scholarly journals Clinical Significance of Additional Cytogenetic Abnormalities (ACA) Acquired at the First Relapse in Adult Acute Myeloid Leukemia (AML) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3673-3673
Author(s):  
Hiroaki Shimizu ◽  
Akihiko Yokohama ◽  
Nahoko Hatsumi ◽  
Satoru Takada ◽  
Takayuki Saitoh ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Clinical Significance ◽  
Induction Chemotherapy ◽  
Multiple Logistic Regression Analysis ◽  
Predisposing Factors ◽  
Prognostic Impact ◽  
Cytogenetic Abnormalities ◽  
Cytogenetic Changes ◽  
First Relapse

Abstract Background: Cytogenetic changes between the time of diagnosis and the first relapse are found in 30 to 60% of relapsed AML cases. ACA, the most frequent form of cytogenetic changes, are considered as a result of genetic instability and clonal evolution of AML cells. However, because the clinical significance of ACA has not been elucidated in adult AML patients, we conducted a large-scale retrospective study to address this unsolved issue. Patients and methods: Of the 375 adult patients diagnosed with AML between 1990 and 2010, 144 relapsed patients whose cytogenetic abnormality data both at diagnosis and at the first relapse were available were included in this study. All these patients underwent intensive chemotherapy. Patients with acute promyelocytic leukemia were excluded. Cytogenetic changes between the time of diagnosis and the first relapse were classified into four groups: (1) no change, (2) ACA was acquired at time of the first relapse, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the time of the first relapse, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the time of the first relapse. In this study, groups 2 and 4 were defined as those with ACA acquisition. Overall survival (OS) was defined as the interval from the date of the first relapse to the date of death. Fisher’s exact test was used to compare binary variables. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Multiple logistic regression analysis and the Cox proportional hazard model were used for multivariate analysis of predisposing factors and prognostic factors, respectively. Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 144 patients included in this study, 81 patients were male, and 63 were female. The median age was 53 years (range, 15–79 years). According to the definition described above regarding cytogenetic changes between the time of diagnosis and the first relapse, 83 (58%), 55 (38%), 2 (1%), and 4 (3%) patients were categorized into group 1, 2, 3, and 4, respectively; thus, 59 patients (41%) acquired ACA at the first relapse. With univariate analysis, t(8;21), complex karyotype, fewer than 12 months duration of the first remission, and relapse after allogeneic stem cell transplantation (allo-SCT) were extracted as statistically significant predisposing factors for ACA acquisition at the first relapse. Of these four factors, the first three were confirmed with multivariate analysis to be independent predisposing factors. Excluding four patients that directly proceeded to allo-SCT without re-induction chemotherapy, the 140 patients with ACA acquisition showed a significantly lower second remission rate compared with those without ACA acquisition (20.0% vs. 72.5%, respectively; p < 0.001). Furthermore, among all 144 patients, the 3-year OS rate after the first relapse in patients with ACA acquisition was significantly poorer than that in those without ACA acquisition (8.5% vs. 36.8%, respectively; p < 0.001). Multivariate analysis revealed that ACA acquisition was the strongest negative prognostic factor compared to all other reported factors (hazard ratio: 2.13, p < 0.001). Of the 59 patients with ACA acquisition (median age: 51, range; 15–79 years), 27 underwent allo-SCT after the first relapse. Eight patients were in remission at the time of transplant, and one directly proceeded to allo-SCT without re-induction chemotherapy. The 3-year OS rates after the first relapse were significantly different between patients undergoing allo-SCT after the first relapse and those treated only with chemotherapy (17.8% vs. 0%; p = 0.007). With multivariate analysis, undergoing allo-SCT after the first relapse was identified as an independent prognostic factor, in addition to the cytogenetic risk group at diagnosis. Conclusion: These findings suggested that ACA acquisition at the time of the first relapse was associated with chemo-refractive disease and poor prognosis. As ACA acquisition showed the most potent prognostic impact, treatment approaches for relapsed AML patients should be determined with consideration of this phenomenon. Clarification of the biological background of ACA acquisition may contribute to the development of novel therapeutic strategies and improved treatment outcomes in adult AML patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic Impacts of Additional Cytogenetic Abnormalities Acquired at the First Relapse in Adult Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplant in Second Complete Remission

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3380-3380
Author(s):  
Hiroaki Shimizu ◽  
Junichi Mukae ◽  
Naoki Shingai ◽  
Takashi Toya ◽  
Yuho Najima ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Statistical Significance ◽  
Cell Transplant ◽  
Reduced Intensity Conditioning ◽  
Cytogenetic Abnormalities ◽  
Cytogenetic Changes ◽  
Conditioning Regimens ◽  
First Relapse

