scholarly journals Risk Stratification of Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Chemotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2294-2294
Author(s):  
Helene Gardeney ◽  
Jose Miguel Torregrosa Diaz ◽  
Caroline Basle ◽  
Emilie Cayssials ◽  
Sabrina Bouyer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
University Hospital ◽  
Risk Category ◽  
Intensive Chemotherapy ◽  
Significant Difference ◽  
Unfit Patients ◽  
Acute Myeloid

Abstract Background. Acute myeloid leukemia (AML) incidence increases with age, but elderly patients are often too frail to receive intensive chemotherapy (IC). Instead, treatment with hypomethylating agents (HMAs) is usually proposed, even if they have not demonstrated any real improvement over best supportive care. However, clinical practice has shown a significant difference in overall survival (OS) between responding and non-responding patients to HMAs. Thus, we aimed to assess predictive criteria of HMA response in elderly and frail AML patients. We reviewed the literature for any existing scores: none was found for elderly unfit patients. On the other hand, 3 models/scores existed for fit elderly patients undergoing IC : in the ALFA 9803 trail published by Malfuson and al, the HOCSG model in the MRC AML11 and LRF AML trails by Wheatley and al and finally the MDACC model by Kantarijan and al. Methods. We reviewed all patients aged ≥ 60 years old (y.o) diagnosed with AML, unfit for IC and treated with Azacytidine (AZA) alone in first line from July 2015 to December 2019 in Poitiers' University Hospital. The ineligibility to IC was defined by an age > 75 y.o and/or the appreciation by the physician based on performance status (ECOG) and the evaluation of comorbidities with Charlson Comorbidity Index (CCI). The type of AML (de novo versus secondary) and the 2017 ELN prognosis score were also assessed. Results. Among 63 patients recruited, 86% were older than 70 y.o and 29% older than 80. Frailty criteria were found with a ECOG ≥ 2 in 11 (17%) and a CCI ≥ 3 in 29 (45%) patients. Secondary AML was found in 41 (63%) of patients. Adverse karyotype was detected in 21 (32%) patients and 2017 ELN score was quoted as adverse in 25 (38%) patients. After a median follow up of 10.75 months (IQR 3.98 - 17.94) for the whole cohort, median OS was 10.75 months (95%CI 6.37476 - 14.984). Among 54 (86%) evaluable patients, 50 reached some response: at least hematological improvement according to 2003 International Working Group criteria in 20 of them (37%), and stable disease in 30 (55.6%) patients. Patients reaching at least hematological improvement were able to complete a median of 11.5 cycles (IQR 7.5 - 17) vs 6.5 cycles (IQR 3 - 12). Sadly 23 (35%) patients died before achieving 6 cycles. In our cohort the 2017 ELN score failed to predict risk assessment in elderly frail patients. The ALFA model and HOCSG score were also not able to identify treatable patients neither to predict mortality in our cohort. Interestingly the MDACC high-risk category was able to identify the patients who would not benefit from AZA treatment with worst survival rates (HR 3.01; 95%CI 1.04 - 8.79). Conclusion. To date, stratification scores were developed for young fit patients, undergoing IC. Those scores predict poorly response to HMA and OS in unfit patients. In the era of new treatments and combinations with AZA, there is an urgent and growing need for dedicated prognosis model for unfit elderly AML patients. Disclosures Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support.

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy

2020 ◽  
Vol 38 (30) ◽  
pp. 3506-3517 ◽  
Author(s):  
Chong Chyn Chua ◽  
Andrew W. Roberts ◽  
John Reynolds ◽  
Chun Yew Fong ◽  
Stephen B. Ting ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
Acute Myeloid

PURPOSE The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. PATIENTS AND METHODS Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. RESULTS Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. CONCLUSION Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).

scholarly journals Genetic Landscape of Mitochondrial Regulatory Region in Pediatric Acute Myeloid Leukemia: Changes from Diagnosis to Relapse

2019 ◽  
Vol 08 (04) ◽  
pp. 193-197
Author(s):  
Anudishi Tyagi ◽  
Raja Pramanik ◽  
Radhika Bakhshi ◽  
Sreenivas Vishnubhatla ◽  
Sameer Bakhshi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Regulatory Region ◽  
Mt Dna ◽  
Pediatric Acute Myeloid Leukemia ◽  
Loop Region ◽  
Significant Difference ◽  
D Loop ◽  
Acute Myeloid

AbstractThis prospective study aimed to compare the pattern of mitochondrial deoxyribonucleic acid D-loop (mt-DNA D-loop) variations in 41 paired samples of de novo pediatric acute myeloid leukemia (AML) (baseline vs. relapse) patients by Sanger's sequencing. Mean mt-DNA D-loop variation was 10.1 at baseline as compared with 9.4 per patients at relapse. In our study, 28 (68.3%) patients showed change in number of variations from baseline to relapse, 11 (26.8%) patients showed increase, 17 (41.6%) patients showed decrease, and 7 (17.1%) patients who suffered a relapse had a gain at position T489C. No statistically significant difference was observed in the mutation profile of mt-DNA D-loop region from baseline to relapse in the evaluated population of pediatric AML.

Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy.

1997 ◽  
Vol 15 (6) ◽  
pp. 2262-2268 ◽  
Author(s):  
M Wetzler ◽  
M R Baer ◽  
S H Bernstein ◽  
L Blumenson ◽  
C Stewart ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Poor Response ◽  
Significant Difference ◽  
De Novo Aml ◽  
Cd34 Expression ◽  
Acute Myeloid

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

Prognostic Significance of NQO1 Polymorphism and GST-M1 Deletion in De Novo Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4846-4846
Author(s):  
Yeo-Kyeoung Kim ◽  
Hee-Je Kim ◽  
Woo-Sung Min ◽  
Jong- Ho Won ◽  
Deog-Yeon Jo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Outcomes ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Induction ◽  
Repair System ◽  
Significant Difference ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Background: Although the most powerful prognostic factor of acute myeloid leukemia (AML) patients is the karyotype of the leukemic blast, data have not been obtained almost entirely in patients with heterogeneous cytogenetics. Further, some patients with favorable cytogenetics may show the poor treatment outcomes. Previous reports suggested that the single nucleotide polymorphisms of genes coding drug detoxification enzymes such as cytochrome P450 family or DNA repair system may influence the treatment outcomes in the patients with AML. We evaluated the role of polymorphisms in XRCC1, XRCC4, CYP1A1, GST-T1, GST-M1, NOQ1, and NAT2*6A in predicting therapeutic outcomes of adults with AML. Methods: XRCC1 (rs25487), XRCC4 (rs1056503), NQO1 (rs1800566), CYP-4501A1*2B (rs1048943), NAT2*6A (rs1799930) gene polymorphisms and deletion of GST-M1/GST-T1 were evaluated in 460 bone marrow (BM) samples obtained at initial diagnosis from de novo AML patients. Genotyping method is pyrosequencing using genomic DNA from BM samples. Homozygous deletions of GST-M1 and GST-T1 genes were detected with a multiplex PCR technique. All patients except APL (acute promyelocytic leukemia) received one or two rounds of intensive induction chemotherapy consisting of 3 days of idarubicin and 7 days of cytarabine. APL patients treated with AIDA regimen consisting of 45 days of ATRA (all-trans retinoic acid) and 3 days of idarubicin. Results: Of total 460 patients, ninety-nine patients (21.5%) were APL. Seventy-one (15.4%) were AML with t(8;21), twenty-three (5%) were AML with inv(16), and 179 patients (38.9%) showed normal cytogenetics. The median age of patients was 44 years (range, 14–75 years). In all cytogenetic risk group, the patients carrying homozygous NQO1 gene polymorphism (TT) showed significantly lower rate of complete remission (CR) than in those with negative or heterogyzous polymorphisms (TT: 72.7% vs. CC/CT: 85.9%, p=0.03). There was no significant difference in relapse rate, leukemia-free survival (LFS) and overall survival between homo- and heterozygote groups in these polymorphsims. In subgroup analysis, APL patients carrying TT genotype in NQO1 also showed lower rate of CR (TT: 77.8% vs. CC/CT: 95.4%, p=0.04). In AML patients except APL, NQO1 homozygous polymorphsim (TT) was also associated with lower CR rate (TT: 69.6% vs. CC/CT: 84.2%, p=0.005). In normal cytogenetics, the patients with del GST-M1 showed shorter LFS compared with those carrying GST-M1 (18.0 ± 5.7ms. vs. 34.6 ± NA. p=0.04). Conclusions: This study revealed an association between NQO1 polymorphism and GST-M1 deletion and the treatment outcomes for AML patients. Further study and larger sample size are needed to reach the definite conclusion on these associations. However, a stratified treatment plan in remission induction chemotherapy such as augmentation or addition of other chemotherapeutic agents may be warranted for AML patients harvoring homozygous NQO1 polymorphism (TT) or del GST-M1.

Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7052-7052
Author(s):  
B. C. Medeiros ◽  
J. R. Gotlib ◽  
S. E. Coutre ◽  
C. Jones ◽  
S. A. Khan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Elderly Patients ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Low Doses ◽  
Npm1 Mutation ◽  
Acute Myeloid

7052 Background: High treatment-related mortality and low response rates often discourage elderly patients with acute myeloid leukemia from receiving treatment. Previous data demonstrate that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Protracted exposure to low doses of temozolomide can significantly inhibit AGAT enzymatic activity. Methods: Phase II clinical trial of tailored temozolomide therapy to high-risk AML patients according to AGAT methylation promoter status. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200 mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) received protracted doses of temozolomide (100 mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Patients who achieved CR were given up to 5 consolidation treatments. Results: Fifteen patients have completed treatment to date. The median age was 78 (68–83) and nine were male. De novo AML was diagnosed in eight patients and five patients had s-AML. Nine patients had a normal karyotype and three patients had a complex karyotype. Two patients had only a NPM1 mutation and one had NPM1mut/FLT3-ITD. In 13 patients, the AGAT promoter was found to be unmethylated. AGAT protein was present in 5/11 patients. All patients had an intact mismatch repair pathway. Thirteen patients had HCT-CI scores of 0–2. Six patients (6/13) achieved a complete remission (CR) after 1 cycle of therapy (1/2 for patients with methylated and 5/11 for patients with unmethylated AGAT promoter). Nonhematologic toxicities were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Three patients remain in CR with a median duration of 22 weeks (14–36 weeks). Seven patients have died from disease progression, while two patients died of neutropenic sepsis (early deaths). With a median follow-up of 38 weeks (10–48), the median overall survival for the entire population is 12 weeks (3.5 - 38) weeks (responders 26.5 weeks). Conclusions: These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status. [Table: see text]

Age-Specific Differences in Oncogenic Pathway Dysregulation in Patients With Acute Myeloid Leukemia

2009 ◽  
Vol 27 (33) ◽  
pp. 5580-5586 ◽  
Author(s):  
Arati V. Rao ◽  
Peter J.M. Valk ◽  
Klaus H. Metzeler ◽  
Chaitanya R. Acharya ◽  
Sascha A. Tuchman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Treatment Strategies ◽  
Gene Set Enrichment Analysis ◽  
Oncogenic Signaling ◽  
Younger Patients ◽  
Pathway Activation ◽  
Acute Myeloid

Purpose To define the biology driving the aggressive nature of acute myeloid leukemia (AML) in elderly patients. Patients and Methods Clinically annotated microarray data from 425 patients with newly diagnosed de novo AML from two publicly available data sets were analyzed after age-specific cohorts (young ≤ 45 years, n = 175; elderly ≥ 55 years; n = 144) were prospectively identified. Gene expression analysis was conducted utilizing gene set enrichment analysis, and by applying previously defined and tested signature profiles reflecting dysregulation of oncogenic signaling pathways and altered tumor environment. Results Elderly AML patients as expected had worse overall survival and event-free survival compared with younger patients. Analysis of oncogenic pathways revealed that older patients had higher probability of RAS, Src, and tumor necrosis factor (TNF) pathway activation (all P < .0001). Hierarchical clustering revealed that younger patients with AML in cluster 2 had clinically worse survival, with high RAS, Src, and TNF pathway activation compared with patients in cluster 1. However, among elderly patients with AML, those in cluster 1 also demonstrated high RAS, Src, and TNF pathway activation but this did not translate into differences in survival. Conclusion AML in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathway variations that contributes to poor survival. These insights should enable development and adjustments of clinically meaningful treatment strategies in the older patient population.

Sorafenib in Combination With Intensive Chemotherapy in Elderly Patients With Acute Myeloid Leukemia: Results From a Randomized, Placebo-Controlled Trial

2013 ◽  
Vol 31 (25) ◽  
pp. 3110-3118 ◽  
Author(s):  
Hubert Serve ◽  
Utz Krug ◽  
Ruth Wagner ◽  
M. Cristina Sauerland ◽  
Achim Heinecke ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Controlled Trial ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Subgroup Analyses ◽  
Acute Myeloid

Purpose The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML. Patients and Methods All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary objective was to test for an improvement in event-free survival (EFS). Overall survival (OS), complete remission (CR) rate, tolerability, and several predefined subgroup analyses were among the secondary objectives. Results Age, sex, CR and early death (ED) probability, and prognostic factors were balanced between both study arms. Treatment in the sorafenib arm did not result in significant improvement in EFS or OS. This was also true for subgroup analyses, including the subgroup positive for FLT3 internal tandem duplications. Results of induction therapy were worse in the sorafenib arm, with higher treatment-related mortality and lower CR rates. More adverse effects occurred during induction therapy in the sorafenib arm, and patients in this arm received less consolidation chemotherapy as a result of higher induction toxicity. Conclusion In conclusion, combination of standard induction and consolidation therapy with sorafenib in the schedule investigated in our trial is not beneficial for elderly patients with AML.

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