Standard-dose Daunorubicin Research Articles

Comparison of Overall Responses after Standard Induction with High Dose Daunorubicin Versus Standard Dose Daunorubicin with Gemtuzumab Ozogamicin in Favorable Risk Acute Myeloid Leukemia

Background: Patients with favorable risk acute myeloid leukemia (AML) by European LeukemiaNet (ELN) criteria are treated with intensive chemotherapy that yields high remission rates and is often curative. Intensive chemotherapy typically includes cytarabine and anthracycline (7+3) with high-dose daunorubicin (dauno 90mg/m2). When compared to 45mg/m2, dauno 90mg/m2 yields superior survival in younger, favorable risk AML patients. Since the re-approval of gemtuzumab ozogamicin (GO), standard practice now incorporates GO in the 7+3 backbone for favorable risk disease, however, it is typically with dauno 60mg/m2 rather than 90mg/m2. We aim to describe responses after 7+3 (dauno 90mg/m2) and 7+3 (dauno 60mg/m2) plus GO (7+3GO) in favorable risk AML. Methods: We retrospectively annotated 56 favorable risk AML patients (pts) who received upfront intensive chemotherapy at Moffitt Cancer Center between 2013 and 2019. They were divided in two cohorts: Cohort A) 7+3 with dauno 90mg/m2; Cohort B) 7+3 with dauno60mg/m2 plus GO at any time during induction or consolidation. Clinical and molecular data were abstracted for each patient in accordance with Institutional Board Review approved protocol. Overall response rates (ORR) included pts achieving complete remission (CR) with minimal residual disease negativity (CRMRD-), CR, CR with incomplete count recovery (CRi). MRD testing included quantitative Real-Time polymerase chain reaction (qRT-PCR) of t(8;21), inv(16) and nucleophosphin 1 (NPM1) tested at least after 2 cycles of intensive chemotherapy. Fisher's Exact method was used to determine significance for categorical variables. All p-values are two-sided. Results: Fifty-six pts were analyzed, including 41 in cohort A and 15 in cohort B. Pt demographics are noted in Table 1. In cohort B, 40.0% received GO on day 1 only (3mg/m2, capped or uncapped), 33.3% received fractionated dosing (3mg/m2 days 1,4,7) and 33.3% received GO during consolidation only. 39.3% of pts had inv(16), 23.2% had t(8;21)(q21.3q22) and 33.9% had mutated NPM1. In all 56 pts, ORR was 94.6%. ORR was 95.1% in cohort A and 93.3% in cohort B (p=0.79). CR rates were 85.4% in cohort A and 73.3% in cohort B (p=0.3) (Table 2). Rate of CRMRD- at any point was higher in cohort B vs cohort A, but did not reach statistical significance (45.8% vs. 20%, p=0.11). CRMRD- was significantly higher in pts with core binding factor (CBF) leukemia in cohort B vs cohort A (81.8% vs. 18.2%, p=0.008). The improvement in CRMRD- was seen in both inv(16) (A vs. B: 22.2% vs. 77.8%, p=0.049) and t(8;21) (0% vs. 100%, p=0.040). In pts with NPM1 mutations, a trend toward higher CRMRD- rates was noted in cohort B but this did not reach statistical significance (A vs. B: 40.0% vs. 100%, p=0.15). Although the median follow up time in cohort B is significantly shorter (12.3 mos in cohort B vs 38.3 mos in cohort A), no difference was observed in the 1-year EFS (68.4% in cohort A and 87.5% in cohort B (p=0.46)) or OS (83.0% in cohort A and 89.0% in cohort B (p=0.96)). No difference was seen in early mortality (30-day) between the two arms (7.3% and 6.7% in cohorts A and B, respectively (p=0.93)). Conclusions: We demonstrate that incorporation of GO to 7+3 with dauno 60mg/m2 yields comparable remission rates to 7+3 with dauno 90mg/m2. Importantly, GO based regimens produce higher rates of MRD negativity compared to 7+3 with dauno 90mg/m2 in CBF leukemia. Longer follow up is needed in order to accurately assess the impact of GO based regimens on overall survival outcomes and whether GO-induced higher MRD negativity rates will translate into superior survival for patients with favorable-risk cohort when compared to 7+3 with high dose daunorubicin. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau. Komrokji:celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Kuykendall:Janssen: Consultancy; Abbvie: Honoraria; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. Padron:Incyte: Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy.

Comparison of anthracyclines used for induction chemotherapy in patients with FLT3-ITD-mutated acute myeloid leukemia

This retrospective analysis compared anthracyclines (as part of an induction regimen) in 128 newly diagnosed FLT3-ITD-mutated AML patients. Induction regimens comprised high-dose daunorubicin (HD-DN; 90 mg/m2/d × 3d; n = 44), standard-dose daunorubicin (SD-DN; 45 mg/m2/d × 3d; n = 51), or idarubicin (IDA; 12 mg/m2/d × 3d; n = 33) in combination with cytarabine (100–200 mg/m2/d × 7d). Fifty-three patients showing persistent leukemia on interim bone marrow examination received a second course of induction chemotherapy comprising 2 days of daunorubicin (45 mg/m2/d) or IDA (8 or 12 mg/m2/d) in addition to 5 days of cytarabine. Complete remission (CR) rates were 77.3%, 56.9%, and 69.7% for HD-DN, SD-DN, and IDA, respectively (P = 0.101; HD-DN vs. SD-DN, P = 0.036; HD-DN vs. IDA, P = 0.453; IDA vs. SD-DN, P = 0.237). The HD-DN showed higher overall survival (OS) and event-free survival (EFS) than SD-DN and IDA: the differences between HD-DN and SD-DN (P = 0.009 for OS and P = 0.010 for EFS) were statistically significant.Results of in vitro studies using FLT3-ITD-mutated cell lines supported these findings. In conclusion, HD-DN improved the CR rate, OS, and EFS of FLT3-ITD-mutated AML patients. HD-DN also tended to yield better outcomes than IDA, though the difference was not significant. The superiority of HD-DN over IDA should be confirmed in future studies.

