Cytarabine Dose of 36 g/m2 Compared With 12 g/m2 Within First Consolidation in Acute Myeloid Leukemia: Results of Patients Enrolled Onto the Prospective Randomized AML96 Study

2011 ◽  
Vol 29 (19) ◽  
pp. 2696-2702 ◽  
Author(s):  
Markus Schaich ◽  
Christoph Röllig ◽  
Silke Soucek ◽  
Michael Kramer ◽  
Christian Thiede ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Adults ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
High Dose ◽  
Serious Adverse Events ◽  
Hematopoietic Stem ◽  
Acute Myeloid ◽  
Intermediate Dose

Purpose To assess the optimal cumulative dose of cytarabine for treatment of young adults with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. Patients and Methods Between 1996 and 2003, 933 patients (median age, 47 years; range 15 to 60 years) with untreated AML were randomly assigned at diagnosis to receive cytarabine within the first consolidation therapy at either a intermediate-dose of 12 g/m2 (I-MAC) or a high-dose of 36 g/m2 (H-MAC) combined with mitoxantrone. Autologous hematopoietic stem-cell transplantation or intermediate-dose cytarabine (10 g/m2) were offered as second consolidation. Patients with a matched donor could receive an allogeneic transplantation in a risk-adapted manner. Results After double induction therapy including intermediate-dose cytarabine (10 g/m2), mitoxantrone, etoposide, and amsacrine, complete remission was achieved in 66% of patients. In the primary efficacy analysis population, a consolidation with either I-MAC or H-MAC did not result in significant differences in the 5-year overall (30% v 33%; P = .77) or disease-free survival (37% v 38%; P = .86) according to the intention-to-treat analysis. Besides a prolongation of neutropenia and higher transfusion demands in the H-MAC arm, rates of serious adverse events were comparable in the two groups. Conclusion In young adults with AML receiving intermediate-dose cytarabine induction, intensification of the cytarabine dose beyond 12 g/m2 within first consolidation did not improve treatment outcome.

High-Dose Cytarabine Consolidation With or Without Additional Amsacrine and Mitoxantrone in Acute Myeloid Leukemia: Results of the Prospective Randomized AML2003 Trial

2013 ◽  
Vol 31 (17) ◽  
pp. 2094-2102 ◽  
Author(s):  
Markus Schaich ◽  
Stefani Parmentier ◽  
Michael Kramer ◽  
Thomas Illmer ◽  
Friedrich Stölzel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Outcome ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Disease Free Survival ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Purpose To assess the treatment outcome benefit of multiagent consolidation in young adults with acute myeloid leukemia (AML) in a prospective, randomized, multicenter trial. Patients and Methods Between December 2003 and November 2009, 1,179 patients (median age, 48 years; range, 16 to 60 years) with untreated AML were randomly assigned at diagnosis to receive either standard high-dose cytarabine consolidation with three cycles of 18 g/m2 (3× HD-AraC) or multiagent consolidation with two cycles of mitoxantrone (30 mg/m2) plus cytarabine (12 g/m2) and one cycle of amsacrine (500 mg/m2) plus cytarabine (10 g/m2; MAC/MAMAC/MAC). Allogeneic and autologous hematopoietic stem-cell transplantations were performed in a risk-adapted and priority-based manner. Results After double induction therapy using a 3 + 7 regimen including standard-dose cytarabine and daunorubicin, complete remission was achieved in 65% of patients. In the primary efficacy population of patients evaluable for consolidation outcomes, consolidation with either 3× HD-AraC or MAC/MAMC/MAC did not result in any significant difference in 3-year overall (69% v 64%; P = .18) or disease-free survival (46% v 48%; P = .99) according to the intention-to-treat analysis. Furthermore, MAC/MAMAC/MAC led to additional GI and hepatic toxicity and a higher rate of infection and bleeding, resulting in significantly shorter 3-year overall survival in the per-protocol analysis compared with 3× HD-AraC (63% v 72%; P = .04). Conclusion In younger adults with AML, multiagent consolidation using mitoxantrone and amsacrine in combination with high-dose cytarabine does not improve treatment outcome and confers additional toxicity.

scholarly journals Extramedullary acute myeloid leukemia presenting in young adults demonstrates sensitivity to high-dose anthracycline: a subset analysis from ECOG-ACRIN 1900

Haematologica ◽  
2018 ◽  
Vol 104 (4) ◽  
pp. e147-e150 ◽  
Author(s):  
Hugo F. Fernandez ◽  
Zhuoxin Sun ◽  
Mark R. Litzow ◽  
Selina M. Luger ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Adults ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Subset Analysis ◽  
Acute Myeloid

