scholarly journals Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801

2020 ◽  
Vol 4 (4) ◽  
pp. 696-705 ◽  
Author(s):  
Guido Marcucci ◽  
Susan Geyer ◽  
Kristina Laumann ◽  
Weiqiang Zhao ◽  
Donna Bucci ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
Disease Free ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) with either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) is referred to as core binding factor (CBF) AML. Although categorized as favorable risk, long-term survival for these patients is only ∼50% to 60%. Mutated (mut) or overexpressed KIT, a gene encoding a receptor tyrosine kinase, has been found almost exclusively in CBF AML and may increase the risk of disease relapse. We tested the safety and clinical activity of dasatinib, a multi-kinase inhibitor, in combination with chemotherapy. Sixty-one adult patients with AML and CBF fusion transcripts (RUNX1/RUNX1T1 or CBFB/MYH11) were enrolled on Cancer and Leukemia Group B (CALGB) 10801. Patients received cytarabine/daunorubicin induction on days 1 to 7 and oral dasatinib 100 mg/d on days 8 to 21. Upon achieving complete remission, patients received consolidation with high-dose cytarabine followed by dasatinib 100 mg/d on days 6 to 26 for 4 courses, followed by dasatinib 100 mg/d for 12 months. Fifteen (25%) patients were older (aged ≥60 years); 67% were CBFB/MYH11–positive, and 19% harbored KITmut. There were no unexpected or dose-limiting toxicities. Fifty-five (90%) patients achieved complete remission. With a median follow-up of 45 months, only 16% have relapsed. The 3-year disease-free survival and overall survival rates were 75% and 77% (79% and 85% for younger patients [aged <60 years], and 60% and 51% for older patients). Patients with KITmut had comparable outcome to those with wild-type KIT (3-year rates: disease-free survival, 67% vs 75%; overall survival, 73% vs 76%), thereby raising the question of whether dasatinib may overcome the negative impact of these genetic lesions. CALGB 10801 was registered at www.clinicaltrials.gov as #NCT01238211.

scholarly journals Conventional chemotherapy for acute myeloid leukemia: a Brazilian experience

2000 ◽  
Vol 118 (6) ◽  
pp. 173-178 ◽  
Author(s):  
Kátia Borgia Barbosa Pagnano ◽  
Fabiola Traina ◽  
Tatiana Takahashi ◽  
Gislaine Borba Oliveira ◽  
Marta Soares Rossini ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Free Survival ◽  
Conventional Chemotherapy ◽  
Free Survival ◽  
Disease Free ◽  
Acute Myeloid

CONTEXT: Young patients affected by acute myeloid leukemia (AML) achieve complete remission (CR) using conventional chemotherapy in about 55-85%. However, 30% of patients fail to achieve CR and the remission duration is often only about 12 months. More intensive treatment after CR seems to be necessary in order to maintain CR and obtain a definitive cure. In Brazil, few reports have been published on this important subject. OBJECTIVE: The aim of this study was to describe a Brazilian experience in the treatment of "de novo" acute myeloid leukemia (AML) in younger adult patients (age < 60 years). DESIGN: Retrospective analysis. SETTING: University Hospital, Hematology and Hemotherapy Center, State University of Campinas, Brazil. PARTICIPANTS: Newly diagnosed cases of "de novo" AML in the period from January 1994 to December 1998 were evaluated retrospectively, in relation to response to treatment, overall survival (OS) and disease free survival (DFS). Cases with acute promyelocytic leukemia (APL) were also included in this analysis. RESULTS: On the basis of an intention to treat, 78 cases of AML, including 17 cases of APL, were evaluated. The overall median follow-up was 272 days. The complete remission (CR) rate was 63.6% in the AML group (excluding APL) and 78% in the APL group. The 5-year estimated disease-free survival (DFS) was 80% for the APL group and 34% for the AML group (P = 0.02). The 5-year estimated overall survival (OS) was 52% for the APL group and 20.5% for the AML group, respectively (P = NS). Relapse was observed in 12/39 (30.7%) patients with AML and 1/11 (9%) with APL. CONCLUSIONS: These results are similar to those reported in the literature. However, relapse and mortality rates remain high, and a search for more aggressive strategies in order to prevent relapse is recommended.

