Twice Daily Fludarabine and Cytarabine Combination Is Effective in Patients with Relapsed/Refractory Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndromes, and Blast Phase Chronic Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3629-3629
Author(s):  
Naval Daver ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Jorge E. Cortes ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Complete Remission ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Abnormal Karyotype ◽  
Blast Phase ◽  
Acute Myeloid

Abstract Abstract 3629 Background: High dose cytarabine containing regimens are still considered standard options for patients (pts) with AML relapsing after a first CR lasting more than 12 months. In a phase I study, 65 patients received fludarabine 15 mg/m2 every 12 hours and cytarabine 0.5 g/m2. Five days of administration were found to be safe and effective with a CR rate of 28%. Aim: This phase II study was conducted to evaluate the efficacy and safety of the combination of twice daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). Methods: Pts with R/R AML, intermediate-2 and high-risk MDS, and CML-BP, whose disease relapsed or was refractory to frontline and/or salvage therapy were eligible. Pts with performance status 0–3 and adequate organ function, received fludarabine 15 mg/m2 intravenously (IV) q12 hours on Days 1 to 5 and cytarabine 0.5 g/m2 IV over 2 hours q12 hours on Days 1 to 5. Gentuzumab ozogamycin (GO) was administered at 3 mg/m2 IV on day 1 in the first 59 pts. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Results: 107 pts were enrolled. The median age was 62 years (range, 19 to 85). 93 pts had AML, 5 had high-risk MDS, and 9 had CML-BP. All pts had received prior therapy. 65 (61%) pts had failed previous intensive chemotherapy, while 42 (39%) had failed targeted and hypomethylating agents. Cytogenetics analysis showed diploid karyotype in 36 (33%) and unfavorable chromosomal abnormalities involving chromosome 5 and 7 in 22 (21%). Of the 107 pts, 52 were in first salvage: first CR duration of less than 12 months in 43 (40%) pts, and more than 12 months in 9 (9%). Overall, 22 pts (21%) achieved complete remission (CR) and 5 (5%) achieved a complete remission without platelet recovery (CRp), for an overall response rate (ORR) of 26% (Table 1). The CR rates for patients with relapsed AML with first CR duration (CRD1) ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 56%, 26%, and 11%, respectively. These compare favorably with the expected response rates in matched cohorts treated at our institution where the ORR were 50%, 11%, and 7%, respectively. A multivariate analysis identified the following 3 factors to be independent adverse prognostic factors for response: abnormal karyotype (versus diploid), second salvage (versus first salvage regardless of the duration of the first CR), and older age (Table 2). With a median follow-up of 7 months, the 6-month event-free survival, overall survival, and complete remission duration (CRD) rates were 18%, 35%, and 70%, respectively. Abnormal karyotype, older age, an increasing in the peripheral blood blasts percentage, and low platelets count (<30 × 109/L) were independently associated with a significant worse overall survival. The most common side effects observed were gastro-intestinal toxicities, including nausea, vomiting, diarrhea, and mucositis. The overall 4-week mortality rate was 9%. Conclusion: BIDFA is active with an ORR of 26% in a heavily pre- treated population. This combination is safe with a low rate of 4-week-mortality of 9%. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Azacitidine Maintenance after Allogeneic Stem Cell Transplantation Is Feasible in Patients with Acute Myeloid Leukemia and Myelodysplasia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5884-5884 ◽  
Author(s):  
Ahmad Antar ◽  
Mohamed A Kharfan-Dabaja ◽  
Hussein Abou Ghaddara ◽  
Rami Mahfouz ◽  
Ali Bazarbachi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Abnormal Karyotype ◽  
Acute Myeloid

