Timed Sequential Therapy Research Articles

Timed sequential therapy with high-dose cytarabine and mitoxantrone as an induction regimen for acute myeloid leukemia: An update on adverse events.

e18524 Background: Traditionally, patients eligible for induction chemotherapy for AML are treated with the “7+3” regimen, standard doses of infusional cytarabine and an anthracycline, with historical CR rates of 50-60%. We present a retrospective analysis of an alternate induction regimen. Based on timed sequential therapy, it consists of a 2-day treatment with high dose cytarabine, which improves remission rates when used in induction, and dose intensified anthracycline therapy, which improves outcomes while maintaining an acceptable safety profile. Methods: 200 patients were treated from 2010-2015. Patients received 2 doses of cytarabine 2 gm/m2 (1.5 gm/m2 age > 70 years) IVPB over 3 hours, 12 hours apart followed by 1 dose of mitoxantrone 30 mg/m2 IVPB over 1 hour on days 1 and 5. Cytogenetics and adverse events data were collected. IWG remission criteria were used to determine remission status. Results: Median age 57.6 years (range 23-79); 105 (53%) age > 60. 119 male; 81 female. Risk stratification: 12 favorable; 108 intermediate; 80 unfavorable . Overall CR rate (CRR: CR+CRi+CRp) for all patients was 68.5%. CR rates based on risk karyotypes: favorable 100%, intermediate 76.8%, unfavorable 52.5%. Most common G3-4 adverse events: anemia (60% G3, 40% G4), neutropenia (1% G3, 99% G4), thrombocytopenia (0.5% G1, 99.5% G4). 196 patients (98%) had neutropenic fever; 134 (67%) documented infections (100 with G3/4), 62 (31%) neutropenic fever with no source. 52 (26%) experienced bleeding (15 G1, 31 G2, 4 G3, 1 G4, 1 G5). G3/4 renal or hepatic toxicity was rare. No cerebellar toxicity occurred during induction. 30 day mortality 0.5%; 60 day mortality 3%. 62 (31%) patients are still alive; 122 died, 16 lost to follow-up. Conclusions: This two-day induction regimen is an effective treatment for AML with an acceptable safety profile including patients age >60. There is a high response rate, particularly for favorable and intermediate risk karyotypes, with a low rate of early mortality. The high response rates and tolerability with this regimen provides a platform for further clinical trials to enhance outcome by combining with novel targeted therapies for AML.

Effective Immunomodulation with Pomalidomide Beginning at Early Lymphocyte Recovery during Induction Timed Sequential Therapy (TST) for Acute Myeloid Leukemia (AML) and High-Risk Myelodysplasia (HR-MDS)

Introduction: Adults with AML have immune aberrations leading to immune suppression, exhaustion, evasion, and senescence. Early lymphocyte recovery (ELR) after induction TST is dominated by an expansion of oligoclonal peripherally derived regulatory T cells (Tregs). Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), leads to the selective ubiquitination of Aiolos and Ikaros by cereblon; this ubiquitination increases IL-2 production, inhibits Tregs, and inhibits angiogenesis. We hypothesize that Pom administration after induction TST may enhance anti-leukemic activity through immune modulation.Methods: A multicenter phase 1 dose escalation study was conducted to determine the safety and tolerability of Pom administration after induction TST in newly diagnosed AML and HR-MDS patients 18-65 years. Favorable-risk cytogenetics were excluded. All patients received induction TST with AcDVP16: Cytarabine 667 mg/m2/day continuous IV days 1-3, daunorubicin 45 mg/m2 IV days 1-3 (or idarubicin 8-12 mg/m2 IV days 1-3 in daunorubicin shortage), etoposide 400 mg/m2 IV days 8-10, followed by Pom administration at ELR (after day 14 and within 3 days of the total white blood cell (WBC) reaching ≥0.2x109/L above nadir, but no later than day 30). Pom dose escalation occurred in 2 cohorts: 10 days versus 21 days of administration, in a traditional 3+3 design.Results: A total of 51 patients were enrolled and 43 (AML: n=39, HR-MDS: n=4) received Pom across 3 institutions (Table 1). Eight patients did not receive Pom due to no ELR by day 30 (n=3), sepsis (n=3), noncompliance with treatment (n=1), and death prior to ELR due to acute respiratory distress syndrome (n=1). Median time for Pom initiation after AcDVP16 induction was day 21 (range: 15-30 days). Pom maximal tolerated dose (MTD) was 4 mg for 21 consecutive days at ELR. The most common non-hematologic grade ≥3 toxicities related to Pom were febrile neutropenia (30%), maculopapular rash (14%), and aminotransferase elevation (5%). Dose-limiting toxicities (DLTs) of Pom at 8 mg for 21 days were grade 3 ALT/AST elevation and grade 4 respiratory failure, respectively. Pom was discontinued early (median duration = 7 days; range: 3-20 days) in 14 (33%) patients due to disease progression (n=4), grade 3 rash (n=3), DLT (n=2), patient decision (n=2), progressive cytopenias (n=1), and grade 4 acute kidney injury (n=1).Overall, 32/43 (74%) achieved CRc (CR: n= 30, CRi: n=2). Among the 4 HR-MDS patients, 2 (50%) achieved CRc, whereas 77% (30/39) of AML patients achieved CRc. Of the 32 CRc patients, 19 (59%) had no evidence of minimal residual disease (MRD) by standard testing (flow cytometry, FISH, cytogenetics, and/or molecular PCR). Encouraging CR rates were seen in poor-risk subsets: Age ≥60 years: 75% CRc (9/12); Secondary AML: 71% CRc (10/14); Adverse-risk cytogenetics: 82% CRc (14/17). Thirty- and 60-day mortality were 0 and 2%, respectively. Median time to neutrophil (≥1.0x109/L) and platelet (≥100x109/L) recovery was 38 (range: 28-86) and 33 days (range: 24-75), respectively. With a median follow-up of 23.9 months, median overall survival, disease-free survival and event-free survival were 33.8 months, 20.3 months, and 8.7 months, respectively.Pharmacodynamic biomarker studies revealed a significant decrease in the expression of Aiolos in peripheral blood CD4+ and CD8+ T cells when compared with AML controls who received AcDVP16 induction but did not receive pomalidomide (p <0.05; Figure 1). Moreover, these findings were corroborated in the bone marrow where Aiolos expression in CD4+ and CD8+ T cells substantially decreased after pomalidomide initiation.Conclusions: Pom can be added at the time of ELR after induction TST without increased toxicity and CR rates that compare favorably with historical controls of TST and other standard induction therapies. Despite administration at the time of profound cytopenias, Pom was well tolerated and did not significantly prolong hematologic recovery. Correlates suggest that Aiolos expression may be a pharmacodynamic biomarker of activity. Identification of immune biomarkers to predict for response and duration of response are ongoing. Further exploration of Pom both at the time of induction TST and during CR are warranted. [Display omitted] DisclosuresZeidner:Rafael Pharmaceuticals: Other: Travel Fees; Merck: Research Funding; Asystbio Laboratories: Consultancy; Takeda: Other: Travel fees, Research Funding; Tolero: Honoraria, Other: Travel Fees, Research Funding; Celgene: Honoraria. Zeidan:Agios: Consultancy; Incyte: Employment; Novartis: Consultancy; Celgene: Consultancy; Ariad: Consultancy, Speakers Bureau; Gilead: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy. Pratz:Astellas: Consultancy, Research Funding; Agios: Research Funding; Boston Scientific: Consultancy; AbbVie: Consultancy, Research Funding; Millenium/Takeda: Research Funding. Foster:Shire: Honoraria; Pfizer: Research Funding; Macrogenics: Research Funding; Celgene: Research Funding. Coombs:H3 Biomedicine: Honoraria; AROG: Other: Travel fees; DAVA Oncology: Honoraria; Abbvie: Consultancy; Incyte: Other: Travel fees. Luznik:WIndMIL Therapeutics: Equity Ownership, Patents & Royalties. Gojo:Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Merck inc: Research Funding; Amgen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.