Abstract Background: Additional cytogenetic abnormalities (ACA), the most frequent form of cytogenetic changes, are considered as a result of genetic instability and clonal evolution of leukemia cells. Recently, we described that ACA at the first relapse was associated with the significantly lower second complete remission (CR2) rate and poor survival in adult acute myeloid leukemia (AML) patients (Hematol Oncol. 2018;36:252-257). However, the prognostic impact of ACA after allogeneic stem cell transplant (allo-SCT) has not been elucidated in adult AML patients. Patients and methods: Of the 145 adult AML patients who underwent the first allo-SCT in CR2 between 1997 and 2019, 98 patients whose cytogenetic abnormality data both at diagnosis and at the first relapse were available were included in this study. Cytogenetic changes between at diagnosis and the first relapse were classified into four groups: (1) no change, (2) ACA was acquired at the first relapse, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the first relapse, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the first relapse. In this study, groups 2 and 4 were defined as ACA acquisition. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p &lt; 0.20) in univariate analyses were subjected to multivariate analysis. The Cox and Fine-Gray proportional hazard model were used for multivariate analysis of prognostic and risk factors, respectively. Values of p &lt; 0.05 were considered to indicate statistical significance. Results: Of the 98 patients included in this study, 57 were male, and 41 were female. The median age at transplant was 45 years (range, 17-71 years). The median duration of CR1 was 12.4 months (range, 1.3-70.3 months) and cytogenetic risk groups were good, intermediate, and poor in 26 (27%), 70 (71%), and two patients (2%), respectively. Donor types were related, unrelated, and cord blood in 23 (24%), 59 (60%), and 16 patients (16%), respectively, and 86 (87%) and 61 patients (62%) were conditioned with myeloablative and total body irradiation-containing regimens, respectively. According to the definition described above, 20 patients (20%) acquired ACA at the first relapse. There was no significant difference in baseline characteristics and transplant procedures between patients with and without ACA acquisition. The OS rates were not significantly different between two groups (55% vs. 72% at three years after transplant; p = 0.28). The CI of relapse was significantly higher in patients with ACA acquisition than those without ACA acquisition (59% vs. 15%; p &lt; 0.01), while the CI of NRM were not significantly different between two groups (5% vs. 19%; p = 0.17). Multivariate analysis for OS revealed that age over 50 years (hazard ratio [HR] = 2.4; p &lt; 0.01), but not ACA acquisition, was identified as an independent prognostic factor. ACA acquisition (HR = 4.7; p &lt; 0.01) was extracted as an independent risk factor of relapse, while use of reduced intensity conditioning regimens (HR = 3.1; p = 0.03) and more than or equal to 1 of performance status at transplant (HR = 2.7; p = 0.04) showed independent risks of NRM. The similar OS rates between two groups might resulted from an offset of the lower relapse rate with the higher NRM rate in patients without ACA acquisition despite not reaching statistical significance. This increasing NRM rates in those without ACA acquisition was potentially associated with use of reduced intensity conditioning regimens in larger proportion (0% vs. 15%; p = 0.12). Conclusion: These findings suggested that ACA acquisition at the first relapse was associated with a higher risk of relapse even after allo-SCT in CR2 in adult AML patients. As AML cells with ACA acquisition was resistant to not only chemotherapy but also graft-versus-leukemia effect, innovative therapeutic strategy is warranted. Disclosures Handa: Janssen: Honoraria; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Chugai: Research Funding; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding.

scholarly journals Prognostic Impact of Cytogenetic Abnormalities in Adult Patients with Philadelphia-Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL) Who Underwent Allogeneic Stem Cell Transplant (allo-SCT)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2024-2024
Author(s):  
Hiroaki Shimizu ◽  
Takayuki Saitoh ◽  
Shinichiro Okamoto ◽  
Yoshinobu Kanda ◽  
Heiwa Kanamori ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Complete Remission ◽  
Research Funding ◽  
Pharmaceutical Research ◽  
Patient Characteristics ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Cytogenetic Abnormalities ◽  
Significant Difference