Abstract IA26: Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies

Abstract Clinical, cytogenetic, and gene-based studies have been used to inform biology and improve prognostication for patients with acute myeloid leukemia (AML), myelodysplasia (MDS), and myeloroliferative neoplasms (MPN). Most recently, a series of candidate gene and whole-genome studies have identified recurrent somatic mutations in AML patients including TET2, ASXL1, DNMT3A, and cohesin complex mutations. Moreover, these mutations can be used to improve risk stratification in AML independent of established clinical parameters. Integrating mutational data with dose-intensity revealed that high-dose daunorubicin improved survival in patients with DNMT3A/NPM1 mutations or MLL translocations relative to treatment with standard-dose daunorubicin, but not in patients wild-type for these alterations. These data provide important clinical implications of genetic alterations in AML by delineating mutation combination genotypes that predict outcome in AML and improve AML risk stratification. Of biologic importance, the TET family of proteins have been shown to place a hydroxyl mark on methylated DNA and lead to DNA demethylation. We and others have found that TET2/IDH mutations lead to loss of DNA hydroxymethylation and a hypermethylation phenotype in leukemia patients. In addition, in vitro and in vivo studies show that TET2 loss or neomorphic IDH1/2 mutations lead to impaired hematopoietic differentiation, increased stem cell self-renewal, and myeloid transformation in vivo. We have also investigated the role of mutant DNMT3A in AML pathogenesis, and shown that these mutations cooperate with other disease alleles to induce leukemic transformation and to confer chemoresistance due to impaired DNA damage sensing. We will present novel data showing how these mutations coopt the epigenetic state of hematopoietic stem/progenitor cells in order to contribute to transformation and that these mutations have biologic and prognostic relevance. Citation Format: Ross Levine. Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA26.

Role of Daunorubicin Dose Intensification for Induction Therapy in Acute Myeloid Leukemia Patients with FLT3-ITD Mutants

BackgroundPatients with FLT3-ITD mutated acute myeloid leukemia (AML) have generally poor survival. Recent update of ECOG trial comparing standard- vs. high-dose daunorubicin showed that daunorubicin dose intensification improved survival in AML with FLT3-ITD mutants (Blood 2016;127:1551). In subgroup analysis of our previous randomized trial, high-dose daunorubicin seemed to be more effective than idarubicin in AML patients with FLT3-ITD mutants (ASH abstract No. 2535, 2015). In this retrospective investigation, we aimed to evaluate the role of daunorubicin dose intensification for induction therapy in AML patients with FLT3-ITD mutants who were treated at a single institute.MethodsWe analyzed data from 120 patients of newly diagnosed FLT3-ITD mutated AML patients who received induction chemotherapy between January 2002 and March 2016. The regimens consisted of high-dose daunorubicin (HD-DN, 90 mg/m2/d x 3d, n=39), standard-dose daunorubicin (SD-DN, 45 mg/m2/d x 3d, n=48), or idarubicin (IDA, 12 mg/m2/d x 3d, n=33) in combination with cytarabine (200 mg/m2/d x 7d). Patients with acute promyelocytic leukemia were not included.ResultsAfter the first round of induction chemotherapy, 53 patients had persistent leukemia; 50 received the second round of induction chemotherapy consisting of daunorubicin (45 mg/m2/d x 2d) or idarubicin (8 mg/ m2/d x 2d) in addition to cytarabine (200 mg/m2/d x 5d) and 3 received other regimens. A total of 81 patients achieved CR, and the CR rates were 76.9%, 58.3%, and 69.7% in HD-DN, SD-DN, and IDA, respectively (P=0.175). The 4-year cumulative incidence of relapse (CIR) of these 81 patients was 48.8%. With the median follow-up duration of survivors of 59.9 months (range, 4.6-170.7), 4-year overall survival (OS) and event-free survival (EFS) were 57.1%/27.7%/35.7% (P=0.025) and 45.2%/23.9%/36.0% (P=0.042) in HD-DN, SD-DN, and IDA, respectively. HD-DN showed statistically higher OS (hazard ration [HR], 0.424; P=0.005) and EFS (HR, 0.497; P=0.01), and lower CIR (P=0.036) than SD-DN, while OS and EFS differences between HD-DN and IDA were not statistically significant.ConclusionDaunorubicin dose intensification for induction therapy seemed to be effective in AML patients with FLT3-ITD mutants. Further studies are needed to investigate whether HD-DN is superior to IDA in this population. Considering high relapse rate, combination strategies of daunorubicin dose intensification and targeted agents such as FLT3 inhibitors should be developed. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups

AbstractThe initial report of the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group trial E1900 (#NCT00049517) showed that induction therapy with high-dose (HD) daunorubicin (90 mg/m2) improved overall survival in adults <60 years old with acute myeloid leukemia (AML); however, at initial analysis, the benefit was restricted to younger patients (<50 years) and patients without unfavorable cytogenetics or a FLT3-ITD mutation. Here, we update the results of E1900 after longer follow-up (median, 80.1 months among survivors), focusing on the benefit of HD daunorubicin on common genetic subgroups. Compared with standard-dose daunorubicin (45 mg/m2), HD daunorubicin is associated with a hazard ratio (HR) for death of 0.74 (P = .001). Younger patients (<50 years) benefited from HD daunorubicin (HR, 0.66; P = .002), as did patients with favorable and intermediate cytogenetics (HR, 0.51; P = .03 and HR, 0.68; P = .01, respectively). Patients with unfavorable cytogenetics were shown to benefit from HD daunorubicin on multivariable analysis (adjusted HR, 0.66; P = .04). Patients with FLT3-ITD (24%), DNMT3A (24%), and NPM1 (26%) mutant AML all benefited from HD daunorubicin (HR, 0.61, P = .009; HR, 0.62, P = .02; and HR, 0.50, P = .002; respectively). HD benefit was seen in the subgroup of older patients (50-60 years) with the FLT3-ITD or NPM1 mutation. Additionally, the presence of an NPM1 mutation confers a favorable prognosis only for patients receiving anthracycline dose intensification during induction.