Autologous Bone Marrow Transplantation as an Intensive Consolidation Therapy for Adult Patients in Remission from Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5121-5121
Author(s):  
Andre S. Jung ◽  
Asad Bashey ◽  
Peter R. Holman ◽  
Eva Carrier ◽  
Januario Castro ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Consolidation Therapy ◽  
Free Survival ◽  
Risk Patients ◽  
Disease Free ◽  
Acute Myeloid

Abstract Introduction: Autologous peripheral blood stem/progenitor cell transplantation (APBSCT) has been investigated as a potential therapeutic option to improve outcome in patients with acute myeloid leukemia. The optimal consolidation therapy for adults in remission without a histo-compatible donor has yet to be clearly established. Patients and Methods: This was a retrospective analysis of forty patients (23 females and 17 males) diagnosed with de novo acute myeloid leukemia, who were without a histo-compatible donor, that underwent APBSCT between the year 2000 and 2006 at a single institution. The patients’ age ranged from 18 to 73 with a median age of 50. Cytogenetic analysis was available on 37 of the patients. Complete remission (CR) was confirmed by bone marrow morphology and immunophenotype analysis by flow cytometry. Patients in remission were further consolidated with variable cycles of chemotherapy prior to stem cell transplantation. For stem cell mobilization, patients received high-dose cytarabine (2000mg/m2) and etoposide (5mg/kg) for three days followed by G-CSF at 10μg/kg, starting 10 days after the chemotherapy, before the peripheral stem cell collection. The preparative regimen prior to transplantation with unpurged stem/progenitor cells consisted of a combination of intravenous busulfan (0.8 mg/kg for 16 doses) and cyclophosphamide (60 mg/kg for two doses) (37 patients) or busulfan and melphalan (3 patients). Patients were then followed for treatment-related mortality, disease free survival, and overall survival. The analysis was stratified according to age, cytogenetic risk, and remission state. Results: There was no treatment-related mortality. Nineteen out of forty patients had relapse of their disease. The relapse rate was lowest in the low risk cytogenetic group who were under the age of 60 and highest in the high risk cytogenetic group who were over the age of 60. The overall 5 year survival for all patients was 47%. When stratified for cytogenetic risk and age, the overall survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 67%, 59%, and 75% respectively. The overall survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0% respectively. The projected rate of disease free survival at 5 years was 40%. When stratified for cytogenetic risk and age, the disease free survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 33%, 52%, and 50% respectively. Disease free survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0%. Comparing patients in CR1 versus patients in CR2, the overall survival was 47% in CR1 and 50% in CR2. The disease free survival, when grouped as above, were 41% for those in CR1 and 33% for those in CR2. Conclusion: APBSCT is a reasonable and safe intensive consolidation therapy for those patients without a compatible HLA matched donor in first or second complete remissions, notably for those under the age of 60 regardless of their cytogenetic risk. The number of standard consolidations prior to APBSCT may be an important variable predicting outcome.

scholarly journals Prognostic significance of serum ferritin levels on initial diagnosis in patients with acute myeloid leukemia

2021 ◽  
Vol 2 (4) ◽  
pp. 362-370
Author(s):  
Dejan Dudok ◽  
Marijana Virijević
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Serum Ferritin ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Early Death ◽  
Induction Phase ◽  
Free Survival ◽  
Disease Free ◽  
Acute Myeloid

Introduction/Aim: Acute myeloid leukemia (AML) is a heterogenous malignant disease whose course and outcome are influenced by a number of prognostic factors. Serum ferritin (SF) is often elevated in oncology patients, and it has been shown that it strongly influences an unfavorable outcome in various malignancies. The aim of this study is to assess the effect of high SF values on overall survival and disease-free survival, as well as to assess the correlation of SF values with other prognostic markers, such as clinical and laboratory parameters. Methods: Retrospective analysis included 108 patients diagnosed with AML at the Clinic for Hematology of the Clinical Center of Serbia (CCS), in Belgrade, in the period 2017 - 2019. Patients with acute promyelocytic leukemia, acute mixed lineage leukemia, secondary AML and patients treated with palliative therapy were excluded from the study. Patients were grouped based on the SF cutoff value of 800 µg/L. Results: Patients with higher SF values had a significantly higher incidence of early death (p = 0.020), sepsis in the induction phase of therapy (p < 0.010), and significantly lower initial hemoglobin levels (p = 0.040), as compared to patients with lower SF values. SF at diagnosis appeared to be a significant independent predictive factor of overall survival (p = 0.019) and of disease-free survival (p = 0.040). Conclusion: Our study showed a significant association of high SF values with sepsis in induction, early death, mean hemoglobin, overall survival, and disease-free survival. Identification of SF as an independent prognostic factor and a potential target site of the action of new drugs could contribute to a better prognosis of AML patients.

