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.

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.

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.

ETV6 Rearrangements Are Recurrent Genetic Events In Myeloid Malignancies and In AML Are Associated with NPM1- and RUNX1-Mutations and An Intermediate Prognosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2758-2758
Author(s):  
Claudia Haferlach ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
Torsten Haferlach
Keyword(s):  
De Novo ◽  
Normal Karyotype ◽  
Employment Equity ◽  
Childhood All ◽  
Myeloid Malignancies ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Diagnostic Work ◽  
Work Up

Abstract Abstract 2758 Introduction: The ETV6 gene (formerly TEL) is located in the chromosomal band 12p13 and is a frequent target of deletions and chromosomal translocations in both myeloid and lymphoid leukemias. In ALL the most frequent partner gene of ETV6 is RUNX1. ALL with ETV6-RUNX1 fusions are observed in 20% of childhood ALL and are associated with favorable outcome. In contrast ETV6 rearrangements are less frequent and not well described in myeloid malignancies. Therefore, the aim of this study was to analyze ETV6 rearrangements in myeloid malignancies with respect to frequency, partner genes and impact on prognosis. Patients/Methods: 55 cases with ETV6 rearrangements were identified in a total cohort of 9,550 cases (0.5%) with myeloid malignancies (de novo AML: n=3,090, s-AML: 486, t-AML: 222, MDS: n=3,375, MDS/MPN overlap: n=210, CMML: n=447, MPN: n=1,720) which had been sent to our laboratory between 08/2005 and 07/2010 for diagnostic work-up. In all cases chromosome banding analysis was performed and in cases with abnormalities involving 12p13 FISH was carried out in addition to verify the ETV6 rearrangement. Results: ETV6 rearrangements were observed in 31 patients with de novo AML (1.0% of investigated cases), 8 with s-AML (1.7%), 5 with t-AML (2.3%), 6 with MDS (0.2%) and 5 with MPN (0.3%). No ETV6 rearrangements were detected in the cohorts of MDS/MPN or CMML. ETV6 rearrangements were significantly more frequent in s-AML and t-AML as compared to de novo AML (p<0.001). Median age in AML was 59.9 years. In 15 cases with de novo AML FAB-subtypes were available: M0: n=8, M1: n=4, M2: n=1, M4: n=1, and M7: n=1. Thus, ETV6 rearrangements are closely related to immature AML subtypes. In 25/55 cases (45.5%) the ETV6 rearrangement was the sole abnormality. Recurrent additional abnormalities were 7q-/-7 in 10 cases and del(5q) in 8 cases. 36 different partners of ETV6 were observed, recurrent partners were located on 3q26 (EVI1, n=11), 5q33 (PDGFRB, n=4), 22q12 (n=3), 2q31 (n=2), 5q31 (ACSL6, n=2), 12p12 (n=2), 17q11 (n=2). Molecular analysis was performed in addition in AML with ETV6 rearrangements for mutations in NPM1 (n=26 investigated), FLT3-ITD (n=33), FLT3-TKD (n=11), MLL-PTD (n=25) and RUNX1 (n=7). NPM1-mutations were observed in 5 cases (19.2%), FLT3-ITD in 3 cases (9.1%), FLT3-TKD in 2 cases (18.2%), MLL-PTD in 1 case (4%) and RUNX1 mutations in 4 cases (57.1%), respectively. Clinical follow-up data was available of 47 cases. No differences in overall survival (OS) and event-free survival (EFS) were observed in cases with ETV6 rearrangement whether or not additional cytogenetic abnormalities or 7q-/-7 or del(5q) were present. Next 30 de novo AML with ETV6 rearrangement were compared to 819 AML without ETV6 rearrangement. Based on cytogenetics cases were assigned into 9 subgroups: 1) t(15;17)(q22;q21), n=48; 2) t(8;21)(q22;q22), n=29; 3) inv(16)(p13q22)/t(16;16)(p13;q22), n=19; 4) 11q23/MLL abnormalities, n=28; 5) inv(3)(q21q26)/t(3;3)(q21;q26), n=6; 6) normal karyotype, n=424; 7) complex karyotype, n=71; 8) other abnormalities, n=194 and 9) ETV6 rearrangements, n=30. Median OS was not reached for groups 1, 2, 3, 4, and 6 and was 10.6 mo, 11.8 mo, 32.2 and 26.3 mo for groups 5, 7, 8, and 9 respectively. OS at 2 yrs was 95.6%, 96.3%, 76.6%, 64.9%, 26.7%, 63.3%, 23.9%, 58.5% and 60.1% for groups 1–9, respectively. The respective data for median EFS were: not reached for groups 1 and 2 and 15.9 mo, 13.5 mo, 5.1 mo, 16.6 mo, 7.5 mo, 12.5 mo and 14.0 mo for groups 3–9, respectively. Conclusions: ETV6 rearrangements are rare in myeloid malignancies. ETV6 is rearranged with a large variety of partner genes. The highest frequency of ETV6 rearrangements was observed in s-AML and t-AML. OS and EFS of AML with ETV6 rearrangements are comparable to AML with normal karyotype. Thus, the detection of ETV6 rearrangements is associated with in intermediate prognosis. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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.