Timed sequential therapy with high-dose cytarabine and mitoxantrone as an effective and safe induction regimen for acute myeloid leukemia.

7055Background: Traditionally, patients eligible for induction chemotherapy for AML are treated with the “7+3” regimen, which includes standard doses of infusional cytarabine and an anthracycline, ...

Timed sequential therapy for acute myelogenous leukemia: Results of a retrospective study of 301 patients and review of the literature

Timed sequential therapy (TST) aims to improve outcomes in acute myelogenous leukemia (AML) by harnessing drug-induced cell cycle kinetics of AML, where a second drug is timed to coincide with peak leukemia proliferation induced by the first drugs. We analyzed outcomes in 301 newly diagnosed AML patients treated from 2004–2013 with cytarabine, anthracycline, and etoposide TST induction. Median age was 52 (range 20–74) and complete remission rate 68%. With median follow-up 5.8 years, 5-year DFS and overall survival (OS) were 37% (95% CI 31–45%) and 32% (95% CI 27–38%), respectively. In multivariate analysis, older age, unfavorable cytogenetics, and WBC≥50×109/L resulted in worse OS. Among patients not undergoing blood and marrow transplant, a propensity score analysis, which reduces imbalance in baseline characteristics, showed consolidation with TST compared with 1 or more cycles high-dose cytarabine trended toward lower DFS and post-remission survival with hazard ratio (HR) 1.9 (95% CI 0.9–4.0), and 1.6 (95% CI 0.7–3.6), respectively. Our results demonstrate the efficacy and feasibility of TST induction for newly diagnosed patients with AML, with results comparable to that seen in clinical trials with other TST therapies and 7+3.

Phase 1 Study of Pomalidomide Given at the Time of Early Lymphocyte Recovery after Induction Timed Sequential Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS)

Introduction: AML pts have a poor prognosis with conventional chemotherapy regimens. Early lymphocyte recovery (ELR) following intensive timed sequential therapy (TST) induction is characterized by a dysfunctional immunosuppressive state. Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), has direct effects on T cell co-stimulation by promoting the ubiquitination of Aiolos, an IL-2 transcriptional repressor. We hypothesized that the administration of Pom at the time of ELR after induction TST may influence T cell differentiation and enhance an anti-leukemia immune effect.Methods: A multicenter phase 1 dose escalation study was conducted to determine the safety and tolerability of Pom after intensive induction TST in newly diagnosed AML and HR-MDS pts 18-65 years. Core-binding factor AML was excluded. All pts received induction chemotherapy with AcDVP16: cytarabine 667 mg/m2/day IV continuous infusion days 1-3, daunorubicin 45 mg/m2/day IV days 1-3, etoposide 400 mg/m2/day IV days 8-10. Pom was administered at the assigned dose and schedule after day 14 and within 3 days of the total white blood cell count (WBC) reaching >0.2x109/L above nadir, defined as ELR. Three dose levels were planned (2 mg, 4 mg and 8 mg) within 2 cohorts: 10 days of Pom and 21 days of Pom, in a traditional 3+3 dose escalation design.Results: 25 pts were enrolled on this study January 2014-June 2016 across 3 institutions (Table 1). Pom administration occurred at a median of 21 days after AcDVP16 induction. There were no dose-limiting toxicities (DLTs) in the first cohort of Pom x 10 days within each dose level- 2 mg (n=3), 4 mg (n=3) and 8 mg (n=7). There were no DLTs seen at 4 mg x 21 days (n=7). Two DLTs were seen at Pom 8 mg x 21 days (Grade 3 ALT increase and Grade 3 hypoxia, respectively). Thus, Pom 4 mg x 21 days will be further expanded.Nine (36%) pts discontinued Pom early (median duration = 5 days) due to: grade 3 rash (n=3), physician discretion (decreased WBC: n=1, fever and increased creatinine: n=1), grade 3 ALT increase (n=1), grade 3 hypoxia (n=1), disease progression (n=1), and pt preference (n=1). Adverse events (AEs) possibly associated with Pom that were seen in >1 pt included fever (n=8), rash (n=7), AST/ALT increase (grade 1: n=4, grade 3: n=1), mucositis (n=2), and fatigue (n=2). All of these AEs were self-limiting with supportive care and/or discontinuation of Pom.60-day mortality was 0%. A complete remission (CR) was achieved in 18 pts and 1 achieved CR with incomplete platelet recovery (CRp) with a combined CR + CRp = 19/25 (76%). Among pts with adverse-risk AML, 5/6 (83%) achieved CR. One pt achieved a partial remission and 5 pts were refractory to treatment. Of the 19 CRs, 15 had no evidence of minimal residual disease by cytogenetics, FISH, or flow cytometry. Among pts who completed a course of Pom (10 days or 21 days), 14/16 (88%) achieved CR. As previously reported, a dramatic decrease of Aiolos expression via flow cytometry in T cell subsets was observed in vivo for the duration of POM treatment with doses > 2 mg, but the effect was lost after Pom was stopped. Figure 1 displays the pattern of cytokine production of CD4+ T cells visualized with pie charts, and shows a significantly different subset composition at ELR in Pom-treated pts compared to the same pts at full recovery (p=0.02), and compared to control AML pts at the same time point (p=0.004). Furthermore, there was a significant increase in TNF-α production (p=0.009) and the combination of TNF-α and IL-2 production (p=0.03) in stimulated CD4+ T cells during Pom treatment, which was reduced to baseline values after Pom was discontinued at full recovery (Figure 1: data analysis performed with the SPICE software).Conclusions: Pom can be safely administered at the time of ELR after intensive induction TST. Fever and rash are the most common AEs seen after Pom administration. Inhibition of Aiolos and consequent increase in both IL-2 and TNF-α expression, as measured by flow cytometry, appear to be reliable markers of Pom-induced T cell modulation in vivo. Planned expansion of the cohort of 4 mgx 21 days will allow further evaluation of safety and activity of Pom in AML. [Display omitted] [Display omitted] DisclosuresZeidner:Takeda: Research Funding; Merck: Research Funding; Agios: Honoraria; Otsuka: Consultancy; Tolero: Research Funding. Zeidan:Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Smith:Celgene: Consultancy, Other: member of DSMB. Levis:Millennium: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Foster:Celgene: Research Funding.

