Prognostic Value of Immunophenotype in Patients with Non-Promyelocytic Acute Myeloid Leukemia Treated with Intensive Chemotherapy. A Single Centre Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2391-2391
Author(s):  
Pau Montesinos ◽  
Amparo Sempere ◽  
Federico Gomis ◽  
Jose Cervera ◽  
Mariluz Perez-Sirvent ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Cell Surface ◽  
Myeloid Leukemia ◽  
Surface Markers ◽  
Cell Surface Markers ◽  
Intensive Chemotherapy ◽  
The Impact ◽  
Cd34 Positivity ◽  
Acute Myeloid

Abstract Background: The prognostic significance of the expression pattern of certain cell surface markers in acute myeloid leukemia (AML) is controversial. Objectives: Analyze the impact of the expression of certain cell surface markers on complete remission rate (CR) and relapse free survival (RFS), in a large series of adult patients with non-promyelocytic AML treated with intensive chemotherapy. Methods: From 1989 to 2007, 451 adult patients (median age 57 years, range 15–80 years) diagnosed with non-promyelocytic AML, received first induction chemotherapy in our institution. Induction therapy consisted of the combination of cytarabine and anthracycline with or without a third agent in 95% of patients and other regimens in the remaining 5%. The post-remission treatment consisted of consolidation chemotherapy followed or not by stem cell transplantation. The inmunophenotypic analysis of bone marrow samples at diagnosis was evaluable in 395 patients (88%). Positivity was defined as more than 20% blasts expressing a specific antigen. It was possible to evaluate the percentage of positive blasts for the following antigens: CD33 (395 patients), CD13 (391), HLA-DR (382), CD14 (375), CD34 (364), CD7 (354), CD11b (350), CD4 (347), CD36 (343), CD15 (326), CD9 (321), CD2 (315), CD38 (250), CD71 (233), myeloperoxidase (MPX) (186), CD117 (178) and CD56 (173). We conducted a univariate and mutivariate analysis in order to define the impact of the expression of cell surface markers on CR rate and RFS. Results: Overall, 256 patients (58.3%) achieved a CR. The following characteristics were associated with a lower probability of CR: age >60 years, performance status by means of ECOG scale ≥2, peroxidase staining in <75% of blasts, and high-risk karyotype (in all, p<0.001). The positivity of CD34 and the negativity of CD15 and MPX, were associated with a lower CR rate (p=0.005, p=0.04 and p<0.001, respectively), due to a higher rate of resistance (p<0.001, p=0.004 and p<0.001, respectively). Multivariate analysis showed that WBC >50×109/l, high-risk karyotype, CD34 positivity and MPX negativity were independent unfavourable factors for CR. The median follow-up of the cohort was 81 months and the overall RFS at 5 years was 35%. The following factors are associated with a lower RFS: CR achievement with 2 cycles (15% vs 37%, p<0.001), age >60 years (16% vs 44%, p<0.001), peroxidase staining in <75% of blasts (26% vs 49%, p=0.001), high-risk karyotype (0% vs 39%, p=0.03), CD2 positivity (11% vs 40%, p=0.008) and MPX negativity (16% vs 40%, p=0.02). Multivariate analysis showed that age >60 years, CR achievement with 2 cycles and MPX negativity were independent unfavourable factors for RFS. Conclusion: The AML with an immature immunophenotype, like those with CD34 positivity or MPX negativity, shows a higher resistance to induction chemotherapy. We also have observed a shorter remission duration in those AML with CD2 positivity or MPX negativity.

scholarly journals Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome:

Cancer ◽  
2006 ◽  
Vol 106 (5) ◽  
pp. 1090-1098 ◽  
Author(s):  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Jorge Cortes ◽  
Francis Giles ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

scholarly journals Gemtuzumab Ozogamicin Reduces Relapse Risk in FLT3-ITD+ Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 486-486
Author(s):  
Katherine Tarlock ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Susana C. Raimondi ◽  
Betsy A. Hirsch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Cell Transplant ◽  
Intensive Chemotherapy ◽  
Conventional Chemotherapy ◽  
Hematopoietic Stem ◽  
Poor Outcomes ◽  
The Impact ◽  
Acute Myeloid

