Treatment for Primary Acute Myeloid Leukemia: Results of Two Consecutive Trials From the Spanish CETLAM Group Showing Improvement with the Use of G-CSF Priming and Precise Risk-Adapted Therapy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1066-1066
Author(s):  
Jorge Sierra ◽  
Montserrat Hoyos ◽  
Josep F. Nomdedeu ◽  
Jordi Esteve ◽  
Rafael F. Duarte ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Adult Patients ◽  
High Dose ◽  
Phase Ii Trials ◽  
Molecular Abnormalities ◽  
Factors Influencing ◽  
Leukocyte Counts ◽  
Postremission Therapy ◽  
Acute Myeloid

Abstract Abstract 1066 Different approaches have been investigated to improve the prognosis of adult patients with primary acute myeloid leukemia. In two consecutive phase II trials our group has explored the use of intermediate-dose cytarabine in induction associated with idarubicin and etoposide, the addition of G-CSF priming to the previous combination, and risk-adapted postremission therapy. Objective: To compare the results of two consecutive trials for primary AML and to analyze the factors influencing the outcome. Patients and methods: Adult patients between 17 and 60 years of age with de novo AML, diagnosed between 1999 and 2009, were included in the CETLAM AML-99 and AML-03 trials. Induction chemotherapy (CT) included one or two courses of idarubicin 12 mg/m2 IV days 1,3,5, cytarabine 500 mg/m2/12h over 2h IV days 1,3,5,7 and etoposide 100 mg/m2 IV days 1,2,3. This was followed by one consolidation with mitoxantrone 12 mg/m2 IV from day 4 to 6, and cytarabine 500 mg/m2/12h IV from day 1–6. In the AML 03 trial, patients also received G-CSF priming, 150 mg/m2 subcutaneously (SC) from day 0 to the last day of induction and consolidation CT. Postremission therapy consisted of high-dose cytarabine (CBF AML), autologous or allogeneic hematopoietic transplantation depending on cytogenetics, courses to complete remission (CR), and in the AML-03 protocol also based on molecular abnormalities involving FLT3 or MLL genes and/or the persistence of minimal residual disease after consolidation. Results: Overall, 788 patients were included, 353 in the AML-99 trial and 435 in the AML-03. Median age of the patients was 46 years (range 17–60). There were no differences between patients included in the two protocols regarding age, gender, leukocyte counts, cytogenetics and proportion of favourable and unfavourable molecular cases in the group with intermediate-risk karyotype. The main results achieved appear in the table. Multivariate analysis confirmed the favourable impact of AML-03 protocol on outcome. Other significant factors influencing survival were age, leukocyte counts and cytogenetics. Conclusion: G-CSF priming improved the CR rate of adult patients with primary AML and favourable or unfavourable cytogenetics. This fact and a more precise risk-adapted therapy taking into account genetic data and MRD studies translated into improved overall survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Varying intensity of postremission therapy in acute myeloid leukemia

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1924-1930 ◽  
Author(s):  
PA Cassileth ◽  
E Lynch ◽  
JD Hines ◽  
MM Oken ◽  
JJ Mazza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mortality Rate ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Allogeneic Bone ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Postremission Therapy ◽  
Acute Myeloid

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6- thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four- year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therapy do not differ significantly, a larger number of patients need to be studied before concluding that they are equivalent.

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.

Most Risk-Stratification Molecular Markers in Acute Myeloid Leukemia (AML) Are Rarely Found in Early Childhood AML in the Middle Eastern Population