Cooperating Molecular Mutations in AML1/RUNX1 Mutated AML Differ Dependent on the Cytogenetic Subgroup.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 365-365
Author(s):  
Susanne Schnittger ◽  
Frank Dicker ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
Claudia Haferlach
Keyword(s):  
De Novo ◽  
Normal Karyotype ◽  
Trisomy 13 ◽  
Nras Mutation ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Additional Mutation ◽  
Specific Subgroup ◽  
De Novo Aml ◽  
Highly Correlated

Abstract Certain mutations and chromosome aberrations have been shown to cooperate in AML leukemogenesis e.g. t(15;17) + FLT3 mutations, t(8;21) + KITD816 mutations, TP53 + complex aberrant karyotype. Previously AML1/RUNX1 mutations were associated with activating mutations e.g. in FLT3 and NRAS. We now performed a detailed analysis focused on distinct cytogenetic subgroups. A total of 120 selected AML with normal karyotype or recurrent aberrations were analyzed: normal karyotype (NK) (n=43); monosomy 7 (n=32), trisomy 8 (n=10), trisomy 13 (n=14), trisomy 21 (n=9), inv(3)/t(3;3) AML (n=12). Of these 105 were de novo, 7 had t-AML after previous chemotherapy (1 with NK, 4 with −7, 1 with +8, 1 inv(3)) and 8 had sAML after MDS (1 NK, 6 with −7, 1 with inv(3)). RUNX1 mutations were detected in cases with NK: 5/43 (11.6%); −7: 10/32 (31%); +8: 2/10 (20%); +13: 14/14 (100%); +21: 5/9 (55.6%), and inv(3)/t(3;3): 2/12 (12%). Thus, the subgroup with the highest RUNX1 mutation rate was +13 followed by +21. All cases were also analysed for FLT3-length mutations (FLT3-LM), FLT3-TKD mutations, MLL-PTD, NRAS, NPM1 and 38 in addition for CEBPA. NPM1mut and CEBPAmut were found to be nearly mutually exclusive of RUNX1mut. Further analysis was done for subgroups. NK subgroup: In 2 of 5 (40%) RUNX1mut AML with NK a FLT3-LM, in 2 a MLL-PTD, and 1 an NRAS mutation was detected. Thus within the 5 RUNXmut NK-AML a cooperating mutation was detected in all cases. −7 subgroup: No additional mutation was detected in the 10 RUNX1mut cases with −7. In contrast in RUNX1 unmutated cases (RUNX1wt) with −7 1/21 had FLT3-LM, 2/21 (9.5%) CEBPAmut, and 7/20 (35%) an NRASmut. + 8 subgroup: In 2 RUNXmut cases with +8 no further mutation was detected. In contrast 2 of the RUNXwt with +8 had an FLT3-LM, 3 a NPM1mut and 2 a NRASmut. +13 subgroup: All cases with +13 were RUNX1mut and 2/14 (14.3%) had a FLT3-LM and 1/14 (7.1%) a MLL-PTD. In this specific subgroup a 4-fold-elevated FLT3 expression was suggesting to be a specific cooperating event. +21 subgroup: All 5 RUNXmut with +21 had an additional aberration, 4 (80%) had FLT3-LM and 1 NPM1mut. Inv(3) subgroup: In both RUNX1mut inv(3) cases no additional mutation was found. In contrast 3/9 RUNX1wt cases with inv(3)/t(3;3) were NRAS mutated. Overall, additional mutations in RUNX1 mutated AML are very frequent in subgroups with NK and +21 (100%), unfrequent in +13 (21%) and absent in others (−7, +8, inv(3)/t(3;3)). In total (except +13, where no RUNX1wt cases were available), the frequency of additional mutations was higher in the RUNX1wtcases (41.6% vs. 87.8%) This is in contrast to previous reports that suggested that additional activating mutation in RUNX1mut AML are frequent. In contrast we found a high incidence of NRASmut in inv(3) (33%), −7 (35%), +8 (29%) and normal karyotype (14.3%) in cases with RUNX1wt. Monosomy 7 + RUNX1mut + NRASmut previously has been highly correlated to therapy related AML and AML after MDS. In our cohort with predominantely de novo AML we found a high correlation of RUNX1mut with −7 and a high correlation of −7 with NRAS, but no association of RUNX1mut with NRASmut. In addition, FLT3-LM has been highly correlated to AML1mut. We found this correlation only in cases with +21. In conclusion, FLT3-LM and NRAS mutations were detected as frequent cooperating mutations in RUNX1mut AML with NK and +21. No mutation cooperating with RUNXmut was detected in −7, +8, +13, and inv(3)/t(3;3). Here alternative mechanisms may drive leukemogenesis e.g. overexpression of FLT3 in +13 or dosage effects due to monosomies or trisomies.

