Multivariate Evaluation of the Prognostic and Therapeutic Relevance of Cytogenetics in a Merged European-American Cohort of 3860 Patients with MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 247-247 ◽  
Author(s):  
Detlef Haase ◽  
Elihu H. Estey ◽  
Christian Steidl ◽  
Ulrich Germing ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Supportive Care ◽  
Median Survival ◽  
Survival Data ◽  
De Novo ◽  
Normal Karyotype ◽  
Epigenetic Therapy ◽  
Chemotherapy Response ◽  
Trisomy 8 ◽  
Therapy Regimen ◽  
Secondary Mds

Abstract This study investigated the influence of cytogenetic findings on survival in MDS, after accounting for other known prognostic parameters and type of treatment. We identified 3210 patients with a known therapy regimen from our large database, including 3860 patients with MDS and secondary AML following MDS. This data pool was collected in the framework of a cooperative project merging data from the German-Austrian MDS study group (55% of pts.) and the MD Anderson Cancer Centre (MDA), Houston, USA (45% of pts.). Median age of all study patients was 65.9 years, the female-male ratio 1:1.53. After accounting for age, sex, % marrow blasts, de novo vs. primary MDS, treatment (supportive care, AML-type, and epigenetic therapy) and site of treatment(Germany/Austria vs.MDA) we looked at the effect of cytogenetic subgroups on survival. Survival data was available for 95.8% of all pts. The distribution of main cytogenetic categories was as follows: normal (1.727, 45%), 5q- (208, 5%), 5q- +1 abnormality (73, 2%), −7/7q- not complex (222, 6%), +8 not complex (203, 5%), complex with −5/−7 (627, 17%), other complex (195, 5%), 20q- not complex (69, 2%), and other not complex (475, 13%). Chemotherapy (c) was applied in 32.9% while 67.1% were treated with supportive care (sc) or epigenetic therapy. The cytogenetic prognosis according to IPSS-criteria was favourable in 1704 (53.1%) and unfavourable in 839 (26.13%) of the 3210 study patients. Multivariate analysis revealed the following non-cytogenetic parameters as unfavourable: age >60, male sex, blasts >5%, secondary MDS, AML-like chemotherapy, MDA as site (due to overrepresentation of high risk MDS). After accounting for these variables the following relative Hazard ratios (HR of 1.0 for normal karyotype) were calculated allowing a relative ranking of cytogentic findings: 5q-: 0.93, 5q- +1: 1.06, other not complex: 1.11, 20q-: 1.31, +8: 1.65, complex without −5/−7: 1.76 −7/7q-: 2.09, complex with −5/−7: 3.88. The effect of cytogenetics in pts. with either supportive care (sc) or chemotherapy (c) measured as relative HR (see above) were: 20q- (sc: 1.25, c: 1.51), 5q- (sc: 0.93, c: 0.73), other not complex (sc: 1.07, c: 1.04), −7/7q- (sc: 2.10, c: 2.09), +8 (sc: 2.05, c:1.54), complex without −5/−7 (sc: 2.23, c: 1.75), complex with −5/−7 (sc: 4.78, c: 3.77) showing that cytogenetics remains it’s prognostic relevance independent from the therapy applied. In Kaplan-Meier-analyses median survival in pts. showing favourable karyotypes was 37.9 months with supportive treatment as compared to 26.4 months with chemotherapy (p<0.01). We observed no therapy-related survival differences with regard to patients of the unfavourable cytogenetic subgroup. The occurrence of complex abnormalities (n=670) was associated with an identical median survival comparing the therapy groups (c: 7.0, sc: 7.1 months). We also investigated groups with distinct abnormalities (5q-, −7/7q-, +8, 20q-) and found significant differences in survival between the therapy groups: Patients with 5q- and 20q- benefited from supportive care while −7/7q- was related with a better survival when chemotherapy was applied. Patients with trisomy 8 showed no differences in survival. Regarding these data, chemotherapy response, expressed by survival, is closely associated with cytogenetics. Complex abnormalities always show a dramatically reduced outcome, independent from the therapeutic strategy.