Safety and feasibility of outpatient high-dose cytarabine and intermediate-dose cytarabine for consolidation therapy in acute myeloid leukemia

2021 ◽  
pp. 107815522110465
Author(s):  
Wenhui Li ◽  
Katherine Richter ◽  
Jamie Lee ◽  
Kevin McCarthy ◽  
Timothy Kubal
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Outpatient Setting ◽  
Cancer Center ◽  
High Dose ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Incidence Of Hospitalization ◽  
Acute Myeloid ◽  
Intermediate Dose

Introduction The standard of care consolidation therapy for acute myeloid leukemia is high-dose cytarabine or intermediate-dose cytarabine, which are traditionally given inpatient. At Moffitt Cancer Center, we have moved the administration of high-dose cytarabine and intermediate-dose cytarabine to the outpatient setting through the inpatient/outpatient program. To facilitate outpatient administration, high-dose cytarabine and intermediate-dose cytarabine are given in a shorter interval of every 10 h instead of 12 h. The safety of a shorter duration interval of high-dose cytarabine and intermediate-dose cytarabine is unknown. This study aims to assess the safety and feasibility of administering high-dose cytarabine and intermediate-dose cytarabine consolidation therapy in the inpatient/outpatient setting. Methods This is a retrospective chart review to analyze acute myeloid leukemia patients treated with inpatient/outpatient high-dose cytarabine or intermediate-dose cytarabine consolidation therapy at Moffitt Cancer Center from January 1, 2015, through November 1, 2018. The primary objective was to determine the incidence of hospitalization during the inpatient/outpatient administration of high-dose cytarabine or intermediate-dose cytarabine. Results Two hundred fifty-three of 255 cycles of high-dose cytarabine/intermediate-dose cytarabine were delivered outpatient over the reviewed time period to 118 patients. No patients receiving outpatient high-dose cytarabine/intermediate-dose cytarabine consolidation required hospitalization during chemotherapy. Our incidence of hospitalization (24%) after chemotherapy is consistent with the reported literature. Through the inpatient/outpatient administration of high-dose cytarabine and intermediate-dose cytarabine, 1265 inpatient days were saved with an approximate revenue of $3,135,176 generated in our study period. Conclusion Inpatient/outpatient administration of high-dose cytarabine and intermediate-dose cytarabine is both safe and feasible. Moving high-dose cytarabine/intermediate-dose cytarabine administration to the outpatient setting resulted in significant additional revenue vs. inpatient administration.

Distinct association of RUNX family expression with genetic alterations and clinical outcome in acute myeloid leukemia

2020 ◽  
Vol 29 (3) ◽  
pp. 387-397
Author(s):  
Yangli Zhao ◽  
Tingjuan Zhang ◽  
Yangjing Zhao ◽  
Jingdong Zhou
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Genetic Alterations ◽  
Differentially Expressed ◽  
Aberrant Expression ◽  
Hematopoietic Stem ◽  
Frequent Event ◽  
Acute Myeloid

BACKGROUND: The runt-related transcription factor family (RUNXs) including RUNX1, RUNX2, and RUNX3 are key transcriptional regulators in normal hematopoiesis. RUNXs dysregulations caused by aberrant expression or mutation are frequently seen in various human cancers especially in acute myeloid leukemia (AML). OBJECTIVE: We systemically analyzed the expression of RUNXs and their relationship with clinic-pathological features and prognosis in AML patients. METHODS: Expression of RUNXs was analyzed between AML patients and normal controls from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Correlations between RUNXs expression and clinical features together with survival were further analyzed. RESULTS: All RUNXs expression in AML patients was significantly increased as compared with controls. RUNXs expression was found to be significantly associated with genetic abnormalities such as RUNX1 mutation, t(8;21) and inv(16)/t(16;16). By Kaplan-Meier analysis, only RUNX3 overexpression was associated with shorter overall survival (OS) and disease-free survival (DFS) among non-M3 AML patients. Notably, in high RUNX3 expression groups, patients received hematopoietic stem cell transplantation (HSCT) had markedly better OS and DFS than patients without HSCT among both all AML and non-M3 AML. In low RUNX3 expression groups, there were no significant differences in OS and DFS between HSCT and non-HSCT groups among both all AML and non-M3 AML. In addition, a total of 835 differentially expressed genes and 69 differentially expressed microRNAs were identified to be correlated with RUNX3 expression in AML. CONCLUSION: RUNXs overexpression was a frequent event in AML, and was closely associated with diverse genetic alterations. Moreover, RUNX3 expression may be associated with clinical outcome, and helpful for guiding treatment choice between HSCT and chemotherapy in AML.