Abstract CD33 is variably expressed on most acute myeloid leukemia (AML) blasts and is the target of gemtuzumab ozogamicin (GO), a calicheamicin-conjugated anti-CD33 monoclonal antibody. COG studies AAML03P1 and AAML0531 evaluated the safety and efficacy of GO combined with conventional chemotherapy to determine the impact of GO on treatment outcomes. We have previously demonstrated that those with high CD33 expression are more susceptible to GO. As FLT3-ITD is associated with high levels of CD33 expression, this group of patients represents a subgroup of particular interest for this therapeutic approach. Patients with high-allelic ratio (HAR) FLT3-ITD have poor outcomes with conventional chemotherapy alone and experience improvement with allogeneic hematopoietic stem cell transplant (HCT). Thus, COG AAML0531 allocated HAR FLT3-ITD+ patients enrolled after April 14, 2008 to consolidation allogeneic HCT with the best available donor. In combined evaluation of COG AAML0531 and its preceding pilot study AAML03P1, 479 patients received conventional MRC based induction chemotherapy (0531 Arm A) and 735 patients received conventional chemotherapy + GO (03P1 and 0531 Arm B). A total of 183 FLT3-ITD+ patients were treated on 0531 Arm A (n=71) and on 03P1/0531 Arm B (n=112). Overall, patients with FLT3-ITD had significantly lower rates of complete remission (CR) compared to FLT3-ITD negative patients, 64% v. 77% respectively (p<0.001). Among FLT3-ITD+ patients, CR rates were identical in those with or without induction GO exposure of 64% vs. 64% respectively (p=0.98). Analysis of 5-year outcomes for FLT3-ITD+ patients treated with GO compared to no GO demonstrated no difference in overall survival (OS) (50% v 49% respectively, p=0.74). Importantly, cumulative incidence of relapse (CIR) at 5 years from CR for patients treated with GO was 37% vs. 59% in those who did not receive GO (p=0.018). This GO-associated improvement in relapse was offset by higher treatment related mortality (TRM) among GO compared to no GO recipients (16% v 0% respectively, p=0.008), leading to similar DFS of 47% vs. 41% respectively (p=0.45). The benefit of decreased relpase risk (RR) was most significant for patients receiving GO in addition to HCT. Among FLT3-ITD+ patients who underwent HCT, those who received GO (n=33) had a 5-yr RR of 22% compared to 56% for the no GO cohort (n=25, p=0.003). There was a trend towards increased TRM among patients receiving GO compared to no GO (22% v. 4% respectively, p=0.078), with a corresponding DFS in GO recipients of 56% vs. 40% for the no GO cohort (p=0.09). Evaluation of the 8 GO recipients who died at HCT revealed that 3 (38%) were the result of complications from transplant-associated sinusoidal obstructive syndrome. Patients with HAR FLT3-ITD, who experience poor outcomes with conventional chemotherapy alone, were analyzed separately to evaluate the impact of induction GO on outcomes. Among HAR FLT3-ITD+ patients who underwent HCT, those treated with GO (n=26) had a significantly lower RR of 15% compared to 53% among no GO recipients (n=15, p=0.007). Additionally, patients receiving GO had a trend towards higher DFS of 65% compared to 40% for no GO group, (p=0.079). In this cohort, TRM in GO vs. no GO recipients was 19% vs. 7% respectively (p=0.297). Among HAR FLT3-ITD+ patients who did not receive HCT, there were no significant differences in DFS, RR, and TRM among the GO versus no GO recipients. Data from the two consecutive COG studies AAML03P1 and AAML0531 suggest that FLT3-ITD+ patients may benefit from the addition of GO to intensive chemotherapy. There is further evidence that HCT may augment the therapeutic impact of induction GO by further reducing the risk of relapse. However, clinical impact of GO was tempered by higher incidence of TRM in GO recipients. CD33 targeting represents an attractive approach in FLT3-ITD+ patients as they often have elevated blast CD33 expression. Further understanding of the toxicity profile of GO, especially when used in conjunction with intensive chemotherapy and HCT, is needed to enhance its therapeutic benefit. Additionally, its impact may be most significant in certain biologic subsets of AML. Our findings demonstrate that CD33 targeting is an important treatment strategy in AML that warrants further investigation in FLT3-ITD+ patients. Disclosures No relevant conflicts of interest to declare.