scholarly journals Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2873-2882 ◽  
Author(s):  
OI Olopade ◽  
M Thangavelu ◽  
RA Larson ◽  
R Mick ◽  
A Kowal-Vern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Normal Karyotype ◽  
Intensive Chemotherapy ◽  
Trisomy 8 ◽  
Cytogenetic Abnormalities ◽  
Favorable Prognosis ◽  
Multiple Abnormalities ◽  
French American British

Abstract We have performed a retrospective analysis of the clinical, morphologic, and cytogenetic findings in 26 patients diagnosed between January 1969 and September 1991 with acute erythroblastic leukemia de novo (EL or AML-M6). Clonal chromosomal abnormalities were found in 20 (77%) patients (95% confidence interval [CI], 61% to 93%). Loss of all or part of the long arm (q) of chromosomes 5 and/or 7 was observed in 17 (65%) patients (95% CI, 47% to 83%). In addition, the karyotypes were often complex, with multiple abnormalities and subclones. Among the remaining nine patients, six had a normal karyotype and one each had trisomy 8, t(3;3), or t(3;5). The overall frequency of abnormalities of chromosomes 5 and/or 7 observed in our M6 patients is similar to that observed in our patients with therapy-related acute myeloid leukemia (t-AML; 99 of 129 patients, 77%), but substantially higher than that noted in our other patients with AML de novo (French- American-British [FAB] subtypes M1-M5: 52 of 334 patients, 16%). Our M6 patients with abnormalities of chromosomes 5 and/or 7 were older and had a shorter median survival (16 v 77 weeks [P = .005]) than did the M6 patients without these abnormalities. We found no correlation between morphologic features and either cytogenetic abnormalities or clinical outcome. Of note was the finding that the percentage of myeloblasts, which may account for only a small fraction of the total marrow elements when the revised FAB criteria are applied, had no bearing on prognosis. We conclude that acute erythroblastic leukemia, when defined by morphologic criteria, consists of two distinctive subgroups: one group tends to be older, has complex cytogenetic abnormalities, especially of chromosomes 5 and/or 7, and shares biologic and clinical features with t-AML; the other group, with simple or no detectable cytogenetic abnormalities, has a more favorable prognosis when treated with intensive chemotherapy.

scholarly journals Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes

Blood ◽  
1986 ◽  
Vol 67 (6) ◽  
pp. 1765-1772 ◽  
Author(s):  
RH Jacobs ◽  
MA Cornbleet ◽  
JW Vardiman ◽  
RA Larson ◽  
MM Le Beau ◽  
...  
Keyword(s):  
Median Survival ◽  
Myelodysplastic Syndromes ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Normal Karyotype ◽  
Refractory Anemia ◽  
Survival Times ◽  
Trisomy 8 ◽  
Leukemic Transformation ◽  
Abnormal Karyotype

Abstract Forty-nine patients with primary myelodysplastic syndromes (MDS) were subclassified according to French-American-British (FAB) Cooperative Group criteria. Eight patients had acquired idiopathic sideroblastic anemia (AISA), ten had chronic myelomonocytic leukemia (CMMoL), 14 had refractory anemia (RA), nine had refractory anemia with excess blasts (RAEB), and five had refractory anemia with excess blasts in transformation (RAEB-T); three patients could not be subclassified. The actuarial median survival for patients with AISA or with RA had not been reached at 60 months of follow-up. The median survival times for patients with CMMoL, RAEB, and RAEB-T were 25, 21, and 16 months, respectively. The percentages of patients with each subtype who developed ANLL were none in AISA, 20% in CMMoL, 7% in RA, 56% in RAEB, and 40% in RAEB-T. Patients with CMMoL had a poor prognosis independent of transformation to acute nonlymphocytic leukemia (ANLL), whereas patients with RAEB and RAEB-T had a high incidence of transformation and short survival times. Clonal chromosomal abnormalities were present in bone marrow cells from 19 patients at the time of diagnosis, and two others developed an abnormal karyotype at the time of leukemic transformation. The most frequent abnormalities, including initial and evolutionary changes, were trisomy 8 (9 patients), deletion of 5q (4 patients), and deletion of 20q (4 patients). The median survival times were 32 months for patients with an abnormal karyotype, and 48 months for those with a normal karyotype (P = 0.2). Specific chromosomal abnormalities were not associated with particular histologic subtypes; however, a high percentage of patients with RAEB and RAEB-T had an abnormal clone (89% and 80%, respectively). The percentages of patients with clonal abnormalities were 13% for AISA, 20% for CMMoL, and 29% for RA. The MDS transformed to ANLL in 42% of patients with an abnormal karyotype, compared to 10% of those with an initially normal karyotype (P less than .01). Among patients with RA, RAEB, and RAEB-T, the risk of leukemic transformation was confined to those with an abnormal karyotype (P less than .01). Thus, in the present study, morphology and karyotype combined were the best indicators of outcome in patients with MDS.