High-dose versus standard-dose daunorubicin in induction therapy for young patients with de novo acute myeloid leukaemia: a meta-analysis of randomised trials

Purpose: To compare the efficacy and safety of high-dose versus standard-dose daunorubicin for young patients with de novo acute myeloid leukaemia (AML) using meta-analysis.Methods: Two trials were taken from 2,481 full-text articles. Heterogeneity was assessed using the I2 index. Quality assessment was performed with the Cochrane Collaboration’s risk-of-bias tool.Results: The analysis showed that high-dose daunorubicin induction therapy was associated with higher complete remission (CR) rate (n = 965; RR = 1.80; 95% CI = 1.36–2.38; p < 0.0001; I2 = 0%) and improved overall survival (n = 1040; HR = 0.74; 95% CI = 0.63–0.87; p = 0.0003; I2 = 0%) compared with standard-dose daunorubicin. However, there was no significant interaction between treatment efficacy and prognostic category based on cytogenetics (favourable, intermediate and unfavourable) (p = 0.44, I2 = 0%).Conclusion: High-dose daunorubicin therapy could increase CR rate and improve long-term outcome for young patients with de novo AML. However, further study is needed to identify those who can benefit from high-dose daunorubicin.

Abstract CN08-01: Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies

Abstract Clinical, cytogenetic, and gene-based studies have been used to inform biology and improve prognostication for patients with acute myeloid leukemia (AML), myelodysplasia (MDS), and myeloroliferative neoplasms (MPN). Most recently, a series of candidate gene and whole genome studies have identified recurrent somatic mutations in AML patients including TET2, ASXL1, DNMT3A, and cohesin complex mutations. Moreover, these mutations can be used to improve risk stratification in AML independent of established clinical parameters. Integrating mutational data with dose-intensity revealed that high-dose daunorubicin improved survival in patients with DNMT3A/NPM1 mutations or MLL translocations relative to treatment with standard dose daunorubicin, but not in patients wild-type for these alterations. These data provide important clinical implications of genetic alterations in AML by delineating mutation combination genotypes that predict outcome in AML and improve AML risk stratification. Of biologic importance, the TET family of proteins have been shown to place a hydroxyl mark on methylated DNA and lead to DNA demethylation. We and others have found that TET2/IDH mutations leads to loss of DNA hydroxymethylation and a hypermethylation phenotype in leukemia patients. In addition, in vitro and in vivo studies show that TET2 loss or neomorphic IDH1/2 mutations leads to impaired hematopoietic differentiation, increased stem cell self-renewal, and myeloid transformation in vivo. We have also investigated the role of mutant DNMT3A in AML pathogenesis,a and shown these mutations cooperate with other disease alleles to induce leukemic transformation and to confer chemoresistance due to impaired DNA damage sensing. We will present novel data showing how these mutations coopt the epigenetic state of hematopoietic stem/progenitor cells in order to contribute to transformation and that these mutations have biologic and prognostic relevance. Citation Format: Ross L. Levine, Alan Shih, Olga Guryanova, Cem Maydan, Ari Melnick. Role of mutations in epigenetic regulators in pathogenesis of myeloid malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN08-01.

High Dose Daunorubicin Improves Survival in AML up to Age 60, Across All Cytogenetic Risk Groups Including Patients with Unfavorable Cytogenetic Risk, and FLT3-ITD Mutant AML: Updated Analyses from Eastern Cooperative Oncology Trial E1900

