP3 expression did not differ between low-risk and high-risk MDS patients according to FAB and WHO classifications, and IPSS. Methylation of BNIP3 promoter was detected in 19% (4/21; 2/14 low-risk and 2/7 high-risk) MDS and 26% (4/15) AML patients, but not in any of the 6 healthy donors evaluated. BNIP3 expression was detected in all myeloid cell lines studied (K562, HL60, U937 and P39 cells). The lowest expression was found in U937, which presented methylation of BNIP3 promoter. Interestingly, in U937 cells, DAC treatment resulted in upregulation of BNIP3 expression (3.7-fold), total inhibition of colony formation, increased apoptosis and autophagy (50% for both). The effect of DAC on cell apoptosis was reduced by BNIP3 silencing; apoptosis was reduced by 48%±4.3 in shBNIP3 cells compared to 59%±5.7 in shControl cells (p<0.05). Autophagy was not modulated by DAC treatment in BNIP3 silenced cells. In bone marrow cells from MDS and AML patients, the low frequency of methylated BNIP3 promoter suggests that DNA methylation is not the single reason for the decreased BNIP3 expression in these patients. Other mechanisms, such as histone deacetylation, may be involved in aberrant BNIP3 expression. DAC treatment in BNIP3 silenced cells had no effect on autophagy, suggesting that other mechanisms besides increasing BNIP3 expression is involved in this cell function. On the other hand, DAC treatment in U937 cells was able to induce apoptosis, especially in cells expressing BNIP3, supporting the hypothesis that BNIP3 methylation is a molecular target for DAC. Disclosures: No relevant conflicts of interest to declare.

EUTOS Score Is Predictive of Event-Free Survival, but Not for Progression-Free and Overall Survival in Patients with Early Chronic Phase Chronic Myeloid Leukemia Treated with Imatinib: A Single Institution Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1681-1681 ◽  
Author(s):  
Katia B. Pagnano ◽  
Irene Lorand-Metze ◽  
Eliana C M Miranda ◽  
Vagner O Duarte ◽  
Marcia T Delamain ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Low Risk ◽  
Event Free Survival ◽  
Free Survival ◽  
Sokal Score ◽  
Eutos Score

Abstract Abstract 1681 Recently the European LeukemiaNet has developed a new scoring system (European Treatment and Outcome Study [EUTOS] score) for newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) treated with imatinib. The EUTOS score classifies patients in high or low risk on the basis of the percentage of basophils in the peripheral blood and the spleen size at diagnosis, with significant correlations with the achievement of an 18-month complete cytogenetic response (CCyR) and progression-free survival (PFS). The aim of this work was to evaluate EUTOS score in CML-CP treated in our center with imatinib as a predictive factor for overall survival (OS), event-free survival (EFS) and PFS. Patients and methods: Between February 2003 and May 2012 consecutive patients with newly diagnosed CML-CP were treated with imatinib 400 mg daily (n= 144) or imatinib 600–800 mg daily (n= 14) were included in the analysis. The criteria recommended by European LeukemiaNet (ELN) were used for the definitions of CCyR and the progression to accelerated phase (AP) or blast phase (BP). The EUTOS score was defined by (7×basophils) plus (4×spleen size) at diagnostic. A EUTOS score of more than 87 indicates high risk, and less than or equal to 87 low risk. EFS was measured from the start of imatinib treatment to the date of any of the following events: death from any cause at any time, loss of complete hematologic response, loss of CCyR, or progression to AP or BP. PFS was measured from the start of treatment to the date progression to AP or BP, last follow-up, or death from any cause. Survival probabilities were estimated by the Kaplan-Meier method and compared by the log-rank test whereas it was applied cumulative incidence for the probability to achieve CCyR. Results: A total of 158 patients were treated, 94 (59.5%) male. The median age at Imatinib was 47 years (17–86 years). The median time from diagnosis to TKI therapy was 2 (0–6) months, with 153 (96.8%) receiving previous treatment with Hydrea. The median follow-up was 29 (1–110) months. The median splenomegaly size was 4 (0–29) cm and the median basophil percentage was 2.5% (0–18%). According to the Sokal score, 43 (34,4%) patients, 46 (36,8%), and 36 (28,8%) were in low, intermediate, and high Sokal score category, respectively (33 not available). Concerning the Hasford score, 60 (48,3%), 50 (40,4%) and 14 (11,3%) were in low, intermediate and high risk categories (34 NA). A total of 137 (86,8%) patients were in the low EUTOS score category and 21 (13,2%) in the high risk category. The cumulative probability of achieving a CCyR and MMR at 36 months for all patients was 78% and 64%, respectively. Patients who had not achieved CCyR after 6 months (51/153 – 33%) had a 2% risk of subsequent progression, which increased to 12% after 12 months, 14% in 18 months and 19% after 24 months. EFS, PFS, and OS rates for the whole group were 60%, 89%, and 92%, respectively. Patients with a low EUTOS score had higher rates of cumulative CCyR compared with patients with high EUTOS score (82% vs. 53%, p= 0.06) (figure 1). There were no differences in the cumulative CCyR rates in patients stratified by Sokal or Hasford scores (and 0.21 and P=0.82, respectively). Patients with CCyR at 18 months had a higher EFS (81% vs. 18%, p< 0.0001) and PFS rates (96% vs. 82%, p= 0.03). There was no difference in PFS (figure 2) and OS rates between patients with low and high EUTOS score. However, patients with high and intermediate Sokal score had an inferior PFS rates in comparison with low risk group (77%, 84% and 100%, respectively, p= 0.02). There was a superior EFS rates in low risk in comparison with high EUTOS score (63% vs. 36%, p= 0.01) (figure 3), whereas the overall survival there was no difference (91% vs. 100%). Sokal scores EFS rates were 68%, 60% and 40% for low, intermediate and high risk groups respectively (p= 0.03). In conclusion, similarly to the original report, EUTOS score seems to predict CCyR, but not PFS in our population. However, EFS was significantly better in the low than high risk group. The score can discriminate patients with poor outcome, with lower probability of achieving responses to first line imatinib therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias

Blood ◽  
1996 ◽  
Vol 88 (3) ◽  
pp. 1026-1034 ◽  
Author(s):  
T Pabst ◽  
J Schwaller ◽  
MJ Bellomo ◽  
M Oestreicher ◽  
D Muhlematter ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Loss Of Heterozygosity ◽  
Tumor Suppressor Genes ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Normal Karyotype ◽  
Lymphocytic Leukemia ◽  
Genetic Event ◽  
Replication Errors ◽  
Adult Leukemia

Abstract Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.

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