High Frequency of AML1/RUNX1 Mutations in Specific Cytogenetic Subgroups in De Novo Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 986-986
Author(s):  
Frank Dicker ◽  
Claudia Haferlach ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
Susanne Schnittger
Keyword(s):  
Trisomy 21 ◽  
De Novo ◽  
Normal Karyotype ◽  
Clinical History ◽  
Trisomy 13 ◽  
Complex Karyotype ◽  
Trisomy 8 ◽  
Cytogenetic Aberrations ◽  
De Novo Aml ◽  
Acute Myeloid

Somatic mutations in the DNA-binding domain, the socalled Runt homology domain, of the AML1/RUNX1 gene have been identified to occur in acute myeloid leukaemia (AML) with the highest incidence in AML M0, in therapy-related myelodysplastic syndrome (t-MDS), in therapy-related AML (t-AML) and AML after MDS (s-AML). Cytogenetic aberrations that are associated with RUNX1 mutations (RUNX1mut) have been reported to be trisomy 13 in AML and trisomy 21 in myeloid malignancies, but also loss of chromosome 7q, mainly in t-MDS but rarely in t-AML. So far the majority of RUNX1mut have been described in secondary or therapy-related cases. Thus, we characterized a cohort of 119 patients (pts) with de novo AML and compared these results to 19 MDS and s-AML, 2 t-MDS (n=2) and 8 t-AML. The cohort was selected for specific cytogenetics with high reported frequencies of RUNX1mut: trisomy 13 (n=17), trisomy 21 (n=9), −7/7q- (n=34). In addition pts with normal karyotype (NK) (n=42), inv(3)/t(3;3) (n=12), trisomy 8 (n=11), complex karyotype (n=13) and 10 pts with various other cytogenetic aberrations (other) were analyzed. The incidence of RUNX1mut in the different cytogenetic subgroups was: 94% (16/17) in +13, 56% (5/9) in +21, 29% (10/34) in −7/7q-, 10% (4/42) in NK, 17% (2/12) in inv(3)/t(3;3), 18% (2/11) in +8, 0% (0/13) in complex karyotype and 20% (2/10) in other, respectively. Based on clinical history we observed RUNX1 mutations in: 6/19 (32%) in MDS/s-AML, 1/10 (10%) in t-MDS/t-AML and 34/119 (29%) in de novo AML. Of the 6 RUNXmut cases with MDS/s-AML the karyotypes were heterogeneous NK (n=1), −7 (n=2) +13 (n=1), +21 (n=1), and inv(3) (n=1). The only recurrent cytogenetic aberration in MDS/s-AML was −7, thus the frequency of RUNXmut in the MDS/s-AML group with −7 was 2/8 (25%). Also the only RUNX1mut case with t-AML revealed a −7. These data correspond to those reported in the literature. We further focussed on the analyses of RUNX1 in de novo AML which is rarely reported so far. In the de novo AML group only we detected RUNX1mut with the highest frequency in +13 (16/16; 100%) followed by +21 (4/8; 50%) −7 (7/21; 33%), + 8 (2/10, 20%), inv(3) (1/8; 12.5%), and NK (3/33; 9.1%). In addition, in the group with “other” aberration 2/8 were mutated. Interestingly, these 2 mutated cases displayed a high number of trisomies including +8 and +13. No RUNX1mut were detected in AML with complex karyotype (n=10). These data for the first time show that RUNX1mut are not strongly correlated to MDS, s-AML or t-AML. With almost the same frequency they can be observed in de novo AML if specific cytogenetic groups are considered. Thus the RUNXmut seem to be more related to these cytogenetic subgroups than to the MDS, s-AML or t-AML.