Immune Modulation with Pomalidomide after Induction Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia (AML)

Background: We recently showed that early lymphocyte recovery (ELR) following intensive induction chemotherapy in AML patients (pts) is characterized by complex immune system aberrations. (Blood 117(2):608, 2011) Full characterization of lymphoid T cell dynamics during this period can provide critical insights into their dysfunction and rationale for targeted therapeutic intervention to augment anti-leukemia immunity. Pomalidomide (POM), a small molecule immunomodulatory agent (IMiD), has direct effects on T cell co-stimulation by promoting the ubitiquitination of IL-2 transcriptional repressor Aiolos (IKZF3). (Br J Haematol 164(6):811, 2014) We hypothesized that administration of POM at the time of ELR may influence T cell differentiation and function in vivo.Methods: We serially collected peripheral blood (PB) samples at the time of ELR from 31 AML pts (median age 57, range 29-76 years; 26 de novo and 5 secondary AML) treated with intensive induction chemotherapy (18 with timed-sequential therapy (TST) and 13 with standard 7+3: cytarabine and idarubicin), 11 AML pts (median age 52, range 31-66 years; 6 de novo, and 5 secondary AML) treated on NCI/CTEP#9524 study of TST induction (AcDVP16: cytarabine, daunorubicin, and etoposide) followed by POM given daily for 10 days at ELR at escalating doses: 2mg (3pts)-4mg (3pts)-8mg (5pts) (Figure 1) and 17 healthy controls (HC) (median age 40, range 25-71 years). ELR was defined as absolute white blood cell (lymphocyte) count >200/mm3 above nadir. Using multi-parameter flow cytometry we performed extensive phenotypic characterization of lymphocyte populations, focusing on T cell differentiation status (CD45RA, CCR7), activation/proliferation (Ki-67), expression of POM-target gene Aiolos (IKZF3), and cytokine secretion. Statistical significance was determined using multiple t-tests using GraphPad Prism software. All protocols were IRB approved.Results: Administration of POM at ELR did not affect absolute lymphocyte count (ALC) compared to control pts not receiving POM (P=>0.5). ALC values ranges (both groups): pre-treatment 2538-3645/mm3, ELR 428-525/mm3, and 931-1360/mm3 at full count recovery (FR1), respectively. The percentages and total numbers of CD4+ and CD8+ T cells behaved similarly; however, POM pts had increase in the frequency of CD4+ central memory subset (CD45RA- CCR7+) (P=0.001) at FR1 and decrease in the terminally differentiated effector memory subset (CD45RA+ CCR7-) of CD8+ T cells only for the duration of POM administration at ELR (P=0.04). Tregs (CD4+ FoxP3+ Tcells) increased in control pts during ELR (p=0.004; n=26) but not in POM-treated group (n=5). A dramatic but dose-dependent decrease of Aiolos expression in T cell subsets in vivo (P<0.001, n=9; Figure 2) was observed for the duration of POM treatment but the effect was lost after POM was stopped (FR1) while Aiolos remained unchanged in pts treated with chemotherapy only (n=7). A trend toward increased IL-2 expression in CD4+ T cells of POM pts was noted as well (P=0.1, n=3) and exceeded the levels produced by HC (n=4).Conclusions: ELR represents an interesting time period for therapeutic intervention to modulate immunity following chemotherapy in AML pts. POM administration phenotypically and functionally affected several T cell subsets in vivo. Our data suggest that inhibition of Aiolos, an IL-2 transcriptional repressor, is a reliable pharmacodynamic marker of POM activity on T cells in vivo. Further studies with longer POM administration schedules as well as examination of other compartments such as bone marrow are ongoing to better define the role of immune modulation with POM in the treatment of pts with AML. [Display omitted] [Display omitted] DisclosuresOff Label Use: Pomalidomide is not FDA approved for acute myeloid leukemia..

Timed-sequential therapy with mibefradil and temozolomide in patients with recurrent high-grade gliomas: A phase I Adult Brain Tumor Consortium study.

2033 Background: Mibefradil (MIB) is a selective T-type calcium channel blocker that had previously been approved for treatment of hypertension. MIB has shown significant preclinical activity in ma...