Abstract Background: 5-Azacidine (5-AZA) is a DNA hypomethylating agent with proven clinical activity in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A recent non-randomized study reported promising results with the use of lower doses of 5-AZA as maintenance therapy after hematopoietic stem cell transplantation (HSCT). It is important to note that 5-AZA has an immunomodulatory effect and might enhance the graft-versus-leukemia (GVL) effect. Here, we report the successful use of 5-AZA maintenance following allogeneic HSCT in patients with high risk AML and MDS. Patients and methods: Nine patients (M=6, F=3; median age=49 (36-65) years ) with high-risk AML (n=6 including 2 abnormal karyotypes) or MDS (n=3 including 1 abnormal karyotype) received 5-AZA as post-transplant maintenance at a dose of 32mg/m2 daily for 5 days every 4 weeks starting at a median time of 100 (30-210) days post-transplant. All patients were in complete remission at initiation of 5-AZA. A median of 12 cycles (1-18) were delivered. Patients’ characteristics, treatment details, response and side effects are summarized in Table I. Results: After a median follow-up of 19 months post HSCT and 15 months after starting 5-AZA treatment, five patients with normal karyotype are still in CR. Conversely, all three patients with abnormal karyotype rapidly developed disease recurrence while they were receiving 5-AZA after a median of 3 months. Overall, the actuarial 1-year progression free and overall survival rates were 65% and 90%, respectively. 5-AZA was generally well tolerated with only mild thrombocytopenia observed in 2 patients. No clinically evident graft-versus-host disease exacerbation was observed. Conclusion: These results suggest that Low-dose 5-AZA is an effective maintenance therapy post- allogeneic SCT in high-risk AML and MDS particularly when a normal diploid karyotype is present. The relative lack of efficacy in the presence of an abnormal karyotype is intriguing and questions whether these subjects might benefit from higher doses of 5-AZA or other novel therapies within the context of a well-designed clinical trial. Prospective clinical trials and longer follow-up are needed to confirm these observations. Abstract 5884 TABLE I.Patients characteristics and Outcomes After Azacitidine maintenanceSubject #123456789Age at transplant655848433649495851genderMMFMFMFMMDiseaseAMLAMLAMLAMLSecondary AMLSecondary AMLMPD/MDSMDS (RAEB-2)MDS (RAEB-2)cytogeneticnormalnormalT(6,9)normalDel 5normalnormalnormalHypoploidy(43-45)Molecular abnormalityNoneNoneNoneFLT3 ITDNoneNoneNoneNoneNoneDisease status at HSCTCR2CR3CR1CR1RefractoryCR1PRPRCR1Donor typeMRDMRDMRDMRDMUDMRDMRDMRDMRDConditioningFB2+ATGFB3+ATGFB3+ATGFB4+ATGFB3+ATG+ TBI (4Gy)FB4+ATGFB4+ATGFB3+ATGFB2+ATGGVHD prophylaxisCSACSACSACSACSACSACSACSACSA, mycophenolate mofetilTime from HSCT to 5-AZA (days)37701001503021010055104Disease status at 5-AZACRCRCRCRCRCRCRCRCRnb of cycles12131241218129ToxicityNoneNoneNoneNoneGrade II thrombocytopeniaGrade II thrombocytopeniaNoneNoneNoneGVHD after 5-AZANoNoYesYesYesNoYesNoNoDisease recurrencenonoyesnoyesnononoyesSalvage therapy if recurrenceN/AN/AChemotherapy followed by DLIN/ANoneN/AN/AN/AChemotherapy followed by DLIProgression free survival, months13+24+124+319+21+18+10Status at last follow upCRCRCRCRdiedCRCRCRCRSurvival, months13+24+18+24+519+21+18+34+ Stem cell source for all patients: peripheral blood; CR: complete remission; PR: partial remission; CSA: cyclosporine A; MRD: matched related donor; MUD: matched unrelated donor; PBSC: peripheral blood stem cell; CCR: continuous complete remission; FB4: 5 days fludarabine plus 4 days busulfan (130 mg/m2/day); FB3: 5 days fludarabine plus 3 days busulfan (130 mg/m2/day); FB2: 5 days fludarabine plus 2 days busulfan (130 mg/m2/day) ATG: anti-thymoglobuline; DLI: donor lymphocyte infusion. Disclosures Off Label Use: Azacitidine maitenance post HSCT.

scholarly journals Relative survival following response to 7 + 3 versus azacytidine is similar in acute myeloid leukemia and high-risk myelodysplastic syndromes: an analysis of four SWOG studies