▪Background: Eastern Cooperative Oncology Group trial E1900 (E1900) showed that induction therapy with a high daily dose of daunorubicin (90 mg/m2) (DNR 90) improves survival in younger patients (pts) (<50 yrs) and intermediate (int) cytogenetic risk AML, but at 2 years of follow-up no benefit was seen in older pts (50-60 yrs), or in those with unfavorable cytogenetic risk or FLT3-ITD mutant AML (Fernandez et al. N Engl J Med 2009). Here we update results of E1900 with longer follow-up, focusing on the benefit of DNR 90 in cytogenetic and common molecular subgroups.Methods: Overall survival (OS) was measured from randomization for induction therapy to death from any cause (censored at last contact). Hazard ratios (HR) for death were computed using univariate and multivariable Cox proportional hazards models; multivariable Cox models were adjusted for sex, age, hemoglobin level, leukocyte count, platelet count, and cytogenetic profile. All conclusions regarding the impact of DNR 90, unless noted, are similar based on univariate and multivariable analysis.Results: Overall, 657 pts were enrolled with a median follow-up of 80.1 months. The HR for death in the DNR 90 group as compared with the standard-dose daunorubicin (45 mg/m2) (DNR 45) group was 0.74 (p=0.001). Pts <50 yrs benefited from DNR 90 (p = 0.002) while those >=50 yrs were not proven to benefit (p = 0.12). Pts with favorable (fav) and int. cytogenetic risk benefited from DNR 90 (p = 0.03 and p = 0.02, respectively). A benefit for pts with unfavorable cytogenetic risk was seen on multivariable analysis (p = 0.04).Impact of DNR 90 by mutation status: The 3 most common mutations were FLT3-ITD (24%), NPM1 (26%), and DNMT3A (24%). AML pts with any of these 3 mutations benefited from DNR 90 (p = 0.009, p = 0.002, and p = 0.02, respectively). FLT3-ITD pts who received DNR 90 had a 4-yr OS of 31%. Benefit was seen in pts age 50-60 with FLT3-ITD or NPM1 mutation (p = 0.02 and p = 0.04, respectively). No benefit of DNR 90 was seen in a small cohort of pts with MLL-PTD (p = 0.06). Benefit of DNR 90 in FLT3-ITD, NPM1, and DNMT3A mutant AML was confirmed in the int. cytogenetic risk group.Impact of DNR 90 on prognostic impact of NPM1: The presence of an NPM1 mutation conferred an improvement in OS in the DNR 90 group which was not seen in the DNR 45 group (p = 0.01 vs p = 0.3). This finding was confirmed in the int. cytogenetic risk group.Conclusion:With median follow-up of over 6 years on E1900, we confirm that DNR 90 improves outcome in pts with fav/int cytogenetic risk, DNMT3A or NPM1 mutant AML, or age < 50 (Patel et al. N Engl J Med 2012). Additionally, we now demonstrate that DNR 90 additionally benefits pts with FLT3-ITD AML, and pts with unfavorable cytogenetic risk, regardless of age. Moreover, we show that the favorable prognostic impact of the NPM1 mutation is only present when pts receive DNR 90. Given the benefit of DNR 90 across all cytogenetic risk groups as well as common molecularly defined subgroups of AML, DNR 90 should be the standard for all pts up to age 60 who are candidates for induction chemotherapy.TableHR for death by AML cohort.SubgroupNUnivariate ModelDNR 45DNR 90HR (DNR 90/DNR 45) & 95% CIWald PAll patients (n=657)Overall3303270.74 (0.61, 0.89)0.001Age< 50 yrs³ 50 yrs188 142172 1550.66 (0.50, 0.85) 0.81 (0.62, 1.06)0.002 0.12CytogeneticFavorable Intermediate Unfavorable38 232 5951 212 630.51 (0.28, 0.93) 0.76 (0.61, 0.96) 0.79 (0.54, 1.16)0.03 0.02 0.22FLT3-ITDWT MUT215 83241 640.74 (0.59, 0.92) 0.61 (0.42, 0.89)0.008 0.009MLL-PTDWT MUT290 16296 150.70 (0.58, 0.86) 0.46 (0.21, 1.04)0.0004 0.06NPM1*WT MUT180 65192 650.70 (0.55, 0.89) 0.50 (0.32, 0.78)0.003 0.002DNMT3AWT MUT177 61194 580.66 (0.52, 0.85) 0.62 (0.41, 0.94)0.001 0.02*Statistically significant test of interaction (p<0.2) [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Results of the ECOG E1900 Trial in Younger Adults with AML Using an Event Free Survival Endpoint Are Concordant with Results Based on Overall Survival: Potential for a Surrogate Endpoint to Facilitate Rapid Approval of Therapies in AML

Background: Novel therapies are required to improve the outcome of patients with AML. New agents are asked to demonstrate an overall survival (OS) benefit before qualifying for FDA approval. The long duration of clinical trials required in order to achieve this endpoint hampers quick evaluation of candidate therapies, including novel agents. Identification of reliable surrogate endpoints for OS in AML is needed. Here we compare the results of therapy for patients with untreated AML ages 16-60 years on the Eastern Cooperative Oncology Group 1900 trial (E1900) of induction chemotherapy followed by consolidation and autologous transplant in order to evaluate the validity of an event free survival (EFS) endpoint as a surrogate for OS.Methods:OS was measured from randomization for induction therapy to death from any cause (censored at last contact). EFS was measured from randomization to induction treatment failure, relapse after compete response (CR), or death in remission (censored at last contact). Hazard ratios (HR) were computed using Cox proportional hazards models. The association between EFS and OS was evaluated using the Kendall tau-a rank correlation for censored data.Results:There were657 patients enrolled of which 426 patients relapsed or had induction treatment failure before death or date of last contact. Median EFS and OS were 8.0 months (95% CI, 6.3 to 9.7 months) and 23.6 months (95% CI, 16.9 to 23.6 months), respectively. With a median follow-up of 80.1 months, there is a statistically significant correlation between EFS and OS (Kendall tau-a = 0.467, 95% confidence interval (CI) = (0.425, 0.510), p<0.001). This correlation was similarly significant at a median follow-up of 25.2 months (Kendall tau-a = 0.361, 95% CI (0.323, 0.400), p <0.001) when the E1900 trial was originally reported (Fernandez et al. NEJM 2009).Key findings reported based on the original OS endpoint are similar when analyzed with an EFS endpoint (Table 1). High-dose daunorubicin (90 mg/m2) (DNR 90) confers both an EFS and OS benefit in patients aged < 50 years and patients with intermediate cytogenetic risk, and does not confer an EFS or OS benefit in older patients and patients with unfavorable cytogenetic risk, on univariate analysis. Divergent results are only seen in the small subset of favorable cytogenetic risk patients, where DNR 90 conferred an OS benefit (p=0.027) without an EFS benefit (p=0.32).Both EFS and OS endpoints consistently reflect the impact of mutation status on survival. The presence of a FLT3-ITD or DNMT3A mutation has a negative impact on both EFS and OS while an IDH2 mutation has a favorable impact on EFS and OS. The presence of a NPM1 mutation confers a favorable impact on EFS and OS in patients who received DNR 90 and did not impact EFS or OS in patients receiving standard-dose daunorubicin (45 mg/m2) (DNR 45). The presence of an IDH1 mutation does not impact EFS or OS.Conclusions:The results of E1900 demonstrating superiority of DNR 90 in AML induction in patients up to age 60 are concordant when using an EFS or OS endpoint. This is true for the group as a whole as well as for subgroups for which targeted agents are in development (FLT3/IDH2 inhibitors). Further investigation of whether EFS is a reliable surrogate for OS is warranted in AML. If confirmed, its use as a primary endpoint could be adopted by regulatory agencies in order to allow more rapid completion of clinical trials in AML and bring new therapies to AML patients in a timely fashion.Table 1Results of E1900 based on an EFS endpoint versus an OS endpoint.SubgroupNOS HR (DNR 90/DNR 45) & 95% CIWald PEFS HR (DNR 90/DNR 45) & 95% CIWald PDNR 45DNR 90Age< 50 yrs ³ 50 yrs188 142172 1550.66 (0.50, 0.85) 0.81 (0.62, 1.06)0.002 0.1180.64 (0.50, 0.82) 0.86 (0.67, 1.10)0.0004 0.23CytogeneticFavorable Intermediate Unfavorable38 141 5951 127 630.51 (0.28, 0.93) 0.68 (0.50, 0.92) 0.79 (0.54, 1.16)0.027 0.012 0.2250.76 (0.44, 1.31) 0.63 (0.47, 0.83) 0.72 (0.49, 1.05)0.32 0.001 0.09SubgroupNOS HR (MUT/WT) & 95% CIWald PEFS HR (MUT/WT) & 95% CIWald PFLT3-ITDWT MUT456 1471.62 (1.31, 2.01) <.00011.48 (1.21, 1.82) 0.0002DNMT3AWT MUT371 1191.30 (1.03, 1.65) 0.031.23 (0.98, 1.54) 0.07IDH1WT MUT465 360.88 (0.59, 1.33)0.550.91 (0.62, 1.34)0.64IDH2WT MUT451 500.63 (0.43, 0.93)0.020.68 (0.48, 0.97)0.03NPM1DNR 45 DNR 90245 2570.84 (0.61, 1.16) 0.60 (0.41, 0.89)0.30 0.010.90 (0.66, 1.22) 0.59 (0.41, 0.84)0.49 0.004 DisclosuresNo relevant conflicts of interest to declare.