Myeloablative Timed Sequential Busulfan Is Safe in Older Patients

▪Background: Reduced intensity conditioning regimen (RIC) extends allogeneic hematopoietic cell transplantation (HCT) to older patients and patients with comorbidities. Compared to myeloablative (MA) conditioning, RIC has higher rate of relapse but lower rate of non-relapse mortality (NRM), resulting in similar survival. BMT CTN is conducting a prospective study to compare these two approaches. To further improve survival for older patients, a MA regimen with low NRM is needed. Timed sequential therapy (TST), giving two courses of chemotherapy 1 week apart, has higher antileukemic effect in in-vitro and in-vivo in studies of patients with AML, including phase 3 studies. We hypothesized that MA dose of busulfan delivered per principles of TST enhances antileukemic effect without increasing toxicity. We therefore designed a study to test safety of two MA schedules of busulfan targeting busulfan exposure (AUC) of 16000 μmol.min and 20000 μmol.min. AUC of 20000 μmol.minis close to total average drug exposure achieved with IV busulfan fixed dose of 12.8mg/kg.Methods: Patients were randomized to receive total busulfan exposure of 16,000 μmol.min(16K) or 20,000 μmol.min( 20K). Patients received IV busulfan 80 mg/m2 per day on day -13 and -12 in outpatient clinic, fludarabine 40 mg/m2 day x 4 (day -6 to -3) and IV busulfanx 4 (day -6 to -3). Busulfan was dosed to achieve target AUC of 16K or 20K based on pharmacokinetic studies done on day -13 and day -6. GVHD prophylaxis was Tacrolimus (day -2 onwards) and mini dose methotrexate-5mg/m2 on day 1, 3, 6, and 11. Stem cells were infused on day 0. Primary endpoint of the study was to compare 100 day non-relapse mortality in two arms with stopping rules built in for safety. Patients with hematological malignancies were eligible for the study if they had adequate organ function and 8/8 matched related or unrelated donor. We enrolled patients on this study who were suitable for RIC. When the study began, upper age limit for eligibility was 70 years, but this was increased to 75 years during the course of the study as safety was established. Fisher’s exact test was used to compare toxicity and NRM rates between arms. Cox proportional hazards regression was used to estimate the effects of clinical variables on overall survival.Results: 97 patients were enrolled on the study until the DSMB stopped the randomization and permitted continued accrual onto the higher dose arm with busulfan AUC of 20,000 μmol.min. 49 were randomized to busulfan AUC of 16K and 48 to 20K. For all patients, median age was 60 (18-75) years. 3 (2%) patients were less than 40 years of age, 12 (12%) 40-49, 33 (34%) 50-59, 39 (40%) 60-69, and 10 (10%) 70-79 years. 53 patients had AML/MDS, 24 CML/MPD, 16 myeloma, and 4 lymphoid malignancies. Based on revised disease risk index, 3 had low risk, 53 intermediate risk, 35 high risk, and 6 very high risk disease. Donor was related for 43 and unrelated for 54. Comorbidity scores were 0 in 23, 1-2 in 24, and ≥ 3 in 50.With a median follow up of 9.2 months (range 1.8-24) in surviving patients, 100 day NRM was similar in two groups, 4% in 16K and 6% in 20K (p=0.68). Maximum toxicity per patient was not significantly different between arms (Table 1, p=0.37). The 1-year unadjusted survival rates (95% CI) in combined disease risk indexes low and intermediate vs high and very high were 67 (50-79)% and 38 (19-57)%, respectively for all 97 patients. Multivariable Cox regression analysis for overall survival showed increased risk of death for older age (HR 1.05; p=0.03), comorbidity 3 and higher (HR 1.89 p=0.08), and high or very high risk index (HR 2.04; p= 0.05). After also accounting for donor relation and cell type, Bu AUC of 20k showed improved overall survival and a 50% reduction in the risk of death (HR 0.50, P= 0.058).Table 1Maximum grade of toxicity per patient, N (Row %)MaximumGrade per PatientAUC=16kAUC=20kTotalp-value57 (54%)6 (46%)130.3746 (50%)6 (50%)12323 (44%)29 (56%)52211 (73%)4 (27%)1512 (40%)3 (60%)5Total Patients494897Conclusion: Myeloablative timed sequential busulfan regimen is safe in older patients and patients with comorbidities. The regimen with busulfan AUC of 20,000 μmol.min appears promising and needs to be studied further. DisclosuresPopat:Otsuka: Research Funding. Off Label Use: Busulfan.

Randomized multicenter phase II trial of timed-sequential therapy with flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus “7+3” for adults with newly diagnosed acute myeloid leukemia (AML).

7002 Background: Serial studies have demonstrated that induction therapy with flavopiridol (50 mg/m2 days 1-3), a multi-serine-threonine cyclin-dependent kinase inhibitor, followed by cytarabine (6...

Randomized Phase II Trial of Timed-Sequential Therapy (TST) with Flavopiridol (Alvocidib), Ara-C and Mitoxantrone (FLAM) Versus “7+3” for Adults Ages 70 Years and Under with Newly Diagnosed Acute Myeloid Leukemia (AML)