scholarly journals A randomized study of high-dose cytarabine in induction in acute myeloid leukemia [see comments]

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1710-1717 ◽  
Author(s):  
JF Bishop ◽  
JP Matthews ◽  
GA Young ◽  
J Szer ◽  
A Gillett ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
Dose Effect ◽  
Induction Treatment ◽  
High Dose ◽  
Remission Duration ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years, presenting with newly diagnosed acute myeloid leukemia (AML) were randomized to receive either high-dose cytarabine, 3 g/m2 12 hourly on days 1, 3, 5, and 7 for 8 doses, daunorubicin 50 mg/m2 days 1 to 3, etoposide 75 mg/m2 days 1 to 7, (HIDAC-3–7) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above (7–3–7). Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5–2–5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC- 3–7 and 74% with 7–3–7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3–7 and 12 months with 7–3– 7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3–7 and 24% on 7–3–7. Patients in CR tended to survive longer with HIDAC-3–7 but there were no overall survival differences between the two arms. HIDAC-3–7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7–3–7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3–7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC- 3–7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.

Low Platelet Counts at Diagnosis Predict Better Survival for Patients with Intermediate-Risk Acute Myeloid Leukemia

2019 ◽  
Vol 143 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Yimin Zhang ◽  
Haihui Gu ◽  
Qi Chen ◽  
Ying Zhang ◽  
Hui Cheng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Negative Impact ◽  
Disease Free Survival ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Risk Patients ◽  
Immature Cells ◽  
Acute Myeloid

Background: Aggressive growth of primitive and immature cells in the bone marrow results in reductions in megakaryocyte and platelet (PLT) counts, leading to thrombocytopenia in acute myeloid leukemia (AML). However, not all AML patients show thrombocytopenia at the time of diagnosis, and the association of PLT count with patient survival is largely unknown. Methods: A retrospective study was performed to determine PLT counts at diagnosis in the peripheral blood in 291 newly diagnosed AML patients and assess the association of PLT counts with the overall survival (OS) and disease-free survival (DFS) of these patients. Results: Low PLT counts (≤40 × 109/L) were associated with better outcomes for the whole cohort (5-year OS, 55.1 ± 3.8 vs. 35.3 ± 3.5%, p < 0.001; 5-year DFS, 49.1 ± 3.8 vs. 25.7 ± 4.0%, p < 0.001) and intermediate-risk patients (5-year OS, 64.5 ± 5.4 vs. 41.0 ± 4.8%, p < 0.001; 5-year DFS, 60.8 ± 5.6 vs. 28.6 ± 5.6%, p < 0.001). Moreover, low PLT counts were related to deeper molecular remission. Low PLT counts correlated with better survival of intermediate-risk AML patients treated with chemotherapy only. Allogeneic hematopoietic stem cell transplantation attenuated the negative impact of high PLT counts on the survival of intermediate-risk patients. Furthermore, univariate and multivariate analyses demonstrated that PLT count at diagnosis was an independent prognostic factor for intermediate-risk AML. Conclusion: PLT count at diagnosis predicts survival for patients with intermediate-risk AML.

Mitoxantrone, Etoposide, and Intermediate-Dose Cytarabine in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia : Single-Center Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4007-4007
Author(s):  
Hwa Jung Sung ◽  
Eui Bae Kim ◽  
Se Ryeon Lee ◽  
Hee Yun Seo ◽  
Kyong Hwa Park ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Salvage Chemotherapy ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Relapsed Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Background: The results of salvage chemotherapy for patient with refractory or relapsed acute myeloid leukemia(AML) have been generally disappointing with low response rates and occasional long-term survivors in most studies. Since therapeutic failure seems to be inevitable in the great majority of these patients, development of more effective salvage therapy is warranted. Recent approaches to the treatment of previously treated AML generally involved the use of cytarabine in intermediate or high-dose alone or in association with new intercalating agents, such as amsacrine, mitoxantrone or idarubicin, etoposide, or asparaginase. Methods: A single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for 1 hour, and cytarabine (Ara-C) 1g/m2 IV for 6 hours daily for 6 days (MEC), has been proposed as a salvage regimen. Between October 1998 and May 2005, thirty refractory/relapsed AML patients have been treated by MEC salvage chemotherapy. Twenty two patients were in relapse and eight patients were refractory after conventional induction chemotherapy including cytarabine and idarubicin or mitoxantrone. Two patient were in relapse after allogenous hematopoietic stem cell transplantation(SCT). Results: Complete remission(CR) was obtained in 12 of 30 patients(40%) and 3 of 30(10%) died during salvage treatment: 2 due to intracranial hemorrhage and 1 due to fungemia sepsis. After CR achievement, 5 patients received consolidation chemotherapy. Two patients with an HLA-identical sibling donor underwent allogeneic SCT, and one patient received autologous SCT. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 90% of patients. Nonhematologic toxicity was minimal. At the time of analysis, 9 of 11 patients who achieved CR have relapsed. Median disease-free survival was 12 months. Median overall survival was 13.5 months. There were only two longterm remitters. Several clinicolaboratory and treatment-related variables were analyzed to determine their prognostic significance for CR achievement, duration of CR, overall survival. Conclusions: Our results suggest that MEC combination chemotherapy might induce CR in a patient with refractory or relapsed AML, although new agents or new therapeutic strategies should be required for long term remission.