Abstract Background: Cytogenetic abnormalities at diagnosis are recognized as a potent prognostic factor for acute leukemia patients. Among acute myeloid leukemia patients, the prognostic implications of cytogenetic abnormalities have been established for those treated with chemotherapy as well as those undergoing allo-SCT. In the context of Ph-negative ALLpatients, cytogenetic abnormalities at diagnosis clearly stratify the prognosis, whereas it has not been elucidated whether similar prognostic stratification is applicable to allo-SCT recipients. Objective: The aim of this retrospective study was to assess the prognostic impact of cytogenetic abnormalities in adult Ph-negative ALL patients who underwent allo-SCT. Patients and Methods: The study cohort included 373 adult Ph-negative ALL patients aged over 15 years who underwent allo-SCT for the first time between January 2001 and December 2012 at the 23 institutions participating in the Kanto Study Group for Cell Therapy (KSGCT). Patients' clinical data were collected from the KSGCT database. The Institutional Review Board of Gunma University approved the protocol of this study. Karyotypes considered high risk (HR) included t(4;11), t(8;14), low hypodiploidy, and complex (equal or more than five abnormalities), and all other karyotypes were designated standard risk (SR). On this basis, 308 patients (82.6%) were categorized as SR and 65 patients (17.4%) were categorized as HR at diagnosis. Of the 373 patients, 267 underwent allo-SCT in complete remission (CR) (224 in the SR group and 43 in HR group), and 106 in non-CR (84 in the SR group and 22 in HR group). For analysis, the study population was stratified based on disease status at the time of transplant. Almost all patients were conditioned with total body irradiation (TBI)-containing myeloablative conditioning (MAC) regimens prior to transplantation. Overall survival (OS) was defined as the interval from the date of transplantation to the date of death. Non-relapse mortality (NRM) was defined as any death in continuous complete remission (CR). The Fisher's exact test was used for comparison of binary variables. OS and RFS were estimated by the Kaplan-Meier method, and compared using the log-rank test. Cumulative incidences (CI) of relapse and NRM were compared using the stratified Gray test. P < 0.05 was considered as statistically significant. Results: [Patients in CR] No significant difference in patient characteristics and transplant procedures was observed between the SR and HR groups. The 5-year OS rates were similar between the SR and HR groups (60.5% vs. 74.1%, respectively; p = 0.225) (Figure 1). Similarly, there were no significant differences in the 5-year CI of relapse and NRM rates between the two groups (relapse: 26.3% vs. 24.8%, respectively; p = 0.498, NRM: 19.6% vs. 10.0%, respectively; p = 0.232). Multivariate analysis for OS identified MAC and TBI-containing regimens, not cytogenetic risk, as significant positive prognostic factors. [Patients in non-CR] No significant difference was observed between the SR and HR groups in terms of patient characteristics or transplant procedures, although there was a female predominance in the HR group. Patients in the SR group had a significantly superior 5-year OS rate compared to the HR group (15.4% vs. 4.5%, respectively; p = 0.022). There was no significant difference in the 5-year CI of relapse between the SR and HR groups (60.3% vs. 50.0%, respectively; p = 0.411), whereas the 5-year CI of NRM in the SR group was significantly lower than that in the HR group (24.8% vs. 45.5%, respectively; p = 0.024). Multivariate analysis revealed cytogenetic risk group as an independent prognostic factor. Conclusion: These findings suggest that adult Ph-negative ALL patients in remission with HR cytogenetic abnormalities have similar transplant outcomes to those in the SR group. Considering the reported equality of the CR rates between the two groups, allo-SCT at an early clinical phase is recommended for HR group patients, reminiscent of Ph-positive ALL patients in the pre-imatinib era. Current transplant procedures do not improve outcomes for patients who are not in remission, especially those with HR cytogenetic abnormalities. Disclosures Usuki: MSD: Other: personal fees, Research Funding; SymBio Pharmaceutical: Other: personal fees, Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Shionogi: Other: personal fees; Fujimoto Pharmaceutical: Research Funding; Bristol-Myers Squibb: Other; Takeda Pharmaceutical: Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; Sanofi: Other: personal fees, Research Funding; Shire: Research Funding; Kyowa Hakko Kirin: Other: personal fees, Research Funding; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Novartis: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Chugai Pharmaceutical: Other: personal fees; Fuji Film RI Pharma: Other: personal fees; Taiho Pharmaceutical: Other: personal fees, Research Funding; Astellas: Research Funding. Nakaseko:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Otsuka: Honoraria, Research Funding.

scholarly journals Development and Analysis of a Weighed Prognostic Model in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 47-48
Author(s):  
Xue-Han Mao ◽  
Yan Xu ◽  
Yuting Yan ◽  
Jiahui Liu ◽  
Huishou Fan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Factor ◽  
Prognostic Model ◽  
Cytogenetic Abnormalities ◽  
Total Score Range ◽  
Prognosis Model

Background and Objective: Multiple myeloma (MM) is characterized with significant cytogenetic changes and complex tumor microenvironment, thus patient survival is extremely heterogeneous. Various disease-related or patient-related factors affect the prognosis of patients. This study tried to analyze the prognostic indicators of patients with newly-treated MM, especially explored the prognosis of multiple cytogenetic abnormalities and the ratio of lymphocytes to monocytes (LMR). Additionally, we established a comprehensive prognostic model to help determine the patient prognosis. Methods: After screening, 603 patients of untreated MM from January 2008 to June 2017, with complete baseline indicators were enrolled into the study. By univariate and multivariate Cox analysis, risk factors related to the prognosis of patients were evaluated, and a weighted prognosis model was established to compare the survival differences of patients in each risk stratification. Result: Optimal thresholds of ALC, LWR, NLR and LMR were determined by ROC curve and Youdex index: ALC = 1.415, LWR = 0.325, NLR = 1.935, LMR = 2.95. Survival analysis showed that patients with LMR ≤ 2.95, ALC ≥ 1.415 and LWR ≥ 0.325 had significantly better survival compared with their respective control groups. Cox multivariate analysis showed that among the four indicators, only LMR≤2.95 was an independent adverse prognostic factor for overall survival (OS)(Figure 1A). 17p deletion, 1q21 amplification, t (4; 14) / t (14; 16) were define as high-risk cytogenetic abnormalities (HRA). Of the 603 patients, about 60% were associated with at least one high-risk cytogenetic event. Among them, the occurrence of cumulative 0, 1, 2, and 3 HRA were 39.6% (239/603), 42.5% (256/603), 16.6% (100/603), and 1.3% (8/603), respectively. There was no significant difference in survival among patients with same number of HRAs. The median OS of patients with 0, 1 and ≥ 2 HRA were not reached, 62.1 months (95% CI, 49.3-74.9) and 30.4 months (95% CI, 24.5-36.3), respectively (p &lt;0.001)(Figure 1B).Final Cox regression model showed that age 65 ~ 74 (HR=1.77, 95%CI, 1.24-2.51, p=0.001), age ≥75 (HR=2.46, 95%CI, 1.69-3.58, p &lt; 0.001), LDH≥247 U/L (HR =1.65, 95%CI, 1.07-2.51, p=0.023), ISS stage III (HR=1.76, 95%CI, 1.24-2.50, p=0.002), LMR≤2.95 (HR=1.53, 95%CI, 1.08-2.18, p=0.017), 1 HRA (HR=1.87, 95%CI, 1.27-2.75, p=0.002) and ≥2 HRA (HR=3.48, 95%CI, 2.22-5.45, p&lt;0.001) are independent adverse prognostic factors for OS. Then weighted risk factors were summed to establish a comprehensive prognosis model, with a total score range of 0-6 points. Accordingly, the whole cohort was divided into low risk (0-1 points, 45.4%), intermediate risk (2 points, 27.9%), high risk (3 points, 19.2%) and ultra-high risk (4-6 points, 7.5 %) groups. The median OS of the four risk groups were 85.8 months (67.1-104.5), 49.0 months (44.7-53.3), 35.4 months (31.3-39.5), and 23.2 months (18.8-27.6), respectively (p&lt;0.001). The C-statistics of this prognostic model is 0.68 (95% CI, 0.64-0.71), which is significantly better than the D-S stage (C-statistics = 0.52, 95% CI, 0.50-0.55, p &lt;0.001), ISS (C-statistics = 0.60, 95% CI, 0.57-0.64, p &lt;0.001) and R-ISS stage (C-statistics = 0.60, 95% CI, 0.57-0.63, p &lt;0.001). Bootstrap resampling and calibration curve showed that the model has an accurate predictive effect on both short-term and long-term prognosis of patients(Figure 1C). Conclusion: In our analysis, ALC, LWR, LMR were associated with poor prognosis in NDMM patients, while NLR had no significant prognostic significance. Among the four indicators, LMR≤2.95 was the only independent prognostic factor. In NDMM patients, survival of patients with the same number of high-risk cytogenetic abnormalities were comparable with each other, regardless of whichever combination of HRA. Higher number of high-risk cytogenetic abnormalities were associated with worse prognosis. Cox multivariate analysis showed that, old age (65-74 years old, ≥75 years old), increased LDH (≥247 U/L), decreased LMR (≤2.95), ISS III, 1 HRA and ≥ 2 HRA were independent adverse prognostic factors that affect the OS of MM patients. 4. A comprehensive weighted prognostic model was established with the above factors, which was proved to effectively distinguish different prognosis of patients. Figure 1 Disclosures No relevant conflicts of interest to declare.