AbstractAbstract 47 BackgroundIn adults with newly diagnosed, poor-risk AML we previously demonstrated that induction therapy with Flavopiridol in combination with Ara-C and Mitoxantrone (FLAM,) in a timed-sequential manner, yields complete remission (CR) rates of 67% and median disease-free survival (DFS) of 13.6 months. These data suggest that FLAM might improve outcomes relative to standard “7+3” in newly diagnosed AML with poor-risk features. Thus, we are conducting a phase II randomized trial comparing the CR rates with FLAM vs. 7+3 induction for all newly diagnosed adult patients with AML with intermediate and poor-risk features. We also previously identified a population of CD34+CD38− cells with intermediate aldehyde dehydrogenase (ALDH) activity that appears to represent a leukemic stem cell (LSC) population. We are examining the effects of FLAM vs. 7+3 in eradicating this LSC population and determining if persistence of LSC’s predicts for relapse. ObjectivesThe primary objective is to compare the rate of CR after 1 cycle of FLAM vs. 1 cycle of 7+3. The secondary objectives are to compare toxicities, survival rates, and presence or absence of minimal residual disease (MRD) after both induction regimens. MethodsAll newly diagnosed adult patients aged 18–70 without favorable risk features were randomized in a 2:1 fashion between FLAM and 7+3 at 90 mg/m2 of Daunorubicin. To achieve balanced randomization, patients were stratified by age, secondary AML and leukocyte count. CD34+ cell subsets were analyzed by flow cytometry for CD38 expression and ALDH activity by Aldefluor. The trial is ongoing. ResultsTo date, 62 patients are evaluable for the primary end point. Demographics and results are depicted in table 1. Patient characteristics were similar in both arms, although there were more patients with poor risk features in the FLAM arm than 7+3. Overall grade > 3 toxicity was similar between both arms. However, there were 3 cases of grade > 3 tumor lysis syndrome (TLS) with FLAM, with 1 death, vs. 0 with 7+3. There were also 3 deaths with FLAM before day 60 vs. 0 with 7+3. CR rate with FLAM was 68% (28/41), with 1 cycle of 7+3 was 48% (10/21) (p = 0.17), and with 2 cycles (7+3 + 5+2) was 52% (11/21). CR rates based on specific risk factors are depicted in table 2. There was a trend toward improved CR rates in patients with adverse genetics with FLAM (p = 0.17). Putative AML LSC’s were distinguished from normal hematopoietic stem cells based on ALDH activity. The persistence of putative LSC’s in patients after therapy was highly predictive of subsequent clinical relapse. ConclusionsBased on the current CR rate of 68%, FLAM holds promise as a therapeutic option for patients with newly diagnosed AML with intermediate and poor risk features. In this preliminary analysis, there is a suggestion that FLAM leads to higher CR rates in patients with adverse genetics than 7+3. Additionally, the detection of MRD consisting of a residual putative LSC population strongly portended subsequent relapse, even in patients without evidence of leukemia. [Display omitted] [Display omitted] Disclosures:Off Label Use: Flavopiridol (Alvocidib) is an anti-leukemia agent.

Invasive Fungal Infections in Adults with Newly Diagnosed AML Undergoing Intensive Chemotherapy: Characterization, Risk Factors, and Outcomes in a Single Institution

Abstract 4254 Background:Invasive fungal infections (IFI) are a significant cause of morbidity and mortality in patients with acute myelogenous leukemia (AML) undergoing chemotherapy treatment. However, the epidemiology, risk factors, and outcomes of IFI in these patients have been poorly described. Methods:A single-center retrospective analysis was performed to study the epidemiology, risk factors, clinical outcomes, and mortality predictors of IFIs in AML patients undergoing intensive, multi-agent induction timed sequential therapy (TST) between January 2005 and June 2010. Newly diagnosed AML patients, with exception of acute promyelocytic leukemia, were studied. IFIs were defined using the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. Results:254 consecutive patients (57% male; median age 54, range 20–78) were analyzed. 123 (48%) of patients had an IFI; of which, 15 patients (12%) had a proven candidal infection, and 108 patients (88%) had a mould infection (5 proven/probable (5%) and 103 (95%) possible mould infections). 237 (93%) patients received antifungal therapy during their treatment course (median day 8, range day -15 to 30). Of those, 63 (27%) received monotherapy (46% liposomal amphotericin, 44% voriconazole) and the rest received multiple antifungal agents.Significant risk factors and trends for developing +IFI shown from univariate analyses are listed in Table 1. Prolonged neutropenia, duration of mucositis, and concurrent bacterial infections did not significantly affect the development of +IFI. Using multivariate analyses, mortality was impacted by patients' baseline organ function (p=0.002 [1.3,3.1]), specifically, by bilirubin < 2 mg/dL (p=0.003 [1.38,4.57]) and creatinine < 1.5 mg/dL (p=0.01 [1.23,5.4]).Table 1Significant risk factors and trends for development of + IFINo IFI+ IFIP-valueMale Gender (%)50640.023Leukemia from a secondary cancer (%)1540.003Duration of parenteral nutrition (days)*9.5170.057Candida Colonization (%)85930.043Grade 3+ mucositis (%)42590.05*values are median daysPatients with +IFI did not significantly impact overall survival. However, patients with candidal IFIs had a significantly lower overall survival compared to patients with mould IFIs and no IFI (HR 2.01 [1.06, 3.8]) (Figure 1). Candida colonization prior to or during the first week of chemotherapy, and development of mucositis were associated with the development of candidal IFIs (p=0.07). [Display omitted] Conclusion:IFIs, particularly mould infections, remain a significant problem in patients with AML. Although overall survival did not appear to be significantly affected by mould infections, patients with candidal infections were more likely to die. Identification of risk factors for each type of IFIs may help to develop effective targeted preventive antifungal strategies. Disclosures:No relevant conflicts of interest to declare.

治療抵抗性急性骨髄性白血病6例に対するmitoxantrone, etoposide, cytarabine timed-sequential療法 (EMA療法) の有用性

治療抵抗性急性骨髄性白血病6例に対するmitoxantrone, etoposide, cytarabine timed-sequential療法 (EMA療法) の有用性

Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)

AbstractAbstract 186Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML TherapyF is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below.Age# < 50Secondary AMLAdverse GeneticsMDS/MPDt-AMLSingleComplexFlt3ARM A (n = 36)59ü(24–78)31956133Total 24/36 = 67%Total 22/36 = 61%ARM B (n = 34)58ü(20–73)51698105Total 25/34 = 74%Total 23/34 = 68%Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens. Disclosures:No relevant conflicts of interest to declare.

Timed Sequential Induction Therapy with Cytarabine and Mitoxantrone In Acute Myeloid Leukemia (AML): A Well-Tolerated Regimen with High Response Rates In Older Patients and Transformed AML.

