Intermediate-dose Cytarabine Research Articles

The Poorer-Risk AML, the Weaker Immunologic Surveillance? --Higher PD-L1 Expression on Non-APL AML Cells Is Associated with Poorer Risk Status According to Cytogenetics and Molecular Abnormailties

BackgroudThe specific recurrent cytogenetic and molecular abnormalities are significantly associated with prognosis and have been used to establish risk stratification which directs the therapeutic strategy in AML. Whether the immune surveillance contributes to the prognosis according to the cytogenetic and molecular risk status is unknown. The checkpoint PD-1/PD-L1 pathway is involved in the tumor surveillance. Down-regulation of PD-1/PD-L1 pathway caused a slower AML progression in mouse models through anergy of CD8+ CTL cells. Clinical trials of PD-1/PD-L1 inhibitor-based regimens in patients with AML are ongoing and seem to have promising results. But few studies investigated clinical significance of PD-L1 expression on leukemic cells in AML patients.MethodWe prospectively observed 120 consecutive adult patients with non-APL AML. PD-L1 mRNA of bone marrow mononuclear cells at diagnosis was detected by RT-PCR and the specific fluorescence indices (SFI) of PD-L1 expression on bone marrow blast cells was determined by flow cytometry. Cytogenetic and molecular genetic risks were assessed according to NCCN AML guideline (2016 version 2). Patients with age >60 years or failure of karyotype analysis were excluded. All remaining 95 patients were treated with "3+7" idarubicine and cytarabine induction regimen. Patients with response of ≥PR were administered the same regimen as the initial chemotherapy, and then consolidated with intermediate-dose cytarabine for four cycles followed by MA, AA, HA and AE regimens subsequently. Patients at poor risk or with unsatisfied controlled minimal residual disease were recommended allogeneic transplantation (allo-HCT). Among the patients with indication of allo-HCT, those who had both donor and desire received allo-HCT after 3 cycles of consolidation in their first CR (CR1).ResultThe diagnoses according to morphology included AML-M0 (n=1), AML-M1 (n=5), AML-M2 (n=55), AML-M4 (n=19), AML-M5 (n=13) and AML-M6 (n=2). Twenty patients were at favorable risk, 43 were at intermediate risk and 32 were at poor risk. We found a correlation between SFIs of PD-L1 and PD-L1 mRNA (r=0.413, P<0.001). After the base 10 logarithm transformation, quantity of PD-L1 mRNA in mononuclear cells of bone marrow were different among all risk groups (P=0.025). Post Hoc multiple comparisons showed PD-L1 mRNA of poor-risk group was higher than that of favorable-risk group (P=0.008). PD-L1 mRNA of the intermediate-risk group was also higher when compared to that of favorable-risk group (P=0.029). SFIs of PD-L1 on leukemic cells was higher in poor-risk group than in either intermediate-risk (P=0.040) or favorable-risk group (P=0.042), although no statistic difference was found among three groups (P=0.057). With ROC curves, we found PD-L1 mRNA could well predict both the early CR defined as the CR achieved after the initial chemotherapy (AUC=0.736, P=0.050) and the final CR defined as CR1 achieved after any cycles of induction chemotherapy (AUC=0.911, P=0.006). SFI of PD-L1 on leukemic cells could only predict the final CR (AUC=0.889, P=0.009). With both the best specificity of 0.833 and sensitivity of 1.000 for predicting final CR and specificity of 0.667 and sensitivity of 0.917 for predicting early CR, the cutoff value of PD-L1 mRNA was identified as 0.0681. SFI of PD-L1 less than 1.852 was a good predictor for achieving final CR with the sensitivity of 0.800 and specificity of 1.000. PD-L1 mRNA≥0.0681 was the only independent poor-risk factor for the early CR (HR=12.697, 95%CI 2.710-59.481, P<0.001).ConclusionAML cells with poorer-risk cytogenetic and molecular abnormalities seemed to have a higher PD-L1 expression which may compromise the leukemic immune surveillance by CTL suppression. Higher PD-L1 expression on AML cells was associated with poorer response to IA-based induction regimens. DisclosuresNo relevant conflicts of interest to declare.