scholarly journals Clinical and experimental efficacy of gemtuzumab ozogamicin in core binding factor acute myeloid leukemia

2017 ◽  
Vol 9 (3) ◽  
Author(s):  
Michele Gottardi ◽  
Federico Mosna ◽  
Sergio De Angeli ◽  
Cristina Papayannidis ◽  
Anna Candoni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Gemtuzumab Ozogamicin ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
Clonogenic Potential ◽  
Acute Myeloid

Leukemia-initiating cells of core binding factor (CBF) acute myeloid leukemia (AML) likely derive from early committed hematopoietic precursors expressing CD33. As such, targeting CD33 could ameliorate the chance of cure of CBF AML patients. We compared 12 CBF AML patients treated with Fludarabine, Cytarabine, Idarubicin and Gemtuzumab Ozogamicin (FLAI-GO regimen) with 25 CBF AML patients treated with the same schedule, but without GO. With the limit of small numbers, we observed a consistent trend toward better overall survival, disease free survival and event free survival in the FLAI-GO group. We also demonstrated the ability of GO to induce the disappearance <em>in vitro</em> of the AML1-ETO molecular transcript in a polymerase chain reaction-positive graft without decreasing the clonogenic potential of CD34+/CD38- cells. This represent the proof of principle for using GO in a purging strategy before autologous stem cell transplantation. Therefore, our data argue in favor of the reinstitution of GO in the therapy of CBF AML.

Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1302-1311 ◽  
Author(s):  
Anthony H. Goldstone ◽  
Alan K. Burnett ◽  
Keith Wheatley ◽  
Alastair G. Smith ◽  
R. Michael Hutchinson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Disease Free Survival ◽  
Free Survival ◽  
To Receive ◽  
Disease Free ◽  
Acute Myeloid

In an attempt to improve induction chemotherapy for older patients with acute myeloid leukemia (AML),1314 patients were randomized to 1 of 3 induction treatments for 2 courses of DAT (daunorubicin, cytarabine, and thioguanine) 3 + 10, ADE (daunorubicin, cytarabine, and etoposide) 10 + 3 + 5, or MAC (mitoxantrone-cytarabine). The remission rate in the DAT arm was significantly better than ADE (62% vs 50%; P = .002) or MAC (62% vs 55%;P = .04). This benefit was seen in patients younger and older than 70 years. There were no differences between the induction schedules with respect to overall survival at 5 years (12% vs 8% vs 10%). A total of 226 patients were randomized to receive granulocyte colony-stimulating factor (G-CSF) or placebo as supportive care from day 8 after the end of treatment course 1. The remission rate or survival were not improved by G-CSF, although the median number of days to recover neutrophils to 1.0 × 109/L was reduced by 5 days. Patients who entered remission (n = 371) were randomized to stop after a third course (DAT 2 + 7) or after 6 courses, ie, a subsequent COAP (cyclophosphamide, vincristine, cytarabine, and prednisolone), DAT 2 + 5, and COAP. The relapse risk (81% vs 73%), disease-free survival (16% vs 23%), and overall survival at 5 years (23% vs 22%) did not differ between the 3-course or 6-course arms. In addition to a treatment duration randomization, 362 patients were randomized to receive 12-month maintenance treatment with low-dose interferon, but no benefit was seen with respect to relapse risk, disease-free survival, or overall survival.

Abnormal Cytogenetics at Date of Morphologic Complete Remission Predicts Short Overall and Disease-Free Survival, and Higher Relapse Rate in Adult Acute Myeloid Leukemia: Results From Cancer and Leukemia Group B Study 8461

2004 ◽  
Vol 22 (12) ◽  
pp. 2410-2418 ◽  
Author(s):  
Guido Marcucci ◽  
Krzysztof Mrózek ◽  
Amy S. Ruppert ◽  
Kellie J. Archer ◽  
Mark J. Pettenati ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Free Survival ◽  
Group B ◽  
Leukemia Group ◽  
Disease Free ◽  
Acute Myeloid