AbstractAbstract 1068 Background:Patients with AML who are eligible for chemotherapy are traditionally treated with infusional cytarabine and an anthracycline. CR rates with this combination have been approximately 50–60% with an induction mortality of 10–25%. However, this treatment is less effective in older patients in terms of CR attainment, remission duration, and overall survival.We present a retrospective analysis of an induction regimen that was designed based on the concept of timed sequential therapy. An initial pulse of chemotherapy is administered to eradicate cells in S phase. This is followed by a rest period during which previously quiescent cells that enter the cell cycle can be targeted by a second pulse of chemotherapy. The regimen incorporates high dose cytarabine, which has been shown to improve remission duration when used in induction, and dose-intensified anthracycline therapy, which has been shown to improve outcomes in younger patients. This report highlights the responses and tolerability of the study regimen, particularly in elderly patients and patients with prior myelodysplastic syndrome (MDS). Patients and Methods:One hundred sixty six patients were treated with timed sequential chemotherapy from 1998–2009. The treatment consisted of two doses of cytarabine 2 gm/m2 IVPB over 3 hours administered 12 hours apart followed by one dose of mitoxantrone 30 mg/m2 IVPB over 1 hour on days 1 and 5. Data on pre-therapy cytogenetics and MDS was collected for each patient. Remission status was assigned per the IWG response criteria for AML. Results:Median age of the patients was 54.5 years (range 17–85). There were eighty males and eighty-six females. Out of 166 patients, 11 (6.6%) patients had favorable, 83 (50%) had intermediate, and 72 (43.4%) had unfavorable karyotypes. One-third of the patients (57 pts) had AML transformed from MDS.The overall response rate (ORR: CR+CRi+CRp) for all patients was 69.9%. In patients who had de novo AML, the ORR was 79.8%, regardless of age. Patients over age 60 with de novo AML had an ORR of 74%. For those patients under the age of 60, the ORR was 82%. The ORR for patients with transformed AML was 52.6% (53% in pts over age 60, 52% in pts less than 60).The 30 day mortality rate was 3.4% (6/166). Five of the six patients who died had an unfavorable karyotype with 2 patients having therapy-related AML. The 30 day mortality for patients older than 60 was 3.3% (2/61) and for all patients was 3.6% (6/166). The 60 day mortality rate in all patients was 10.8% (18/166). Of the additional 12 patients, seven died from progressive disease and only 3 died of suspected therapy-related complications. Grade 3/4 hematologic toxicities were the most common adverse events seen. Conclusion:This is a convenient, 2-day induction regimen that is well-tolerated with comparatively low 30 and 60 day mortality and high response rates in older patients and those patients with AML transformed from MDS. This would be an excellent initial regimen for remission induction in a select population of patients in whom novel consolidation or maintenance therapies can be incorporated to further improve outcome. Disclosures:No relevant conflicts of interest to declare.

Intensively timed combination chemotherapy for the induction of adult patients with acute myeloid leukemia

Despite advances in therapy, the majority of adult patients diagnosed with acute myeloid leukemia (AML) develop disease recurrence and die of their disease. Early intensification of treatment for AML using timed sequential therapy (TST) has been proposed as a means of improving the survival outcome in children. The Children's Cancer Group demonstrated that children with AML who were randomized to receive 2 courses of daunorubicin, cytarabine, thioguanine, etoposide, and dexamethasone (the DCTER regimen) given 10 days apart had an improved event-free survival (EFS) and disease-free survival (DFS) (42% ± 7% and 55% ± 9%, respectively, at 2 years). Reports have suggested an improved outcome in adult patients with AML using TST (at the cost of increased toxicity). The current study was conducted to evaluate the feasibility and effectiveness of the intensively timed DCTER regimen for non-core-binding factor AML in adult patients aged <50 years. Between February 2004 and August 2005, 61 patients received this timed sequential induction regimen. Their outcomes were compared with matched historical patients treated with the combination of idarubicin and cytarabine (IA). The median follow-up for surviving patients was 67 months (range, 35-85 months). The timed sequential DCTER regimen had a lower complete remission (CR) rate when compared with the IA combination,, (71% vs 80%, respectively), but this appeared to be counterbalanced by a higher long-term leukemia-free survival rate using the intensified regimen (48% vs 30%, respectively) in patients who achieved a CR (P = .06). The intensively timed regimen of DCTER was found to induce durable remissions in adult patients with AML, including those patients with high-risk disease. The identification of patients who would potentially benefit from such an intensive regimen may justify the higher early risk of early treatment failure that was found to accompany the intensified DCTER regimen in selected patients.

Epidemiology, risk factors, and outcomes of invasive fungal infection in adults with acute myelogenous leukemia undergoing intensive induction chemotherapy.

6579 Background: The epidemiology and outcomes of invasive fungal infections (IFI) in patients with acute myelogenous leukemia (AML) have been poorly described. Methods: We performed a single center, retrospective analysis of the epidemiology, risk factors and clinical outcomes of IFIs in newly-diagnosed AML patients undergoing intensive, multi-agent induction timed sequential therapy (TST). Patients did not receive antifungal prophylaxis. IFIs were defined using EORTC/MSG criteria. Results: Of 97 consecutive patients (58% male; median age 53, range 22-72) admitted in 2007 and 2008, 27 (28%) had IFI, of which 7 (26%) were proven, 1 (4%) probable, and 17 (68%) possible with lung CT findings characteristic of fungal (mold) pneumonia. Of 8 proven/probable cases, 4 were due to molds and 4 were due to yeasts. Of 91 (94%) receiving antifungal therapy beginning median day 7 (range day -14 through day 25) of AML treatment; 41 (42%) received monotherapy (66% liposomal amphotericin B, 34% voriconazole) and the rest received multiple antifungals. Using univariate analysis, we identified risk factors for IFIs (Table 1). Occurrence of IFI was associated with lower complete remission rate (52% vs. 70% -IFI, p=0.06) and a decrease in 6 month survival (58% vs. 85% -IFI, p=0.01). Conclusions: AML patients with IFIs are more likely to die within 6 months of beginning intensive induction TST. Through this analysis, we are able to identify risk factors that may be associated with development of IFIs. Such identification may help to develop effective preventive antifungal strategies for high risk AML patients. Risk factors for + IFI cohort (overall), and for IFIs due to yeasts and molds No IFI (N=70) IFI (N=27) P- value IFI- yeasts (N=4) P-value IFI-moulds (N=23) P-value Age > 50 years (%) 49 70 0.07 75 NS 70 0.09 Presenting blast count > 10,000 (%) 26 44 0.09 50 NS 43 0.12 Time to ANC < 100 cells/mm3* 7 5 0.08 4 0.16 5 0.16 Time to recovery of ANC >100 cells/mm3* 22.5 26 0.07 25 NS 27 0.12 Onset of mucositis** 14 11.5 0.03 8.5 0.14 12 0.06 Duration of parenteral nutrition* 10 15 0.04 15 NS 14.5 0.07 NS: Non significant, ANC: Absolute neutrophil count. * Median Days of AML therapy (begins on Day 1) No significant financial relationships to disclose.

