Monosomal Karyotype in MDS and Secondary AML: Do Autosomal Monosomies Have the Same Poor Prognostic Impact As Monosomy 5 and 7?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4867-4867
Author(s):  
Paolo Bernasconi ◽  
Marina Boni ◽  
Marianna Rossi ◽  
Rita Zappatore ◽  
Irene Dambruoso ◽  
...  
Keyword(s):  
Disease Progression ◽  
Median Time ◽  
Median Survival ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
Cell Percentage ◽  
Conventional Cytogenetics

Abstract Abstract 4867 Background: A monosomal karytype (MK) is defined by the presence of at least two or more distinct autosomal monosomies or an autosomal monosomy along with a structural defect. In AML this cytogenetic pattern has a very well-known poor prognostic significance independently of the specific chromosome involved. Currently, in MDS this negative prognostic influence is also emerging as recent data suggest that any monosomy in a complex karyotype (≥3 abnormalities) may have the same poor prognostic impact as monosomy 5 and 7 (−5,−7). Objectives: Thus, the principal goal of the present study was to test whether a MK further worsen the already poor prognostic influence of a complex karyotype and to establish whether autosomal monosomies have the same unfavourable prognostic impact on OS and progression free interval (PFI) as −5/−7. Methods: The eighty-five consecutive MDS patients with a complex karyotype analysed by the present study were included in a series of 631 patients who came at our observation in the period January 2000-December 2010. They were thirty-two females and fifty-three males with a median age of 65 years (range 25–85). Fifty-five patients were diagnosed as MDS and were subdivided in 3 RARS, 6 RA, 6 RCMD, 2 RCMDS, one MDS-u, 13 RAEB-1 and 24 RAEB-2. The IPSS score was intermediate-1 in 5, intermediate-2 in 23 and high in 27. During the follow-up 31 MDS patients died and 41 experienced disease progression (3 RARS, 5 RA, 4 RCMD, one MDS-u, 9 RAEB-1 and 19 RAEB-2). Thirty patients were diagnosed as AML evolved from MDS. Fifteen of them received supportive treatment only, the remaining single agent chemotherapy to control leukocytosis. Nineteen of these thirty patients died of disease related complications. Results: On conventional cytogenetics 37 patients (4 RA, 5 RCMD, one MDS-u, 8 RAEB-1, 12 RAEB-2 and 7 AML) presented a complex karyotype without monosomies and 48 (3 RARS, 2 RA, 2 RCMDS, one RCMD, 5 RAEB-1, 12 RAEB-2, 24 AML) a complex karyotype with monosomies. These two patients subgroups were comparable in terms of age, sex distribution, haemoglobin level, leukocyte or platelet counts, bone marrow blast cell percentage and IPSS score. However, median survival was 8 months (range 1–131) for patients with a complex karyotype without monosomies and 5 months (range 1–81) for those with a complex karyotype with monosomies (p=0.001). Twenty patients (54.0%) without monosomies died after a median time of 6 months (range 2–35), whereas 30 patients (62.5%) with monosomies died after a median time of 5 months (range 1–24). Disease progression was observed in 22 (59.4%) and 19 (39.5%) patients respectively (p=0.001). The 48 patients with a MK were further subdivided in those with −5/−7 versus those with other autosomal monosomies. The 23 patients with −5/−7 presented a median survival of 4 months (range 1–15) and the 25 with other monosomies presented a median survival of 5 months (range 1–81) (p=Not Significant). Fourteen −5/−7 patients died after a median time of 4 months (range 1–15) and 13 patients with autosomal monosomies died after a median time of 6 months (range 1–24). Disease progression occurred in 12 (52.1%) and 7 (28%) respectively. Conclusions: i) a MK further refines the prognostic stratification of MDS with a complex karyotype as it identifies a subgroup of patients with an extremely poor clinical outcome; ii) autosomal monosomies have an impact on disease outcome as detrimental as −5/−7. Disclosures: No relevant conflicts of interest to declare.

Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid.

