Older-age AML: Disease biology and dose response

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7058-7058
Author(s):  
T. Buchner ◽  
W. E. Berdel ◽  
C. Haferlach ◽  
T. Haferlach ◽  
S. Schnittger ◽  
...  
Keyword(s):  
Dose Response ◽  
De Novo ◽  
Older Age ◽  
High Dose ◽  
Flt3 Mutation ◽  
The Poor ◽  
Disease Biology ◽  
Age Related ◽  
De Novo Aml ◽  
Sequential Trials

7058 Background: In 2602 pts entering two sequential trials the 47% pts of 60+y compared to the younger pts achieved 55 vs 71% CR, 19 vs 41% OS and 77 vs 54% RR (relapse risk) at 3 years. While the trials addressed various options for both de-novo and secondary AML understanding the age related biology of AML required restriction to pts comparable in history, therapy and availability of risk factors. Methods: We therefore selected from the two trials pts with de-novo AML and known karyotype assigned to one of two different intensity induction regimens, either TAD-HAM (HAM, high-dose araC 3(age <60) and 1(age 60+) g/m2x6), or HAM-HAM. All pts received TAD consolidation and monthly reduced TAD maintenance. Results: In the 1284 selected pts the CR rate is 60% in pts of 60+y and 70% in those of 16 −<60y (p<.001), the OS is 23 vs 41% (log rank p<0.001) and the RR is 73 vs 50% (p<.001). There are advantages for younger pts in favorable (16 vs 7%) and unfavorable (18 vs 24%) karyotypes (p<.001) whereas WBC (p=.002) and LDH (p=.002) are lower in the older pts. Among normal karyotypes (52%) the favorable NPM mutation in absence of Flt3 mutation account for 33% of NPM/Flt3 combinations in older and 37% in younger pts (n.s.). The inferior CR, OS and RR in the older vs younger pts is seen in all prognostic subgroups. Thus, the OS at 3 years is 36 vs 62% in favorable (p=.001), 2 vs 14% in unfavorable karyotypes (p=.001), 25 vs 42% in low WBC (p<.001), 21 vs 38% in high WBC (p<.001), 23 vs 42% in low LDH (p<.001), 16 vs 38% in high LDH (p<.001), 30 vs 43% in low day 16 blasts (p<.001), 19 vs 38% in high day 16 blasts (p<.001) and even 50 vs 63% in pts with NPM+/Flt3- mutation (p=.020). In contrast, outcome does not vary by randomization for TAD-HAM vs HAM-HAM chemotherapy. Conclusions: The lack of dose response and the modest age related differences in defined risk profiles suggest hitherto unknown determinants of the poor outcome in older age AML across all subsets. These experiences may indicate the way toward novel experimental options instead of further escalation. No significant financial relationships to disclose.

Changes in the Hierarchy of Risk Factors with Older Age in De-Novo Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1977-1977
Author(s):  
Thomas Buchner ◽  
Wolfgang E. Berdel ◽  
Claudia Schoch ◽  
Torsten Haferlach ◽  
Hubert L. Serve ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Complete Remission ◽  
De Novo ◽  
Older Age ◽  
High Dose ◽  
Age Group ◽  
Risk Profiles ◽  
Age Related ◽  
De Novo Aml

Abstract After recent reports addressed prognostic factors and outcome in older age AML (Burnett et al. Blood106:162a,2005; Wheatley et al. Blood106:199a,2005; Appelbaum et al. Blood107:3481–5,2006; Farag et al. Blood108:63–73,2006) we evaluated 764 patients of 60–85 (median 66) years reduced to those with de-novo AML, known karyotype, and identical consolidation-maintenance chemotherapy, who were part of the 1992 and 1999 multicenter randomized trials by the German AMLCG (Buchner et al. J Clin Oncol21:4496–504,2003;24:2480–9,2006). 521 patients were 60 -< 70 (median 64) and 243 patients were 70–85 (median 73) years of age. 64% and 50% patients respectively went into complete remission, 24% and 29% remained with persistent AML, 12% and 21% succumbed to early and hypoplastic death (p<.001). The overall survival in the younger (60- < 70y) and older (70+) patients was at a median of 13 vs 6 months and 18% vs 8% survived at 5 years (p<.001). Once in complete remission, the remission duration was 14 vs 12 months (median) and equally 18% at 5 years; the relapse-free survival is 13 vs 11 months (median) and 14% vs 13% at 5 years. While all patients were randomized up-front for 2 versions of induction either by TAD-HAM (HAM, high-dose araC 1g/m2x6 and mitox 10mg/m2x3) or by HAM-HAM, response and survival did not differ between the two arms in neither age group. In contrast to response and survival between the younger (60-<70y) and older (70+y) age group corresponding differences in the risk profiles were missing. Thus, favorable/intermediate/unfavorable karyotypes accounted for 8% vs 4% / 67% vs 73% / and 25% vs 24% of patients (p=.073); WBC > 20.000/ccm was found in 40% vs 39% (p=.52); LDH > 700U/L was remarkably 26% vs 18% (p=.014), and the day 16 b.m. blasts ≥ 10% accounted for 41% and 41% of patients. Conclusion: Approximately 50% of patients 70 years of age or older benefit from standard or intensive chemotherapy by complete remission which continues after 1 year in about 50% of responders. The inferior overall survival in the patients of 70+ versus those of 60- < 70 years is mainly explained by more frequent early and hypoplastic death (21% vs 12%) (p=.0016) and death with persistent AML (26% vs 18%) (p=.0145); while death in remission (7% vs 6%), relapse rate (50% vs 53%) and death after relapse (21% vs 26%) did not show this trend. In contrast to the important differences in outcome, established risk factors such as cytogenetic groups, WBC, and early blast clearance show concordance between the two age groups. The even lower LDH may support assumptions of older age AML as a less proliferative disease (Appelbaum et al. Blood 107:3481–5,2006). Thus, the hierarchical risk profiles cannot predict the age related outcome beyond 60 years in patients with de-novo AML.