Inhibition of HDAC8 Reactivates p53 and Abrogates Leukemia Stem Cell Activity in CBFβ-SMMHC Associated Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 363-363
Author(s):  
Jing Qi ◽  
Qi Cai ◽  
Sandeep Singh ◽  
Ling Li ◽  
Hongjun Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Cell Activity ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Acute Myeloid

Abstract The inv(16)-created CBFβ-SMMHC fusion protein inhibits differentiation of hematopoietic stem and progenitor cells (HSPCs) and creates pre-leukemic populations predisposed to acute myeloid leukemia (AML) transformation. However, the molecular mechanism underlying the leukemogenic function of CBFβ-SMMHC has been elusive. Given the low TP53 mutation rate in AML, alternative mechanisms disrupting p53 function are expected. We showed thatCBFβ-SMMHC impairs p53 acetylation and p53 target gene activation through formation of an aberrant protein complex with p53 and HDAC8 (Blood, 120: A772; 122(21): 224). We now show that CBFβ-SMMHC binds to p53 and HDAC8 independently through distinct regions and that HDAC8 mediates the deacetylation of p53 associated with CBFβ-SMMHC. In addition, we generated mice carrying a floxed Hdac8 (Hdac8f) allele and crossed with Cbfb56M/+/Mx1-Cre (Kuo YH et al, Cancer Cell 2006). Deletion of Hdac8 signifiacntly (p<0.0001) reduced the incidence of AML and prolonged disease-free survival. Pharmacologic inhibition of HDAC8 activity with HDAC8-selective inhibitors (HDAC8i) reactivates p53 and selectively induces apoptosis of inv(16)+ AML CD34+ cells while sparing normal HSPCs. To test the effect of HDAC8i on LSC engraftment and leukemia-initiating capacity, we generated Cbfb56M/+/Mx1-Cre mice with a Cre-reporter line expressing tdTomato fluorescence protein following Cre-mediated recombination. AML cells (dTomato+/cKit+) treated with HDAC8i (22d) ex vivo showed reduced engraftment (p=0.025) and enhanced survival (p=0.025) in transplanted mice. To examine whether HDAC8i 22d treatment affects the engraftment capacity on surviving cells, we transplanted equal number (2 x 106) of AML cells treated with either 22d or vehicle in another cohort of mice (n=4). We show that HDAC8i 22d treatment reduced the engraftment of dTomato+/cKit+ AML cells and enhanced survival, suggesting that the engraftment capacity is altered in addition to reducing AML cell survival. We next performed preclinical studies to determine the efficacy of in vivo administration of HDAC8i 22d. AML transplanted mice were randomized into two groups, one group treated with vehicle and the other treated with HDAC8i 22d for 2 weeks. Flow cytometry analysis revealed significantly reduced frequency (p=0.0097) and number (p=0.0101) of dTomato+/cKit+ AML cells in the bone marrow and spleen of 22d treated mice compared to vehicle treated group. To further assess the impact on LSC activity, we transplanted bone marrow cells from these treated mice into secondary recipients and analyzed for AML engraftment. Significant reduction in the frequency (p<0.0001) and the number (p=0.0006) of dTomato+/cKit+ AML cells was observed in the bone marrow and spleen. Furthermore, HDAC8i 22d treated transplants showed no signs of leukemia while vehicle treated transplants are moribund with aggressive AML. These results indicate that HDAC8 inhibition by 22d treatment effectively eliminates engraftment and leukemia-initiating capacity of AML LSCs. In conclusion, our studies identify a novel post-translational p53-inactivating mechanism and demonstrate selective HDAC8 inhibition as a promising approach to target inv(16)+ AML LSCs. Disclosures No relevant conflicts of interest to declare.

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