scholarly journals Integrated Genomic Analysis Identifies UBTF Tandem Duplications As a Subtype-Defining Lesion in Pediatric Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 2) ◽  
pp. LBA-4-LBA-4
Author(s):  
Masayuki Umeda ◽  
Jing Ma ◽  
Benjamin J. Huang ◽  
Kohei Hagiwara ◽  
Tamara Westover ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Screening Method ◽  
Normal Karyotype ◽  
Rna Seq ◽  
Trisomy 8 ◽  
De Novo Aml ◽  
Pediatric Aml ◽  
Tandem Duplications

Abstract Children with acute myeloid leukemia (AML) have a dismal prognosis due to a high relapse rate; however, the molecular basis leading to relapsed pediatric AML has not yet been fully characterized. To define the spectrum of alterations common at relapse, we performed integrated profiling of 136 relapsed pediatric AML cases with RNA sequencing (RNA-seq), whole-genome sequencing, and target-capture sequencing. In addition to well-characterized fusion oncoproteins, such as those involving KMT2A (n=36, 26.5%) or NUP98 (n=18, 13.2%), we also identified somatic mutations in UBTF (upstream binding transcription factor) in 12 of 136 cases (8.8%) of this relapsed cohort. Somatic alterations of the UBTF gene, which encodes a nucleolar protein that is a component of the RNA Pol I pre-initiation complex to ribosomal DNA promoters, have rarely been observed in AML. In our cohort, all alterations can be described as heterozygous in-frame exon 13 tandem duplications (UBTF-TD), either at the 3' end of exon 13 of UBTF or of the entire exon 13 (Fig. A). As we noticed limited detection in our pipeline as a result of complex secondary indels alongside the duplications, we established a soft-clipped read-based screening method to detect UBTF-TD more efficiently. Applying the screening to RNA-seq data of 417 additional pediatric AMLs from previous studies and our clinical service, we identified 15 additional UBTF-TDs, many of which have not been previously reported. At the amino acid level, UBTF-TDs caused amino acid insertions of variable sizes (15-181 amino acids), duplicating a portion of high mobility group domain 4 (HMG4), which includes short leucine-rich sequences. UBTF-TD AMLs commonly occurred in early adolescence (median age: 12.6, range: 2.4-19.6), and 19 of the total 27 cases had either normal karyotype (n=12) or trisomy 8 (n=7). UBTF-TD is mutually exclusive from other recurrent fusion oncoproteins, such as NUP98 and KMT2A rearrangements (Fig. B), but frequently occurred with FLT3-ITD (44.4%) or WT1 mutations (40.7%). The median variant allele fraction (VAF) of the UBTF-TD was 48.0% (range: 9.7-66.7%). In four cases with data at multiple disease time points, the identical UBTF-TDs were present at high allele fractions at all time points, suggesting that UBTF-TD is a clonal alteration. tSNE analysis of the transcriptome dataset showed that UBTF-TD AMLs share a similar expression pattern with NPM1 mutant and NUP98-NSD1 AML subtypes, including NKX2-3 and HOXB cluster genes (Fig. C) . Altogether, these findings suggest that UBTF-TD is a unique subtype of pediatric AML. To address the impact of UBTF-TD expression in primary hematopoietic cells, we introduced UBTF-TD and UBTF wildtype expression vectors into cord blood CD34+ cells via lentiviral transduction. UBTF-TD expression promotes colony-forming activity and cell growth, yielding cells with a persistent blast-like morphology (Fig. D). Further, transcriptional profiling of these cells demonstrated expression of HOXB genes and NKX2-3, similar to UBTF-TD AMLs in patients, indicating that UBTF-TD is sufficient to induce the leukemic phenotype. To investigate the prevalence of UBTF-TDs in larger de novo AML cohorts, we applied the above UBTF-TD screening method to the available de novo AML cohorts of TCGA (n=151, adult), BeatAML (n=220, pediatric and adult), and AAML1031 (n=1035, pediatric). We identified UBTF-TDs in 4.3% (45/1035) of the pediatric AAML1031 cohort, while the alteration is less common (0.9%: 3/329, p=0.002) in the adult AML cohorts (Fig. E). In the AAML1031 cohort, UBTF-TDs remain mutually exclusive with known molecular subtypes of AML and commonly occur with FLT3-ITD (66.7%) and WT1 (40.0%) mutations and either normal karyotype or trisomy 8. The presence of UBTF-TDs in the AAML1031 cohort is associated with a poor outcome (Fig. F, median overall survival, 2.3 years) and MRD positivity; multivariate analysis revealed that UBTF-TD and WT1 are independent risk factors for overall survival within FLT3-ITD+ AMLs. In conclusion, we demonstrate UBTF-TD defines a unique subtype of AMLs that previously lacked a clear oncogenic driver. While independent of subtype-defining oncogenic fusions, UBTF-TD AMLs are associated with FLT3-ITD and WT1 mutations, adolescent age, and poor outcomes. These alterations have been under-recognized by standard bioinformatic approaches yet will be critical for future risk-stratification of pediatric AML. Figure 1 Figure 1. Disclosures Iacobucci: Amgen: Honoraria; Mission Bio: Honoraria. Miller: Johnson & Johnson's Janssen: Current Employment. Mullighan: Pfizer: Research Funding; Illumina: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company.