A Clinical Measure of DNA Methylation Predicts Outcome in De Novo AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2591-2591
Author(s):  
Marlise R. Luskin ◽  
Phyllis Gimotty ◽  
Catherine Smith ◽  
Alison Loren ◽  
Maria Figueroa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Board Of Directors ◽  
Prognostic Value ◽  
De Novo ◽  
Older Age ◽  
High Dose ◽  
Advisory Committees ◽  
Recurrent Mutations ◽  
The Mean ◽  
De Novo Aml

Abstract Background: Despite advances, the majority of patients (pts) with acute myeloid leukemia (AML) will die of their disease. Current genetics-based risk classification schemes inadequately predict outcome. We sought to determine if a novel methylation-based biomarker could enhance risk stratification in AML. Methods: Using a novel methylation assay (xMELP) validated for the clinical laboratory, we performed DNA methylation assessment at 17 previously identified prognostic loci to calculate a summary methylation statistic (M-score, Wertheim et al. Clin Chem 2015) for 166 pts with de novo AML treated at the University of Pennsylvania (UPENN). Targeted next-generation sequencing (NGS) of 33 hematologic malignancy-associated genes was performed for a 136 pt subset. The association of M-score with other prognostic variables and outcome [complete remission (CR) and overall survival (OS)] was evaluated. Median follow-up was 68.1 mos (range 1.4-150.2) among 38 survivors and 10.5 mos (range 0.1-95.2) among those (n=128) deceased. The optimal M-score for identifying groups with differing OS in the total UPENN cohort defined a binary classifier. The classifier was validated in UPENN subgroups and in a separate ECOG ACRIN E1900 trial cohort. Results: The mean and median M-score for the UPENN cohort was 92.3 (95% confidence interval [CI], 87.4-97.2) and 91.4 (range, 30.8-97.3), respectively; the M-score was not significantly associated with age, gender, specimen type, blast percent, NPM1, or FLT3-ITD. Patients with favorable cytogenetics had a lower mean M-score than those with non-favorable cytogenetics; there was no difference between intermediate and unfavorable cytogenetic groups. Univariate analyses demonstrated that a 10-unit increase in M-score was associated with a 10% increase in the hazard of death (HR 1.1; P<.0001) and a 20% increase in the odds of failing to achieve CR (OR 1.2, P<.0001). In multivariable Cox analysis, higher M-score (HR 1.1, P=.011) and older age (P=.001) were significantly associated with increased hazard of death, while NPM1+/FLT3-ITD-status (P=.031) was associated with decreased hazard of death. In a multivariable logistic analysis, higher M-score (HR, 1.1, P=.034) and older age (P=.007) were associated with increased odds of failing to achieve CR, while favorable cytogenetics (P=.030) was associated with achievement of CR. Based on the maximization of the log-rank statistic, the optimal M-score cutpoint was 86, which defined a binary risk classifier (hazard of death for high vs low M-score: unadjusted HR 2.5, P<.0001; adjusted HR 1.9, P=.003). Median OS was 26.6 vs. 10.6 mos for low and high M-score groups (Figure). The CR rates for low and high M-score groups were 84% and 61%, respectively. The performance of the M-score classifier was confirmed in pts ≤ 60 yrs with intermediate cytogenetics (log-rank P=.001, OS in high vs low M-score groups: 36.4 vs 14.0 mos) and among pts who achieved CR with initial therapy (log-rank P<.00001, OS 43.9 vs 17.2 mos). The M-score classifier identified groups with different outcome regardless of allogeneic transplant. The M-score classifier was validated in the E1900 cohort (n=383). The mean and median M-scores were similar to the UPENN cohort and M-score was significantly associated with OS on multivariable analysis (P<0.0001). The M-score classifier identified E1900 subgroups with different OS (log-rank P<.00001; OS 29.5 vs 12.6 mos), a finding confirmed in the intermediate cytogenetics group, in those aged <50 and ≥50 yrs, and among pts assigned to both standard and high dose daunorubicin. Notably, high dose daunorubicin benefited patients with high M-scores (P=.001), but not those with low M-scores (P=.328). We also evaluated the prognostic value of the M-score in the context of an extended molecular profile. Random forest analysis of the UPENN cohort showed that M-score and age are the most robust predictors of OS, while a subset of recurrent mutations (FLT3-ITD, NPM1, IDH2, TET2, TP53, NRAS, CEBPA) also contribute to prognosis, but to a lesser degree. Conclusion: The M-score and associated classifier represent promising tools for clinical decision-making in AML and deserve further investigation. The prognostic value of the M-score may be superior to mutational analysis. Optimal methods for integration of M-score, clinical and genetic information are being defined. Figure 1. Figure 1. Disclosures Loren: Merck: Research Funding. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Adult Patients With De Novo Acute Myeloid Leukemia and t(9; 11)(p22; q23) Have a Superior Outcome to Patients With Other Translocations Involving Band 11q23: A Cancer and Leukemia Group B Study