Post-Remission Treatment with Autologous or Allogeneic Bone Marrow Transplantation or Intensive Chemotherapy in Younger AML Patients: Long-Term Follow-up Results of the EORTC/Gimema AML-8A Study

*The 2 first authors contributed equally to the work.Background. The best post-remission treatment for younger acute myeloid leukemia (AML) patients has remained controversial (Cornelissen JJ &Blaise D, Blood 2016, 127, 62-70) and there is paucity of studies comparing intensive chemotherapy to autologous (auto) or allogeneic (allo) bone marrow transplantation (BMT).Aim. The main objective of this study was to provide a long-term follow-up evaluation of patients previously enrolled in the pivotal EORTC/GIMEMA AML-8A (Zittoun et al., New England Journal of Medicine 1995, 332, 217-223).Methods. The EORTC/GIMEMA AML-8A prospectively assessed the impact of 3 post-remission treatments on disease-free survival (DFS) and overall survival (OS) in younger (<60 years of age) AML patients who reached a complete remission (CR) after induction with cytarabine and daunorubicin. All patients received a consolidation chemotherapy course (ICT1) including intermediate-dose cytarabine and amsacrine. Patients who had an HLA-identical sibling donor were then allocated to allo-BMT while remaining patients, at the start of ICT1, were randomized to receive auto-BMT or a second course of intensive chemotherapy consisting of high-dose cytarabine and daunorubicin (ICT2 group) after recovery of ICT1. At the time of the publication of the results (Zittoun et al., New England Journal of Medicine 1995, 332, 217-223), the median follow-up from inclusion was 3.3 years.Results. In the current report, median follow-up was 11.1 (range, 0-28) years. For the whole population (n=422), the 5-, 10 and 15-year OS rates from inclusion were 35%, 32% and 31%, respectively. After the completion of ICT1, 168 patients were allocated to theallo-BMT arm, while 254 patients were randomized to auto-BMT (n=128) or ICT2 (n=126). DFS from CR was longer afterallo-BMT than auto-BMT and DFS from CR was longer after auto-BMT than ICT2, due to a lower relapse incidence (P<0.001). Details are provided in table 1. Patients randomized to the auto-BMT arm had still a longer DFS from CR than patients in the ICT2 group (P=0.11) due to a lower incidence of relapse (P=0.047). Regarding OS, the differences between the 3 groups was no longer significant. In the ICT2, the improved outcome regarding OS as compared to DFS was due to a higher proportion of ICT2 patients who received a salvage auto-BMT.Conclusions. This long-term follow-up of the EORTC/GIMEMA AML-8A study confirms a better DFS with allo-BMT or auto-BMT when compared to ICT2 for AML patients in first CR. Further, this long-term follow-up study revealed that the vast majority of patients alive in first CR at 5-year remains disease-free survivors 5 years later. Although indications of allogeneic hematopoietic stem cell transplantation (allo-HCT) are nowadays largely driven by cytogenetic/molecular AML profile, long-term results of AML8A study demonstrate that auto-BMT remained superior to ICT2 in younger AML patients not candidate for an allo-HSCT. [Display omitted] DisclosuresEfficace:TEVA: Consultancy, Research Funding; Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; Lundbeck: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; Roche: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy, Speakers Bureau.

Persistence of minimal residual disease assessed by multiparameter flow cytometry is highly prognostic in younger patients with acute myeloid leukemia.

