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.

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.

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.

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.

Bortezomib+Chemotherapy Based Salvage Combinations in Refractory AML, Preliminary Results

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4000-4000
Author(s):  
Miklos Udvardy ◽  
Attila Kiss ◽  
Bela Telek ◽  
Robert Szasz ◽  
Peter Batar ◽  
...  
Keyword(s):  
Cell Lines ◽  
De Novo ◽  
Case Reports ◽  
Fatal Outcome ◽  
Normal Karyotype ◽  
Secondary Aml ◽  
Poor Risk ◽  
Group 2 ◽  
De Novo Aml ◽  
Group 1

Abstract Bortezomib (Velcade) proved to be the standard element of refractory myeloma 2nd and 3rd line treatment, while many studies are suggesting excellent results in 1st line. Proteasome inhibition, the block of angiogenesis, modification of the NF-kappa-B system seems to be a challenging target in other malignant diseases, including refractory acute myeloid leukemia (AML), as well. In vitro data clearly support, that bortezomib exerts antiproliferative and pro-apoptotic effects in different AML cell-lines, along with human AML cell cultures, and moreover bortezomib was able to restore, or at least improve anthracyclin and possibly ARA-C sensitivity in different cell-lines (including AML). More recently, a Phase I trial showed bortezomib monotherapy efficient (only in few percents) in childhood refractory acute leukemia. Some case reports were shown at ASH 2007. We have tried bortezomib containing first or second line combinations in 27 (14 female, 13 male, mean age 57.6 years) patients with refractory or poor risk AML, in a small retrospective survey. The combinations were as follows: HAM or Flag-Ida, combined with bortezomib 1,3 mg pro sqm, day O and seven). The following groups were considered as refractory or poor risk AML: De novo AML, 2nd line: No response/remission to first line standard treatment (“3+7”), n=2 (Velcade- Flag-Ida treatment) De novo AML 1st line: bilineal or biphenotypic (flow-cytometry) n=2 (Velcade-Flag- Ida treatment) De novo AML with complex (numerical or more than 3 abnormalities) karyotype or normal karyotype with flt-3 TKD mutation, n=9, 1st line (Velcade-Flag-Ida n=6, Velcade- HAM protocol, n=3) Secondary AML or AML with evidence of previous more than 6 mo duration high grade MDS, n=14, 1st line: (Velcade-Flag-Ida n=9, Velcade-HAM n=5) RESULTS: Complete remission (CR) 12/27, partial remission (PR) 9/27, no remission 5/27, progression during treatment: 1/27.Best responses were seen in de novo cases. CR had been achieved in all patients of group 1 (two standard risk patients not responding to 3+7 protocol), and group 2 (biphenotypic, bilineal). The CR rate was quite appreciable in group 3, i.e. 6/9 (complex karyotype or normal karyotype with FLt-3 mutation – the response rate was excellent with flt-3 mutated cases). In group 4. (MDS, secondary AML) the results were less impressive. There were no major differences according to protocol (Flag-Ida or HAM) Allogeneous stem cell transplantation could have been performed in 1st CR in two patients (one from group 1. and another from group 2.). One of them died due to relapse, the other one is in CR since then. The combinations seem to be relatively safe. Induction related death rate was low (1 elderly patient acute thrombocytopenic bleeding with refractory MDS-AML). 5 other patients had severe neutropenic sepsis (2 with fatal outcome). Pulmonary syndrome, which may follow Velcade+ARA-C had not been documented. Other adverse events did not differ from the pattern observed with standard induction therapies.

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.

JAK2 Mutation Screening and Chromosome Analysis Are Necessary for a Comprehensive Diagnostic Work up in CMPD: A Study on 469 Cases.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4963-4963
Author(s):  
Susanne Schnittger ◽  
Torsten Haferlach ◽  
Petro E. Petrides ◽  
Wolfgang Kern ◽  
Claudia Schoch
Keyword(s):  
De Novo ◽  
Blast Crisis ◽  
Mutation Screening ◽  
Melting Curve ◽  
Therapy Response ◽  
Normal Karyotype ◽  
Chromosome Analysis ◽  
Molecular Monitoring ◽  
Jak2 Mutation ◽  
De Novo Aml