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4532-4538 ◽  
Author(s):  
Krzysztof Mrózek ◽  
Kristiina Heinonen ◽  
David Lawrence ◽  
Andrew J. Carroll ◽  
Prasad R.K. Koduru ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Extra Chromosome ◽  
Response To Therapy ◽  
High Dose ◽  
Postremission Therapy ◽  
De Novo Aml ◽  
Group B ◽  
Acute Myeloid

Abstract Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.

Outcomes in CCG-2961, a Children’s Cancer Group Phase III Trial for Untreated Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 169-169 ◽  
Author(s):  
Beverly J. Lange ◽  
Franklin O. Smith ◽  
Patricia A. Dinndorf ◽  
Carola A.S. Arndt ◽  
Dorothy R. Barnard ◽  
...  
Keyword(s):  
De Novo ◽  
Interleukin 2 ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Remission Induction ◽  
High Dose ◽  
Free Survival ◽  
Cancer Group ◽  
De Novo Aml

Abstract CCG-2961 tested an intensively timed induction therapy consisting of cytarabine (AC), etoposide, thioguanine, dexamethasone, idarubicin and daunorubicin. Patients in remission after induction were randomized to a second induction course (Arm A) or a 3-drug combination of fludarabine, AC, and idarubicin (Arm B). Course 3 for patients with related donors was bone marrow transplantation (BMT); for those without donors, high dose AC/l-asparaginase. After Course 3 patients without donors were randomized to 14 infusions of Interleukin 2 (IL2) over 18 days or follow-up. CNS prophylaxis was intrathecal AC. Eligibility included all subtypes of de novo AML except acute promyelocytic leukemia and AML in patients with Down syndrome. CCG-2961 opened in Oct.1996 and closed in Dec. 2002. The DSMC suspended the study between Oct. 1999 and May 2000 while the 2961 Committee developed supportive care policies to reduce treatment-related mortality (TRM). CCG-2961 enrolled 900 de novo patients aged 3 days to 21 years, with 495 and 405 patients accruing pre-and post suspension respectively. Remission induction rate is 88.5%. With median follow-up of 3.6 years (range: 0 – 8.1 years), event-free survival (EFS) at 3 years is 44±3% and survival (OS) 57±3%. Disease-free survival (DFS) following Course 2 Arms A and B are not different, although relapse is significantly higher in Arm A (7.3% .vs. 3.1% P=0.018) and TRM more common in Arm B (7.9% vs.4.2% P=0.059), despite 7 less days of neutropenia in Arm B (P&lt;0.001). DFS is 65±9% for patients with a donor versus 50±5% for patients without a donor (P=0.005); respective OS, 74±8% and 66±5% (P=0.221). However, among 98 patients in CR1 with t(8;21) or inv(16) cytogenetics, outcomes in those without and with a donor were no different: DFS (61±12% vs. 72±18%, P = 0.49) and OS (78±10% vs. 77±17%, l P= 0.85). DFS with and without IL2 is 55±9% and 60±8%(P=0.606). Outcomes improved progressively over time. EFS pre- and post-suspension are 41±4% and 47±5%(P=0.038); OS, 52±5% and 63±5%(P=0.005); TRM is 17±3% pre- and 12±3% post-suspension (P=0.039). Factors predictive of inferior EFS are age &gt;17 years, Afro-American and Hispanic ethnicity, body mass index &lt;10th or &gt;95th percentile for age, absence of related marrow donor, WBC &gt; 50,000/mm3, karyotype with −7/7q, −5/5q- or &gt; cytogenetic 5 abnormalities, FLT3/ITD, &gt;15 % morphologic blasts on day 14 or &gt;0.5% immunologically detectable blasts at the end of induction. CCG-2961 confirms the efficacy and high TRM of intensively timed therapy. Neither fludarabine nor IL2 increases DFS or OS, and availability of a donor does not improve outcomes in those with favorable cytogenetics.