Predicting outcomes for patients with acute myeloid leukemia (AML) on the basis of pretreatment predictors has been the cornerstone of management. Posttreatment prognostic factors are increasingly being evaluated. Among 280 younger patients who were treated with intermediate-dose cytarabine (total ≥ 5 g/m2 ) and idarubicin-based induction chemotherapy and achieved remission, 186 were assessed for minimal residual disease (MRD) with an 8-color multiparameter flow cytometry panel performed on bone marrow specimens with a sensitivity of 0.1% or higher. One hundred sixty-six patients had samples available 1 to 2 months after induction at the time of complete remission (CR), and 79% became negative for MRD, with an MRD-negative status associated with an improvement in relapse-free survival (RFS; P = .0002) and overall survival (OS; P = .0002). One hundred sixteen were evaluated for their MRD status during consolidation, and 86% were negative, with an MRD-negative status associated with a significant improvement in RFS (P < .0001) and OS (P < .0001). Sixty-nine patients were evaluated for their MRD status after completion of all therapy, and 84% were negative, with an MRD-negative status associated with an improvement in RFS (P < .0001) and OS (P < .0001). In a multivariate analysis including age, cytogenetics, response (CR vs CR with incomplete platelet recovery/incomplete blood count recovery), and MRD, achieving an MRD-negative status was the most important independent predictor of RFS and OS at response (P = .008 and P = .0008, respectively), during consolidation (P < .0001 for both), and at the completion of therapy (P < .0001 and P = .002, respectively). Achieving an MRD-negative status according to multiparameter flow cytometry is associated with a highly significant improvement in the outcomes of younger patients with AML receiving cytosine arabinoside plus idarubicin-based induction and consolidation regimens. Cancer 2017;123:426-435. © 2016 American Cancer Society.

Vosaroxin: innovative anticancer quinolone for the treatment of acute myelogenous leukemia

ABSTRACTIntroduction: A first-in-class anticancer quinolone derivative with topoisomerase II activity, mechanistically, vosaroxin is similar to the anthracycline class. However, vosaroxin displays advantageous pharmacokinetic properties such as minimal metabolism, a lack of free radical production, is not a substrate for the P glycoprotein efflux pump, and can exert its antineoplastic activity independently of P53 function. Vosaroxin has shown encouraging results when combined with cytarabine in older patients with relapsed or refractory acute myeloid leukemia (AML) while balancing early toxicity and mortality, making it a compelling novel therapy for acute myelogenous leukemia.Areas covered: Herein, we review the clinical data from published and internationally presented clinical trials utilizing vosaroxin for AML in the elderly, and relapsed and refractory population. Pivotal trials reviewed include the multicenter, phase II, REVEAL-1 study of single-agent vosaroxin in untreated elderly patients and the multicenter, phase III, VALOR study of vosaroxin in combination with intermediate dose cytarabine for patients with relapsed or refractory AML.Expert opinion: Outcomes for older adults with AML, and for patients with relapsed or refractory disease are persistently poor. Improvement in outcomes in the elderly population highlight the utility of this agent in a difficult to treat, often more resistant and intolerant to therapy, group of patients. The expected and observed lack of cardiotoxicity makes this drug particularly suitable for the older population, especially those that may have received prior anthracycline based therapy.

High-Dose Cytarabine Alone Versus Cytarabine Plus Anthracycline for Consolidation Therapy in Non-Promyelocytic Acute Myeloid Leukemia

Standard consolidation therapy of acute myeloid leukemia (AML) contains high-dose cytarabine (HiDC). However, optimal dose of cytarabine and benefit of additional chemotherapeutic agents remain unresolved problems. One hundred and forty-two patients among 173 newly diagnosed AML patients, who achieved complete remission following induction chemotherapy and subsequently received different consolidation therapies in 4 independent institutes, were retrospectively analyzed. Patients were divided into 3 groups by consolidation regimens: HiDC (1.5-3g/m2, bid, Days 1,3,5) alone in 44 patients (Group A), HiDC plus anthracycline in 46 patients (Group B), and intermediate-dose cytarabine (1g/m2, bid, Days 1,3,5) plus anthracycline in 52 patients (Group C). Overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS), and event-free survival (EFS), were not significantly different in Group A vs. Group B. However, Group B showed longer RFS, DFS, and EFS, as compared with Group C. Treatment-related mortality was significantly higher in Group B, as compared with Group A (P =0.040) and Group C (P =0.013). Cytogenetic risk was the only significant prognostic factor in OS, RFS, DFS and EFS.In this study, the addition of anthracycline to HiDC as consolidation chemotherapy in AML patients did not improve treatment outcomes, and had more toxicity. HiDC enhanced RFS, DFS, and EFS, as compared with intermediate-dose cytarabine. Therefore, HiDC single therapy could be considered as standard consolidation therapy for non-promyelocytic AML DisclosuresChoi:Alexion Pharmaceuticals: Research Funding.