Idarubicin appears equivalent to dose-intense daunorubicin for remission induction in patients with acute myeloid leukemia

Daunorubicin has historically been considered the anthracycline of choice at many cancer centers for the treatment of acute myeloid leukemia (AML). Drug shortages have required the substitution of daunorubicin with idarubicin. Randomized studies have shown idarubicin (10–12mg/m2) to be comparable or superior to standard dose daunorubicin (45–60mg/m2) for achieving complete remission (CR). Whether these results can be extrapolated to dose-intense daunorubicin (90mg/m2), recently shown to improve CR rates when compared to standard daunorubicin doses remains uncertain. This observational study was conducted at Northwestern Memorial Hospital (NMH) to compare CR rates. The results suggest idarubicin is equivalent to daunorubicin, and for some subsets of patients, idarubicin may have superior CR rates.

IS5-4 - Induction Chemotherapy in Patients with Acute Myeloid Leukemia

ABSTRACT Background A randomized trial conducted by the ECOG showed that intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d x 3d) improved both complete remission (CR) rate and survival duration compared with those of young adults with acute myeloid leukemia (AML) receiving standard daunorubicin dose (45 mg/m2/d x 3d) (Fernandez HF et al. N Engl J Med 2009;361:1249). We also conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with AML (Lee JH et al. Blood 2011;118:3832). Methods Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m2/d x 3d) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m2/d x 3d) in addition to cytarabine (200 mg/m2/d x 7d) to induce CR. Results The CR rates were 72.0% in SD-DN arm and 82.5% in HD-DN arm. At a median follow-up time of 52.6 months, overall (OS) and event-free (EFS) survival were higher in HD-DN arm than in SD-DN arm (OS, 46.8% versus 34.6%; EFS, 40.8% versus 28.4%). Differences in CR rate and both OS and EFS remained significant after adjustment for other variables (CR, HR, 1.802, P = 0.024; OS, HR, 0.739, P = 0.032; EFS, HR, 0.774, P = 0.048). Conclusions Given the results of both our study and the ECOG work, high-dose daunorubicin (90 mg/m2/d) for 3 days should be the future standard of care for induction of patients with AML. However, it is not known whether a dose of 90 mg/m2/d is superior to a dose of 45–90 mg/m2/day. It is also necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin. For these reasons, we began another randomized trial comparing two induction regimens in young adults with AML: high-dose daunorubicin (90 mg/m2/d x 3d) versus idarubicin (12 mg/m2/d x 3d) in addition to cytarabine (200 mg/m2/d x 7d). This study is now recruiting patients and the results of interim analysis will be presented at the 10th annual meeting of Japanese Society of Medical Oncology.

Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia

BackgroundAcute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML.MethodsWe performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients.ResultsWe identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67).ConclusionsWe found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.)

A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia

AbstractWe conducted a phase 3 randomized trial comparing 2 different doses of daunorubicin as induction chemotherapy in young adults (60 years of age or younger) with acute myeloid leukemia (AML). Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m2 per day times 3 days) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m2 per day times 3 days) in addition to cytarabine (200 mg/m2 per day times 7 days) to induce complete remission (CR). The CR rates were 72.0% in the SD-DN arm and 82.5% in the HD-DN arm (P = .014). At a median follow-up of 52.6 months, overall (OS) and event-free (EFS) survival were higher in the HD-DN arm than in the SD-DN arm (OS, 46.8% vs 34.6%, P = .030; EFS, 40.8% vs 28.4%, P = .030). Differences in CR rate and both OS and EFS remained significant after adjusting for other variables (CR, hazard ratio [HR], 1.802, P = .024; OS, HR, 0.739, P = .032; EFS, HR, 0.774, P = .048). The survival benefits of HD-DN therapy were evident principally in patients with intermediate-risk cytogenetic features. The toxicity profiles were similar in the 2 arms. In conclusion, HD-DN improved both the CR rate and survival duration compared with SD-DN in young adults with AML. This study is registered at www.clinicaltrials.gov as #NCT00474006.