Twice Daily Fludarabine and Cytarabine Combination (BID-FA) Is Effective in Pts with De Novo Acute Myeloid Leukemia (AML), Relapsed/Refractory (R/R) AML, High-Risk Myelodysplastic Syndromes (MDS), and Blast Phase Chronic Myeloid Leukemia (CML-BP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4939-4939
Author(s):  
Hady Ghanem ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
To Receive

Abstract Abstract 4939 Background: High dose cytarabine containing regimens are still considered standard options for pts (pts) with AML relapsing after a first complete remission (CR1) lasting more than 12 months. No standard options exist for pts relapsing after shorter remission duration or with primary refractory disease. We conducted a phase II study assessing the efficacy and safety of twice daily fludarabine and cytarabine (BID FA) in pts with R/R AML, high-risk MDS and CML-BP. Pts and Methods: 147 pts with de Novo AML, R/R AML, intermediate-2 and high-risk MDS, and CML-BP, with a performance status of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive fludarabine 15 mg/m2 intravenously (IV) q12 hrs on days 1 to 5 as well as cytarabine at the dose of 0. 5 g/m2IV over 2 hrs q12 hrs on days 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1 for the first 70 pts enrolled. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Four pts with AML who had FLT3 mutation were allowed to receive BID FA and sorafenib. Results: A total of 147 pts were treated. The median age was 63 years (range, 20 to 85 years). 131 (89%) had AML, 7 (5%) had high-risk MDS, and 9 (6%) had CML-BP. Of the 131 AML pts, 17 (12%) were de novo AML, 50 (38%) were in first salvage: first CR duration (CRD1) of less than 12 months in 39 pts (29%), and more than 12 months in 11 (9%) pts. Cytogenetic studies showed diploid karyotype in 52 pts (35%) and unfavorable chromosomal abnormalities involving chromosomes 5 and 7 in 30 pts (20%). 128 pts (87%) had a PS ≥1. Sixty-four pts (44%) had failed previous intensive chemotherapy, while 21 (14%) had failed targeted and hypomethylating agents. Forty-three (29%) pts had failed both. Overall, 34 pts (23%) achieved a complete remission (CR) and 8 (6%) achieved a CR without platelet recovery (CRp), for an overall response rate (ORR) of 29%. 6 pts received reinduction therapy, of which 3 achieved a CR. The CR rates for AML pts with frontline therapy, with relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 47%, 64%, 21%, and 14%, respectively. In CML-BP, 2 (22%) of 9 pts had objective responses (1 CR, 1 CRp). 1 of the 7 pts with MDS responded (Table 1). The treatment was well tolerated with only 7 of the pts experiencing grade 3 and 4 toxicities including mainly skin rash and increased liver enzymes. The overall 4-week mortality rate was 13%. With a median follow-up of 24 months (range, 10 to 33), 20 patients (14%) remained alive. The overall 6-month survival rate was 44%. The median overall survival (OS) and event free survival (EFS) were 5 months (range, 0. 1 to 33) and 1 month (range, 0. 1 to 33), respectively. The median CR/CRp duration was 12 months. Median OS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 8, 12, 5, and 4 months respectively. Median EFS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 3, 7, 1 and 1 month respectively. Conclusion: BID FA appears to be active with an ORR of 29% in a heavily pre-treated population. This combination is safe with a low rate of 4-week-mortality of 13%. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A 17-Gene Leukemia Stem Cell (LSC) Score in Adult Patients (Pts) with Acute Myeloid Leukemia (AML) Reveals a Distinct Mutational Landscape and Refines Current European Leukemianet (ELN) Genetic Risk Stratification

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 289-289 ◽  
Author(s):  
Marius Bill ◽  
Deedra Nicolet ◽  
Ann-Kathrin Eisfeld ◽  
Krzysztof Mrózek ◽  
Christopher J. Walker ◽  
...  
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Expression Data ◽  
Age Related ◽  
Mutational Status ◽  
Multivariable Analyses ◽  
De Novo Aml ◽  
Favorable Group