scholarly journals Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2873-2882
Author(s):  
OI Olopade ◽  
M Thangavelu ◽  
RA Larson ◽  
R Mick ◽  
A Kowal-Vern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Normal Karyotype ◽  
Intensive Chemotherapy ◽  
Trisomy 8 ◽  
Cytogenetic Abnormalities ◽  
Favorable Prognosis ◽  
Multiple Abnormalities ◽  
French American British

We have performed a retrospective analysis of the clinical, morphologic, and cytogenetic findings in 26 patients diagnosed between January 1969 and September 1991 with acute erythroblastic leukemia de novo (EL or AML-M6). Clonal chromosomal abnormalities were found in 20 (77%) patients (95% confidence interval [CI], 61% to 93%). Loss of all or part of the long arm (q) of chromosomes 5 and/or 7 was observed in 17 (65%) patients (95% CI, 47% to 83%). In addition, the karyotypes were often complex, with multiple abnormalities and subclones. Among the remaining nine patients, six had a normal karyotype and one each had trisomy 8, t(3;3), or t(3;5). The overall frequency of abnormalities of chromosomes 5 and/or 7 observed in our M6 patients is similar to that observed in our patients with therapy-related acute myeloid leukemia (t-AML; 99 of 129 patients, 77%), but substantially higher than that noted in our other patients with AML de novo (French- American-British [FAB] subtypes M1-M5: 52 of 334 patients, 16%). Our M6 patients with abnormalities of chromosomes 5 and/or 7 were older and had a shorter median survival (16 v 77 weeks [P = .005]) than did the M6 patients without these abnormalities. We found no correlation between morphologic features and either cytogenetic abnormalities or clinical outcome. Of note was the finding that the percentage of myeloblasts, which may account for only a small fraction of the total marrow elements when the revised FAB criteria are applied, had no bearing on prognosis. We conclude that acute erythroblastic leukemia, when defined by morphologic criteria, consists of two distinctive subgroups: one group tends to be older, has complex cytogenetic abnormalities, especially of chromosomes 5 and/or 7, and shares biologic and clinical features with t-AML; the other group, with simple or no detectable cytogenetic abnormalities, has a more favorable prognosis when treated with intensive chemotherapy.

scholarly journals Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3269-3274 ◽  
Author(s):  
E Matutes ◽  
V Brito-Babapulle ◽  
J Swansbury ◽  
J Ellis ◽  
R Morilla ◽  
...  
Keyword(s):  
Median Survival ◽  
Normal Karyotype ◽  
Skin Lesions ◽  
Variant Form ◽  
Type I ◽  
Chromosome 14 ◽  
Trisomy 8 ◽  
Laboratory Findings ◽  
Prolymphocytic Leukemia ◽  
Human T Cell

We describe the clinical and laboratory findings of 78 adult patients with T-prolymphocytic leukemia (T-PLL) studied over the last 12 years. The main disease features were splenomegaly (73%), lymphadenopathy (53%), hepatomegaly (40%), skin lesions (27%), and a high leukocyte count (greater than 100 x 10(9)/L in 75%) with nucleolated prolymphocytes. A variant form with small, less typical cells was recognized in 19%. Membrane markers defined a postthymic phenotype TdT- , CD2+, CD3+, CD5+, CD7+; in 65%, the cells were CD4+ CD8-, in 21%, they coexpressed CD4 and CD8, and, in 13%, they were CD4- CD8+. Serology for human T-cell leukemia/lymphoma virus Type-I (HTLV-I) was negative in the 27 cases investigated. Cytogenetic analysis in 30 cases showed a consistent abnormality of chromosome 14, usually inv (14), with breakpoints at q11 and q32 in 76% of cases. Trisomy 8, including iso8q, was shown in 53%; t (11;14)(q13;q32) was documented in one case; and one had a normal karyotype. The clinical course was progressive with a median survival of 7.5 months. Thirty-one patients were treated with 2′ deoxycoformycin and 15 responded (3 complete remissions and 12 partial remissions); the response rate (48%) increased to 58% in patients with a CD4+ CD8- phenotype. The median survival of responders was 16 months and of nonresponders 10 months; other treatments were less effective. T-PLL is a distinct clinico-pathologic entity with aggressive course and characteristic chromosome abnormalities. A subgroup of patients may benefit from deoxycoformycin.