Purpose As most patients with acute myeloid leukemia (AML) with morphologic complete remission (CR) ultimately relapse, better predictors for outcome are needed. Recently, Cheson et al suggested using cytogenetic remission (CRc) as part of the criteria for CR. To our knowledge, ours is the first relatively large study evaluating the usefulness of CRc attained immediately following induction chemotherapy. Patients and Methods We included AML patients treated on Cancer and Leukemia Group B front-line studies with cytogenetic samples obtained at diagnosis and at the first day of documented CR following induction. Patients with abnormal cytogenetics at diagnosis, and normal cytogenetics at CR (NCR; n = 103) were compared with those with abnormal cytogenetics both at diagnosis and at CR (ACR; n = 15) for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). Cox proportional hazards models determined the prognostic significance of cytogenetics at CR, adjusting for other covariates. Results Clinical features were similar for both groups, with the exception of favorable cytogenetics [t(8;21), inv(16)/t(16;16), t(15;17)] at diagnosis, which was more frequent (P = .03) in the NCR group. Median follow-up was 3.1 years (range, 1.0 to 11.4 years). ACR patients had significantly shorter OS (P = .006) and DFS (P = .0001), and higher CIR (P = .0001). In multivariable models, the NCR and ACR groups were predictors for OS (P = .03), DFS (P = .02), and CIR (P = .05). The relative risk of relapse or death was 2.1 times higher for ACR patients than for NCR patients (95% CI, 1.1 to 3.9). Conclusion Our data suggest that converting to normal karyotype at the time of first CR is an important prognostic indicator and support the use of CRc as a criterion of CR in AML.

Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 252-257 ◽  
Author(s):  
Mustafa Benekli ◽  
Zheng Xia ◽  
Kathleen A. Donohue ◽  
Laurie A. Ford ◽  
Lynda A. Pixley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Treatment Outcome ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Signal Transducer ◽  
Free Survival ◽  
Stat Proteins ◽  
Disease Free ◽  
Acute Myeloid

Signal transducer and activator of transcription (STAT) proteins are involved in hematopoietic cytokine receptor signaling pathways that regulate cell proliferation, differentiation, and survival. STATs are dysregulated in acute myeloid leukemia (AML); mechanisms of dysregulation include constitutive activation and truncation of the C-terminal transactivation domain; the latter results in a β isoform that has a trans-dominant negative effect on gene induction mediated by the full-length STATα form. It was hypothesized that constitutive STAT activity might correlate with unfavorable treatment outcome in AML. Pretreatment bone marrow samples from 63 adult patients with AML were analyzed by electrophoretic mobility shift assay for the presence of STAT DNA-binding activity. Isoforms and relative levels of STAT proteins were determined by immunoblotting. Constitutive STAT3 activity was detected in samples from 28 (44%) patients. Pretreatment clinical characteristics, expression of STATα/β isoforms, and treatment regimens did not differ significantly between patients with and without constitutive STAT3 activity. Disease-free survival (DFS) was significantly shorter in patients with than in patients without constitutive STAT3 activity (median 8.7 vs 20.6 months;P = .01). Overall survival did not differ significantly. The subgroup of patients with constitutive STAT3 activity and the STAT3β isoform had the shortest DFS (P = .006) and shorter overall survival (P = .049) than all other patients. Whether adverse treatment outcome is attributable to constitutive STAT activity itself or to a process that leads to constitutive STAT activity remains to be determined. This is the first demonstration of a prognostic significance for STAT proteins in a malignancy.

scholarly journals The Clinical and Biological Effects of the Expression of Dedicator of Cytokinesis 1 (DOCK1) in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1695-1695 ◽  
Author(s):  
Lee Sze Hwei ◽  
Wen-Chien Chou
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
Free Survival ◽  
Disease Free ◽  
Lower Expression ◽  
Acute Myeloid