Risk-Group Stratified and Minimal Residual Disease (MRD)-Guided Treatment with Extended ATRA and Reduced-Anthracycline Chemotherapy in Childhood Acute Promyelocytic Leukemia (APL): Results from ICC APL Study 01 (NCT01226303; EudraCT 2008-002311-40)

The combined treatment of all-trans retinoic acid (ATRA) and anthracyclines at high cumulative doses (>500-600 mg/m2) is associated with good outcomes in adults and children with acute promyelocytic leukemia (APL). However, high cumulative anthracyclines doses carry a significant risk of late cardiotoxicity, especially in children. In addition, children are more susceptible to ATRA-related side effects (particularly pseudo-tumor cerebri). This suggests that children should receive a lower dose of ATRA. We therefore established an international consortium on childhood APL, ICC APL, and developed the first multinational, multicenter childhood APL study, ICC APL Study 01, with the aim of investigating the safety and efficacy of a regimen with reduced anthracycline cumulative doses and modified ATRA. In some countries the protocol treatment was delivered out as a treatment guideline. Eligible patients had either typical cytogenetics (t(15;17)) or ATRA-sensitive molecular aberration (predominantly PML-RARα). Treatment was stratified by risk group (standard-SR or high-HR, based on white blood cell (WBC) count at diagnosis < or > 10x109/L) and minimal residual disease (MRD) level during post-remissional treatment. SR patients received induction (ATRA plus idarubicin on days 3-5-7) followed by two consolidation courses (I: ATRA, intermediate-dose cytarabine, mitoxantrone; II: ATRA plus idarubicin). HR patients received ATRA plus idarubicin (days 1-3-5) in induction, followed by 3 consolidation courses (I and II identical to SR patients, III: ATRA, intermediate-dose cytarabine, idarubicin). This therapy was followed by 2 years of maintenance in all patients with ATRA given every 3 months, methotrexate weekly and mercaptopurine daily. The daunorubicin-equivalent dose of anthracyclines was 355 mg/m2 and 405 mg/m2 for SR and HR patients, respectively. The cytarabine dose was 6,000 mg/m2 and 12,000 mg/m2 for SR and HR patients, respectively. ATRA was given at a dose of 25mg/m2. Treatment was guided by MRD bone marrow monitoring at the end of consolidation and 3 monthly during and for one year after maintenance completion. SR patients with persistent molecular disease after consolidation received a third course of treatment identical to that given to HR patients. Children with persistent molecular disease after 3 courses, and those with molecular or frank relapse during or after treatment, were eligible for salvage arsenic-trioxide (ATO) treatment. A total of 227 patients were enrolled into the study between January 2008 and May 2015; median age was 10,7 years (range, 0 - 19,9) and 53% of patients were female. FAB type was M3 in 81% and M3 variant in 16% (data N/A for 3% of patients). One hundred and twenty-nine (57%) and 98 (43%) were assigned to the SR and HR groups, respectively. Median WBC and platelet count at diagnosis were 6.1x109/L (range, 0.59-454) and 26x109/L (range, 2-262), respectively. PML/RARα fusion transcript was bcr 1 in 100, 2 in 6, 3 in 88 and not known in 33 patients. Clinical response and MRD data are available for 179/227 patients (79%). Early death rate was 3.1%. MRD positivity decreased over time; 80% of patients MRD were positive after induction, 31% after consolidation course I, 11% after consolidation course II and 4% after consolidation course III. A frank or molecular relapse occurred in 6 (all HR) and 8 (4 HR; 4 SR) patients, respectively; salvage ATO treatment was effective in 12 of these patients. One patient died of therapy-related leukemia. The 3-year probability of overall survival was 95% in the whole cohort of patients (96.5% and 93% in SR and HR patients, respectively; p 0.17). The 3-year probability of event-free survival was 83% for all patients (87% and 79% in SR and HR patients, respectively; p 0.09). In summary, the ICC APL study 01 produced an outcome comparable to that of children treated with AIDA 2000 protocol, which employed higher anthracyclines doses (650 mg/m2 daunorubicin-equivalent) (Testi et al. ASH 2010). These results confirm those reported by Creutzig et al. (BrJHaematol 2010), delivering reduced anthracyclines (cumulative dose 350 mg/m2) with extended ATRA and cytarabine. Data from a randomised study published by Lo Coco et al. (NEJM 2013) urged our consortium to develop ICC APL Study 02, in which SR patients will be treated with ATRA plus ATO and HR patients with ATRA, ATO and gemtuzumab ozogamicin; a front-line treatment without conventional chemotherapy. DisclosuresKaspers:Janssen-Cilag: Research Funding.