Abstract Introduction: Prognosis of AML pts is still poor mainly because of refractoriness to or relapse after intensive chemotherapy. High rates of relapse are also attributed to LSCs, which are a small subset of cells with acquired abnormal self-renewal capacity and increased resistance to chemotherapy. A better understanding of LSCs is critical to improve outcomes of pts with AML. Ng et al. (Nature 2016;540:433) defined a 17 stemness-associated gene score that was highly prognostic. Aims: The aim of this study was to validate the prognostic relevance of the 17-gene LSC score and explore its utility in the context of the ELN classification. We also examined gene mutations associated with the 17-gene LSC score. Methods: We analyzed a total of 934 pts [729 aged <60 years (y) and 205 aged ≥60 y] with de novo AML. We used whole transcriptome expression data (RNAseq) to calculate the aforementioned 17-gene LSC score for each pt in our cohort. Similar to Ng et al., we used the median of the whole cohort to discriminate between pts with LSChigh and LSClow scores. The mutational status of 80 cancer- and leukemia-associated genes (Eisfeld et al. Leukemia 2017;31:2211) were determined using a targeted next-generation sequencing panel, CEBPA mutations using Sanger sequencing, and an internal tandem duplication (ITD) of the FLT3 gene using fragment analysis in pretreatment bone marrow or blood samples. All pts were treated on frontline Cancer and Leukemia Group B/Alliance protocols. Results: A comparison of pretreatment clinical and genetic features revealed that LSChigh pts were older (P<.001; median age, 53 vs 46 y) and had higher platelet counts (P<.001; median, 63 vs 50x109/L) than LSClow pts. Pts with a LSChigh score more frequently had FLT3-ITD (P<.001) and mutations in the ASXL1 (P=.001), DNMT3A (P<.001), RUNX1 (P=.002), SRSF2 (P=.02), STAG2 (P=.009), TET2 (P=.008) and TP53 (P<.001) genes. Conversely, these pts had a lower frequency of biallelic CEBPA (P<.001), GATA2 (P=.008) and KIT (P<.001) mutations. Because of differences in treatment intensity, we analyzed outcomes of younger and older pts separately. Younger pts with a LSChigh score had a lower complete remission (CR) rate (P<.001; 63% vs 87%), shorter disease-free survival (DFS; P<.001; 3-y rates, 26% vs 48%; Figure 1A) and overall survival (OS; P<.001; 3-y rates, 27% vs 59%; Figure 1B) compared to those of LSClow pts. In multivariable analyses including clinical and genetic factors that impact on outcome, a LSChigh score associated with lower remission rates (P<.001; HR: 0.36), shorter DFS (P<.001; HR: 1.67) and OS (P<.001; HR: 1.88) after adjusting for other co-variates. We also analyzed the prognostic impact of the LSC score with respect to the 2017 ELN classification. We found that LSC score associated with different ELN groups (P<.001), with LSChigh pts being more often classified in the Adverse or Intermediate group and less often in the Favorable group. Within the ELN Favorable and Adverse groups, LSChigh score retained its prognostic impact and identified pts with a lower CR rate and shorter DFS and OS (Table1). In older pts, a LSChigh score also associated with lower CR rate (P=.004; 50% vs 72%), shorter DFS (P=.04; 3-y rates, 6% vs 17%; Figure 1C) and OS (P<.001; 3-y rates, 9% vs 27%; Figure 1D). In multivariable analyses, LSC score remained significant only for OS (P<.003; HR: 1.70) after adjusting for other co-variates. Regarding the ELN classification, pts with LSChigh score in the Favorable group had shorter OS (P=.05; 3-y rates, 17% vs 50%) and, by trend, shorter DFS (P=.09; 3-y rates, 17% vs 39%); no significant differences were found in Intermediate or Adverse groups. Conclusions: We used RNAseq expression data and applied the previously established 17-gene LSC signature to score 934 de novo AML pts. We detected distinct mutational differences between LSChigh and LSClow pts, with LSChigh pts more often carrying gene mutations associated with age-related clonal hematopoiesis (i.e., ASXL1, DNMT3A, TET2, SRSF2 and TP53 mutations). Moreover, this score, derived from the expression of stemness-associated genes, has not only a prognostic impact on its own but also in the context of the current 2017 ELN classification. Disclosures Kolitz: Magellan Health: Consultancy, Honoraria. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Efficacy of a Two Day Induction Regimen for De Novo and Secondary AML with Intermediate and Adverse Cytogenetic Profiles

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4027-4027
Author(s):  
Melissa L. Larson ◽  
Ann M. Thomas ◽  
Nitin Goyal ◽  
Jamile M. Shammo ◽  
John J. Maciejewski ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Complete Remission ◽  
De Novo ◽  
Response Rates ◽  
High Dose ◽  
Bone Marrow Biopsies ◽  
Secondary Aml ◽  
Number Of Patients ◽  
Induction Regimen ◽  
De Novo Aml