Abstract The diagnosis of BCR-ABL negative chronic myeloproliferative disorders (CMPD) is still a challenge for the morphologist and clinician, mainly because of overlapping phenotypes of essential thrombocythemia (ET), polycythemia vera (PV), idiopathic myelofibrosis (IMF) and non-malignant reactive phenotypes. Recently, a new mutation in JAK2 leading to V617F exchange in exon 12 was described in these entities. Therefore, we developed a rapid and easy LightCycler based melting curve assay and screened 469 patients with various malignancies for the respective JAK2 mutation using cDNA prepared from mononucleated cells. All cases tested positive were confirmed by sequencing and without any exception all mutations were G to T exchanges at nucleotide 1849. In total, 61 cases with PV were analysed. 56 (91.8%) were mutated (see table). A karyotype was available in 36 cases. Of the JAK2- cases 4 had normal karyotypes and one 20q-. Of the JAK2+ cases 21 had normal karyotype; four (7.1%) had +9, one +8, one +22, one 20q-, and three showed a complex aberrant karyotype. Of the 47 analyzed ET 26 (55%) were mutated. Cytogenetics was available in 20 cases (9 JAK2-, 11 JAK2+). All JAK2- cases all had normal karyotypes. Of the JAK2+ 10 had a normal karyotype and one a t(9;13)(p24;q22) involving the JAK2 locus. Of the 25 IMF cases 14 (56%) were mutated. Karyotype was available in 17 cases (7 JAK2-, 10 JAK2+). All 7 JAK2- had normal karyotype. Of the 10 JAK2+ 6 had normal karyotype and four were aberrant (+9:n=2; 20q-: n=2). In addition, 2/7 cases (28.6%) with CMML were JAK2+. Furthermore, we analysed 89 BCR-ABL negative MPS that were not further specified. V617F was detectable in 43 patients (48.3%). At next 128 AML were analyzed (84 novo AML, 11 t-AML after a previous malignancy, 15 secondary to MDS, and 16 secondary to MPS (PV:n=7, ET:n=5, OMF:n=2). No V617F was detected in all cases with t-AML and s-AML after MDS. In contrast, in de novo AML 6/84 (7.1%) were JAK2+, of which 4 were proven homozygous. Surprisingly, 4 of these six cases had a +9. In AML secondary to a previous CMPD 11/16 (68.8 %) were JAK2+. Of these 2 had +9, one a normal karyotype and 12 a complex aberrant karyotype. These data suggest that acquisition of +9 may lead to progress or blast crisis in JAK2 mutated MPS and supports the gain of function mechanism of the mutation. In conclusion, more than half of all BCR-ABL-negative MPS harbour a V617F mutation. This helps in the differential diagnosis of MPS versus reactive disorders. V617F is more frequently associated with aberrant karyotype than wildtype JAK2. In addition, there is an increasing level of aberrant cytogenetics and mutation rate with respect to incidence and status from ET&lt;IMF&lt;PV indicating that these diseases might be overlapping or even a continuum. It demonstrates that the present classification is artificial and a new classification of “JAK2” positive diseases may be more adequate. In addition, the same mutation was observed in most cases of AML secondary to CMPD. It was also found in few cases with de novo AML and correlated with +9. JAK2V617F is a new and promising target for therapy as well as for molecular monitoring of therapy response in CMPD. Distribution of JAK2 mutation in various malignancies ET IMF PV MPS* CMML de novo AML AML after MPS *not further specified total 47 25 61 89 7 84 16 mutated (n=) 26 14 56 43 2 6 11 mutated (% of all) 55.0 % 56.0 % 91.8 % 48.3 % 28.6 % 7.1 % 68.8 % homozygous (n=) 3 9 33 19 1 4 7 homozygous (% of all) 6.4 % 36.0 % 54.1 % 21.3 % 14.3 % 4.8 % 43.8 %

Attenuated Dose of Idarubicin for the Elderly De Novo Acute Myeloid Leukemia with Normal Karyotype.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4608-4608
Author(s):  
June-Won Cheong ◽  
Yuri Kim ◽  
Sun Young Park ◽  
In Hae Park ◽  
Jin Seok Kim ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
De Novo ◽  
Normal Karyotype ◽  
The Elderly ◽  
Remission Induction ◽  
Conventional Dose ◽  
The Difference ◽  
Group 2 ◽  
De Novo Aml ◽  
Group 1

Abstract The incidence of acute myeloid leukemia (AML) increases with age. Because of poor performance status, co-morbidity and treatment-related side effects, a conventional dose chemotherapy containing anthracyclins may be toxic to the majority of elderly patients. In contrast, the administration of suboptimal dose of myelosuppressive chemotherapy could lead to an unsuccessful clinical outcome including lower complete remission (CR) rate. To evaluate the effect of attenuated dose of idarubicin, compared to the standard dose, on the clinical outcome and chemotherapy-related complications, we analyze the consecutive 32 elderly de novo AML patients (range, 60 – 74 years) with normal karyotype. Eleven patients received one cycle of conventional-dose remission induction chemotherapy (idarubicin, 12 mg/m2/day on days 1–3 and cytarabine 100mg/m2/day on days 1–7) (Group 1) and 21 patients received attenuated-dose idarubicn (8 mg/m2/day on days 1–3) and cytarabine (100mg/m2/day on days 1–7) (Group 2). Six cases (54.5%) in Group 1 and 12 cases (57.1%) in Group 2 had CR. The difference of CR between the two groups was not significant (P = 0.59). The intervals from the chemotherapy-starting date to the date of CR documentation were not also different between two groups (median 31.5 days on Group 1 vs 27.0 days on Group 2) (P = 0.29). The median number of transfusion requirement during the induction therapy was not different in the red blood cells (10 units, each) and platelets (16.5 units in Group 1 vs 18.0 units in Group 2; P > 0.05). Thirty patients received the recombinant human granulocyte colony-stimulating factor (G-CSF) three days after termination of chemotherapy. The duration of G-CSF administration was not different between two groups (P = 0.86). However, the frequency of septicemia and septic shock after induction chemotherapy was statistically significantly higher in Group 1 (54.5% and 9.5%, respectively) compared to that in Group 2 (36.3% and 0.5%, respectively) (P < 0.01). We also observed a higher incidence of clinically-documented invasive fungal infection in Group 1 (45.5%) compared to Group 2 (15.0%), although the difference was not statistically significant (P = 0.095). The incidence of other regimen-related toxicities including renal dysfunction, hepatic dysfunction and heart failure was not different between two groups. Overall survival and disease-free survival also were not different between the groups. In conclusion, the attenuated dose of idarubicin can be recommended for the remission induction chemotherapy for the elderly de novo AML patients with normal karyotype since it is associated with lower incidence of sepsis and septic shock with comparable CR rate.

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