Randomized Comparison of Intermediate-Dose Cytarabine Plus Mitoxantrone (IMA) Versus Standard-Dose Cytarabine Plus Daunorubicin (DA) for Induction Therapy in AML Patients >60 Years. Results from the SAL 60+ Trial

Background:Most patients (pts) diagnosed with Acute Myeloid Leukemia (AML) are older than 60 years. Although intensive induction chemotherapy in medically fit pts is still the standard practice and a prerequisite for long-term survival, elderly pts have a higher risk of treatment related morbidity and lower remission rates than younger AML pts. An optimized induction treatment would combine high complete remission (CR) rates with tolerable toxicity. The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) has been reported to result in high CR rates (73.5%) with acceptable toxicity in 86 elderly AML pts (Niederwieser et al., Blood 2002, abstr. 1337). We present the mature final results of a randomized-controlled trial comparing efficacy and tolerability of IMA with the standard 7+3 induction regimen consisting of daunorubicin plus cytarabine (DA).Patients and Methods:In the 60+ trial of the Study Alliance Leukemia (SAL), AML pts >60 years and medically fit for chemotherapy were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 BID days 1,3,5,7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). All pts in CR after DA received intermediate-dose cytarabine plus amsacrine (MAMAC) as consolidation treatment, whereas pts in CR after IMA were consolidated with standard-dose cytarabine plus mitoxantrone (2+5). Primary study endpoint was the CR rate with an expected difference of 15% in favor of IMA. Secondary endpoints were the incidence of serious adverse events (SAEs), time to relapse (TTR), relapse-free survival (RFS), and overall survival (OS).Results:Between February 2005 and October 2009, 852 pts were screened for study inclusion and 485 pts started study treatment, of which 241 pts were randomized for treatment arm A (DA) and 244 for treatment arm B (IMA). The median age was 69 years. Pt characteristics were equally distributed between the two arms. According to a strict definition, all patients with early death, study drop-out, or failed remission assessment were categorized as being not in CR. The CR rate amongst all 485 pts treated in the study was 47%. The CR rate after DA was 39% (95%-CI; 33-45) versus 55% (95%-CI; 49-61) after IMA (OR 1.89, p=0.001). If all first CRs were taken into account including those achieved after trial discontinuation, the CR rates after DA versus IMA induction were 55% versus 64% (p=0.043). Separate analyses addressing age, cytogenetics, de novo AML, NPM1 and FLT3-ITD confirmed higher CR rates after IMA induction throughout these subgroups. Six-week mortality was 14% in both arms. The median duration of ≥ grade 3 neutropenia was 23 days after DA I and 25 days after IMA (p=0.031). The median duration of thrombocytopenia ≥ grade 3 was 16 versus 20 days after DA I and IMA I, respectively (p<0.001). The incidences of non-hematologic toxicities were not significantly different except for a higher incidence of liver toxicity (odds ratio IMA/DA = 0.52; p=0.001) and gastrointestinal symptoms (OR IMA/DA = 0.62; p=0.041) after DA.In the course of treatment, 11 pts in each arm (5%) received allogeneic stem cell transplantation.After a median follow-up of 66 months, RFS curves are superimposable in the first year with a similar median RFS of 11 months and 10 months after DA and IMA, respectively. However, a separation of RFS curves developed with longer follow up, resulting in 1-year RFS rates of 45% versus 46%, but 3-year RFS rates of 29% versus 14% in the DA versus IMA arms, respectively (p=0.042). The median OS for all randomized pts was 10 months in both arms; 1-year and 3-year OS rates were 45% and 19% after DA versus 44% and 19% after IMA (p=0.513).Conclusion:The results indicate that elderly AML pts benefit from a dose escalation of cytarabine in induction therapy by significantly higher CR rates and similar toxicity compared to a standard 7+3 approach. In our trial, this did not translate into a survival advantage, most likely due to differences in consolidation treatment of the respective treatment arms. In combination with an effective consolidation strategy such as high-dose cytarabine or allogeneic transplantation, our current results favor the use of intermediate dose cytarabine in induction for pts with a curative AML treatment approach. [Display omitted] DisclosuresEinsele:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Platzbecker:Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Ehninger:Cellex GmbH: Equity Ownership.