Abstract Background: Cytogenetic data remains one of the most powerful prognostic factors for predicting response and survival in adult AML patients. The relationship between cytogenetics and induction response to the standard “7+3” regimen has been analyzed in the past. In a CALGB study, patients with favorable cytogenetics achieved a complete remission (CR) rate of 88%, those with intermediate cytogenetics achieved a 67% CR rate and those with adverse cytogenetics had a 32% CR rate (Byrd et al. Blood100: 4325, 2002). We present a retrospective analysis of the correlation between the hierarchical cytogenetic groups and complete remission rate following induction of AML using a novel induction regimen. This regimen was developed based on the concept of timed sequential therapy. The first pulse of chemotherapy recruits leukemic cells into the cell cycle while the second pulse is given at a time of peak cell recruitment. It utilizes two highly active anti-leukemic drugs: cytarabine, a cell cycle-specific drug, and mitoxantrone, which has a favorable cardiac toxicity profile. Patients and Methods: One hundred four patients with AML were treated with two days of chemotherapy given 96 hours apart from April 1997 to April 2008. Each day consisted of two doses of cytarabine 2gm/m2 (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15). Bone marrow biopsies were performed for assessment of leukemia-free state (day 14) and to document remission response. Cytogenetic results were classified into favorable, intermediate, and unfavorable categories based on CALGB data. Responses were defined per the Revised IWG Recommendations (Cheson et al, J Clin Onc21: 4642, 2003). Results: Median age of the 104 patients was 57 years [range 17–79]. There were 47 males and 57 females. Forty-two patients (40%) were 60 years of age and older, and the remaining 62 patients (60%) were younger than 60. Sixty-four patients (61.5%) had de novo AML. Five patients had favorable cytogenetics with 100% of them achieving CR. All of the patients with favorable cytogenetics were less than 60 years of age. For the 61 patients with intermediate cytogenetics, the ORR was 83.6% with a CR of 61%. In patients younger than 60, the ORR was 83.8%% (26 CR, 3 CRi, 2 CRp) with CR of 70%. For patients 60 years and older, the ORR was 83.3% (11 CR, 3 CRi, 5 CRp, 1 RMDS). In the 38 patients with unfavorable cytogenetics, the ORR was 57.9% with CR of 37%. For patients younger than 60 and 60 years and older, the overall responses were 75% and 38.8%, respectively. Of the 40 patients with secondary AML due to pre-existing MDS, the ORR was 65% with CR of 27.5%. In patients with de novo AML, the ORR was 81% with CR of 70%. Patients with prior MDS were more likely to have CRi (20% vs 1.5%), TF due to refractory disease (25% vs 15.6%) or aplasia (7.5% vs 1.5%) as compared to patients without MDS. The rates of CRp (10% vs 9%) were similar for both groups. MDS patients with intermediate cytogenetics had an ORR of 77.7% as compared to 54.5% in those with unfavorable cytogenetics. De novo patients with intermediate cytogenetics had ORR of 86% and those with unfavorable cytogenetics had ORR of 62.5%. Conclusion: Our data reflects the overall effectiveness of high dose cytarabine and mitoxantrone for induction therapy of AML. In the favorable cytogenetic group, the CR rate was higher than previously reported response rates; however, the number of patients was small. In the intermediate and unfavorable cytogenetic groups, the response rates for de novo AML compare favorably to historic controls. Patients with secondary AML respond equally well as compared to those with de novo AML; though, the influence of cytogenetics was similar to that seen in de novo AML. This regimen is very effective in producing a high response rates across cytogenetic categories.

Severe Toxicities During Pediatric Acute Myeloid Leukemia Chemotherapy: A Report From the Children's Oncology Group.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1071-1071 ◽  
Author(s):  
Lillian Sung ◽  
Richard Aplenc ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Soheil Meshinchi ◽  
...  
Keyword(s):  
Supportive Care ◽  
De Novo ◽  
Fungal Infections ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Sterile Site ◽  
De Novo Aml ◽  
Grade 3 ◽  
Severe Hyperbilirubinemia ◽  
Severe Grade