RUNX1 Mutations Can Be Found in 34% of De Novo AML with Normal Karyotype or Single Chromosomal Imbalances and Are Associated with Good Prognosis but Turn to Unfavourable Outcome If Further Cytogenetic or Molecular Mutations Are Acquired

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 146-146 ◽  
Author(s):  
Susanne Schnittger ◽  
Frank Dicker ◽  
Nicole Wendland ◽  
Tamara Weiss ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
De Novo ◽  
Normal Karyotype ◽  
Combination Group ◽  
Npm1 Mutation ◽  
Chromosomal Imbalances ◽  
Mutational Status ◽  
De Novo Aml ◽  
Molecular Aberrations ◽  
Genetic Events

Abstract Mutations in the DNA-binding domain, the Runt homology domain of the AML1/RUNX1 gene have been described mostly in therapy-related myelodysplastic syndrome, in therapy-related AML as well as in AML after MDS (s-AML). Recently we have shown that RUNX1 mutations also can be found in de novo AML with normal karyotype and single or simple chromosomal imbalances. To further address the importance of RUNX1 in these kind of AML we analyzed the RUNX1 mutational status in a selected cohort of 389 de novo AML with: normal karyotype (NK): n=221, +8 (n=40), +11 (n=9), +13 (n=26), +21 (n=14), rare trisomies (n=11), −7/7q- (n=22), 5q- (n=3), 9q- (n=6), 20q- (n=4), or any combinations of these (n=33). Median age was 67.5 years (range: 20.4–88.2), male:female ratio was 216:173. In this selected cohort 134/389 mutations (34.4%) were detected, showing that RUNX1 is one of the most frequently mutated genes in certain de novo AML. The mutations were not randomly distributed according to FAB subtypes: AML M0 (58.3%, n=36), M1 (32.1%, n=84), M2 (34%, n=126), M4 (20.5%, n=39), but only 10.5% in M6 (n=19) and never detected in M5 (n=12). Also within the single different cytogenetic groups the RUNX1 mutations (RUNX1mut) revealed different frequencies: NK: 28.5%; +8: 35%, +11: 44 %, +13: 96%, +21: 56%, −7/7q-: 27%, 20q-: 75% and 23.5% in the combination group. The patients (pts) were also analyzed for CEBPA, FLT3ITD, FLT3TKD, JAK2, MLLPTD, NPM1 and NRAS. 49/134 RUNX1mut cases (36.6%) revealed at least one of these additional mutations. CEBPA and JAK2 mutations were never detected in combination with RUNX1. An NPM1 mutation was observed in one RUNX1mut pts with +21. The mutation found most frequently together with RUNX1 was MLLPTD that was detected in 28/134 pts (20.9%) followed by FLT3-ITD that was detected in 24/134 cases (17.9%). The distribution of additional mutations in the different cytogenetic groups was heterogeneous. Of the 63 pts with RUNX1mut NK 20 had MLLPTD (31.7%) and 13 had FLT3ITD (20.6%). In 14 pts with +8 and RUNX1mut no MLLPTD but 3 (21.4%) FLT3ITD were detected, in addition to one case with NRAS. Two of the 4 RUNX1mut +11 pts had MLL-PTD. The 8 cases with RUNX1 mut and +21 had a very high additional mutational