1986 ◽  
Vol 4 (5) ◽  
pp. 685-696 ◽  
Author(s):  
D Machover ◽  
E Goldschmidt ◽  
P Chollet ◽  
G Metzger ◽  
J Zittoun ◽  
...  
Keyword(s):  
Survival Time ◽  
Folinic Acid ◽  
Disease Progression ◽  
Median Time ◽  
Gastric Adenocarcinoma ◽  
Median Survival ◽  
Median Survival Time ◽  
Single Agent ◽  
High Dose ◽  
Gastric Adenocarcinomas

We report the results of an expanded trial of 5-fluorouracil (5-FU) combined with high-dose folinic acid for treatment of patients with advanced colorectal or advanced gastric adenocarcinoma. In each treatment course, the patients received both 5-FU (340 to 400 mg/m2/d by intravenous (IV) infusion for a period of 15 minutes) and folinic acid (200 mg/m2/d by IV bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete and partial response rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to 5-FU attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates greater than 10(-5) mol/L were achieved after a rapid single IV injection of 200 mg/m2 of folinic acid. Comparisons of our results with those reported in previous studies on 5-FU administered as a single agent suggest that, in advanced colorectal and gastric adenocarcinoma, folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly. Furthermore, some colorectal tumors that were previously resistant to 5-FU become sensitive to this drug. The survival of the patients who responded to therapy was markedly improved over that observed in reported series of untreated patients with advanced colorectal and gastric adenocarcinomas.

scholarly journals FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Naval Daver ◽  
Sangeetha Venugopal ◽  
Farhad Ravandi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Prognostic Significance ◽  
Treatment Algorithm ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

A Complex Karyotype but Not Monosomy 7 Is an Independent Prognostic Factor in Advanced Childhood MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2452-2452
Author(s):  
Gudrun Gohring ◽  
Kyra Michalova ◽  
Berna Beverloo ◽  
David Betts ◽  
Jochen Harbott ◽  
...  
Keyword(s):  
Chromosome Aberrations ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Prognostic Significance ◽  
Complex Karyotype ◽  
Similar Frequency ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Significant Difference ◽  
Secondary Mds

Abstract Disclosure: No relevant conflicts of interest to declare. To study the clinical significance of recurrent chromosome aberrations in childhood MDS, cytogenetic data of 394 consecutive children with refractory cytopenia (RC) (N=215), RAEB (N=141) and RAEB-T (N=38) analyzed in the regional cytogenetic reference centers and registered in the prospective study EWOG-MDS 98 between 1998 and 2005 were evaluated. At diagnosis, a karyotype could be defined in 279/394 patients (pts) (71%). No karyotype was obtained in 16% of pts with RC compared to 8% pts with RAEB and RAEB-t (p<0.001). Clonal chromosome aberrations were more common in pts with advanced MDS (RAEB and RAEB-T, 61%) compared to RC (29%), and in pts with secondary (69%) compared to primary MDS (36%) (p<0.001). Monosomy 7 was the most frequent aberration occurring with similar frequency in RC (47% of abnormal karyotypes) compared to advanced MDS (49%) and in primary (53%) compared to secondary (41%) MDS. In addition, aberrations typical for de novo AML such as aberrations involving 11q23 or 3q, t(6;9) and del(9q) were noted in morphologically and clinically unequivocal MDS cases. Recurrent aberrations of adult MDS like isolated del(5q), del(20q) and -Y were very uncommon indicating a different pathogenesis of these cases. In pts with advanced MDS, there was no significant difference in overall survival (OS) of pts with normal karyotype (44% ± 18) compared to pts with monosomy 7 (58% ± 19) and patients with other karyotypes (61% ± 22). However, pts with advanced MDS and a complex karyotype (defined by ≥ 3 chromosome aberrations, presence of structural aberrations and excluding clonal evolution of monosomy 7) had a shorter OS (16% ±15, p<0.01). OS and event-free survival after hematopoietic stem cell transplantation (HSCT) in pts with complex karyotypes was inferior compared to that of pts with other cytogenetic aberrations (p=0.012 and 0.039, respectively). Within the group of pts with secondary MDS, complex karyotypes were found in MDS evolving from inherited bone marrow failure disorders or after radio-/ chemotherapy, but absent in familial MDS and cases evolving from acquired aplastic anemia. As shown in a multivariate Cox analysis, advanced MDS, secondary MDS, the presence of a complex karyotype and HSCT were identified as independent prognostic factors for OS. Thus, this study demonstrates the prognostic significance of cytogenetic findings in advanced childhood MDS independent of HSCT.