Prognostic Implications of the IDH1 synonymous SNP rs11554137 In Pediatric and Adult AML: a Children's Oncology Group and Southwest Oncology Group Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2737-2737
Author(s):  
Phoenix A. Ho ◽  
Todd A. Alonzo ◽  
Kenneth J. Kopecky ◽  
Kristen L. Miller ◽  
Julia Kuhn ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Expression Profiling ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Wild Type ◽  
Bone Marrow Blast ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Pediatric Aml

Abstract Abstract 2737 Synonymous SNPs may directly impact gene function through various translational or post-translational mechanisms. Further, such “silent” SNPs in the mutational hotspots of AML-associated genes have recently been reported to carry prognostic impact. We aimed to determine the prevalence, clinical associations, and prognostic significance of a known SNP in exon 4 of IDH1, near the location of the frequently-mutated R132 codon. Diagnostic marrow specimens from 253 pediatric AML patients (treated on the COG trial AAML03P1) and 274 adult AML patients (treated on SWOG trials S9031, S9333, or S9500) were analyzed for the presence of SNP rs11554137 via direct sequencing. In the pediatric cohort (median age 9.8 years), SNP rs11554137 was present in 27 of 253 (10.7%) patients. SNP+ pediatric patients did not differ significantly from wild-type patients in terms of sex, racial distribution (African American patients accounted for 23% of SNP+ patients vs. 14% of wild-type patients, P=0.24), bone marrow blast percentage, or age distribution, except in patients aged 0–2 years, who accounted for 44% of SNP+ patients vs. 23% of wild- type patients (P=0.013). Recurrent cytogenetic abnormalities occurred with similar frequencies in both the SNP+ and wild-type pediatric populations, as did FLT3/ITD, NPMc, and CEBPA mutations. Miscellaneous cytogenetic abnormalities accounted for 33% of SNP+ patients vs. 14% of wild-type patients, P=0.033. IDH1 SNP status had no prognostic impact on survival in the pediatric cohort, as SNP+ and wild-type patients had similar rates of five-year overall survival (OS, 76% vs. 63%, P=0.50), disease-free survival (DFS, 48% vs. 53%, P=0.97), and relapse rate (RR, 39% vs. 39%, P=0.94). In the adult cohort (median age 63 years), the IDH1 SNP was present in 30 of 274 (10.9%) patients. A slight female predominance for the SNP (63% vs. 37%, P=0.052) occurred among adult patients. The SNP was more prevalent in African American patients, who accounted for 30% of the SNP+ patients vs. 7% of wild-type patients, P=0.0046. SNP+ patients also had somewhat higher diagnostic bone marrow blast percentages (medians 80% vs. 70%, P=0.025). The normal karyotype subset accounted for similar proportions of SNP+ vs. wild-type patients (42% vs. 46%, P=0.83). Notably, SNP rs11554137 was not present in adult core-binding factor AML. Miscellaneous cytogenetic abnormalities were significantly more common in SNP+ patients (46% vs. 22%, P=0.022). SNP status was not significantly associated with FLT3/ITD status when all adult patients were considered (P=0.14). However, within the normal karyotype subset, FLT3/ITD was present in 90% of SNP+ patients vs. 59% of wild-type patients (P=0.0053). SNP+ patients had somewhat poorer 5 year OS (10% vs. 18%, hazard ratio [HR]=1.17) though this difference was not statistically significant (P=0.44). Among the 142 patients who achieved complete remission (CR), however, 5-year relapse-free survival (RFS) was significantly worse for SNP+ patients (0% vs. 25%, HR = 2.89, P=0.0014). Of the 14 SNP+ patients who achieved CR, 13 relapsed and the 14th patient died of sepsis in remission after 61 days. In multivariate analysis, after adjusting for the effects of age and cytogenetic group, SNP rs11554137 retained an independent prognostic effect (P=0.0062) regarding RFS. Notably, when FLT3/ITD status is included in multivariate analysis, SNP positivity loses independent prognostic significance (HR=1.72, P=0.18). Genome-wide expression profiling was performed on 134 pediatric AML specimens in whom IDH1 SNP status was known. By comparing SNP+ patients with wild-type patients, we derived a distinct gene-expression signature for patients with SNP rs11554137. Among the most upregulated probe sets in the SNP+ cohort were those representing PEX6 and NFYA, both of which interact with the TGF-beta/SMAD signaling network; the retinoid × receptor beta gene RXRB; and the FER gene, a tyrosine kinase critical to FLT3 signaling. The IDH1 SNP rs11554137 is present in approximately 11% of pediatric and adult AML patients, and gene expression profiling data suggests that leukemia in SNP+ patients may have unique biologic features. The SNP was an independent predictor of decreased RFS in adult AML in univariate analysis, but not in multivariate analysis when adjusting for FLT3/ITD status. Disclosures: No relevant conflicts of interest to declare.