Benefit of Anti-Infectious Prophylaxis in Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome Receiving Frontline “Targeted Therapy”.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2858-2858 ◽  
Author(s):  
Nitin Jain ◽  
Gloria N. Mattiuzzi ◽  
Jorge Cortes ◽  
Jennifer Cassat ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Targeted Therapy ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Fungal Infections ◽  
Antifungal Prophylaxis ◽  
Intensive Chemotherapy ◽  
Standard Chemotherapy ◽  
Antibacterial And Antifungal ◽  
Acute Myeloid

Abstract Background Patients with high risk (HR) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have significant toxicities such as mucositis, protracted neutropenia and severe infections when treated with standard chemotherapy. This had led to the development of ‘less intense’ chemotherapy (targeted therapy, TT). These treatments are expected to produce less toxicities, especially less immunosuppression. Antibiotic and antifungal prophylaxis are routinely given to patients undergoing intensive chemotherapy. It is not clear if the same strategy should be used for patients receiving less intensive chemotherapy. The objective of this study is to evaluate the outcome of patients receiving TT according to the use of antimicrobial prophylaxis. Methods We retrospectively reviewed the medical records of patients with AML and HR MDS that received TT as induction therapy from January 2000 to July 2007 at our institution. Baseline characteristics and antibiotic usage was recorded. All courses of TT received from start of therapy until outcome (response or failure) was assessed were evaluated, and infections or death occurring during any of these courses constituted an event. Results 225 patients received TT [decitabine or azacitidine n = 137 (61%); miscellaneous (tipifarnib, PKC412, imatinib, SAHA, and others) n=88 (39%)] for a total of 583 courses (median course per patient = 2). Median age was 72 years (range 13–89), 60% were male, 95% had Zubroad performance status ≤ 2 and 28% were neutropenic at the start of TT. None of the patients were placed in HEPA-filtered rooms (‘protected environment’) at any time. Each course of therapy was grouped into 1 of 4 groups based on the strategy use for infectious prophylaxis (table 1). Clinically documented infections and FUO were the most frequent type of infection reported in all the groups, followed by bacterial infections. Fungal infections were infrequent (total 5; group 1 = 1; group 2 = 2, group 3 = 2). There was no significant difference in the number of infectious episodes per course between the groups that received both antibacterial and antifungal prophylaxis vs. those who received no prophylaxis (p= 0.984). However, mortality was significantly higher during courses of TT administered without prophylaxis (p= 0.005). Conclusions As opposed to standard chemotherapy, fungal infections are infrequent in the patients treated with TT. Mortality is significantly higher in patients who did not receive any anti-microbial prophylaxis. The use of antibacterial and antifungal prophylaxis should be considered in patients receiving TT. Table 1: Groups based on antimicrobial strategy Strategy Strategy No. of courses No. of infectious episodes (%) No. of death (%) * p=0.984; # p=0.005 No prophylaxis 202 45 (22%) * 12 (5.94%) # Both bacterial and fungal prophylaxis 171 38 (18%) * 1 (0.58%) # Only bacterial prophylaxis 206 31 (15%) 6 (2.91%) Only fungal prophylaxis 4 0 (0%) 0 (0%)

scholarly journals Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2725-2725
Author(s):  
Sayantanee Dutta ◽  
Gudrun Pregartner ◽  
Frank G. Rücker ◽  
Ellen Heitzer ◽  
Armin Zebisch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Scoring Systems ◽  
Advisory Board ◽  
Low Risk ◽  
Missense Mutations ◽  
Tp53 Mutations ◽  
The Impact ◽  
Acute Myeloid