Detection of 13q14 Deletion by FISH Is Not Sufficient to Define a Group of Good Prognosis Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2332-2332
Author(s):  
Virginie Eclache ◽  
Vincent Levy ◽  
Fanny Baran-Marszak ◽  
Remi Letestu ◽  
Florence Cymbalista
Keyword(s):  
Prognostic Markers ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Large Cohort ◽  
Fish Analysis ◽  
Prognostic Impact ◽  
Trisomy 12 ◽  
Conventional Cytogenetics ◽  
The Impact ◽  
13Q Deletion

Abstract Abstract 2332 Poster Board II-309 Deletion of a 13q14.3 region is by far the most common genomic alteration in CLL. In a large cohort of CLL patients, the presence of deletion 13q as sole anomaly detected by FISH was predominantly found in Binet stage A CLL and associated with a favorable outcome (Dohner et al., N Engl J Med 2000). Further studies have evidenced some heterogeneity among CLL cases with 13q deletion, such as the size of the clone carrying the deletion, the existence of mono versus biallelic deletions, and the presence of other concomitant genetic aberrations. Therefore, we aimed at analysing the impact of this heterogeneity on the prognostic value of 13q14 deletion (del13q) in CLL. Patients and methods In a cohort of 329 previously untreated newly diagnosed stage A CLL, we detected del13q by FISH in 172 patients (52%) using the D13S319 probe. Conventional cytogenetics was performed in the 105 cases with del13q followed in our institution. The other important prognostic markers ( ZAP70, IgVH, CD38, proliferation markers) and clinical progression were also available for all patients. Results We first studied the large cohort of stage A patients and found that deletion 13q had no prognostic impact on PFS. When considering more specifically the presence of deletion 13q as sole anomaly (n=143), PFS was not significantly different from that of patients with no aberration detected by FISH analysis (del 13q, del11q, del17p and trisomy 12) (n=98). Moreover, the distribution of prognostic factors (ZAP70, sTK, mutational status, CD38 expression, lymphocytosis) was not statistically different among these two groups. We aimed at deciphering further these del13q cases through analysis of the percentage of deleted cells, the presence of mono versus biallelic deletions, and the presence of additional aberrations as detected by FISH and conventional cytogenetics in the 105 del13q cases followed in our institution. The size of the del13q clone, as reflected by the percentage of del13q cells by FISH, was highly variable, ranged from 7 to 90 %, and had no prognostic significance on PFS. Monoallelic deletions were present in 77 cases, fully biallelic deletions in 9 cases, and concomitant bi and monoallelic deletions in 19 cases. The 9 cases with biallelic deletions had a significantly shorter PFS and were associated with other unfavorable prognostic markers. As biallelic deletions are most likely to represent progression from monoallelic cases, it is understandable that no clear prognostic impact was evidenced between cases with monoallelic deletions and with concomitant variable amount of bi and monoallelic deleted cells. Twenty cases (20 monoallelic and 6 biallelic) were further studied by array-CGH. Minimal deleted region (MDR) was included in all deletions but the size of the deletion was variable and in most cases much larger than MDR. Among the 6 bi allelic cases, one of the deletions was restricted to the MDR in all cases, pointing out to the importance of the level of miRNA expression. Additional aberrations were found in 44/105 del13q cases. In 17 patients, one or more alterations were detected by FISH techniques : del11q (n=8), trisomy 12 (n=8) or del17p (n=5). By conventional cytogenetic all these aberrations were also detected, as well as other rare ones in 16 additional cases, either isolated or associated in a complex karyotype in 5 cases. Presence of additional aberrations had a significant unfavourable impact on PFS, even when excluding del11q, del17p and tri12, and considering the non recurrent aberrations that were detected by conventional cytogenetics only. Conclusion Presence of 13q deletion should not be considered as a good prognostic marker by itself among stage A patients. Moreover, del13q cases are highly heterogeneous, and the presence of deletion 13q should not be interpreted without considering both alleles or the presence of concomitant genetic alterations. Disclosures: No relevant conflicts of interest to declare.