Abstract Background: DOCK1, also known as DOCK180, is the prototype member of the evolutionarily conserved DOCK superfamily. DOCK1 acts as a guanine nucleotide exchange factor (GEF) which regulates the activation of GTPase Rac, thereby influencing several cellular pathways including cell motility, polarity, invasion, phagocytosis and clearance of apoptotic cells. Overexpression of DOCK1 has been associated with cancer cell migration and invasion, however, its significance in acute myeloid leukemia (AML) remains unexplored. Materials and Methods: Expression patterns of DOCK1 were extracted from 347 AML patients recruited in the National Taiwan University Hospital (NTUH) (Illumina HumanHT-12 v4 Expression BeadChip, Illumina, San Diego, CA). We employed several public datasets, including microarray data of various lineages of normal hematopoiesis and AML marrow (GSE12662, GSE24006, and GSE24759) and The Cancer Genome Atlas (TCGA) RNA sequencing data of AML. In our cohort we analyzed the impacts of DOCK1 expression on various clinical parameters and genetic abnormalities. Survival was analyzed in 227 patients who received standard chemotherapy. The global gene expression profiles associated with DOCK1 expression was analyzed by bioinformatics tools. Two independent cohorts, TCGA (N=183) and GSE12417 (N=61), were used for validating the prognostic significance of DOCK1. Results: DOCK1 is a moderately expressed gene in AML (RPKM, 4.2; ranking, 50.5%). Higher DOCK1 expression level was associated with higher percentages of peripheral blasts (p=0.005), but inversely correlated with favorable cytogenetics such as t(8;21) and t(15;17). Moreover, mutations in CEBPA, c-KIT and IDH2 were less often seen in the patients with higher DOCK1 expression, while FLT3-ITD, and mutations in PTPN11, MLL, NPM1, RUNX1, ASXL1 and DNMT3A happened more often in those with higher DOCK1 expression. The Gene Set Enrichment Analysis (GSEA) of published stem cell signatures suggested DOCK1 as a hematopoietic and leukemic stem cell marker (GSEA P < 0.001 and = 0.004, respectively). Furthermore, it was generally co-expressed with homeobox genes, with average correlations ranging from 0.18 to 0.33 in normal samples, and 0.10 to 0.71 in AML datasets. With a median follow up of 57 months, we observed strong correlation between higher DOCK1 expression levels and inferior overall survival (OS) (median 18.0 months vs 116.8 months, P < 0.001) and disease free survival (DFS) (median 6.4 months vs 96.4 months, P < 0.001) (Figure 1A and 1B). These survival impacts could be validated in the two independent cohorts. In addition, multivariate analysis revealed higher DOCK1 expression as a strong unfavorable prognostic factor for OS (p=0.017) independent of age, karyotype, FLT3-ITD, and mutations of PTPN11, RUNX1, MLL and TP53. Conclusion: To our knowledge, we are the first to present the unique clinical, prognostic, and genetic impacts of DOCK1 in AML. Studies on large prospective cohorts are necessary to confirm our observation. The mechanistic functions of DOCK1 in AML await for further studies. Figure 1A Overall survival of AML patients with higher expression versus lower expression of DOCK1 Figure 1A. Overall survival of AML patients with higher expression versus lower expression of DOCK1 Figure 1B Disease free survival of AML patients with higher expression versus lower expression of DOCK1 Figure 1B. Disease free survival of AML patients with higher expression versus lower expression of DOCK1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcome analysis of acute myeloid leukemia patients treated with high dose daunorubicin

2019 ◽  
Vol 6 (9) ◽  
pp. 3347-3351
Author(s):  
Roya Dolatkhah ◽  
Effat Irani Jam ◽  
Alireza Nikanfar ◽  
Ali Esfahani ◽  
Sayed Hadi Chavooshi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Outcome Analysis ◽  
High Dose ◽  
Free Survival ◽  
Significant Difference ◽  
Disease Free ◽  
Acute Myeloid

Abstract: Acute Myeloid Leukemia (AML) is a malignant hematopoietic disease caused by the presence of a malignant clone in the bone marrow. The classic AML treatment includes a combination of an Anthracycline and Cytarabine. This study aimed to evaluate the effect of high doses of Daunorubicin on patients' outcome. Methods: During the study period, 16 AML patients received induction therapy with Cytarabine (100 mg/m2/d) for 7 days and Daunorubicin (90 mg/m2/d) for 3 days. Outcome analysis was performed to evaluate the overall survival (OS) and disease-free survival (DFS) during 2 years of study. Results: The mean age of patients was 38+/-12.38 years, with the age range between 16 and 54 years old. Seven patients (43.8%) were females, and 9 cases (56.3%) were males. OS was 81.3%, with a mean of 396.88 days. (95% CI: 306.99-486.77). DFS was 83.3%, with a mean of 383.57 days (95% CI: 299.88-467.26). The log-rank test showed a significant difference in DFS of AML sub-types, as M1 subtypes had lower DFS (P log-rank= 0.013). Although M1 subtypes had a lower OS, there was no significant difference in OS between subgroups (P log-rank= 0.067). Conclusion: Although disease-free survival was improved by increasing the dose of daunorubicin, there was no difference in the overall survival between the AML subgroups and sexes.  

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