Immune Recovery after Timed Sequential Therapy in Acute Myelogenous Leukemia: Discordant Recovery of Naïve T Lymphocytes and Antigen Driven Regulatory T Cells.

Patients who demonstrate a rapid but limited initial lymphocyte recovery following therapy have a significantly better response rate than patients where lymphocyte recovery is markedly delayed. Timed sequential therapy (TST) is a cell cycle dependent based approach for curative therapeutic potential in acute myelogenous leukemia (AML). Recovery of T cells in this setting can be due to thymic dependent T cell development or as a consequence of directed (antigen) expansion of effector T lymphocytes. The present studies evaluated immunological reconstitution of 26 AML patients following induction or consolidation TST. Thirteen patients received cytarabine, daunorubicin and etoposide (AcDVP-16) induction therapy, 3 patients received cytarabine, daunorubicin and cytarabine (AcDAc) and 10 patients received flavopiridol, cytarabine and mitoxantrone (FLAM) either as induction or consolidation therapy. Peripheral blood lymphocytes were collected during the initial phase of white blood cell reconstitution (>200 cells/ cu mm). Lymphocyte Recovery preceded that of myeloid elements (median of day 24 versus day 30) with peak lymphocyte counts ranging from 300–1800 and a median of 650 cells/cu mm. Multi-color flow cytometric analysis revealed recovery of CD4, CD8 and NK cells with the CD3+CD4+:CD3+CD8+ ratio averaging 4.5:1 (range 1:1– 8:1). Assessment of T cell recombinant excision circles (TREC's) suggested that a significant proportion of the T cells (median 40,000 copies per 100,000 cells; range 100 – 100,000 copies) were recent thymic emigrants. Somewhat surprisingly, there was a significant expansion of the CD4+CD25+Foxp3+ regulatory T cell compartment (median 5.1%; range 2.5 – 12.3%). To examine whether the expansion of this T cell compartment cells was due to endogenous thymic output or developed by homeostatic mechanisms, CD4+CD25+Foxp3+ cells isolated flow cytometrically were assessed for TREC's and by spectratyping for Vb T cell receptor gene utilization. The results revealed that the majority (>90%) of CD4+CD25+Foxp3+ cells did not express TREC's and therefore, did not recently emigrate from the thymus. Moreover, there was a marked oligoclonal skewing as defined by a limited Vb T cell receptor repertoire suggesting expansion did not occur by a non-specific, global homeostatic. In contrast, the repertoire of the non-regulatory T cell compartment (CD4, CD8) was unbiased. These results suggest that the expansion of the CD4+CD25+Foxp3+ T cell compartment is either driven by antigen or by restricted homeostatic mechanisms. The lack of significant, correlative levels of typical homeostatic cytokines (i.e., IL-2, IL-7; Bioplex analysis) may provide an environment where CD4+CD25+Foxp3+ T cells can only be driven to expand by antigenic stimulation. The continued presence of antigen driven regulatory T cells may impede the successful deployment of immunologically directed anti-tumor strategies.

Timed Sequential Therapy Induction and Consolidation in Newly Diagnosed AML: Achievement of Leukemia-Free Survival in Patients Using Two Cycles of Therapy Alone

Long term outcomes for patients with AML are unsatisfactory following induction and consolidation chemotherapy alone except in patients with favorable–risk cytogenetics. The additional administration of the same or different agents starting 8–10 days after start of initial chemotherapy (timed sequential therapy, TST) may enable the killing of leukemic cells synchronized into cell cycling by the initial chemotherapy. However, it is unclear if patients with intermediate and unfavorable cytogenetics achieve improved outcomes using this approach. Sixty-nine unselected patients with AML (42M, 27F; median age = 53, range 16–74; cytogenetic risk group favorable =2, intermediate = 37, unfavorable = 23; 10 with an antecedent hematologic disorder) referred to a tertiary leukemia center received initial chemotherapy with a regimen of cytarabine 667mg/m2/d by 24 hour infusion on d1–3, idarubicin 12mg (age <60) or 8 mg (age >60)/m2/d on d1–3 and etoposide 100mg/m2 on d 8–10. Induction death occurred in 7 patients (10%). Complete remission was achieved following one cycle of induction therapy in 30 patients (43.5%). The corresponding complete response (CR) rates by cytogenetic subgroup were100%, 48.6% and 26% in the favorable, intermediate and unfavorable cytogenetic groups respectively. In patients who achieved CR, median time to ANC > 1000/mm3 and platelets > 100,000/mm3 were 29 d (range 21–76d) and 26d (range 17–83d). Mucositis was the most common non-hematologic toxicity. Of the 69 patients treated, 30 (43%) and 4 (6%) patients proceeded to allogeneic and autologous hematopoietic stem cell transplantation respectively. Of the patients who did not receive stem cell transplantation, eleven patients (median age 54, range 23–72; median WBC 27.1, range 1–250; cytogenetics -9 normal, 1 t(9;22); 1 11q23 abnormality) underwent consolidation with TST–consisting of a single cycle of cytarabine 667mg/m2/d (continuous infusion) on d1–3 and 10–12, and idarubicin (same dose as induction). Two year estimated probabilities of overall survival and relapse in this group were 65% and 26% respectively. In summary, TST as administered in these patients can be safe in patients with newly diagnosed AML, including those patients aged between 60 and 70. However, the regimen does not appear to improve CR rates over that seen using conventional induction regimens. Patients with intermediate risk cytogenetics who achieve CR and are not candidates for stem cell transplantation may receive consolidation with a single additional cycle of TST.

Phase II Clinical Trial of Flavopiridol (FL) Followed by ara-c and Mitoxantrone (AM) for Adults with Relapsed and Refractory Acute Leukemias.