Treatment of Elderly Acute Myeloid Leukemia (AML) Patients with the Combination of Mitoxantrone and Cytarabine (MAC).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4624-4624
Author(s):  
Theodoros Marinakis ◽  
Athanasios G. Galanopoulos ◽  
Athanasios Zomas ◽  
Euridiki Michalis ◽  
George Gortzolidis ◽  
...  
Keyword(s):  
De Novo ◽  
Normal Karyotype ◽  
Blood Dyscrasia ◽  
Trisomy 8 ◽  
Total Response Rate ◽  
Elderly Aml ◽  
Resistant Patient ◽  
De Novo Aml ◽  
Clinical Dilemma ◽  
Improvement In Survival

Abstract The value and exact type of intensive chemotherapy of unselected elderly AML patients in terms of overall survival (OS) and quality of life remains controversial. The lack of large randomized trials comparing intensive to low dose treatment or to just supportive care as well as the selection bias observed in smaller studies in AML patients over 60 years contribute significantly to the clinical dilemma. Despite recent improvements in supportive measures during cytotoxic therapy, elderly AML patients continue to exhibit lower remission rates, higher toxicity, more relapses and eventually a worse survival. The present analysis evaluates in a retrospective manner the outcome of 39 homogeneously treated AML patients >60yrs during a period of 44 months (Nov 2001 to Aug 2005). The protocol schedule included an initial course of mitoxantrone + cytarabine 3+5 (12mg/m2/d and 100mg/m2 q12h respectively) followed by a second abbreviated course of mitoxantrone + cytarabine 2+5, followed by a final course of idarubicin + cytarabine + thioguanine 2+7+7 (10mg/m2/d, 100mg/m2 q12h and 100mg/m2/d respectively). G-CSF at 5μg/Kg was added to all courses to accelerate hematopoietic recovery. Our patient population consisted of 22 cases of de novo AML and 17 cases of secondary AML (MDS 16, NHL 1) classified according to FAB as follows: M0 (5), M1 (4), M2 (19), M4 (3), M5 (2), M6 (5), hybrid-leukemia (1). Their median age was 70 yrs (range 63–80 yrs) and M/F ratio was 27/12. Cytogenetic analysis was performed in 33/39 cases: 6/33 cases failed to produce metaphases, 20/33 cases revealed standard risk abnormalities (seventeen normal karyotype, three trisomy 8) and 7/33 cases had poor risk abnormalities by MRC cytogenetic criteria. Leukocytosis >50X109/L was noted in 6/39 and leukopenia<5X109/L was noted in 19/39 patients. After a median observation period of 9 months (range 1–40) the following results are available: 19/39 (48,7%) patients entered CR (13 de novo, 7 secondary) post-course 2 and their median OS is 15,5 months (range 2–40). An additional 6/39 (15,3%) cases returned to a myelodysplastic phase without excess of blasts achieving thus partial hematological remission. The remaining 14/39 (35,8%) patients proved primary resistant and deceased after a median of 2,5 months (range 1–20) with one resistant patient surviving 20 months with on-going disease. Within the group of remitters 3/19 deceased from complications (MI, fungal infection, sepsis) before the next chemotherapy course. The remaining 11/19 remitters relapsed after a median of 7,5 months (range 1–30); nine of them deceased and two are alive as a result of salvage treatment. Finally 5/19 cases remain alive and disease-free (two interrupted after the second course). Conclusion: Combination chemotherapy with mitoxantrone and cytarabine is well-tolerated and reasonably effective in elderly AML patients fit enough to undergo chemotherapy regardless of karyotype and antecedent blood dyscrasia. With a total response rate of 64% (CR+PR) and an induction death rate of 5,1% (2/39), the current schedule deserves further evaluation in a larger AML population. Furthermore, our data validate the improvement in survival of those patients achieving CR as suggested by other studies.