The Interaction of Response and FISH-Based Risk Stratification to Better Define Clinical Outcome in Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1823-1823
Author(s):  
Kevin D Boyd ◽  
Fiona M Ross ◽  
Mark T Drayson ◽  
Roger G Owen ◽  
Alex J Szubert ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Factor ◽  
Induction Therapy ◽  
Response Rates ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Important Prognostic Factor

Abstract Abstract 1823 Background: The achievement of a complete response (CR) is an important prognostic factor in myeloma. The international staging system (ISS) and tumor genetic lesions detected by FISH also impact survival. It is not known whether response rates are adversely affected by these factors, whether achieving CR overcomes the adverse prognosis associated with these factors, or if achievement of CR is more important in a specific biological subgroup. We have examined the importance of CR in the context of these other prognostic factors in the intensive arm of a phase III randomized trial, MRC Myeloma IX, in which all patients were planned to proceed to autologous stem cell transplant (ASCT) after induction. Patients and Methods: Patients were randomized to a conventional or thalidomide-based induction regimen followed by ASCT, with a second randomization to maintenance thalidomide versus no maintenance. Response was assessed after completion of induction therapy and 100 days post-ASCT. iFISH was performed on diagnostic bone marrow samples and genetic lesions associated with adverse progression free survival (PFS) were defined as t(4;14), t(14;16), t(14;20), +1q and 17p-. Results: To confirm that CR was prognostically important in the data set, patients with a CR at 100 days post-ASCT (N=355) were compared to non-CR (N=344) (comprising VGPR, PR and SD). CR was strongly associated with improved PFS (median 30.8 months vs 38.7 months, P<0.001) but was not associated with improved OS at median follow-up of 3.7 years. Response rates were assessed in the context of other prognostic factors. Interestingly, the presence of high risk FISH lesions was not associated with impaired CR rates following induction therapy (P=0.584) or following ASCT (P=0.314). Patients without adverse genetic lesions had a CR rate of 11.1% post-induction which improved to 48.3% post-ASCT. In comparison, patients with adverse FISH lesions had a 13.3% CR rate, rising to 44.9% post ASCT. Similarly, there was no correlation between ISS stage and response. The absence of adverse FISH lesions (hazard ratio (HR) 2.68 (1.94-3.70) P<0.001) and achievement of CR (HR 1.58 (1.15-2.17) P=0.005) were independently associated with improved PFS in multivariate analysis. The prognostic impact of achieving CR was assessed in various prognostic groups. CR was associated with improved PFS in patients with no adverse FISH lesions (N=179)(median PFS 58.4 vs 37.1 months, P=0.031), and in ISS I (N=182)(median PFS 51.2 vs 33.2 months, P=0.008). In patients with adverse FISH lesions, and in ISS II and III, there was a trend towards improved PFS with CR that was not significant. For patients achieving CR as their maximum response (N=398), in a multivariate analysis including the ISS, the presence of high risk FISH lesions was the most significant factor associated with impaired PFS and OS. Patients with more than 1 adverse FISH lesion were associated with an especially high risk of progression or death (PFS HR 6.63 (3.23-13.53) P<0.001; OS HR 5.35 (1.98-14.45) P=0.001). Conclusion: These data show that attainment of CR is an important prognostic factor associated with improved PFS in patients treated with ASCT, and this benefit was most significant in patients with favorable prognostic factors such as lack of adverse FISH lesions and ISS I. The presence of t(4;14), t(14;16), t(14;20), +1q or 17p- was also strongly associated with PFS, and the impaired outcome associated with these adverse genetic lesions was not overcome by achievement of CR, within the context of the therapies used in this trial. The presence of more than 1 adverse FISH lesion identified a patient group with an especially poor prognosis, despite achieving CR. However, CR rates within these high risk patients were similar to patients without adverse genetic features, showing that they were sensitive to chemotherapy, but progressed quickly after therapy was stopped. The implication of these data is that it may be possible to improve the poor outcome of this genetically-defined high risk group with an alternative treatment strategy aimed at maintaining these responses. Disclosures: Gregory: Celgene: Honoraria. Child:Celgene: Honoraria.