Clofarabine-Based Consolidation Improves Relapse-Free Survival of Younger Adults with Non-Favorable Acute Myeloid Leukemia (AML) in First Remission: Results of the Randomized ALFA-0702/Clara Study (NCT 00932412)

Background: Clofarabine has been shown as effective as single-agent or in combination with cytarabine in various populations of AML patients. Nevertheless, two randomized studies failed to demonstrate prolonged survival when compared to low-dose cytarabine in older AML patients (Burnett, 2013) or intermediate-dose cytarabine (IDAC) in patients aged 55y or more with relapsed/refractory AML (Faderl, 2012). As this was likely due to excessive toxicity and poor compliance in these difficult-to-treat populations, we made the hypothesis that a more apparent benefit might be observed during post-remission therapy. We thus randomly assessed the role of CLARA combination (clofarabine + IDAC) versus high-dose cytarabine (HiDAC) as consolidation cycles in younger AML patients.Methods: Between 2009 and 2013, 713 patients aged 18-60y old with de novo AML (CBF-AML excluded) were enrolled in the ALFA-0702 trial by 33 French centers. They received a timed-sequential induction with daunorubicin (60 mg/m2, day 1-3; 35 mg/m2, day 8-9), cytarabine (500 mg/m2 CI, day 1-3; 1 g/m2/12h bolus, day 8-10) and G-CSF priming. A first salvage with idarubicin and HiDAC may be proposed to patients not achieving CR/CRp after this first course. Patients in CR/CRp with non-favorable AML (according to ELN classification) or those who needed the salvage (late CR/CRp) were eligible for: 1) allogeneic stem cell transplantation (SCT) if they had a sibling or fully matched unrelated donor; or 2) randomization for consolidation with three HiDAC (3 g/m2/12h cytarabine, day 1/3/5; G-CSF priming) or CLARA (30 mg/m2 clofarabine, day 2-6; 1 g/m2/12h cytarabine, day 1-5; G-CSF priming) cycles if no identified donor. Primary endpoint was relapse-free survival (RFS), patients receiving allogeneic SCT in first CR/CRp after randomization (late donor identification) being censored at SCT time. Secondary endpoints were cumulative incidence of relapse (CIR) and death in first CR/CRp (CID), overall survival (OS), and safety. Anticipating a 35% SCT rate in randomized patients, 230 patients should be randomized to demonstrate a 20% gain in 2-year RFS. A sensitivity analysis without SCT censoring was planned.Results: Among 468 CR/CRp patients of interest (465/552 non-favorable AML + 3/161 favorable AML with late CR/CRp), 221 were randomized between HiDAC (n=114) and CLARA (n=107) consolidation and 247 were not randomized for the following reasons: 181 had an identified donor for SCT; 19 had favorable ELN genotype even if no evidence of normal karyotype; and 47 were negatively selected (13 early relapses, 1 early death, 18 AEs, 15 drop-out). The ITT analysis was conducted in these 221 eligible patients (median age, 48y; 136 intermediate-risk, 85 unfavorable-risk; 18 late CR/CRp; without imbalances between randomization arms), the remaining 9 randomized patients having non-eligibility criteria (6 favorable-risk AML and 3 not in