A Network Meta-analysis of Randomized Controlled Trials of Induction Treatments in Acute Myeloid Leukemia in the Elderly

Background The optimal induction treatment of acute myeloid leukemia (AML) in the clinically and biologically heterogeneous group of elderly patients is not well-defined since direct comparisons between treatments is limited. Objective The aim of this study was to estimate the relative effectiveness of induction treatments in AML elderly patients. Methods A network of multiple treatments meta-analysis was performed by combining direct and indirect evidence from published randomized controlled trials (RCTs). The complete remission (CR) was considered as the outcome of interest. We systematically searched PubMed, EMBASE, and Cochrane Library until September 30, 2010, to identify all RCTs published in English that compared diverse induction chemotherapies in elderly AML patients. Our search strategy focused on RCTs that included AML patients >60 years, considering, however, that age stratification was varied between countries and over time and studies were not necessarily designed to compare elderly patients. Regimens were grouped a priori into 42 different types of induction treatment. Prognostic parameters (age, performance status, unfavorable cytogenetics, antecedent malignancy), AML outcomes (median disease-free, overall survival, CR, induction deaths), and myelotoxicity parameters (median duration until neutrophil recovery [>1.0 × 10 9/L], platelet recovery [>100 × 10 9/L], hospitalization duration) were evaluated for each induction type. In combining direct and indirect evidence, we calculated the odds ratio (OR) for each therapy relative to the most commonly used combination of standard-dose daunorubicin (30–60 mg/m 2 for 3 days) and standard-dose cytarabine (100 mg/m 2 for 7–10 days) that was set as the reference induction treatment. Results We identified 65 RCTs (15,110 patients) that described 64 direct comparisons of induction treatments, but only 14 of them showed significant differences in CR after random effects meta-analyses. Median age of included patients was 68, 18.0% had secondary AML, 21.1 % had poor performance status, 26.7% displayed unfavorable cytogenetics, and 49.3% finally achieved CR. No significant differences were observed in the recorded induction toxicity parameters among the treatment arms. Through the network meta-analysis, the addition of all-trans retinoic acids or lomustine to the combination of idarubicin plus cytarabine showed significantly higher CR rate (OR = 1.93 [1.06–3.49] and 1.76 [1.08–2.88], respectively), whereas no treatment, clofarabine, daunorubicin plus topotecan, and the 2 different schedules of gemtuzumab ozogamicin (at 1, 3, and 5 days and at 1 and 8 days) showed a significantly lower CR rate (OR = 0.01 [0.001–0.19], 0.15 [0.04–0.58], 0.03 [0.002–0.64], 0.06 [0.01–0.51], and 0.05 [0.01–0.32], respectively) than that of the reference induction. Median overall survival showed no difference between treatments ( P = 0.150) but was significantly increased during the last 30 years ( P < 0.001), presumably reflecting advances in AML management. Conclusions Compared with the reference induction, significant differences were found for specific induction regimens, although most compared regimens appeared to have similar efficacy profiles. These results, however, should be interpreted with caution because the network was dominated by indirect comparisons. Data from large RCTs that make direct comparisons between treatments are needed to detect the optimal induction regimen for elderly AML patients.

High-dose homoharringtonine versus standard-dose daunorubicin is effective and safe as induction and post-induction chemotherapy for elderly patients with acute myeloid leukemia: a multicenter experience from China

The purpose of the study was to compare the antitumor efficacy and safety profile of high-dose homoharringtonine as induction and post-induction therapy compared to either standard-dose homoharringtonine or daunorubicin in elderly patients with newly diagnosed acute myeloid leukemia. A total of 254 patients, age range 60-77 years received induction and post-induction therapy containing daunorubicin, standard-dose homoharringtonine, or high-dose homoharringtonine. After one course of induction therapy, the overall complete remission rate was similar between treatment arms (58.7%, P = .92). Among 161 patients with acute myeloid leukemia (non-M5 subtype), estimated median overall survival was 39, 29, and 37 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .53). In the 93 patients with acute myeloid leukemia-M5 subtype, there was a significant difference in estimated median overall survival: 24, 24, and 52 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .003). There was no significant difference in drug-related adverse events between treatment arms. High-dose homoharringtonine does not clearly increase the complete remission rate of elderly patients with acute myeloid leukemia. However, in the subset of elderly patients with acute monocytic leukemia, high-dose homoharringtonine as a first-line regimen prolonged overall survival with minimal toxicity.

High-Throughput Mutational Profiling In AML: Mutational Analysis of the ECOG E1900 Trial