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5239-5239
Author(s):  
Hala Abalkhail ◽  
Hassan El-Solh ◽  
Amal Alseraihy ◽  
Asim F Belgaumi ◽  
Abdullah Al-Jefri ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Early Childhood ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Adult Patients ◽  
Intensive Chemotherapy ◽  
Adult Group ◽  
Molecular Abnormalities ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 5239 Background: Acute myeloid leukemia (AML) is biologically heterogeneous with significant molecular and clinical variation. Most of the recent studies suggest that AML in pediatric population differs significantly clinically and biologically from adult AML. Numerous newly described molecular abnormalities in AML have been described in adult patients, but except for rare publications, a little is known about the molecular abnormalities and their clinical relevance in pediatric AML, especially in early childhood and when the patients are treated with intensive chemotherapy followed by hematopoietic stem cell transplant (HSCT). The Saudi Arabian population is known to be genetically homogenous due to high consanguinity. Higher incidence of inherited diseases including certain types of cancer has been reported in Saudi Arabia. We attempted to compare the molecular abnormalities and their clinical relevance in pediatric AML patients from Saudi Arabia with adult AML from the same population. Methods: Samples from 87 adult patients with AML and samples from 40 pediatric AML patients were analyzed for FLT3-ITD and FLT3-D835, IDH1, IDH2, NPM1, and DNMT3A mutations by direct sequencing and by fragment length analysis (FLT3 and NPM1). The prevalence of mutations was compared between the adult and pediatric groups. They included patients with intermediate-risk cytogenetics (N=66 adults, N=26 pediatrics) and adverse cytogenetics (N=21 adults, N=14 pediatrics). The median age of the pediatric patients is 7 years, with a range from less than one year to 14 years. All patients were treated with intensive chemotherapy, followed by HSCT in first remission. Results: FLT3-ITD mutation was detected in 18 patients (21%) of the adult group, but detected only in 3 patients of the pediatric group (7.5%). Two of the 3 patients in the pediatric group carrying the FLT3 mutation died within the first year after the transplant. The FLT3-D835 mutation was detected in 6 patients (7%) of the adult group, while none of the pediatric patients showed this mutation. In addition, the pediatric patients showed no mutations in IDH1 or IDH2, while the adult patients showed IDH1 and IDH2 mutations in 6 (7%) and 7 (8%), respectively. Mutations in the DNMT3A gene were detected in three patients (3%) in the adult group, but were not detected in any of the pediatric AML. NPM1 mutations were detected in 9 (10%) of the adult AML patients, but none of the pediatric patients showed NPM1 mutation. Conclusion: This data suggests that the biology of AML in pediatric patients is significantly different from that in the adult patients. Mutations in FLT3, IDH1, IDH2, NPM1, and DNMT3A genes are very rare in pediatric patients. However, our data involves early childhood (90% younger than 13 years of age) and there is a possibility that older children may have higher incidence of mutations. Most of the currently used molecular markers in risk-stratifying adult AML patients are difficult to use in stratifying pediatric AML patients. Disclosures: No relevant conflicts of interest to declare.

Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study

Blood ◽  
2011 ◽  
Vol 117 (8) ◽  
pp. 2358-2365 ◽  
Author(s):  
Shigeki Ohtake ◽  
Shuichi Miyawaki ◽  
Hiroyuki Fujita ◽  
Hitoshi Kiyoi ◽  
Katsuji Shinagawa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Randomized Study ◽  
Survival Rates ◽  
Adult Patients ◽  
High Dose ◽  
Acute Myeloid

Abstract We conducted a multi-institutional randomized study to determine whether high-dose daunorubicin would be as effective as standard-dose idarubicin in remission-induction therapy for newly diagnosed adult patients younger than 65 years of age with acute myeloid leukemia. Of 1064 patients registered, 1057 were evaluable. They were randomly assigned to receive either daunorubicin (50 mg/m2 daily for 5 days) or idarubicin (12 mg/m2 daily for 3 days) in combination with 100 mg/m2 of cytarabine by continuous infusion daily for 7 days as induction therapy. Complete remission was achieved in 407 (77.5%) of 525 patients in the daunorubicin group and 416 (78.2%) of 532 in the idarubicin group (P = .79). Patients achieving complete remission received intensive postremission therapy that consisted of either 3 courses of high-dose cytarabine or 4 courses of standard-dose therapy. Overall survival rates at 5 years were 48% for the daunorubicin group and 48% for the idarubicin group (P = .54), and relapse-free survival rates at 5 years were 41% and 41% (P = .97), respectively. Thus, high-dose daunorubicin and standard-dose idarubicin were equally effective for the treatment of adult acute myeloid leukemia, achieving a high rate of complete remission and good long-term efficacy. This study is registered at http://www.umin.ac.jp/ctrj/ as C000000157.