KIT Mutations Are Rare Among Elderly AML Patients: A SWOG Report

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2510-2510
Author(s):  
Fabiana Ostronoff ◽  
Megan Othus ◽  
Phoenix A. Ho ◽  
Stephen H. Petersdorf ◽  
Jeanne E. Anderson ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Elderly Patients ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Age Groups ◽  
Prognostic Impact ◽  
Kit Mutation ◽  
Elderly Aml ◽  
Normal Cytogenetics

Abstract Abstract 2510 Background: KIT receptor tyrosine kinase mutations are recurrent genetic alteration found in acute myeloid leukemia (AML) with higher prevalence in those with core binding factor (CBF) AML. Different prognostic significance of these mutations has been found in pediatric and adult AML studies. However, prevalence and prognostic impact of KIT mutations in elderly patients with AML has not been established. In this study, we evaluated the prevalence of KIT mutation and its correlation with cytogenetic, molecular subtypes and clinical outcome in elderly AML patients. Methods: Diagnostic specimens from for 207 patients with AML registered on SWOG trials S-9031 and S-9333 were available for KIT mutation analysis. Both of these clinical protocols enrolled AML patients > 55 years. The samples were analyzed for the presence of KIT mutations via direct sequencing of exons 8 and 17. Results: In the cohort of 207 patients tested, the median age, WBC, and blast count at diagnosis were 68 years (range, 56–88 years), 29,6 × 109/L (range, 7–289 × 109/L) and 67% (0–99%), respectively. Favorable, intermediate and unfavorable cytogenetics were present in 8%, 57% and 26% of the patients, respectively. Nine percent of the patients had cytogenetics abnormalities of unknown significance. Normal cytogenetics was present in 48% of the patients. Fifty-three patients (26%) harbored mutations for FLT3-ITD, 37 (19%) for DNMT3A, 52 (31%) for NPM1 and 50 (24%) for IDH1/2. Only 3 patients were positive for CEBPA mutation. Of the 207 patient specimens tested, KIT exon 17 mutations were detected in 4 patients (2%). Exon 8 mutations were not identified. The characteristics of the 4 patients with KIT mutations are described in the table. Of the 4 patients who harbored the KIT mutation, 2 had intermediate, 1 had unfavorable risk cytogenetics and 1 patient did not have available cytogenetic data. None of the patients with CBF had KIT mutations. In terms of other molecular markers, all 4 patients were wild-type for NPM1, CEBPA, DNMT3A, IDH1/2 and FLT3-ITD. The very small number of KIT mutations in this group of patient precluded correlation between KIT mutations and clinical outcome. Conclusion: The prognostic impact of KIT mutations has been shown to vary according to cytogenetics subgroups. Most studies report a negative prognostic impact of these mutations in patients with CBF AML. The prognostic implications of KIT mutations also seem to vary among different age groups, with pediatric studies indicating they have no prognostic significance and adult studies indicating a negative prognostic impact. To date, there is no large study reporting on the incidence and prognostic impact of KIT mutations in elderly patients with AML. The very low incidence of KIT mutations in our study highlights the age-specific characteristics of AML and may correlate with lower prevalence of CBF translocations in older AML. Further studies investigating the relationship among different somatic mutations in elderly AML patients may help to clarify the pathogenetic mechanism of certain AML subtypes in this patient population. Disclosures: No relevant conflicts of interest to declare.

Jumping Translocation of Homogeneously Staining Region Hsr(11q) in An Erythroid Leukemia: Identification of Amplified Regions by Fluorescence Hybridization, M-FISH and M-Banding.

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4890-4890
Author(s):  
Catherine Helias ◽  
Carine Gervais ◽  
Eric Jeandidier ◽  
Bruno Lioure ◽  
Laurent Mauvieux
Keyword(s):  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Erythroid Cell ◽  
Specific Gene ◽  
Complex Karyotype ◽  
Chromosome 11 ◽  
Hematological Neoplasms ◽  
Selective Growth Advantage ◽  
Blast Cells ◽  
Conventional Cytogenetics