Mitoxantrone and Cytarabine Combination in Untreated Elderly Patients with Acute Myeloid Leukemia (AML): A Retrospective Single-Centre Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4372-4372
Author(s):  
Theodore Marinakis ◽  
Vasilios Xanthopoulos ◽  
Athanasios Galanopoulos ◽  
Evrydiki Michalis ◽  
George Gortzolidis ◽  
...  
Keyword(s):  
De Novo ◽  
Normal Karyotype ◽  
Trisomy 8 ◽  
Total Response Rate ◽  
Elderly Aml ◽  
De Novo Aml ◽  
Improvement In Survival ◽  
Standard Risk

Abstract The value and exact type of intensive chemotherapy of unselected elderly AML patients in terms of overall survival (OS) and quality of life remains controversial. Despite recent improvements in supportive measures during cytotoxic therapy, elderly AML patients continue to exhibit lower remission rates, higher toxicity, more relapses and eventually a worse survival. The present analysis evaluates in a retrospective manner the outcome of 57 homogeneously treated AML patients >60yrs during a period of 70 months (Nov 2001 to Aug 2007). The protocol schedule included an initial course of mitoxantrone+ cytarabine 3+5 (12mg/m2/d and 100mg/m2 q12h respectively) followed by a second abbreviated course of mitoxantrone+ cytarabine 2+5, followed by a final course of idarubicin+cytarabine+ thioguanine 2+7+7 (10mg/m2/d, 100mg/m2 q12h and 100mg/m2/d respectively). G-CSF at 5μg/Kg was added to all courses to accelerate hematopoietic recovery. Our patient population consisted of 30 cases of de novo AML and 27 cases of secondary AML (MDS 26, NHL 1) classified according to FAB as follows: M0 (6), M1 (7), M2 (25), M4 (7), M5 (4), M6 (6), hybrid-leukemia (2). Their median age was 70 yrs (range 63–80, mean 70,3 yrs) and M/F ratio was 35/22. Cytogenetic analysis was performed in 52/57 cases: 6/57 cases failed to produce metaphases, 32 cases revealed standard risk abnormalities (twenty six normal karyotype, six trisomy 8) and 7/52 cases had poor risk abnormalities. Leukocytosis >50X109/L was noted in 12/57 and leukopenia<5X109/L was noted in 22/57 patients. After a median observation period of 9 months (range 1–70) the following results are available: 26/57(45,6%) patients entered CR (15 de novo, 11 secondary) post-course 2 and their median OS is 15 months (range 2–63). An additional 6/57(10,5%) cases returned to a myelodysplastic phase without excess of blasts achieving thus partial hematological remission. The remaining 25/57(43,8%) patients proved primary resistant and deceased after a median of 3 months (range 1–22). One resistant case survive in remission attained off protocol. Within the group of remitters 3/26 deceaced from complications (MI, fungal infection, sepsis) before the next chemotherapy course. The remaining 16/26 remitters relapsed after a median of 8 months (range 1–12,5); fourteen of them deceaced and two are alive for 63 and 16 months respectively (one as a result of salvage treatment and the other with on going disease). Finally 7/26 cases remain alive and disease-free. Due to the short follow up, median OS for the whole cohort was estimated to date at 7,5 months. Conclusion: Combination chemotherapy with mitoxantrone and cytarabine is well-tolerated and reasonably effective in elderly AML patients. With a total response rate of 56,1% (CR+PR) and an induction death rate of 3,4%(2/57), the current schedule deserves further evaluation in a larger AML population. Furthermore, our data validate the improvement in survival of those patients achieving CR as suggested by other studies.

Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4086-4094 ◽  
Author(s):  
Wen-Chien Chou ◽  
Huai-Hsuan Huang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Jih-Luh Tang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Human Leukocyte ◽  
Normal Karyotype ◽  
Trisomy 8 ◽  
Disease Evolution ◽  
Biological Features ◽  
Sex Comb ◽  
Acute Myeloid

Abstract Mutations in the additional sex comb-like 1 (ASXL1) gene were recently shown in various myeloid malignancies, but they have not been comprehensively investigated in acute myeloid leukemia (AML). In this study, we analyzed ASXL1 mutations in exon 12 in 501 adults with de novo AML. ASXL1 mutations were detected in 54 patients (10.8%), 8.9% among those with normal karyotype and 12.9% among those with abnormal cytogenetics. The mutation was closely associated with older age, male sex, isolated trisomy 8, RUNX1 mutation, and expression of human leukocyte antigen–DR and CD34, but inversely associated with t(15;17), complex cytogenetics, FLT3–internal tandem duplication, NPM1 mutations, WT1 mutations, and expression of CD33 and CD15. Patients with ASXL1 mutations had a shorter overall survival than patients without, but the mutation was not an independent adverse prognostic factor in multivariate analysis. Sequential analyses showed that the original ASXL1 mutations were lost at relapse and/or refractory status in 2 of the 6 relapsed ASXL1-mutated patients studied, whereas 2 of the 109 ASXL1-wild patients acquired a novel ASXL1 mutation at relapse. In conclusion, AML bearing ASXL1 mutations showed distinct clinical and biological features. The ASXL1 mutation status can change during disease evolution in a few patients.