AbstractAbstract 851Clinical studies have demonstrated that acute myeloid leukemia (AML) is heterogeneous with respect to presentation and to clinical outcome, and many studies have shown that cytogenetics can be used to improve prognostication. More recently, it has been shown that FLT3, NPM1, and CEBPA mutations can be used to further risk stratify AML patients. Although recent studies have identified novel, recurrent somatic mutations in AML in genes including TET2, ASXL1, IDH1, IDH2, and PHF6, their prognostic value has not yet been evaluated among patients treated on a large phase III clinical trial. Here we report full-length DNA resequencing of FLT3, NPM1, CEBPA, H/K/NRAS, KIT, WT1, TET2, ASXL1, IDH1/2, TP53, RUNX1, PTEN, and PHF6 in pre-treatment genomic DNA from 398 patients with de novo AML younger than 60 years of age enrolled in the ECOG E1900 protocol. We could identify a clonal alteration, defined as a somatic mutation or cytogenetic abnormality, in 91.2% of all patients; 42% had 1 somatic alteration, 36.4% had 2 alterations, 11.3% had 3 alterations and 1.5% had 4 or more somatic alterations. Mutational Analysis: We identified somatic mutations in FLT3 (37% total; 30% ITD, 7% TKD), NPM1 (14%), CEBPA (10%), TET2 (10%), NRAS (10%), WT1 (10%), KIT (9%), IDH2 (8%), IDH1 (6%), RUNX1 (6%), ASXL1 (4%), PHF6 (3%), KRAS (2.5%), TP53 (2%), and PTEN (1.5%) (Figure 1A). We then performed correlation analysis to determine the frequency of different mutational combinations in AML patients. In addition to previously identified mutational correlations (FLT3 and NPM1, KIT and core binding factor leukemia), we found that FLT3 and ASXL1 mutations were mutually exclusive in this large cohort (p =0.0008). In addition, we found that IDH1/IDH2 mutations were mutually exclusive of both TET2 (p=0.02), and WT1 (p=0.01) mutations consistent with overlapping roles in AML pathogenesis (Figure 1B). Integration of mutational data with response data and outcome: Mutations in ASXL1 (CR rate 33.3% versus 66.5% for ASXL1-WT patients; p= 0.009) were enriched in patients who did not respond to induction chemotherapy. We found that mutations in FLT3 (p=0.0005), ASXL1 (p=0.005; Figure 1C), and PHF6 (p=0.02) were associated with reduced OS. Notably, the adverse effects of ASXL1 and PHF6 mutations on outcome were restricted to patients treated with standard dose daunorubicin (p<0.01 for each mutational cohort); ASXL1 and PHF6 mutational status did not affect outcome in patients treated with high-dose daunorubicin, demonstrating that increased intensity induction chemotherapy can improve outcomes in genetically defined poor risk AML subsets. We also found that mutations in CEBPA (p= 0.04) and in IDH2 (p=0.003) were associated with improved OS; the favorable impact of IDH2 mutations on outcome was exclusive to patients with IDH2 R140Q mutations (Figure 1D). Within the subset of patients with cytogenetically defined intermediate risk AML, we found, as expected, that FLT3-ITD mutations were associated with reduced OS and CEBPA mutations were associated with improved OS. Importantly, we found that IDH2 R140Q mutations were associated with improved OS (p=0.003) in patients with intermediate risk AML regardless of FLT3 mutational status. In contrast, TET2 mutations (P=0.0002) and PHF6 (p<0.0001) were associated with reduced OS in intermediate risk, FLT3-WT, AML. Summary: These data provide important clinical implications of genetic alterations in AML and provides insight into the multistep pathogenesis of adult AML. We identified novel mutations that impact response to induction chemotherapy and predict overall outcome, including ASXL1, PHF6, TET2 and IDH2, suggesting these mutations can be used to improve AML risk stratification and therapeutic decisions in AML patients 18–60 years of age. Most importantly, we identify TET2, IDH1/2, and WT1 mutations as mutually exclusive somatic alterations that form a novel mutational complementation group that contributes to AML pathogenesis. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

High dose equals improved response

The current induction therapy for patients with acute myeloid leukemia (AML) is anthracycline plus cytarabine. Complete remission is achieved in 50–75% of patients and the addition of other drugs or dose intensification has not improved survival. Whether dose intensification for induction therapy in patients (<60 years of age) with AML might improve survival has not been addressed. In a randomized phase III trial by the Eastern Cooperative Group (ECOG), Fernandez and colleagues compared standard-dose and high-dose daunorubicin in young adults with AML. The researchers randomly assigned 582 patients with AML, who had not been treated, to receive three once-daily doses of daunorubicin at the standard dose (45 mg/m2) or a higher dose (90 mg/m2), combined with cytarabine. Allogeneic hematopoeitic stem-cell transplantation, with or without a single dose of gemtuzumab ozogamicin, was offered to patients who experienced complete remission. Overall survival was the primary end point of the study and the median follow-up time was 25.2 months. Patients treated with high-dose daunorubicin had a significantly higher rate of complete remission (70.6% versus 57.3%) and improved median overall survival (23.7 months versus 15.7 months) compared with patients who received standard-dose daunorubicin. Moreover, serious adverse events were similar in both groups, indicating that administration of high-dose daunorubicin has a similar safety profile as the standard-dose. The researchers conclude that intensifying induction therapy with high-dose daunorubicin in young patients with AML significantly improved the rate of complete remission and the duration of overall survival; therefore, this treatment strategy should be considered as a standard of care in these patients.

Preliminary Results of a Prospective Multicenter Phase III Trial Comparing High-Dose and Standard-Dose Daunorubicin for Induction of Complete Remission (CR) in Acute Myeloid Leukemia (AML).

The effectiveness of anthracycline dose intensification for induction of CR in AML has not been studied in a randomized fashion. We conducted a prospective randomized trial to compare the therapeutic efficacy and toxicity of two different doses of daunorubicin in combination with cytarabine in AML. This study began on August 2001 and 293 adult patients (younger than 60 years) with newly diagnosed AML except M3 have been enrolled. Fourteen patients were removed from the study and the remaining 279 patients were analyzed. After random assignments, 135 patients received standard-dose daunorubicin (SD-DN, 45 mg/m2/d × 3 d) and 144 patients received high-dose daunorubicin (HD-DN, 90 mg/m2/d × 3 d) in addition to cytarabine (200 mg/m2/d × 7 d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of standard-dose daunorubicin (2 d) plus cytarabine (5 d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 × 6 doses) and 2 cycles of daunorubicin (1 d) plus cytarabine (5 d). For patients in intermediate- or high-risk cytogenetic groups, allogeneic hematopoietic cell transplantation was performed if there was a suitable donor. CR was induced in 98 of 135 patients (72.6%) in SD-DN arm and 119 of 144 (82.6%) in HD-DN arm (P = 0.044). The impact of daunorubicin dose intensification on the CR rates were different by cytogenetic risk group: the CR rates for SD-DN vs. HD-DN arm were 24/25 (96.0%) vs. 35/36 (97.2%) for good-risk group, 63/88 (71.6%) vs. 64/83 (77.1%) for intermediate-risk group, and 10/20 (50.0%) vs. 19/24 (79.2%) for poor-risk group. With a median follow-up of 596 days for surviving patients, the 4-year probabilities of overall survival, disease-free survival, and relapse-free survival were similar between SD-DN and HD-DN arm. Two different doses of daunorubicin (SD-DN vs. HD-DN) showed similar toxicity profiles regarding recovery times from myelosuppression, transfusion requirements, severe toxicities (grades III to IV) classified by NCI-CTC ver 2.0 including cardiac toxicities, and duration of antibiotics administration. In conclusion, high-dose daunorubicin showed higher CR rates in AML patients of intermediate- and poor- cytogenetic risk groups without increase of toxicities compared to standard-dose daunorubicin.