Abstract Abstract 4890 Gene amplification is a mechanism whereby a tumor cell can increase the copy number of specific gene sequences and gain a proliferative advantage. Although amplifications are common in solid tumors, they are relatively rare in hematological neoplasms. We report here on a patient with an acute erythroid leukemia and a jumping translocation of a hsr(11q) in a complex karyotype, without MLL amplification. The patient was 40 years old when he was admitted for asthenia, peripheral blood showing pancytopenia (Hb=111G/L; neutrophils= 0.23 G/L; platelets 92 G/L), without circulating blast cells. Bone marrow was hypercellular with the presence of more than 50% of erythroid precursors and more than 20% of myeloid blast cells in non-erythroid cell population, leading to the diagnosis of erythroblastic acute leukemia. A marked dysgranulopoiesis was also detected. Conventional cytogenetics showed a complex karyotype with a del(5q), a unbalanced t(7;17) leading to partial 7q deletion and homogeneously staining regions (hsr). Fluorescence in situ hybridization confirmed the del(5q), and showed that TP53 was not deleted in the t(7;17). Multi-FISH (M-FISH) pointed out that the hsr consisted of chromosome 11 and was implicated in 3 different translocations with 3 different partner chromosomes in 3 different clones. To further characterize the amplicon and determine which bands were implicated, we used a chromosome 11 m-band probe. It revealed that the bands implicated are the same on the der(3), der(12) and der(20) and are localized between 11q23.3 and 11q25. A series of BAC probes showed that different genes, present in these regions, were amplified: ETS1, FLI1, KCNJ5, NFRKB, SNX19, HNT, OPCM, but not MLL. Amplifications of chromosome 11q usually includes MLL, but more telomeric amplicons have also been reported in AML and myelodysplatic syndromes (MDS). A very close 11q amplification was identified in 3 AML/MDS cases (Crossen et al, 1999; Tyybäkinoja et al, 2006). Also, the ETS1 oncogene was found to be rearranged and 30-fold amplified in a case of acute myelomonocytic leukaemia, in which an hsr occurred on 11q23 (Rovigatti et al, 1986). The role of chromosomal amplifications in leukemia is unclear, but it has been suggested that they are associated with rapid disease progression and short survival. Jumping translocations are an unusual phenomenon and have been rarely reported in hematological malignancies. Whether jumping translocations play a role in tumor genesis or confer a selective growth advantage on tumor cells is unknown. The combination of hsr and jumping translocations as described here are very rare in hematological malignancies. The cases of the literature (Yoshida et al, 1999) and the one presented here suggest that the 11q24-q25 region may harbor new candidate oncogenes, together with unusual chromosomal mechanisms. Disclosures: No relevant conflicts of interest to declare.

AML with Recurrent Genetic Abnormalities and AML with Myelodysplasia-Related Changes Account for Three-Quarters of Previously Untreated Pediatric AML-the Results of a Nation-Wide Central Review in Japan-

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4899-4899
Author(s):  
Akitoshi Kinoshita ◽  
Hayato Miyachi ◽  
Hiromichi Matsushita ◽  
Tomohiko Taki ◽  
Miharu Yabe ◽  
...  
Keyword(s):  
Who Classification ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Genetic Abnormalities ◽  
Precise Diagnosis ◽  
De Novo Aml ◽  
Pediatric Aml ◽  
Mixed Phenotype

Abstract Abstract 4899 [Background] The WHO classification has been widely accepted among physicians who are engaged in treating pediatric AML patients. In 2008, the revised WHO classification has expanded the two categories in AML; AML with recurrent genetic abnormalities and AML with myelodysplasia-related changes. The epidemiology and prognostic significance of these refined categories remains to be explored in children. [Methods] JPLSG AML-05 is a nationwide clinical trial for children with de novo AML, excluding acute promyelocytic leukemia and myeloid leukemia with Down syndrome, which was conducted between November 2006 and December 2010 in Japan. A central review of diagnosis based on the WHO classification was prospectively performed on each case soon after morphological, cytogenetical and immunological data were submitted to data center. Regarding the cases with discrepant results among these parameters, further diagnostic tests including FISH and chimera gene analyses were underwent to confirm the diagnoses. [Results] Four hundred and eighty four patients were enrolled in the study. Thirty patients did not meet the criteria of AML. We could not collected suitable data for diagnosis in 6 patients. Regarding the rest 448 patients, diagnoses based on the WHO classification 2001 and 2008 were determined. According to the 2001 version, 227 (50.6%) had AML with recurrent genetic abnormalities:124 (27.7%) of AML with t(8;21)(q22;q22);(AML1/ETO ), 32 (7.1%) of AML with inv(16)(p13q22); (CBFβ/MYH11), 38 (8.5%) of AML with t(9;11)(p22;q23), and 33 (7.4%) of AML with the other11q23 (MLL) abnormalities, 36 (8.0%) had AML with multilineage dysplasia, and 185 (41.3%) had AML, not otherwise categorized. According to 2008 version, 235 (52.5%) had AML with recurrent genetic abnormalities: 124 (27.7%) of t(8;21)(q22;q22);(AML1/ETO ), 32 (7.1%) of AML with inv(16)(p13q22); (CBFβ/MYH11), 38 (8.5%) of AML with t(9;11)(p22;q23), 33 (7.4%) of AML with the other11q23 (MLL) abnormalities,4 of AML with t(6;9)(p23;q34);DEK-NUP214,2 of AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2);RPN1-EVI13, and 2 of AML with t(1;22)(p13;q13);RBM15-MKL, 88 (19.6.7%) had AML with myelodysplasia-related changes (29 from morphological features of myelodysplasia and 59 from myelodysplasia-related cytogenetic abnormalities), 119 (26.6%) had AML, not otherwise categorized and 7(1.6%) had mixed phenotype acute leukemia (6 of T/myeloid and 1 of B/myeloid). [Discussion] Our comprehensive approach for diagnosis was a useful modality for precise diagnosis of uncertain cases, which might have been assigned to the category of AML, with not otherwise categorized, previously. As a result, the present study shows an increased prevalence of AML with recurrent genetic abnormalities or AML with myeloid dysplasia-related changes among pediatric patients with previously untreated AML. Analysis of the AML-05 trial will elucidate the prognostic impact of these categories. Disclosures: No relevant conflicts of interest to declare.

