Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 3794-3800 ◽  
Author(s):  
Jorge E. Cortes ◽  
Moshe Talpaz ◽  
Francis Giles ◽  
Susan O'Brien ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Imatinib Mesylate ◽  
Multivariate Analyses ◽  
Clonal Evolution ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Poor Prognostic Factor ◽  
Prognostic Relevance ◽  
Independent Poor Prognostic Factor ◽  
Response Versus

Abstract Cytogenetic clonal evolution (CE) is a known poor prognostic factor in Philadelphia chromosome–positive chronic myelogenous leukemia (Ph-positive CML). However, its prognostic relevance in the era of imatinib therapy is unknown. We investigated the independent prognostic relevance of CE in 498 patients with Ph-positive CML treated with imatinib for chronic or accelerated phases. One hundred twenty-one patients had CE alone (n = 70) or with other accelerated phase criteria (n = 51). Patients were compared in 4 categories: chronic phase (n = 295), CE only (n = 70), accelerated phase without CE (n = 82), and accelerated phase with CE (n = 51). Statistical methods used established methodologies for univariate and multivariate analyses. In chronic and accelerated phases of CML, CE was not associated with significant differences in major or complete cytogenetic response rates, but it was an independent poor prognostic factor for survival by multivariate analyses in both chronic (P = .005) and accelerated phase (P = .03). Multivariate analyses conducted at the 3-month landmark (including the 3-month cytogenetic response) identified the lack of cytogenetic response at 3 months to be a stronger independent poor prognostic factor for survival than CE for both chronic (major cytogenetic response versus other) and accelerated phase (any cytogenetic response versus other). We conclude that cytogenetic CE is not an important factor for achieving major or complete cytogenetic response with imatinib mesylate therapy, but it is an independent poor prognostic factor for survival in both chronic and accelerated phases of CML. The 3-month cytogenetic response to imatinib mesylate refined the prognostic relevance of such studies in patients on imatinib mesylate therapy.

The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1628-1633 ◽  
Author(s):  
Michael E. O'Dwyer ◽  
Michael J. Mauro ◽  
Gwen Kurilik ◽  
Motomi Mori ◽  
Suzanne Balleisen ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Imatinib Mesylate ◽  
Chromosomal Abnormalities ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Significant Activity ◽  
Sole Criterion ◽  
The Impact

In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal evolution could allow Bcr-Abl independent proliferation, we analyzed its impact on the outcome of 71 AP patients treated with 600 mg of imatinib mesylate. Fifteen patients had clonal evolution alone (AP-CE), 32 had AP features but no evidence of clonal evolution (HEM-AP), and 24 had AP features plus clonal evolution (HEM-AP + CE). Of the AP-CE patients, 73% had a major cytogenetic response, compared with 31% of the HEM-AP patients (P = .043) and 12.5% of the HEM-AP + CE patients (P = .007). Complete cytogenetic responses were seen in 60% of AP-CE patients, compared with 31% of HEM-AP patients (P = .19) and 8% of HEM-AP + CE patients (P < .001). With mean follow-up of 11.2 months, 35% of all patients failed treatment. The lowest estimated rate of treatment failure at 1 year, 0%, was seen in AP-CE patients, compared with rates of 31% for HEM-AP patients and 69% for HEM-AP + CE patients (P = .0004). After 1 year, 100% of AP-CE patients were still alive, compared with 85% of HEM-AP patients and 67.5% of HEM-AP + CE patients (P = .01). In conclusion, in patients with clonal evolution as the sole criterion of disease acceleration, good responses to imatinib are still possible. Once patients have other signs of acceleration, clonal evolution predicts lower response rates and a shorter time to treatment failure.

Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 451-455 ◽  
Author(s):  
Michael E. O'Dwyer ◽  
Michael J. Mauro ◽  
Carolyn Blasdel ◽  
Melanie Farnsworth ◽  
Gwen Kurilik ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Cox Regression ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Cox Regression Analysis ◽  
Increased Risk ◽  
Complete Hematologic Response ◽  
Significant Factors

Abstract We followed 141 patients treated with imatinib mesylate (&gt; 300 mg) for chronicphase chronic myelogenous leukemia (CML) following failure of treatment with interferon. During 12 months from the start of imatinib mesylate treatment, 96.5% achieved a complete hematologic response, 47.0% achieved a major cytogenetic response, and 32.4% achieved a complete cytogenetic response. The proportion of patients with hematologic relapse was 10.9% at 12 months and 14.6% at 18 months. In a univariate Cox regression analysis, the only pretreatment characteristics that correlated with an increased risk of hematologic relapse were hemoglobin level less than 120 g/L (12 g/dL) (P = .02), increased bands in the peripheral blood (P = .01), and clonal evolution (P &lt; .0001). In a multivariate analysis, an elevated platelet count (P = .03) and clonal evolution (P &lt; .0001) were the only significant factors for hematologic relapse. During treatment, the absence of a major cytogenetic response within the first 6 months also significantly correlated with relapse (P = .03). Notably, patients failing to achieve a major cytogenetic response by 6 months had a significantly higher rate of hematologic relapse (27%) compared with those who achieved a major cytogenetic response by 6 months (3%), and patients with clonal evolution had a significantly higher risk of hematologic relapse (50%) than those without clonal evolution (9%).

scholarly journals Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1590-1595 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Jorge E. Cortes ◽  
Sergio A. Giralt ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Allogeneic Stem Cell Transplantation ◽  
Response Rate ◽  
Chronic Phase ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Blastic Phase

Twenty-eight adults with chronic myelogenous leukemia (CML) that had relapsed after allogeneic stem cell transplantation (SCT) received imatinib mesylate (400-1000 mg/d). Disease was in chronic phase in 5 patients, accelerated in 15, and blastic in 8 (7 medullary, 1 extramedullary); median time from transplantation to relapse was 9 months (range, 1-137 months). Thirteen patients had undergone salvage donor lymphocyte infusion (DLI) (median time from DLI to imatinib mesylate therapy, 4 months [range, 2-39 months]). The overall response rate was 79% (22 of 28 patients); the complete hematologic response (CHR) rate was 74% (17 of 23 patients), and the cytogenetic response rate was 58% (15 of 26 patients; complete response in 9 [35%] patients). CHR rates were 100% for chronic phase, 83% for accelerated phase, and 43% for blastic phase. The patient with extramedullary blastic disease achieved complete response. Cytogenetic response rates were 63% (12 of 19 patients) for chronic or accelerated phases (complete cytogenetic response in 8) and 43% for blastic phase (3 of 7 patients). At median follow-up of 15 months, 19 patients were alive, 9 with no evidence of disease. The 1-year estimated survival rate was 74%. Five patients had recurrence of grade 3 (3 patients) or grades 1 to 2 (2 patients) graft-versus-host disease (GVHD). Severe granulocytopenia developed in 43% of patients and thrombocytopenia in 27%; both conditions reversed with dose adjustments of imatinib mesylate. We conclude that imatinib mesylate effectively controlled CML that recurred after allogeneic SCT, but it was associated with side effects including myelosuppression and recurrence of severe GVHD.

Wilms’ Tumor 1 Gene Mutations in Childhood Acute Myeloid Leukemia: A New Prognostic factor with Implications for MRD Detection

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 144-144 ◽  
Author(s):  
Iris H.I.M. Hollink ◽  
Marry M. van den Heuvel-Eibrink ◽  
Martin Zimmermann ◽  
Brian V. Balgobind ◽  
Susan T.C.J.M. Arentsen-Peters ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Gene Mutations ◽  
Wt1 Gene ◽  
Wild Type ◽  
Poor Prognostic Factor ◽  
Free Survival ◽  
Independent Poor Prognostic Factor ◽  
Mutational Hotspots ◽  
Childhood Aml ◽  
Wt1 Mutation