Leukemia ◽  
2018 ◽  
Vol 33 (2) ◽  
pp. 371-378 ◽  
Author(s):  
Megan Othus ◽  
Mikkael A. Sekeres ◽  
Sucha Nand ◽  
Guillermo Garcia-Manero ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Relative Survival ◽  
Acute Myeloid

scholarly journals Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3294-3301 ◽  
Author(s):  
Mark Levis ◽  
Farhad Ravandi ◽  
Eunice S. Wang ◽  
Maria R. Baer ◽  
Alexander Perl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Randomized Trial ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Platelet Recovery ◽  
First Relapse ◽  
Acute Myeloid

AbstractIn a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

scholarly journals Measurable Residual Disease at Induction Redefines Partial Response in Acute Myeloid Leukemia and Stratifies Outcomes in Patients at Standard Risk Without NPM1 Mutations

2018 ◽  
Vol 36 (15) ◽  
pp. 1486-1497 ◽  
Author(s):  
Sylvie D. Freeman ◽  
Robert K. Hills ◽  
Paul Virgo ◽  
Naeem Khan ◽  
Steve Couzens ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
High Risk Factors ◽  
Risk Patients ◽  
Standard Risk ◽  
Acute Myeloid

Purpose We investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria. Methods As part of the NCRI AML17 trial, 2,450 younger adult patients with AML or high-risk myelodysplastic syndrome had prospective multiparameter flow cytometric MRD (MFC-MRD) assessment. After course 1 (C1), responses were categorized as resistant disease (RD), partial remission (PR), and complete remission (CR) or complete remission with absolute neutrophil count < 1,000/µL or thrombocytopenia < 100,000/μL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD−. Patients without high-risk factors, including Flt3 internal tandem duplication wt/− NPM1-wt subgroup, received a second daunorubicin/cytosine arabinoside induction; course 2 (C2) was intensified for patients with high-risk factors. Results Survival outcomes from PR and MRD+ responses after C1 were similar, particularly for good- to standard-risk subgroups (5-year overall survival [OS], 27% RD v 46% PR v 51% MRD+ v 70% MRD−; P < .001). Adjusted analyses confirmed significant OS differences between C1 RD versus PR/MRD+ but not PR versus MRD+. CRi after C1 reduced OS in MRD+ (19% CRi v 45% CR; P = .001) patients, with a smaller effect after C2. The prognostic effect of C2 MFC-MRD status (relapse: hazard ratio [HR], 1.88 [95% CI, 1.50 to 2.36], P < .001; survival: HR, 1.77 [95% CI, 1.41 to 2.22], P < .001) remained significant when adjusting for C1 response. MRD positivity appeared less discriminatory in poor-risk patients by stratified analyses. For the NPM1-wt standard-risk subgroup, C2 MRD+ was significantly associated with poorer outcomes (OS, 33% v 63% MRD−, P = .003; relapse incidence, 89% when MRD+ ≥ 0.1%); transplant benefit was more apparent in patients with MRD+ (HR, 0.72; 95% CI, 0.31 to 1.69) than those with MRD− (HR, 1.68 [95% CI, 0.75 to 3.85]; P = .16 for interaction). Conclusion MFC-MRD can improve outcome stratification by extending the definition of partial response after first induction and may help predict NPM1-wt standard-risk patients with poor outcome who benefit from transplant in the first CR.

scholarly journals A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia

2020 ◽  
Vol 4 (4) ◽  
pp. 599-606 ◽  
Author(s):  
Kirk E. Cahill ◽  
Yasmin H. Karimi ◽  
Theodore G. Karrison ◽  
Nitin Jain ◽  
Margaret Green ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
High Dose ◽  
Phase 2 ◽  
Phase 1 Study ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.

A Risk Score Combined Clinical and Molecular Profiles Identifies a High-Risk Subgroup within AML1-ETO-Positive Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-19
Author(s):  
Min Yang ◽  
Yi Zhang ◽  
Jinghan Wang ◽  
Lixia Liu ◽  
Chengcheng Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Score ◽  
Myeloid Leukemia ◽  
Validation Cohort ◽  
Concordance Index ◽  
Scoring Model ◽  
Mutation Burden ◽  
Acute Myeloid