The cell cycle inhibitor FL targets cyclin-dependent kinases, induces checkpoint arrest and interrupts transcriptional elongation. We demonstrated in an in vitro model that F causes apoptosis in leukemic blasts and increases A cytotoxicity in remaining blasts (Clin Cancer Res 9: 307–315, 2003). Based on these observations, we have conducted a Phase II trial of timed sequential therapy (TST) with FL 50 mg/m2 daily x 3 days followed by A 2 gm/m2/72 hr infusion beginning day 6 and M 40 mg/m2 day 9 (FLAM). A total of 42 adults (median age 50, range 23–75) received FLAM for acute myelogenous leukemia (AML, 37 pts) or acute lymphoblastic leukemia (ALL, 5 pts). Four pts had new AML (myelodysplasia- or treatment-related), 19 were in relapse after first complete remission (CR; median duration 8 mos, range 1.5 – 20), and 19 had refractory leukemia (9 primary). Four pts had prior allo- or auto-stem cell transplants, 13 (31%) had secondary AML and 25 (60%) had adverse cytogenetics, including 2 with Ph+ ALL. FLAM was well-tolerated with death occurring in only 3/42 (7%, fungemia, respiratory distress, multi-organ failure). Grade ≥ 3 non-hematologic toxicities consisted of oral mucositis (2/42, 5%), diarrhea (1/42, 2%), cardiac arrhythmia or decreased ejection fraction (3/42, 7%). F induced tumor lysis in 14 (33%) within 24 hrs of first F dose and a ≥ 50% fall in WBC after 2 F doses in 18 (43%). Median time to neutrophils ≥ 500/mm3 was day 30 day (range 24–46) and platelets ≥50,000/mm3 was day 35 (range 24 – 55). CR was achieved after 1 course of FLAM in 15/37 (41%) AML: 3/4 new patients (including complex cytogenetics), 11/19 relapse and 1/9 primary refractory. CR was achieved in 1/5 (20%) ALL in a patient with relapsed Ph+ ALL. Two of 4 with prior transplant achieved CR, while no patient who was refractory to multiple chemotherapies achieved CR. Of the 15 achieving CR, 13 received additional therapy. Eight pts (7 CR, 1 partial response; median age 45, range 26–62; 1 new diagnosis, 6 relapse, 1 primary refractory) went on to receive allo-transplant in second CR, with CR 2 durations 4.5–12+ mos. An additional 2 pts (ages 45, 46) who had relapsed after allo-transplant in CR1 were able to receive donor lymphocyte infusions (DLI) after FLAM and remain in CR2 of 8+ mos duration. Three pts over age 65 received a second cycle of FLAM in CR, with CR durations of 8.5+, 10, and 10.5 mos. Induction chemotherapy with FLAM yields a significant CR rate in pts with newly diagnosed poor-risk AML or in pts with short CR1, and allows eligible pts to proceed to allo-transplant in CR2.

Phase II Study of Timed Sequential Therapy (TST) with Topotecan, Cytosine Arabinoside (ARA-C), and Mitoxantrone (TAM) Induction Therapy Followed by Non-Cross-Resistant Consolidation Chemotherapy for Adults with Newly Diagnosed Acute Myelogenous Leukemia (AML).

Clinical results in AML continue to need improvement, particularly for age ≥60, prior MDS or secondary AMLs, and AMLs with adverse cytogenetics (CG) where complete remission (CR) rates are <50% and cure rates are <10%. In an attempt to improve these outcomes, we developed a TST regimen of the topoisomerase I inhibitor Topotecan with ara-C and Mitoxantrone (TAM) as induction therapy for adults with newly diagnosed AML: T, 4.5 mg/m2 IV continuous infusion (CI) over 72 hrs days (d) 1-3; A, 2 gm/m2 IV CI over 72 hrs d 3-5; and M, 40 mg/m2 IV d 10. CR patients with poor risk features received consolidation TST with T, 4.5 mg/m2 CI over 72 hrs d 1-3; A, 2 gm/m2 IV CI over 72 hrs d 3-5; and etoposide (E), 300 mg/m2 IV CI over 72 hrs d 10-12 (TAE); CR patients without poor risk features received consolidation TST with A, 2 gm/m2 CI over 72 hrs d 1-3 and 10-12; and idarubicin (I) 12 mg/m2 IV d 1,2,3 (AIA). From 04/02-2/04, 60 newly diagnosed AML patients (median age 49 yrs, 21–79) received TAM induction chemotherapy. Of 60 pts, 47 (78.5%) had at least one poor prognostic feature: age ≥60, 16 (27%); adverse CG, 28 (47%); MDS/AML, 10 (17%); secondary AML, 3 (5%); and/or WBC >25,000/μl, 23 (38.5%). Of the 41 (68.5%) pts who achieved CR, 32 (78%) received consolidation TST (22 TAE; 10 AIA). The remaining 9 pts received alloBMT (2), alternate therapy (5), or no consolidation (2) due to incomplete reversal of organ damage. Furthermore, 8 pts who finished 2 cycles of TST subsequently received alloBMT (3), autoBMT (2) and maintenance Zarnestra (3). Median overall survival (OS) for all pts is 10.1 mos, with 1yr survival 45.7% (95% CI; 32.5%–58.9%). On multivariate analysis, only antecedent MDS was a significant risk factor for poor OS (HR=2.5, 95% CI 1.13–5.65; p=0.02). For patients who achieved CR, median disease free survival (DFS) was 9.9 mos (95% CI; 5.8–18.2) with 1yr DFS 45.9% (95% CI; 29.4%–62.4%). Preceding MDS (p=0.02), adverse CG (p=0.04) and age ≥50 (p=0.06) were associated with low CR. Induction and consolidation mortality were <10%. Median time for ANC >100/μl was 28 days (22–56) and platelets >50,000/μl was 30 days (22–81) following TAM. For consolidation, median time to ANC >100/μl was 27.5 days (19–48) for TAE and 39 days (26–43) for AIA, and plts >50,000/μl 34 days (19–87) for TAE and 54 days (33–79) for AIA. Toxicities during induction and consolidation were generally ≤grade 3 and consisted of infection (bacteremias, pneumonias), oral and/or GI mucositis, transient elevation in liver function tests, reversible renal insufficiency. Pulmonary hemorrhage (1), GI bleed (3), CNS bleed/infarct (2) and decreased ejection fraction (2) occured during induction/consolidation but resolved. Causes of death during induction were sepsis/multiorgan failure (3), progressive fungal pneumonia (1), grade 5 marrow aplasia (1); during consolidation multiorgan failure (1), renal failure/sepsis (1), pulmonary hemorrhage (1). In summary, TAM induction for AML is associated with significant CR rates and acceptable toxicity, but did not appear to overcome the poor DFS and OS in a high-risk group of adults.