Elderly Patients with De Novo Acute Myeloid Leukemia (AML): Prognostic Factors in 132 Cases.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4454-4454
Author(s):  
Elisa Luño ◽  
Carmen Sanzo ◽  
Fermin Jonte ◽  
Jose Maria Vicente ◽  
Dolores Carrera ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Elderly Patients ◽  
De Novo ◽  
Normal Karyotype ◽  
Independent Factor ◽  
Trisomy 8 ◽  
Short Survival ◽  
De Novo Aml ◽  
Chi Square Analysis ◽  
The Impact

Abstract The aim was to determine the predictive value of karyotype in 132 patients ≥65 years in a series of 404 cases with de novo AML. 61 females and 71 males with median age 71 years (65–91). FAB subtype were: 14 (10.6%) M0, 21 M1, 37 M2, 14 (10.6%) M3, 16 M4 (only one M4Eo), 21 M5, 8 M6, 1 M7 (vs 4% M0, 25,7% M3 in &lt;65 years p=0.004). The prognostic value of clinical, pathologic and cytogenetic factors was evaluated by Kaplan-Meier estimate and compared by log-rank, Breslow and Tarone test, for overall survival (OS) and continuous complete remission (CCR). Chi-square analysis for comparisons of remission rates were. The impact of prognostic factors was studied using Cox regression model. p≤0.01, M=median, m=months. Cytogenetic abnormalities were seen in 62.1% of cases including: 32 (24,2%) complex abnormalities, 18 of them with &gt;5 aberrations (vs 7,3% in &lt;65 years p&lt;0.001), twelve (9,1%) t(15;17), 7 trisomy 8, 3 trisomy 21, 3 trisomy 11, 3 del(7q), 2 t(8;21), 2 t(9;22), 2 del(5q), two 3q21q26 rearrangement, one inv h (16), one 11q rearrangement, one monosomy 7 and 8 with other abnormalities. One normal karyotype had FLT3 and NPM1 mutations. Karyotype was classified by SWOG and MRC classification. 21.2% showed trilineage myelodysplasia (TMDS) (vs 10% in &lt;65 years p=0.003). 80 patients received intensive chemotherapy (11 with AML-M3 also received ATRA). Only 53.8%(43/80) achieved CR(vs 78 % in &lt;65 years p&lt;0.001) and this was lowest in complex karyotype (13.3%).The 5-year OS and CCR probability was: 6,2% (M=2.9 m) and 13,8% (M=1.5 m).The longest OS was for t(15;17) with 41,7% surviving at 5 years (M=10.0 m); normal karyotypes survive 2,28% and other abnormalities had very short survival (p&lt;0.0001). Patients with complex karyotypes survive 0% at 17 months and all had relapsed at 5,3. Probability of relapse in t (15;17) was 51.31 % at 5 years (M 12,30), and this was higher in normal karyotype (93,4%), trisomy 8 (100%) and other abnormalities (100%) (p=0.0008). A longer OS was seen in patients with leucocytes ≤ 10×109/L (p=0.0006), subtype M3 (p=0.009)/t(15;17) (p&lt;0.0001) who received ATRA (p=0.0001) and without TMDS (p=0.0043). FAB subtypes distinct of M3 (p=0.0046), age adapted chemotherapy treatment (p=0.0004) and complex karyotypes (p=0.0007) were unfavourable prognostic factors for CCR. The survival of cytogenetic groups according SWOG and MCR was significantly different (p=0.0005, p =0.0021 for OS; p&lt;0.0001, p=0.0001 for CCR). Multivariate analysis showed that karyotype, TMDS and leucocytes are independent factor for OS. The higher risk of dead is for unfavourable (OR 2.94 p=0,008) and unknown (OR 2,52 p=0,03) cytogenetic SWOG groups. Only unfavourable SWOG karyotypes and chemotherapy without ATRA are independent factor for relapse risk. The elderly novo AML has a similar clinical-biological profile that the secondary AML, because of high frequency in undifferentiated subtypes, frequent TMDS, high percentage of complex abnormalities and poor CR, CCR and OS. This matter suggest that their aetiology is probably a lengthy exposure to environmental toxins. That’s the reason because it’s essential the cytogenetic study to decide induction chemotherapy or palliative support. Elderly patients with de novo AML which shown unfavourable SWOG abnormalities, failure to achieve CR, relapse promptly and have short survival. In this age group, today, only therapy designed to target specific molecular rearrangements has good prognostic.