In more than 50% of human cancers, somatically acquired aberrations of the tumor suppressor gene TP53 are encountered. Approx. 10% of patients with acute myeloid leukemia (AML) reveal TP53 mutations with higher incidences in therapy-related subtypes and erythroleukemias. These mutations are regarded early events of leukemogenesis. In contrast to mere deletions at the TP53 locus, TP53 mutations confer an exceedingly adverse prognosis in AML even when occurring at a subclonal level. However whether different TP53 mutations in AML exhibit a different functional impact on disease progression or outcome remains unknown. In the present study, we have investigated this issue using four TP53 specific, functional scoring systems in a large cohort of patients of the German-Austrian AML study group (AMLSG). The AMLSG cohort consisted of a total of 1537 patients with newly diagnosed AML who were intensively treated within three multicenter, clinical trials. A total of 108 TP53 mutations were detected in 98 patients using targeted amplicon sequencing - 88 (81.4%) missense, 8 (7.4%) nonsense and 6 (5.6%) splice site mutations as well as 6 small insertions and deletions. For each of the four functional TP53 scores, we have assessed their impact on overall survival (OS) and event-free survival (EFS). First, we compared the impact of TP53 missense mutations in 84 patients with all other types of mutations (n= 14). In a next approach, TP53 mutations were grouped into disruptive (n=42) and non-disruptive (n=56) ones, based on the impact of the particular mutations on the protein structure predicted from the crystal structure of p53-DNA complexes (Poeta et al. New Engl J Med 2007). We then classified missense TP53 mutations (n=84) based on their "Evolutionary Action Scores (EAp53)" (Neskey et al. Cancer Res 2015). This algorithm takes evolutionary sensitivity and amino acid conservation into account and scores missense TP53 mutations from 0 to 100. Mutations with the high EAp53 score are considered high risk whereas wild type TP53 has an EAp53 score of zero. We extracted the EAp53 score of those AMLSG patients showing missense mutations from the respective server (http://mammoth.bcm.tmc.edu/EAp53) and used the threshold of 75 from the initial publication to divide the patients into low-risk (<75, n=49) and high-risk groups (≥75, n=35). However, with these three functional scoring systems, no difference regarding OS and EFS could be shown between the mutational groups. The "Relative Fitness Score (RFS)" was recently developed for the TP53 DNA binding domain (DBD) mutants as an indicator of their functional impact (Kotlar et al. Molecular Cell 2018). A catalogue of 9833 TP53 DBD mutants were generated and their selective growth was assessed in p53 null cancer cell lines. The RFS score for each mutant is the median of its relative enrichment or depletion in culture, calculated at 3 time points and depicted as a log (base 2) value. A high RFS indicates selective growth of the mutant corresponding to its higher fitness. We extracted the RFS for the TP53 DBD mutations of the AMLSG cohort (n=83) using the online data resource (GSE115072) and performed a receiver-operating characteristics (ROC) analysis to calculate the optimal threshold of RFS separating deceased from survivors most efficiently. Thereby, the best RFS cut-off value according to the Youden index was -0.135. Applying this threshold (low-risk RFS ≤ -0.135, n=25; high-risk RFS > -0.135, n= 58) we demonstrated a significantly better OS (P=0.009) and EFS (P=0.037) for patients with a low-risk RFS in multivariable analyses adjusting for age, white blood cell count, cytogenetics and type of AML. Using the AML-specific TP53 RFS score, we could show that more than 30% of patients with TP53 mutations (25/83) reveal a significantly better survival indicating that this score is of prognostic value. Based on these findings, we propose that - along with clinical parameters - RFS values of TP53 mutations should also be considered for a comprehensive risk assessment of TP53 mutated AML patients. Disclosures Zebisch: Celgene: Honoraria; Novartis: Honoraria, Other: Advisory board; AbbVie: Other: Advisory board; Roche: Honoraria. Bullinger:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Honoraria; Gilead: Honoraria; Hexal: Honoraria; Menarini: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bayer: Other: Financing of scientific research; Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Sill:Novartis: Other: Advisory board; AbbVie: Other: Advisory board; Astellas: Other: Advisory board; Astex: Other: Advisory board.

scholarly journals Prognostic Significance of 11q23/MLL Fusion Partners in Children with Acute Myeloid Leukemia (AML) - Results from the Children's Oncology Group (COG) Trial AAML0531

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1211-1211 ◽  
Author(s):  
Erin M. Guest ◽  
Betsy A. Hirsch ◽  
E. Anders Kolb ◽  
Todd A. Alonzo ◽  
Robert Gerbing ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Chromosome 1 ◽  
Prognostic Impact ◽  
Fusion Partner ◽  
Complex Karyotype ◽  
Free Survival ◽  
The Impact ◽  
Acute Myeloid