Prognostic Significance Of NPM1 mutations In The Absence Of FLT3-ITD in Older Patients With AML: A SWOG Report

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1315-1315 ◽  
Author(s):  
Fabiana Ostronoff ◽  
Megan Othus ◽  
Soheil Meshinchi ◽  
John E. Godwin ◽  
Kenneth J. Kopecky ◽  
...  
Keyword(s):  
Risk Factor ◽  
Relapse Rate ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Prognostic Significance ◽  
Age Groups ◽  
Adverse Outcomes ◽  
Prognostic Impact ◽  
Age Group ◽  
Npm1 Mutation

Abstract Introduction Younger acute myeloid leukemia (AML) patients with a NPM1 mutation but without FLT3-ITD (NPM1+/FLT3-ITD-) have favorable prognosis, but the prognostic significance of these mutations in patients older than 55 years is less clear. Therefore, we evaluated the prognostic impact of the NPM1+/FLT3-ITD- in older AML patients. Methods Samples were obtained from AML patients enrolled onto SWOG trials S9333, S9031, S9500 and S0106 who were ³55 years and received “7+3 like” induction regimens. Cytarabine/daunorubicin (S9031 and S9033) or HiDAC (9500 and S0106) were used for consolidation. Gemtuzumab ozogamicin, either during induction, consolidation, and/or post-consolidation, was administered to some patients enrolled onto S0106. Samples were examined for FLT3, NPM1, DNMT3A, IDH1/2 mutations using previously reported techniques. Results A total of 1,239 patients enrolled in these trials, and pre-treatment samples were available for 156 patients who were older than 55 years (median age of 60 years, range 55-83). NPM1 and FLT3-ITD mutations were present in 33% and 24% of the patients, respectively. The complete remission (CR) rate, 2-year overall survival (OS) and relapse-free survival (RFS) for the entire cohort were 62%, 31% and 32%, respectively. Increased age, unfavorable cytogenetics and FLT3-ITD were associated with a worse OS and RFS. NPM1 mutations were not significantly associated with OS or RFS. Patients were then divided into two age groups, 55-65 and >65 years, based on previous data that favorable prognostic factors such as good-risk cytogenetics have not been shown to be associated with favorable outcomes for AML patients age >65. Both age groups displayed similar patient characteristics (in regards to white blood cell count, bone marrow blast %, cytogenetics, secondary AML, sex and ECOG performance status), with the exception that >65 years group did not include any patients from S0106 or S9500 due to age restrictions for these trials. Patients >65 had a higher relapse rate (P =0.001) and significantly worse OS (P<0.001) and RFS (P=0.007) than those aged 55-65. FLT3-ITD retained its unfavorable prognostic significance for patients age 55-65, while patients >65 years had such a uniformly poor prognosis that this mutation lost much of its prognostic significance. NPM1 mutations were not significantly associated with either OS or RFS in either age group. We then examined the most favorable NPM1+/FLT3-ITD- genotype, which is currently being used to risk-stratify AML patients. NPM1+/FLT3-ITD- was associated with an improved OS in the 55-65 age group (P<0.001), which was similar to previously described results in younger patients (Figure 1A). Additional analyses showed that the favorable impact of this genotype was not due to the inclusion of patients enrolled onto S0106 and S9500 (Figure 1B). In contrast, patients >65 years with the NPM1+/FLT3-ITD- had a low CR rate and high 1-year relapse rate, which translated into a relatively poor 5-year OS (<30%, Figure 1C) that was not significantly different from patients >65 without this genotype (P=0.33). Since mutations in DNMT3A, IDH1/2 have been associated with adverse outcomes for patients with NPM1 mutations, samples with the NPM1+/FLT3-ITD- genotype were examined for these mutations. The frequencies for DNMT3A, IDH1/2 mutations were similar in both age groups, indicating that these mutations were not responsible for the age-dependent findings. Furthermore, multivariate models adjusting for known prognostic covariates showed that the NPM1+/FLT3-ITD- remained independently associated with improved OS for patients age 55-65 but not those >65. Conclusions This study represents one of the largest investigations on the prognostic significance of NPM1+/FLT3-ITD- in older AML patients. The NPM1+/FLT3-ITD- genotype remains a favorable-risk factor for AML patients age 55-65 years but may not be a favorable-risk factor for patients >65 years, at least not for those treated with standard induction followed by conventional consolidation. Disclosures: No relevant conflicts of interest to declare.