scholarly journals Clinical Significance of Clonal Cytogenetic Heterogeneity (CCH) at Diagnosis in Adult Patients with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2820-2820
Author(s):  
Hiroaki Shimizu ◽  
Nahoko Hatsumi ◽  
Satoru Takada ◽  
Takuma Ishizaki ◽  
Akihiko Yokohama ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Statistical Significance ◽  
Prognostic Impact ◽  
Common Ancestry ◽  
Complex Karyotype ◽  
Abnormal Karyotype ◽  
Cytogenetic Abnormalities

Abstract Background:Although cytogenetic abnormalities at diagnosis are recognized as one of the most potent prognostic factors in acute leukemia patients, CCH acquisition at diagnosis, which are considered as a result of clonal evolution of leukemia cells, is not taken into account in prognostic classifications. Recent studies reported that CCH acquisition was observed in 24 - 32% of adult AML patients with abnormal karyotype, was more likely to occur in patients with older age and complex karyotype, and showed adverse prognostic impact. However, the clinical significance of CCH acquisition has not been investigated in adult ALL patients to date. Patients and methods: Of the 238 adult ALL patients diagnosed between 1990 and 2016, 120 patients with abnormal karyotype at diagnosis, who underwent intensive chemotherapy, were included in this study. CCH was defined as presence of two or more cytogenetically abnormal clones. A defined ancestral clonal evolution included either mother-daughter and/or branched patterns. In the mother-daughter pattern, a daughter clone showed all cytogenetic abnormalities of a mother clone plus additional abnormality(s), which define a distinct subclone. In a branch pattern, all subclones possessed common cytogenetic abnormalities suggesting presence of a common ancestry, but each subclone acquires unique additional abnormality(s), which define them as distinctive subclones. Both patterns of cytogenetic clonal evolution were sometimes seen in a patient. Composite karyotypes were applied to patients where a common ancestry could not be clearly determined because of too complicated cytogenetic findings. Fisher's exact test was used to compare binary variables. The logistic regression model was used for multivariate analysis of predisposing factors. Overall survival (OS) was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. Values of p < 0.05 were considered to indicate statistical significance. Results:Of the 120 patients included in this study, 64 patients were male, and 56 were female. The median age was 50 years (range, 16-79 years). Karyotypes at diagnosis were Philadelphia chromosome (Ph) in 56 patients, complex in 15, and t(8;14) in seven. According to the definition described above, 47 patients (39%) showed CCH at diagnosis, and two (4%) among them were categorized as composite karyotype. Of the 45 patients harboring a defined ancestral clonal evolution, numbers of subclones were two, three, and four in 32 patients (68%), 11 (24%), and 2 (4%), respectively. Mother-daughter pattern, branched pattern, and both were seen in 34 patients (76%), 5 (11%), and 6 (13%). In univariate analysis for predisposing factors of CCH acquisition, only younger age was significantly associated with CCH acquisition (48% in age <= 50 vs. 29% in age > 50; p = 0.04), but not karyotype. This statistical significance was confirmed with multivariate analysis (odds ratio = 0.44; p = 0.03). When investigating the prognostic impact of CCH acquisition, patients were divided into Ph-negative or Ph-positive ALL groups. In the 64 Ph-negative ALL patients, the CR rates were not significantly different between patients with or without CCH (78% vs. 78%, respectively; p = 1.00). The OS rates were similar between two groups (26% vs. 39% at five years, respectively; p = 0.56). Multivariate analysis for OS revealed that complex karyotype and t(8;14) were independent prognostic factors, but not CCH acquisition. Likewise, in the 56 Ph-positive ALL patients, CCH acquisition was not significantly associated with the CR rates (92% vs. 78%, respectively; p = 0.27), and the OS rates did not significantly differ between the two groups (34% vs. 40% at five years, respectively; p = 0.90). In multivariate analysis for OS, no independent prognostic factor was identified. Conclusion: Adult ALL patients with abnormal karyotype acquired CCH at diagnosis with a frequency comparable to that of AML patients. However, unlike AML patients, CCH acquisition was more frequently observed in younger population and did not show any prognostic impact in ALL patients. These findings suggested that biological backgrounds of CCH acquisition at diagnosis were possibly different between in patients with ALL and AML. So, to confirm these important findings, clinical studies with larger study subjects are warranted. Disclosures Handa: Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Waiting time to radiotherapy as a prognostic factor for glioblastoma patients in a scenario of medical disparities

2015 ◽  
Vol 73 (2) ◽  
pp. 104-110 ◽  
Author(s):  
Luiz Victor Maia Loureiro ◽  
Lucíola de Barros Pontes ◽  
Donato Callegaro-Filho ◽  
Ludmila de Oliveira Koch ◽  
Eduardo Weltman ◽  
...  
Keyword(s):  
Health Care ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Retrospective Study ◽  
Prognostic Factor ◽  
Waiting Time ◽  
Adjuvant Treatment ◽  
Extent Of Resection ◽  
Prognostic Impact