rate with 2 MLLPTD and 6 FLT3ITD and 1 FLT3TKD, 1 NPM1 and 1 NRAS (3 double mutated cases). In contrast only 3 of 25 (12%) RUNX1mut pts with +13 had additional mutations (2 MLLPTD and 1 FLT3ITD). Similarily the −7/7q- group with RUNX1mut (n=6) revealed no additional markers. This finding suggest that some chromosomal aberrations are biologically “ more potent” than others and require less additional molecular events to cause overt leukemia. Clinical follow up data were available for 213 pts (74 RUNX1mut and 139 RUNXunmut). A direct comparison of these two groups showed a trend to shorter overall survival (OS) in the RUNX1mut pts (p=0.094) and a significantly shorter event free survival (EFS) (p=0.008). A subanalysis for RUNX1 and MLLPTD showed worse EFS for all three groups (RUNX1+/MLLPTD+ (n=21), RUNX1+/MLLPTD− (n=53), RUNX1−/MLLPTD+ (n=18) compared to the unmutated group (n=121) (p=0.064, 0.009, 0.081). Similar results were obtained for the combination of RUNX1/FLT3ITD with (RUNX1+/FLT3ITD+ (n=15), RUNX1+/FLT3ITD− (n=59), RUNX1−/FLT3ITD+ (n=24)) compared to the unmutated group (n=114) (p=0.006, 0.033, 0.223). Subsequently an analysis in the NK group was performed (25 RUNX1mut, 82 RUNX1wt). Surprisingly, RUNX1mut AML were not worse than the RUNX1unmut AML. In a subanalysis taking MLL-PTD and FLT3-ITD into account there were only 12 sole RUNX1mut pts and all revealed no event for OS and EFS (median follow up time: 196 days). In a further analysis taking cytogenetic as well as molecular aberrations into account it could be shown that RUNX1mut without any of these further aberrations have no event and are favourable compared to pts with single aberrations (p=0.063) and even more favourable compared to those with two or more cytogenetic or molecular aberrations (p=0.031). A multivariate analysis including age, cytogenetics, molecular genetics, and additional further genetic events shows that only age (p=0.027) and additional genetic events (p=0.005) are independent prognostic markers in this analysis. In conclusion, RUNX1 mutations are frequent in AML with NK or single chromosomal imbalaces, tend to go together with additional mutations which differ dependent on underlying cytogenetics. cooperate most frequently with MLL-PTD 4) per se are prognostically favourable as single genetic aberration but deteriorate by acquisition of other cytogenetic and/or molecular aberrations.

scholarly journals Health-Related Quality of Life following Cytoreductive Radical Prostatectomy in Patients with de-novo Oligometastatic Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5636
Author(s):  
Michael Chaloupka ◽  
Lina Stoermer ◽  
Maria Apfelbeck ◽  
Alexander Buchner ◽  
Vera Wenter ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
De Novo ◽  
Health Related Quality ◽  
Significant Difference ◽  
Related Quality ◽  
Health Related