Value of EVI1 Gene Expression Level in Adult Acute Lymphoblastic Leukemia (ALL): A Study from the Group for Research on Adult ALL (GRAALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1081-1081
Author(s):  
Claire Abbal ◽  
Raouf Ben Abdelali ◽  
Marina Lafage ◽  
Françoise Huguet ◽  
Thibaut Leguay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Patient Outcome ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Expression Level ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
Cell Precursor ◽  
Genetic Profiles ◽  
Lower Expression

Abstract Background: EVI1 gene overexpression is found in approximately 10% of acute myeloid leukemia (AML) patients, with a higher frequency seen in AML carrying chromosome 3q26 abnormality or MLL gene rearrangement, and associated with a dismal prognosis. Deregulation of EVI1 expression has also been reported in ALL, but its prognostic impact is unclear. Here, we retrospectively analyzed EVI1 expression in a large cohort of adult ALL patients, its correlation with ALL subsets, and its impact on patient outcome. Patients and Methods: EVI1 gene expression was measured by RQ-PCR detecting all splicing variants, with PBGD as control gene. We used dilutions of EVI1+ SKOV3 (kindly provided by Peter Valk, Rotterdam, The Netherlands) and EVI1-neg HL-60 cell line cDNA to build EVI1 and PBGD standard curves. Results were expressed as EVI1/PBGD ratio x 100. Blast samples from 354 patients treated in the GRAALL-2003/2005 and GRAAPH-2005 trials (191 B-cell precursor [BCP]-ALL, including 138 Ph-neg and 53 Ph+; 163 T-ALL) and 62 controls were analyzed. Immunophenotype results were centrally reviewed. In controls, median EVI1 expression level was 0.33% (Q1-Q3, 0.20-0.69). For prognostic analysis, we used the 1st and 99th percentiles of the controls (0.05% and 1.65%) to define patients with low and high EVI1 expression, respectively. Clinical endpoints were cumulative incidence of failure (CIF, failure meaning primary refractoriness or relapse) and event-free survival (EFS). Results: As illustrated in Figure 1, we observed that, as in one AML series, EVI1 expression may be up or down regulated in adult ALL. When compared to controls, the proportions of low and high EVI1 patients were 21 and 23% in Ph-neg BCP-ALL, 9 and 42% in Ph+ ALL, and 21 and 18% in T-ALL, respectively. In BCP-ALL patients, median EVI1 expression was similar to controls (0.53%; Q1-Q3, 0.11-1.88; p=0.15), but higher in the Ph+ as compared to the Ph-neg subgroup (0.93% versus 0.36%; p<0.001). In T-ALL patients, median expression tended to be lower than in controls (0.22%; Q1-Q3, 0.06-0.85; p=0.058). In these three ALL subgroups, EVI1 expression did not correlate with age or WBC. Among Ph-neg BCP-ALL patients, a lower expression was found in MLL-AF4+ t(4;11) cases (median, 0.04%; p<0.001), while no differences were observed for cases with t(1;19), an14q32, low hypodiploidy/near triploidy, complex karyotype, or IKZF1 deletion. Among T-ALL patients, a lower expression was found in cases with complex karyotype (median, 0.05%; p=0.03), while no differences were observed for cases with TLX1 overexpression, NOTCH1/FBXW7 mutation, N/K-RAS mutation or PTEN alteration. Only one patient had 3q26 abnormality (T-ALL with high EVI1 expression). Low or high EVI1 expression had no prognostic impact in Ph-neg as well as Ph+ BCP-ALL patients. In T-ALL, the proportion of patients with low EVI1 expression was more frequent in early and mature than in cortical T-ALL (33% and 33% vs 11%; p=0.002 and 0.028, respectively) and associated with a higher CIF (HR, 2.03; p=0.017) and shorter EFS (HR, 1.59; p=0.072). Low EVI1 expression was also significantly associated with an early T-cell precursor (ETP) phenotype (37.5% vs 18%; p=0.028). After adjustment on cortical and ETP phenotypes, as well as on 4-gene (NOTCH1/FBXW7/RAS/PTEN) genetic profiles, low EVI1 expression and high-risk genetic profiles remained independently associated with higher CIF (p=0.015 and <0.001, respectively) and shorter EFS (p=0.045 and 0.002, respectively). Conclusion: Overall, these results confirm that EVI1 gene expression is frequently deregulated in adult ALL. In BCP-ALL, down-regulation is observed in t(4;11) and up-regulation in BCR-ABL cases. Further studies are needed to confirm that, in T-ALL, a lower expression is associated with the early, mature and ETP phenotypes and independently predictive of a worse patient outcome. Figure 1 Figure 1. EVI1 gene expression in ALL and control samples. Disclosures No relevant conflicts of interest to declare.