Abstract In an array-CGH screening study of cytogenetically normal AML (CN-AML), we detected a cryptic 11p13-deletion including the WT1 gene in one childhood AML sample. The remaining WT1 allele in this sample carried a nonsense mutation. WT1 gene mutations have recently been identified in approximately 10% of adult CN-AML. Of interest, WT1 mutations were found to be a new independent poor prognostic factor in adult CN-AML (Virappane et al. JCO2008, Paschka et al. JCO2008). WT1 mutations have also been reported in childhood AML; however, their clinical relevance in childhood AML is not known. In this study, we investigated the frequency, clinical characteristics and prognostic value of WT1 mutations (exons 7–10) in a large, well-characterized cohort of childhood AML samples (n=298). Additionally, a subset of these samples was screened for mutations in exons 1–6 (n=68), and for micro-deletions in the WT1 gene (n=24). Survival analysis was restricted to the subset of patients with de novo AML who were treated using uniform DCOG and BFM treatment protocols (n=232). Fifty-three pathogenic WT1 mutations were detected in 35/298 (12%) samples taken at diagnosis. Mutations were mainly located in exon 7 (n=43), but also in exons 1 (n=2), 2 (n=1), 3 (n=2), 8 (n=1) and 9 (n=4). Predominantly frame-shift mutations were found (n=41), next to nonsense mutations (n=6) and missense mutations (n=6); the former two resulting in a truncated WT1 protein. In 19/35 (54%) of the WT1-mutated samples, we detected more than one WT1 aberration. This included either a different WT1 mutation (n=15), a homozygous WT1 mutation (n=2), or a deletion of the other WT1 allele (n=2). WT1 mutations clustered significantly in the CN-AML subgroup (21/94=22%; p&lt;0.001). NPM1 and WT1 mutations were mutually exclusive, but WT1-mutated samples were more likely to carry FLT3/ITD (43% vs. 17%; p&lt;0.001) and CEBPα mutations (26% vs. 9%; p=0.007). Mutations in patients below the age of 3 years were only found sporadically (1/60=2%). The highest frequency was found in the age category 3–10 years (17/76=18%), and decreased above the age of 10 years (17/128=12%; p=0.008). WT1-mutated AML was correlated with a higher white blood cell count at diagnosis (WBC) (57.2×109/l vs. 34.1×109/l; p=0.007); no correlation was found with sex or FAB-classification. WT1-mutated AML patients had a significantly worse outcome when compared with patients with WT1 wild-type AML (5-year overall survival (pOS) 35% vs. 66%; p=0.002; 5-year event-free survival (pEFS) 22% vs. 46%; p&lt;0.001; and 5-year cumulative incidence of relapses (CIR) 70% vs. 44%, respectively; pGray&lt;0.001). Moreover, using multivariate analysis including age, WBC, cytogenetics, FLT3/ITD and stem cell transplantation, WT1 mutations were identified as an independent poor prognostic factor for pOS (HR1.79; p=0.04), pEFS (HR2.05; p=0.005) and relapse-free survival (pRFS) (HR2.44; p=0.001). We identified patients carrying both a WT1 mutation as well as a FLT3/ITD as a very poor prognostic subgroup (5-year pOS 21%). The mutational hotspots in the WT1 gene were located within areas of primer-probe combinations used for WT1-based minimal residual disease (MRD) detection. Furthermore, in 4/28 (14%) wild-type diagnostic-relapse pairs a mutation was gained at relapse, which may also effect MRD detection. In conclusion, WT1 mutations are present in 12% of childhood AML at diagnosis and in 22% of patients with CN-AML, and are a novel independent poor prognostic marker in childhood AML. Furthermore, their presence may have implications for current WT1-based MRD detection.

Dual Translocation Is An Independent Poor Prognostic Factor in Diffuse Large B-Cell Lymphoma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3683-3683
Author(s):  
Kevin Tay ◽  
Gillianne Lai ◽  
Elaine J Chua ◽  
Whee Sze Ong ◽  
Tiffany Tang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factor ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
B Cell Lymphoma ◽  
Survival Outcomes ◽  
Poor Prognostic Factor ◽  
Large B Cell Lymphoma ◽  
Independent Poor Prognostic Factor ◽  
Large B Cell