Objective To evaluate the effect of waiting time (WT) to radiotherapy (RT) on overall survival (OS) of glioblastoma (GBM) patients as a reliable prognostic variable in Brazil, a scenario of medical disparities. Method Retrospective study of 115 GBM patients from two different health-care institutions (one public and one private) in Brazil who underwent post-operative RT. Results Median WT to RT was 6 weeks (range, 1.3-17.6). The median OS for WT ≤ 6 weeks was 13.5 months (95%CI , 9.1-17.9) and for WT > 6 weeks was 14.2 months (95%CI, 11.2-17.2) (HR 1.165, 95%CI 0.770-1.762; p = 0.470). In the multivariate analysis, the variables associated with survival were KPS (p < 0.001), extent of resection (p = 0.009) and the adjuvant treatment (p = 0.001). The KPS interacted with WT to RT (HR 0.128, 95%CI 0.034-0.476; p = 0.002), showing that the benefit of KPS on OS depends on the WT to RT. Conclusion No prognostic impact of WT to RT could be detected on the OS. Although there are no data to ensure that delays to RT are tolerable, we may reassure patients that the time-length to initiate treatment does not seem to influence the control of the disease, particularly in face of other prognostic factors.

A Comprehensive Analysis of Cytogenetic Abnormalities in Myeloma: Results of the FISH Analysis of 1000 Patients Enrolled in the IFM99 Trials.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 622-622 ◽  
Author(s):  
Herve Avet Loiseau ◽  
Michel Attal ◽  
Philippe Moreau ◽  
Catherine Charbonnel ◽  
Frederic Garban ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Mononuclear Cells ◽  
Chromosomal Abnormalities ◽  
Prospective Trial ◽  
High Dose ◽  
Fish Analysis ◽  
Therapeutic Trial ◽  
Prognostic Impact ◽  
The Impact

Abstract Because cytogenetics has been demonstrated to be the most powerful prognostic factor in many hematopoietic malignancies, we hypothesized that chromosomal abnormalities may also predict outcome in MM, as previously suggested by several reports. In order to test this hypothesis, we analyzed the main chromosomal abnormalities in a large series of 1000 patients with newly diagnosed MM, enrolled in the IFM 99 therapeutic trial. This trial enrolled 1083 patients under the age of 65, between May 2000 and December 2003. Briefly, the patients were treated by an induction therapy (4 VAD courses), followed by 2 courses of high-dose melphalan. In patients with less than 2 poor-prognosis factors (del(13) and b2m&gt;3), a maintenance therapy was randomized (none vs pamidronate vs pamidronate + thalidomide). For all the patients, a fresh bone marrow specimen was shipped overnight to the central laboratory in Nantes. After separation of the mononuclear cells, malignant plasma cells were sorted using magnetic beads coated with an anti-CD138 monoclonal antibody. All the analyzed specimens presented a plasma cell purity &gt; 90%. The patients were then analyzed by FISH for the following abnormalities: del(13q14), t(4;14), t(11;14), del(17p13), MYC rearrangements, hyperdiploidy (assessed by interphase FISH as previously reported), and 1q21 gains (CKS1B). Abnormalities were observed in 45%, 14%, 21%, 11%, 13%, 40%, and 40%, respectively, in agreement with previously reported incidences. We then looked at the prognostic impact of these chromosomal abnormalities, analyzing both the overall survival (OS) and the event-free survival (EFS). With a median follow-up of 32 months, t(11;14) and MYC rearrangements were not significant for both OS and EFS, and hyperdiploidy was marginally significant (p=.03, and .02 for EFS and OS, respectively, with a longer survival for hyperdiploid patients). In contrast, del(13), t(4;14), del(17p) and 1q gains significantly negatively impacted both EFS and OS (p&lt;10−5, p=10−7, p&lt;10−6, and p=10−3, respectively for EFS, and p&lt;10−5, p=10−7, p=10−7, and p&lt;10−3, respectively for OS). Further statistical analyses showed significant associations between del(13) and t(4;14) (p&lt;10−12), and between del(17p) and del(13) (p&lt;10−4), but not between del(17p) and t(4;14). Gains of 1q did not represent an independent prognostic factor in the multivariate analysis. A multivariate analysis including the chromosomal abnormalities, b2m, albumin, and CRP levels lead to a model with 3 factors: t(4;14), del(17p), and b2m&gt;3. Three groups of patients can be identified with highly different outcomes: patients with b2m&lt;3, without t(4;14) or del(17p) (35% of the patients), presenting very long OS, patients with either t(4;14) or del(17p), and b2m&gt;3 (15% of the patients) with a median OS &lt; 2 years, and the other patients (half of the cohort) presenting an intermediate prognosis. This analysis, performed on a very large cohort of patients treated in a prospective trial, strengthens the impact of chromosomal analysis in the prediction of survival for patients under the age of 65 treated with high-dose therapy. An updated analysis will be presented at the meeting.

scholarly journals Clinical Significance of Additional Cytogenetic Abnormalities (ACA) at Disease Progression in Patients with High-Risk Myelodysplastic Syndrome (MDS) Treated with Azacitidine

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5434-5434
Author(s):  
Chiaki Naito ◽  
Hiroaki Shimizu ◽  
Yuri Miyazawa ◽  
Takuma Ishizaki ◽  
Akihiko Yokohama ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Disease Progression ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Philadelphia Chromosome ◽  
Complex Karyotype ◽  
Cytogenetic Abnormalities ◽  
Cytogenetic Changes