Abstract Abstract 1071 Background: Treatment of children with acute myeloid leukemia (AML) is associated with considerable toxicity. Children's Oncology Group (COG) AAML0531 trial adopted a modified AML Medical Research Council backbone and reviewed adverse event reports in real time to maximize accurate toxicity data. As of March 31, 2010, AAML0531 had randomized 968 patients with de novo AML to gemtuzumab ozogamicin (GMTZ) versus no GMTZ. Accurate description of toxicities with the backbone regimen as well as increment toxicities of new agents is important to optimize supportive care. Objectives were to describe hepatic, cardiac and infectious toxicities and duration of neutropenia in all patients, and to compare toxicities between treatment arms. Methods: AAML0531 included those ≥ 1 month to ≤ 30 years with de novo AML and used a 5 cycle chemotherapy regimen: Induction (Ind) I and II: cytarabine, daunorubicin, and etoposide (ADE 10+3+5 and 8+3+5); Intensification (Int) I: cytarabine and etoposide; Int II: mitoxantrone and high-dose cytarabine; and Int III: high-dose cytarabine and L'asparaginase. Subjects were randomized to receive or not receive GMTZ 3 mg/m2 during Ind I and Int II. Common Terminology Criteria for Adverse Events v3.0 toxicities were collected prospectively. Hepatic (ALT, bilirubin and veno-occlusive disease (VOD)), cardiac (left ventricular systolic dysfunction (LVSD)) and infection (sterile site bacterial and fungal) toxicities were targeted. All grades of cardiac and VOD toxicities were captured; all other severe (≥ grade 3) toxicities were recorded. Cumulative incidence (CI) of toxicities was calculated only during protocol chemotherapy. Duration of neutropenia was reported from beginning of cycle to absolute neutrophil recovery ≥ 500/uL for patients alive during the cycle. Results: Table describes the prevalence of severe (≥ grade 3) toxicities and illustrates that severe high ALT occurred in 3–10%, high bilirubin was less common and VOD was reported in ≤ 1% of cycles. Severe LVSD also was rare although compliance with suggested cardiac monitoring ranged from 50–80% per course of treatment. In terms of grade 1 or 2 LSVD there were no differences in any course except for Int II where grade 1 or 2 LVSD was higher with GMTZ (8.0% versus 2.4%; P<.05). Severe sterile bacterial infections were very common occurring in about 30% during Ind I and II, 45% during Int I and 60% during Int II and III. The eight month CI of severe high ALT was 19±4%, hyperbilirubinemia was 10±3%, and VOD was 1±1%. CI of severe elevations in ALT were near significantly more common with GMTZ (22±5% versus 16±5%, P=0.053). Severe LVSD CI was 4±2%, sterile site bacterial infection CI was 82±4% and sterile site microbiologically documented fungal infections CI was 14±3%. CI of severe hyperbilirubinemia, VOD, LVSD and infections were not significantly different with GMTZ. The median (range) duration of neutropenia of Ind I and II in the no GMTZ arm were 30 (3-75) and 28 (1-61) days while for Int I, II and III were 27 (1-53), 37 (6-92) and 39 (16-91) days respectively. Administration of GMTZ did not significantly prolong neutropenia. There was no difference in toxic mortality by GMTZ during Ind I or across all courses of chemotherapy. Conclusions: The COG AML0531 backbone regimen is associated with significant toxicities: 19% of patients have severe elevations in ALT and 10% have severe hyperbilirubinemia. VOD is rare and occurs in 1%. Sterile site invasive infections are very common, particularly during high dose cytarabine. Sterile site microbiologically documented fungal infections occurs in 14% in spite of current supportive care practices. GMTZ contributes to increased high ALT and more grade 1 or 2 LVSD, both of which are of questionable clinical significance. Understanding these toxicities is important as this backbone will be carried into future studies of AML. Decreasing both bacterial and fungal infections will be important supportive care initiatives. Disclosures: Smith: Pfizer, Inc: Member, Medical Advisory Committee (for bosutinib, not GO).

WT1 Levels At Diagnosis and POST-Induction Provide Prognostic Information in Adult De Novo AML. Results From the Spanish Cetlam Group.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2524-2524
Author(s):  
Josep F Nomdedeu ◽  
Montserrat Hoyos ◽  
Maite Carricondo ◽  
Elena Bussaglia ◽  
Camino Estivill ◽  
...  
Keyword(s):  
Bone Marrow ◽  
De Novo ◽  
High Dose ◽  
Prognostic Impact ◽  
Post Induction ◽  
Group 3 ◽  
Group 2 ◽  
De Novo Aml ◽  
Intermediate Dose ◽  
Group 1