Abstract Abstract 3683 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of diseases, that are associated with variable survival outcomes depending on the presence of certain genetic and molecular features. Of particular interest is a subset known as the “double-hit” (DH) lymphoma. DH lymphoma (dual translocation) is defined by the presence of a chromosomal breakpoint affecting the MYC/8q24 locus with a second oncogene translocation, most commonly a BCL2 rearrangement, and less commonly involving BCL6 or CCND1 rearrangements. However, the incidence of DH lymphoma remains to be determined. These patients typically have poor prognostic factors, with a dismal outcome when treated with rituximab-CHOP (RCHOP) chemotherapy. The aim of this study was to identify any clinical defining characteristics in patients with DH lymphoma, and to compare their outcomes with that of DLBCL patients without dual translocation. Methods: 202 newly diagnosed DLBCL patients, of whom 90% received rituximab based chemotherapy, were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH), using breakapart FISH probes targeting BCL2, BCL6, MYC, CCND1 and IgH genes. The clinical characteristics and survival outcomes of patients who were identified with DH lymphoma were compared to those without the dual translocation. Results: Out of the 202 patients with DLBCL, we identified 10 cases (5%) with two or more concurrent translocations involving MYC and BCL2, or MYC and BCL6. Among the 10 patients with DH lymphoma, there were 6 patients with concurrent BCL2 and MYC translocations, 1 patient with BCL6 and MYC translocations and 3 patients with all 3 abnormalities. 7 of the 10 patients were male, with a median age of 68 years (42 – 84). Patients with DH lymphoma also presented with a significantly higher incidence of high-risk clinical features, including advanced stage disease, bulky disease, extranodal disease, bone marrow involvement and a high IPI score. Interestingly, the majority of patients with DH lymphoma expressed a germinal center (GC) phenotype (8 out of 9 patients) based on the Han's criteria. These patients also demonstrated a significantly poorer overall survival (OS) when compared to patients without dual translocation (2 yr OS 33% vs 84%, p = < 0.001). On multivariate analysis, the presence of a dual translocation was found to be an independent poor prognostic factor for OS (hazard ratio 8.84, 95% CI 3.54 to 22.08). Other factors predictive of an inferior OS included age, stage, bone marrow involvement and patients treated without rituximab. Conclusions: Our findings showed that the presence of dual translocation is an independent poor prognostic factor in DLBCL. It was present in 5% of our cohort and was associated with more advanced disease. Patients with dual translocation also had a significantly poorer survival following treatment with standard chemotherapy such as RCHOP, even though most patients exhibited the GC phenotype. Therefore, the use of novel agents in combination with chemotherapy is an area that deserves further exploration in this type of lymphoma. Disclosures: No relevant conflicts of interest to declare.

Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome–positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Francis Giles ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Combination Regimens ◽  
Philadelphia Chromosome Positive

Abstract Fifty patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-α with or without hydroxyurea or other interferon-α combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph &lt; 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P &lt; .001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts × 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.

Positive Expression of MUC1 Gene Is a Poor Prognostic Factor in Acute Myelogenous Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4294-4294
Author(s):  
Ren-wei Huang ◽  
Guo-wei Li ◽  
Dong-ning Wang ◽  
Xu-dong Li ◽  
Gui-zhen Lin ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Acute Leukemia ◽  
Residual Disease ◽  
Myelogenous Leukemia ◽  
Muc1 Expression ◽  
Poor Prognostic Factor ◽  
Positive Expression ◽  
Muc1 Gene ◽  
Pcr Products ◽  
Expression Rate

Abstract Objective: To study the expression of MUC1 in acute leukemia and its clinical significance. Methods: Expression of MUC1 mRNA was detected in 73 newly diagnosed and relapsed patients of acute leukemia by reverse transcriptase polymerase reaction(RT-PCR). The MUC1 positive PCR products were analyzed by digestion with pst I. With clinical observation, the relationship of expression of MUC1 gene and treatment results were done. Results: The expression of MUC1 was positive in 36 of 73 AL patients (49.3%). The MUC1 expression rate was 39.1% in ALL and 52.2% in AML and they show no significance difference. MUC1 gene was undetectable in 23 healthy subjects. Nineteen of 21 (90.5%) MUC1-negative non-M3 acute leukemia patients got CR while 14 of 22 (63.6%) MUC1-positive non-M3 acute leukemia patients got CR which showed significance difference (p<0.05); Only 9 of 16 cases of MUC1-positive non-M3 AML patients got CR(56.3%), while 10 of 11 patients of MUC1-negative non-M3 AML got CR(90.9%). The expression of MUC1 could turn negative after CR. There was no mutation of MUC1 gene correlating with digested site of pst I. Conclusion: MUC1 expression is observed in some acute leukemia patients. The positive expression of MUC1 is not different between AML and ALL. The AML patients whose MUC1 gene showed positive got lower CR rate. It indicates that the expression of MUC1 can be used as a poor prognostic factor in AML and a marker for detection of minimal residual disease in AL.

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