Methylation of a Single CpG in the GADD45A Proximal Promoter Is Associated with Poor Survival in Acute Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3540-3540
Author(s):  
Richard J D'Andrea ◽  
Michelle Perugini ◽  
Chung H Kok ◽  
Diana Salerno ◽  
Silke Danner ◽  
...  
Keyword(s):  
Median Survival ◽  
De Novo ◽  
Independent Predictor ◽  
Normal Karyotype ◽  
The Elderly ◽  
Cytotoxic Agents ◽  
Proximal Promoter ◽  
Poor Survival ◽  
De Novo Aml ◽  
Methylating Agents

Abstract Abstract 3540 Background: GADD45A is a tumor suppressor gene that plays cell-type dependent roles in cellular stress, coordinating DNA repair and de-methylation, cell cycle arrest, and pro-apoptotic or pro-survival responses. GADD45A expression is normally rapidly induced in response to radiation and cytotoxic drugs1 and ectopic expression of GADD45A in the M1 leukemic cell line sensitises cells to stress-induced apoptosis in response to a range of genotoxic agents.2 Silencing of GADD45A by promoter methylation is a hallmark of many tumors,3–5 however to date there have been no investigations to determine whether this is associated with response to therapy. In AML, we have shown GADD45A expression is broadly down-regulated6 and here we investigate the mechanism of GADD45A repression in AML and its clinical significance. METHODS: We analysed 131 diagnostic bone marrow mononuclear cell samples from a retrospective cohort of patients with de novo AML. 93 of these patients were treated with induction chemotherapy. Patients 60 years or under were treated with chemotherapy regimens containing idarubicin and high dose cytarabine, and patients older than 60 received idarubicin and standard dose cytarabine. We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Sequenom MassARRAY) to analyze methylation of 4 GADD45A promoter CpG dinucleotides previously shown to be associated with silencing of GADD45A in breast and prostate cancer.4,5 We determined association of CpG hyper-methylation with outcome in our treated patient cohort. For AML cells with GADD45A hyper-methylation, and for those with normal levels of GADD45A promoter methylation, we also determined the response to cytotoxic agents in vitro in the presence and absence of hypo-methylating agents. RESULTS: We observed hyper-methylation of the 4 CpG residues in the proximal promoter of GADD45A in 49 of 131 (37%) de novo AML patients and in 6 AML cell lines. Multivariable analysis showed that methylation of a single CpG (CpG1) was an independent predictor of poor survival in AML overall (median survival 281 days versus 794 days, HR 2.25, p=0.009), in normal karyotype AML (NK-AML) (median survival of 281 versus 793 days, HR 5.77, p=0.03, >250 days), and in the elderly patient group (>60 years, median survival of 218 versus 392 days, HR 2.64, p=0.03)(see Figure 1). Additionally, treatment of AML cell lines and patient blasts with decitabine resulted in selective induction of GADD45A mRNA in samples with GADD45A hyper-methylation, and this was associated with increased sensitivity to daunorubicin. CONCLUSIONS: DNA methylation of the GADD45A proximal promoter is an independent predictor of poor outcome particularly in AML patients with normal karyotype and in the elderly group. Our biological data shows that induction of GADD45A mRNA expression with decitabine in hyper-methylated samples is associated with increased response to cytotoxic agents. Thus GADD45A promoter CpG methylation represents a new biomarker that may provide prognostic information in the heterogeneous NK-AML group, and in elderly patients. Given that recent trials are combining Azacitidine with chemotherapy and other agents for initial induction treatment of AML9, this may represent a marker to help define patients that will benefit from this approach. Elderly patients with GADD45A hyper-methylation may benefit from treatment with hypo-methylating agents which are associated with less toxicity (see Refs 7,8). Disclosures: Wei: Celgene: Honoraria, Research Funding.

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