The Feasibility of Combining Daunorubicin, Clofarabine and Gemtuzumab Ozogamicin Is Feasible and Effective. A Pilot Study.

New treatment combinations are required for older patients with AML. Clofarabine is a novel nucleoside analogue which has been shown in several phase 2 studies in older patients to be active alone or in combination. Gemtuzumab Ozogamicin (GO) is also active in older patients and is currently undergoing evaluation in several randomised trials. As part of the proposed UK NCRI AML16 Trial for patients over 60 years we have undertaken a Pilot Trial to establish the feasibility combining standard dose Daunorubicin (D) (50mg/m2 days 1,3,5), Clofarabine (Clo) and GO (3mg/m2) as a novel combination, with the intention to compare D+Clo vs D+Ara-C both +/− GO on day 1. Five treatment cohorts were planned. Daunorubicin at a dose of 50mg/m2 is included in all cohorts. Cohorts 1–4 combine D with Clo at a dose level of 15mg/m2, 20mg/m2, 25mg/m2 and 30mg/m2 given on days 1–5 for 2 courses, to establish the feasible Clo dose in combination. Cohort 5 comprises D + feasible Clo dose given as above + GO 3mg/m2 on day 1 of course 1. Each cohort initially comprised 6 patients, and cohorts were expanded based on toxicity scoring. If toxicity criteria were satisfied the next cohort was opened. Thirty-four patients have been recruited. Of 6 patients in cohort 1 (15mg) 5 achieved CR without toxicity with one having refractory disease; of 7 patients in cohort 2 (20mg) 6 achieved CR with 1 having refractory disease; of 10 patients in cohort 3 (25mg) 4 achieved CR, 3 had refractory disease and 3 had induction deaths; and of 9 patients in cohort 4 (30mg) 5 entered CR, 2 had RD and 2 ID. Based on this, a dose of 20mg/m2 was chosen for clofarabine. So far cohort 5 has recruited 2 patients, both of whom have entered CR. This cohort will shortly be completed.Toxicity: No toxicity of grade >2 in AST and ALT was seen in any cohort; one patient on Clo (30mg) had a transient grade 3 bilirubin elevation after courses 1 and 2. One patient (30mg) had grade 4 renal toxicity. The mean time on antibiotics was 13.1 days with no difference between the cohorts. The median time to recovery of ANC was 19 (17–24) days and platelets 19 (14–21) days.Conclusion: The combination of Daunorubicin 50mg/m2 on days1, 3 and 5 and Clofarabine 20mg/m2 days 1–5 with Gemtuzumab Ozogamicin 3mg/m2 on day 1 is an effective and feasible combination for prospective evaluation.

Cellular Uptake and Antiproliferative Effects of Therapeutic Concentrations of Idarubicin or Daunorubicin and their Alcohol Metabolites, with or without Cyclosporin A, in MDR1+ Human Leukemic Cells

Ways of restoring an altered drug sensitivity in P-170 glycoprotein (MDRI) positive leuke-mias are being actively sought for, mostly using MDRl negative regulators together with the MDR1-sensitive anthracycline-type drugs daunorubicin and mitoxantrone. Because idarubicin is less vulnerable to MDR1 -mediated transport and could thereby represent a better companion to MDR1 inhibitors, we essed the ability of the anti-MDR1 agent cyclosporin A to modulate this function in multidrug resistant T-lymphoblastic CEM cells challenged in vitro with either daunorubicin or idarubicin. In order to obtain information of potential interest for the design of a clinical trial, we adopted drug plus metabolite concentrations and exposure times close to the in vivo pharmacokinetics of equimyelotoxic doses of intravenous daunorubicin 45 mg/m2 or idarubicin 10–12 mg/m2, respectively, plus infusional cyclosporin A 16 mg/kg/d. Study methods were cytofluorimetry for the detection of intracellular drug uptake, retention and pro-apoptotic effects (binding of fluoresceinated annexin V), and the standard MTT assay as growth inhibition test. The results showed significantly greater drug uptake (at 30'), retention (at 12 hours), and apoptotic cell rates with idarubicinkidarubicinol than dauno-rubicinfdaunorubicinol (p<0.05), and a further potentiation of these effects by cyclosporin A. Differing from daunorubicin, idarubicin intracellular accumulation and, by inference, related apoptotic changes were increased by cyclosporin A only in the early phase of drug-cell interaction; a potential advantage towards a reduced toxicity by CsA delivered as short rather than prolonged infusion in the in vivo setting. MTT assay results were also in favour of idarubicin but greatly influenced by cyclosporin A itself. Altogether, study results in MDR1+ cells incubated with CsA 1500 ng/ml plus idarubicin+idarubicinol 100+20 ng/ml, that are peak levels achievable in vivo with an idarubicin dose ≥212 rng/m2 plus cyclosporin A 16 mg/kg/d, were in the range of those obtained with standard-dose daunorubicin in MDRl- cells (p=n.s.). In summary, an idarubicin plus short-course cyclosporin A combination could be considered for the management of MDRl+ leukemias, where it may represent a more effective and less toxic option than daunorubicin plus continuous infusion cyclosporin A.