Abstract Background: Rearrangement of chromosome 11q23 at KMT2A (MLL+) occurs in ~20% of childhood acute myeloid leukemia (AML) cases and is the most common recurrent cytogenetic abnormality in childhood AML. More than 80 fusion partners of MLL have been characterized and the prognostic impact varies by partner and additional cytogenetic aberrations (ACAs). We previously reported superior event-free-survival (EFS), overall survival (OS), relapse risk (RR) and disease free survival (DFS) for patients with MLL+ on AAML0531 treated with gemtuzumab ozogamicin (GO). The impact of fusion partners has not been described for this trial cohort. Objective: To determine the impact of 11q23/MLL+ fusion partners on outcomes for children with AML who were treated uniformly on AAML0531. Methods: AAML0531 (2006 - 2010) was a randomized phase 3 trial of GO with conventional chemotherapy for children, adolescents, and young adults, ages 0 to 29 years, with de novo AML. The trial enrolled 1022 eligible patients without Down syndrome, and cytogenetic data was available for 988 patients. Of those, 215 (21.8%) were classified as 11q23/MLL+ after central cytogenetic review. The majority of patients with 11q23/MLL+ AML (n=200, 93%) were classified as intermediate risk (IR) and a minority (n=15, 7%) were classified as high risk (HR) based upon high FLT3 internal tandem duplication allelic ratio (FLT3-ITD-AR), monosomy 5/5q deletion, monosomy 7, or >15% blasts by morphology following Induction (Ind) I. HSCT was performed for 30 patients (14%). We defined 11q23/MLL+ subgroups for partners identified in ≥5 cases. Partners in <5 cases were grouped as "other"; unidentified fusions were classified as "unknown". Outcomes of minimal residual disease (MRD) at end of Ind I and complete remission (CR) at end of Ind II, 5-yr EFS and OS from study entry, and 5-yr RR from end of Ind II for patients in CR were compared across subgroups. Univariable and multivariable analyses were performed. Results: The median age for the 11q23/MLL+ cohort was 2.5 years and the distribution was equally male and female. The majority of cases (n=175, 81%) were classified into 8 specific partner subgroups, and the remaining cases were classified as other (n=30, 14%) or unknown (n=10, 5%). The most common translocation was t(9;11)(p22;q23) (n= 82, 38%). Central nervous system involvement was rare (<10% overall and in every subgroup). While extramedullary chloromas were rare (7% overall), chloromas were reported in 83% (n=5) of t(10;11)(p11.2;q23), 40% (n=16) of t(10;11)(p12;q23), and 27% (n=4) of t(6;11)(q27;q23). ACAs were observed in 86 of 211 cases (41%) that underwent central review. ACAs were numerical in 54 cases (26%), most commonly trisomy 8 (n=30, 14%) and structural + numerical in 32 cases (15%), most commonly involving chromosome 1 (n=11, 34%). Molecular findings for 3 studied genes were rare: High FLT3-ITD-AR n=4; NPM1 n=1; CEBPA n=0. Clinical outcomes varied significantly by fusion partner and poorer OS was primarily due to relapse (Table 1). CR rate was 86% overall and did not vary by subgroups. MRD was detected in 21% overall and was most common in t(1;11)(q21;q23) and t(6;11)(q27;q23). Complex karyotype (≥3 abnormalities) was seen in 52 cases (25%) and predicted inferior outcome compared to <3 abnormalities (5-yr EFS 29% vs. 41%, p=0.02; 5-yr OS 44% vs. 63%, p=0.001, respectively). Chromosome 1 abnormalities were associated with very poor outcomes, 5-yr EFS 19% and 5-yr OS 29%. The most unfavorable partners for EFS were t(6;11)(q27;q23), t(10;11)(p11.2;q23), t(10;11)(p12;q23), and t(11;19)(q23;p13.3)(Figure 1). In multivariable comparison to patients with t(9;11)(p22;q23), the former 3 groups maintained inferior EFS (HR 2.51, p=0.006; HR 3.10, p<0.001; HR 2.15, p=0.002, respectively) and OS (HR 2.56, p=0.017; HR 4.8, p=0.006; HR 2.14, p=0.016, respectively). Conclusions: Fusion partners critically impact the prognosis of 11q23/MLL+ AML. In this large, uniformly treated cohort, t(6;11)(q27;q23), t(10;11)(p11.2;q23) and t(10;11)(p12;q23) were independently associated with inferior EFS and OS. Children with these unfavorable partners are at high risk for relapse and allogeneic HSCT should be considered in first CR. Complex karyotype, chromosome 1 aberrations, and extramedullary chloromas were additional adverse prognostic factors. Work is ongoing to confirm these results in the subsequent COG trial, AAML1031. Disclosures No relevant conflicts of interest to declare.

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