The prognostic significance of supradiaphragmatic lymphadenopathy identified on preoperative computed tomography scan in patients undergoing primary cytoreduction for advanced stage epithelial ovarian cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16512-e16512
Author(s):  
V. Kolev ◽  
S. Mironov ◽  
O. Mironov ◽  
C. Moskowitz ◽  
N. M. Ishill ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Ovarian Cancer ◽  
Overall Survival ◽  
Ct Scan ◽  
Epithelial Ovarian Cancer ◽  
Median Survival ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Preoperative Ct

e16512 Background: It has been hypothesized and shown in animal studies that the supradiaphragmatic lymph nodes serve as the principal nodes for lymphatic drainage of the entire peritoneal cavity. The purpose of this study was to determine the prognostic significance of enlarged supra-diaphragmatic nodes noted on preoperative computed tomography (CT) scan in patients with advanced epithelial ovarian cancer (EOC). Methods: We performed a retrospective chart review of all patients (pts) with FIGO stage III and IV EOC who had preoperative CT scans of the supradiaphragmatic region and primary cytoreductive surgery at our institution between 1997 and 2004. All scans were retrospectively reviewed by one board-certified radiologist (SM). To evaluate survival, Kaplan-Meier methods were used, with log rank Pvalues for comparisons. Results: A total of 212 eligible pts who underwent attempted primary cytoreduction followed by platinum-based systemic chemotherapy were identified for evaluation. With a median follow-up time of 52 mos, there were 135 deaths and a median overall survival of 48 mos (95% CI: 44–53). Of the 212 pts, 44 (21%) had supradiaphragmatic adenopathy with nodes >1 cm, while 168 (79%) did not have adenopathy in this distribution. None of the 44 pts with adenopathy had the enlarged nodes removed at primary cytoreduction. The median survival was 49 mos for pts with and 48 mos for patients without adenopathy (p = 0.46). In total, 155 (73%) patients underwent optimal cytoreduction (residual disease ≤ 1 cm). In the optimally cytoreduced pts, the median survival for the 125 pts without supradiaphragmatic adenopathy was 52 mos (95%CI: 45–59) compared to 51mos (95%CI: 41–58) for the 30 pts with supradiaphragmatic adenopathy (p = 0.33). Conclusions: Although a previous study has shown that supradiaphragmatic adenopathy was associated with poorer overall survival in EOC patients, our study did not confirm these findings. In our study, enlarged supradiaphragmatic nodes noted on preoperative CT scan did not have significant prognostic impact and therefore their clinical significance remains uncertain. No significant financial relationships to disclose.

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