(1) Background: local treatment of the primary tumor has become a valid therapeutic option in de-novo oligo-metastatic prostate cancer (PC). However, evidence regarding radical prostatectomy (RP) in this setting is still subpar, and the effect of cytoreductive RP on postoperative health-related quality of life (HRQOL) is still unclear. (2) Methods: for the current study, patients with de-novo oligo-metastatic PC (cM1-oligo), defined as ≤5 bone lesions in the preoperative staging, were included, and matched cohorts using the variables age, body-mass index (BMI), and pT-stage were generated. Patient-reported outcome measures (PROMS) were assessed pre- and postoperatively using the validated EORTC-QLQ-C30, IIEF-5, and ICIQ-SF questionnaires. The primary endpoint for univariate and multivariable analysis was good general HRQOL defined by previously validated cut-off values. (3) Results: in total, 1268 patients (n = 84 (7%) cM1-oligo) underwent RP between 2012 and 2020 at one tertiary care center. A matched cohort of 411 patients (n = 79 with oligo-metastatic bone disease (cM1-oligo) and n = 332 patients without clinical indication of metastatic disease (cM0)) was created. The median follow-up was 25mo. There was no significant difference in good general HRQOL rates between cM1-oligo-patients and cM0-patients before RP (45.6% vs. 55.2%, p = 0.186), and at time of follow-up (44% vs. 56%, p = 0.811). Global health status (GHS) worsened significantly in cM0-patients compared to baseline (−5, p = 0.001), whereas GHS did not change significantly in cM1-oligo-patients (+3.2, p = 0.381). In multivariate analysis stratified for good erectile function (IIEF5 > 18; OR 5.722, 95% CI 1.89–17.36, p = 0.002) and continence recovery (OR 1.671, 95% CI 1.03–2.70, p = 0.036), cM1-oligo was not an independent predictive feature for general HRQOL (OR 0.821, 95% CI 0.44–1.53, p = 0.536). (4) Conclusions: in this large contemporary retrospective analysis, we observed no significant difference in HRQOL in patients with the oligometastatic bone disease after cytoreductive radical prostatectomy, when compared to patients with localized disease at time of surgery.

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.

Retrospective Comparison of Using or Not Using Donor Lymphocyte Transfusion in the Treatment of Hematological Relapse after Allogeneic Stem Cell Transplantation in 489 Adults with Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 298-298
Author(s):  
Christoph Schmid ◽  
Myriam Labopin ◽  
Juergen Finke ◽  
Gerhard Ehninger ◽  
Olle Ringden ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
De Novo ◽  
Patient Age ◽  
Entire Cohort ◽  
Post Transplant ◽  
Patient Âgé ◽  
Retrospective Comparison ◽  
De Novo Aml

Abstract Relapsed AML after allogeneic SCT has a poor prognosis. So far, no standard therapy could be defined. Donor lymphocyte transfusion (DLT) has been effective in a minority, however, no data is available to identify patients who will benefit from the procedure. Neither, the outcome of patients treated with or without DLT have been compared. We retrospectively evaluated overall survival (OS) of 489 adults with de novo AML in hematological relapse after SCT, receiving DLT (n=190) or not (n=299). DLT and noDLTgroups were well balanced in terms of patient age (median:37y in both groups), donor age, cytogenetics (good:5vs7%, intermediate:83vs79%, poor:12%vs14%), WBC at diagnosis, donor type (geno-id:71vs72%, MUD:18% both, mismatched:11vs10%), status at transplantation (CR1:38vs41%, CR2:13vs15%, advanced:49vs44%), conditioning, source of stem cells, and time from transplant to relapse (5vs4.5 months). However, DLT patients had a median of 39% BM blasts, as compared to 54% for the noDLT group (p=0.03). Follow-up was 32 and 30 months. Within the DLT group, chemotherapy was additionally given in 130 cases. Nevertheless, only 33% of patients received DLT in CR or aplasia, 67% had measurable disease. AGvHD developed in 41% of patients following DLT. CR and PR were achieved in 31.1% and 4.8% of DLT patients. In a multivariate analysis, younger patient age (&lt;36 years) (HR=1.53,p=0.02) and a longer interval (&gt; 5 months) from transplant to relapse (HR=7.74,p=0.002) were associated with better OS after DLT. When comparing the outcome of patients receiving or not DLT, OS at 2 years was 10±1% for the entire cohort, 18±3% for DLT and 6±1% for noDLT (p&lt;.0001). In a multivariate analysis, use of DLT (HR=2.11,p&lt;0.0001); recipient’s age&lt;36 y (HR=1.69, p&lt;0.001); longer interval (&gt;5 months) from transplant to relapse (HR=2.40, p&lt;0.0001) and number of BM blasts (&lt;48%) at relapse (HR=1.56,p=0.002) were favorable for OS. In this retrospective analysis the results suggest that DLT may be of advantage in the treatment of AML relapse post transplant, at least in younger patients with a longer post transplant remission and relapsing with smaller amounts of blasts in BM. However, patients receiving DLT might represent a positive selection among all relapsed cases, since a considerable number from the noDLT cohort had died too early to proceed to DLT. An intetion-to-treat analysis and further prospective studies should investigate the role of DLT and other approaches, such as second reduced intensity SCT.

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