Background: AML1-ETO-positive acute myeloid leukemia, is classified as a favorable leukemia subtype according to the European Leukemia Net (ELN) risk stratification. Nevertheless, studies show the biology and prognosis within the AML1-ETO-positive AML are highly different, which suggests that more prognostic factors are needed to be identified. Aims: This study mainly revealed the genomic mutation characteristics and explored more factors which affect the prognosis of Chinese AML1-ETO-positive AML patients. Methods: A total of 167 AML1-ETO-positive patients who diagnosed and treated in Zhejiang Institute of Hematology had cryopreserved DNA for deep target 185-gene regional sequencing. Variants were detected with a variant allele frequency (VAF) cutoff of 0.5%. We used a LASSO Cox regression model to build risk score for predicting overall survival. A nomogram was constructed to display the risk of death in individuals. The discrimination of the risk score was measured by the concordance index (C-index) and areas under time-dependent receiver-operating characteristics (ROC) curves (AUCs), and the calibration of the risk score was explored graphically by calibration plots. Patients (n=75) from other hospital were used as a validation cohort. Results: The median age in analyzed patients was 42(6-78) years. The most common recurrent mutations occurred in KIT(n=84,50%), ASXL2(n=46,28%), NRAS(n=37,22%), FLT3-ITD(n=35,21%) and TET2(n=30,18%). We observed that high KIT mutant allele burden predicts for poor outcome in t(8:21) AML. High KIT VAF(≥15%) correlated with shortened overall survival compared to the other KIT mutated cases including low VAF and wild-type KIT (3-year OS 26.6% vs 59.0% vs 69.6%, HR 1.50, 95%CI 0.78-2.89, P=0.0005). In addition, we also identified some other mutated genes influence the prognosis of patients with t (8;21), such as FLT3-ITD high mutation burden(VAF≥44% vs other cases, 3-year OS 30.0% vs 56.2%, HR 2.94, 95%CI 0.43-20.18, P=0.056), TET2 high mutation burden (VAF≥43% vs other cases, 3-year OS 33.3% vs 56.5%, HR 2.87, 95%CI 0.66-12.46, P=0.018) and DHX15 high mutation burden (VAF≥22% vs other cases, 3-year OS 15.0% vs 58.3%, HR 2.65, 95%CI 0.81-8.73, P=0.011). In univariate analyses for OS, age&gt;42 (3-year OS 46.3% vs 64.4%, HR 1.91, 95%CI 1.14-3.14, P=0.012), WBC&gt;27.1×109/L(3-year OS 34.3% vs 60.0%, HR 2.59, 95%CI 1.13-5.9, P=0.001), BM blast&gt;20% (3-year OS 52.2% vs 92.8%, HR 6.36, 95%CI 2.7-14.97, P =0.035), LDH &gt; 504U/L (3-year OS 44.1% vs 67.1%, HR 2.62, 95%CI 1.50-4.59, P=0.0007), PLT≤28×109/L (3-year OS 47.1% vs 66.9%, HR 1.89, 95%CI 1.13-3.17, P=0.019), HB≤87g/L (3-year OS 49.4% vs 73.8%, HR 2.20, 95%CI 1.27-3.84, P=0.019) were significantly associated with poor OS. Six variables were incorporated in our scoring model by LASSO, including age, WBC, PLT, KIT mutation, FLT3-ITD mutation and TET2 mutation. A risk scoring model was developed incorporating the weighted coefficients of these variables. The risk score grouped AML1-ETO AML patients into two subgroup: low risk (LR, n=68) and high risk (HR, n=86) groups. The 3-year OS for LR and HR groups were 72.7% and 43.0% (P&lt;0.0001, Figure A). The similar results were also observed in validation cohort (3-year OS 79.1% vs 49.5%, P= 0.01; Figure B). Concordance index [train: 0.708, 95% CI (0.680, 0.736), validation: 0.722, 95% CI (0.666, 0.778)] demonstrated well discrimination power and calibration plots showed that the nomograms did well compared with an ideal model. Conclusion: In this study, our findings indicate that the prognostic effect of gene mutation in de novo t(8:21) AML may be influenced by the relative abundance of the mutated allele. A novel scoring model was developed and validated that incorporated molecular and clinical profiles. According to our score model, AML1-ETO AML patients could be further stratified into two subgroups with distinct clinical outcomes. Our data can serve as a basis for guided and risk-adapted treatment strategies for CBF-AML patients. The results are needed to be validated in other independent cohorts and prospective studies before implementation into clinics. Disclosures No relevant conflicts of interest to declare.

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