Abstract Abstract 2524 WT1 monitoring is an almost universal target to follow de novo AML. Its exppression in myeloid malignancies is upregulated in parallel to the blast percentage. Recently, WT1 determination has been standardized as result of an European Leukemia Net initiative. Early reports have demonstrated that the best results are obtained when peripheral blood is used to establish clinical predictions. Pediatric studies in AML have shown that raised WT1 levels after induction associate with unfavourable outcome. Despite all the mentioned, WT1 quantitation has not yet gained widespread use, in part because some AML show normal WT1 levels at diagnosis. To investigate the prognostic impact of the normalized bone marrow WT1 levels at diagnosis and post-induction in a consecutive series of de novo AML patients enrolled in the CETLAM group trials. Available bone marrow samples at diagnosis (586 cases) and post induction (367 cases) were obtained in each participating center and sent to the CETLAM repository center at the Hospital de la Santa Creu i Sant Pau for complete immunophenotype and molecular analyses. One μg of RNA was reverse transcribed to cDNA in a total reaction volume of 20μl containing Cl2Mg 5mM, 10× Buffer, DTT 10mM, dNTP's 10mM each, random hexamers 15μM, RNAsin 20 units (Promega) and 200 units of MMLV enzyme. WT1 expression levels were determined by real-time quantitative polymerase chain reaction (RQ-PCR) in an ABI PRISM 7700® Genetic Analyzer (Applied Biosystems, Foster City, CA) using the primers and conditions described by the ELN group (Cilloni et al J. Clin. Oncol 2009;27:5195-201). For WT1 copy number titration, the IPSOGEN® (Marseille, France) plasmid was employed. Results were expressed as copies and four normal bone marrow samples were used as test controls. Patients were treated between 2004 and 2011 according to the CETLAM03 protocol. Adults up to 70 years of age received induction chemotherapy with idarubicin, intermediate-dose cytarabine and etoposide, followed by consolidation with mitoxantrone and intermediate-dose ara-C. Subsequently, patients with favourable cytogenetics at diagnosis received one cycle of high-dose cytarabine.G-CSF priming during induction and consolidation was used. Patients with favorable cytogenetics and high leukocyte counts at diagnosis were treated with autologous transplantation instead of high-dose cytarabine. Furthermore, patients with a normal karyotype but an adverse molecular profile (FLT3 mutations or MLL rearrangements) were allocated to the treatment for unfavorable cases; this included allogeneic transplantation from an HLA-identical donor. Overall survival (OS) was measured from the date of enrolment until the date of death. Leukemia-free survival (LFS) for patients who achieved a CR was calculated from the date of CR to relapse or death. OS and LFS were plotted by the Kaplan-Meier method; differences between curves were analyzed by the log-rank test. The probability of relapse was calculated using cumulative incidence estimates and taking into account the competing risk of death in remission. A WT1 cut-off value of 5065.2 copies at diagnosis was obtained. Two hundred and four samples had WT1 levels greater than this value, whereas 382 samples showed levels below this cut-off. These groups had statistically different OS 55±3 vs 33±5 p<0.001, LFS 52±3 vs 30±6 p:0.004 and CIR 34±3 vs 56±6 p<0.001. As regards the post-induction results, four groups were established: Group 0 (135 patients) with WT1 levels between 0 and 17.5 copies, Group 1 (107 patients) with WT1 values ranging from 17.6 to 76 copies, Group 2 (54 patients) with WT1 between 76.1 and 170.5 copies and Group 3 (71 patients) with WT1 levels after induction greater than>170.6 copies. These groups showed statistically significant differences(p<0.001) in terms of OS: Group 0 59±4 months, Group 1 50±5 months, Group 2 45±7 months and Group 3 23±6 months. LFS was also statiscally different: Group 0: 58±4, Group 1: 46±5, Group 2: 39±8 and Group 3:19±8 (all p<0.001). Lastlly, CIR was markedly different between the four groups: Group 0:25±4, Group 1: 44±5, Group 2: 46±8 and Group 3: 68±8(p<0.001) . WT1 quantitation at diagnosis and post-induction provide a simple and well standardized measurement of the prognostic risk of adult AML patiens. Larger series need to be analyzed to ascertain whether this determination could be incorporated to initial AML risk stratification. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation Overcomes the Poor Prognosis in MLL-Rearranged Solid Tumor Therapy Related-Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hanzhou Qi ◽  
Hua Jin ◽  
Qifa Liu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Solid Tumor ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
De Novo ◽  
Tumor Therapy ◽  
The Poor ◽  
De Novo Aml ◽  
Solid Tumor Therapy ◽  
Acute Myeloid

BACKGROUND: MLL rearrangement is very common in solid tumor therapy-related acute myeloid leukemia (t-AML). This study investigated the prognosis of MLL t-AML. METHODS: Patients with solid tumor t-AML and MLL de novo AML were enrolled in this retrospective study. The patients were divided into 3 groups: non-MLL t-AML(n=41), MLL t-AML(n=18) and MLL de novo AML(n=98). RESULTS: Of the 157 patients enrolled, 150 patients underwent anti-leukemia therapy. The complete remission (CR) rate was 83.3%, 85.5% and 86.2%(P=0.251), respectively, in MLL t-AML, non-MLL t-AML and MLL AML groups. The 3-years overall survival (OS) was 37.5%, 21.5% and 20.4% (P=0.046). The 3-years leukemia-free survival (LFS) was 28.0%, 32.2% and 22.7% (P=0.031), and the incidence of relapse was 30.0%, 50.4% and 53.5% (P=0.382), respectively, in the three groups. Multivariate analysis revealed that MLL t-AML was a risk factor while allo-HSCT a protective factor for relapse, LFS, and OS (P=0.005, P&lt;0.001 and P&lt;0.001) (P&lt;0.001, P&lt;0.001 and P=0.002, respectively). The 3-years OS was 0%, 17.9% and 0%(P=0.038), LFS was 0%, 23.1% and 0%(P=0.017), and relapse was 100%, 53.1% and 74.4% (P=0.001), respectively among three groups in patients undergoing chemotherapy alone, while OS was 64.3%, 52.7% and 40.7% (P=0.713), LFS was 60.0%, 48.8% and 37.0% (P=0.934), and relapse was 25.0%, 47.4% and 47.5% (P=0.872), respectively, among these group in the patients undergoing allo-HSCT. Intriguingly, MLL t-AML was no longer risk factor for relapse and LFS (P=0.882 and P=0.484, respectively), while it became a favorable factor for OS (P=0.011) in the patients undergoing allo-HSCT CONCLUSIONS: MLL t-AML had poor prognosis compared with non-MLL t-AML and MLL de novo AML,, but allo-HSCT might overcome the poor prognosis of MLL t-AML. Disclosures Liu: Nanfang Hospital, Southern Medical University: Research Funding.

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