Background: Although cytogenetic abnormalities at diagnosis are recognized as one of the most important prognostic factors in MDS patients, their cytogenetic findings are not stable and ACA are sometimes acquired in their clinical courses. We recently described that ACA acquisition at relapse was found in 40% and associated with the lower second complete remission (CR) rate and the inferior overall survival (OS) rate in adult patients with acute myeloid leukemia (AML) and Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-negative ALL). However, this clinical impact of ACA acquisition has not been elucidated in high-risk MDS patients during azacitidine treatment. So, we conducted this retrospective study to address this unsolved issue. Patients and methods: Of the 63 patients who were diagnosed as high-risk MDS according to French-American-British classification and were treated with azacitidine between 2012 and 2019, 34 whose cytogenetic data both at diagnosis and disease progression were available were included in this study. Treatment response to azacitidine was evaluated based on international working group response criteria for myelodysplasia. Cytogenetic changes between the time of diagnosis and disease progression were classified into four groups: (1) no change, (2) ACA was acquired at time of disease progression, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the time of disease progression, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the time of disease progression. In this study, groups 2 and 4 were defined as those with ACA acquisition. OS was defined as the interval from the date of disease progression to the date of death. Fisher's exact test was used to compare binary variables. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. The potential factors evaluated in this analysis were age, gender, blast count in bone marrow (< or => 10%), karyotype (complex or not), revised international prognostic scoring sysytem (high/high-intermediate or not), and response to azacitidine (CR/partial remission or not). Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 34 patients included in this study, 25 were male and 9 were female, and the median age was 66 years (range, 38-78 years). According to the definition described above regarding cytogenetic changes between the time of diagnosis and disease progression, 11 (32%), 14 (41%), 0 (0%), and 9 (26%) patients were categorized into group 1, 2, 3, and 4, respectively; thus, 23 patients (67%) acquired ACA at disease progression with a higher incidence in comparison with that of AML and Ph-negative ALL patients. In univariate analysis, only complex karyotype at treatment initiation was extracted as a significant predisposing factor for ACA acquisition at disease progression (100% vs. 47.6%, respectively; p = 0.002). Among 14 patients (nine and five in patients with and without ACA acquisition, respectively) received chemotherapy after disease progression, only two (14.3%) achieved CR (one and one, respectively). Although the OS rates after disease progression were not significantly different between patients with and without ACA acquisition (19.3% vs. 32.0% at one year, respectively; p = 0.256), in multivariate analysis, only ACA acquisition was identified as a negative prognostic factor of OS after disease progression (hazard ratio: 3.21, p = 0.043). Conclusion: These findings suggested that ACA acquisition at disease progression is frequently observed in high-risk MDS patients treated with azacitidine, especially in those harboring complex karyotype, and is associated with poor prognosis even after azacitidine failure, just like AML and Ph-negative ALL. As clinical impacts of ACA acquisition are common among multiple hematologic malignancies, to clarify the biological basis of ACA acquisition might contribute to the development of novel therapeutic strategies. Disclosures Handa: Ono: Research Funding.

Extracapsular Extension of Pelvic Lymph Node Metastases From Urothelial Carcinoma of the Bladder Is an Independent Prognostic Factor

2005 ◽  
Vol 23 (10) ◽  
pp. 2358-2365 ◽  
Author(s):  
Achim Fleischmann ◽  
George N. Thalmann ◽  
Regula Markwalder ◽  
Urs E. Studer
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Lymph Node ◽  
Prognostic Factor ◽  
Urothelial Carcinoma ◽  
Radical Cystectomy ◽  
Pelvic Lymph Node ◽  
Prognostic Impact ◽  
Extracapsular Extension ◽  
Carcinoma Of The Bladder

Purpose To analyze the prognostic impact of risk factors for urothelial carcinoma of the bladder (UCB) with pelvic lymph node (LN) metastases. Patients and Methods We analyzed a consecutive series of 507 patients with UCB who were preoperatively staged N0M0. One hundred one of 124 eligible patients who were treated with radical cystectomy and standardized extended bilateral pelvic lymphadenectomy with curative intent and had postoperatively confirmed LN metastases were evaluated in regard to recurrence-free and overall survival. Results A median of 22 nodes per patient (range, 10 to 43 nodes) were removed and examined. Median recurrence-free and overall survival durations were 17 months and 21 months (range for both, 1 to 191 months), respectively. In the multivariate analysis for recurrence-free survival, extracapsular extension of LN metastases was the strongest prognostic factor (P = .019). Other variables such as tumor stage (pT1/2 v pT3 and pT4), the number (< five v ≥ five), and the percentage (< 20% v ≥ 20%) of metastatic nodes had a significant influence on recurrence-free and overall survival in the univariate analysis. However, they all failed to be significant prognostic factors in the multivariate analysis. Conclusion The results of this study indicate that radical cystectomy with bilateral lymphadenectomy can have a curative effect in a subset of patients with pelvic LN positive UCB. Provided that a representative number of LNs are removed by meticulous lymphadenectomy and that a thorough histologic examination is performed, prognosis for such patients can be determined quite reliably. In the multivariate analysis, extracapsular extension of LN metastases was the strongest factor predicting prognosis.

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