High-dose cytosine arabinoside and daunorubicin postremission therapy in adults with de novo acute myeloid leukemia

1995 ◽  
Vol 71 (5) ◽  
pp. 219-225 ◽  
Author(s):  
G. Heil ◽  
P. S. Mitrou ◽  
D. Hoelzer ◽  
M. Freund ◽  
H. Link ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cytosine Arabinoside ◽  
Myeloid Leukemia ◽  
De Novo ◽  
High Dose ◽  
Postremission Therapy ◽  
Acute Myeloid

HLA-Mismatched Stem-Cell Microtransplantation As Postremission Therapy for Acute Myeloid Leukemia: Long-Term Follow-Up

2012 ◽  
Vol 30 (33) ◽  
pp. 4084-4090 ◽  
Author(s):  
Mei Guo ◽  
Kai-Xun Hu ◽  
Guang-Xian Liu ◽  
Chang-Lin Yu ◽  
Jian-Hui Qiao ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Chromosome Analysis ◽  
High Dose ◽  
Peripheral Blood Stem Cells ◽  
Postremission Therapy ◽  
Acute Myeloid

Purpose Despite best current therapies, approximately half of patients with acute myeloid leukemia in first complete remission (AML-CR1) with no HLA-identical donors experience relapse. Whether HLA-mismatched stem-cell microtransplantation as a novel postremission therapy in these patients will improve survival and avoid graft-versus-host disease (GVHD) is still unknown. Patients and Methods One hundred one patients with AML-CR1 (9 to 65 years old) from four treatment centers received programmed infusions of G-CSF–mobilized HLA-mismatched donor peripheral-blood stem cells after each of three cycles of high-dose cytarabine conditioning without GVHD prophylaxis. Donor chimerism and microchimerism and WT1+CD8+ T cells were analyzed. Results The 6-year leukemia-free survival (LFS) and overall survival (OS) rates were 84.4% and 89.5%, respectively, in the low-risk group, which were similar to the rates in the intermediate-risk group (59.2% and 65.2%, respectively; P = .272 and P = .308). The 6-year LFS and OS were 76.4% and 82.1%, respectively, in patients who received a high dose of donor CD3+ T cells (≥ 1.1 × 108/kg) in each infusion, which were significantly higher than the LFS and OS in patients who received a lower dose (< 1.1 × 108/kg) of donor CD3+ T cells (49.5% and 55.3%, respectively; P = .091 and P = .041). No GVHD was observed in any of the patients. Donor microchimerism (2 to 1,020 days) was detected in 20 of the 23 female patients who were available for Y chromosome analysis. A significant increase in WT1+CD8+ T cells (from 0.2% to 4.56%) was observed in 33 of 39 patients with positive HLA-A*02:01 antigen by a pentamer analysis. Conclusion Microtransplantation as a postremission therapy may improve outcomes and avoid GVHD in patients with AML-CR1.

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

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.

Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4372-4380 ◽  
Author(s):  
Stefan Fröhling ◽  
Richard F. Schlenk ◽  
Jochen Breitruck ◽  
Axel Benner ◽  
Sylvia Kreitmeier ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Serum Lactate Dehydrogenase ◽  
High Dose ◽  
Remission Duration ◽  
Flt3 Mutations ◽  
High Dose Cytarabine ◽  
Postremission Therapy ◽  
Normal Cytogenetics ◽  
Acute Myeloid

To assess the prognostic relevance of activating mutations of theFLT3 gene in homogeneously treated adults 16 to 60 years of age with acute myeloid leukemia (AML) and normal cytogenetics, pretreatment samples from 224 patients entered into 2 consecutive multicenter treatment trials were analyzed for FLT3internal tandem duplications (ITDs) and Asp835 mutations. Treatment included intensive double-induction therapy and postremission therapy with high cumulative doses of high-dose cytarabine. ITDs were detected in 32% of the patients and were related to de novo AML and to high white blood cell (WBC) counts, percentages of peripheral blood (PB) and bone marrow (BM) blasts, and serum lactate dehydrogenase levels. Asp835 mutations were present in 14% of the patients and were associated with WBC counts and percentages of PB and BM blasts that were higher than those of patients without FLT3mutations. With a median follow-up of 34 months, remission duration and overall survival (OS) were significantly shorter for patients with Asp835 mutations or an ITD than for those without FLT3 mutations (P = .03 and P = .0004, respectively). These results were attributable mainly to the negative prognostic effect of FLT3 ITDs. On multivariate analysis, mutantFLT3 was an independent marker affecting remission duration and OS (hazard ratio, 2.35 and 2.11, respectively). Fluorescence in situ hybridization did not detect monoallelicFLT3 deletions in ITD-positive patients. FLT3mutations identify a subset of young AML patients with normal cytogenetics who do not benefit from intensive chemotherapy, including double-induction and postremission therapy with high-dose cytarabine.

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