CR/CRp). Among these patients, the rate of SCT in first CR/CRp was higher than anticipated (50%; 55 patients in each arm). With a median follow-up of 37.4 months and SCT censoring, 2-year RFS was 52.1% (40-68) in the CLARA arm versus 30.5% (20-46) in the HiDAC arm (HR, 0.62 [0.39-0.99]; p= 0.042). This was due to a lower CIR in the CLARA arm (44.0 versus 67.7%; p= 0.023) with similar CID (3.9 versus 1.9%, p= 0.60). At 2 years, OS was 68.1% (56-82) in the CLARA arm versus 49.8% (38-66) in the HiDAC arm (p= 0.18). Interestingly, the gain in CIR and RFS was observed in both intermediate- and unfavorable-risk groups and persisted after adjustment on AML risk and age. As expected, these gains were lower when not censoring at SCT (2-year RFS, 57.8 versus 45.6%; p= 0.12). In the 110 randomized patients allografted in first CR/CRp, no differences in post-SCT outcome were observed according to randomization arm. In Mantel-Byar time-dependent analysis, longer RFS was observed after SCT in the HiDAC arm (HR, 0.45; p= 0.004), while not in the CLARA arm (HR, 0.71; p= 0.26). Finally, CLARA cycles were associated with higher hematologic toxicity, more infections and more liver toxicities than HiDAC cycles, especially after cycle 1.Conclusions: As compared to HiDAC, clofarabine-based consolidation improved RFS in younger patients with intermediate- and unfavorable-risk AML in first CR/CRp. CLARA combination might thus become a new standard for post-remission therapy in these patients, especially in those who may not benefit from allogeneic SCT. DisclosuresOff Label Use: CLOFARABINE is not currently approved for this indication.. De Botton:Agios pharmaceuticals: Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Second-Line Low-Dose Cytarabine after First-Line Treatment with 5-Azacitidine in Elderly Patients with AML or High-Risk MDS Ineligible for Intensive Chemotherapy. A Retrospective Single Center Analysis

Introduction: Although there have been progress in treatment and outcomes of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in younger patients, treatment of elderly patients, who are not eligible for intensive treatment is still challenging. The demethylating agents azacitidine (AZA) or decitabine recently became a standard of care for first line treatment of elderly or unfit patients with high-risk MDS or AML. Despite the improvement in overall survival with epigenetic therapies, almost all patients eventually develop disease progression, for which no standard therapeutic option is available. The aim of this retrospective analysis was to evaluate the outcome of low-dose cytarabine (LDARAC) treatment compared to best supportive care (BSC) as second-line palliative treatment options after failure of AZA.Patients and Methods: From 2009 to 2014 we treated 75 consecutive patients with newly diagnosed high-risk MDS or de novo AML, with AZA (75mg/m2 sc. d1-7, qd29). Patients who responded to AZA after at least four courses and had a subsequent relapse, as defined by worsening of peripheral blood counts, increase of blasts or increase in transfusion frequency, received a second-line treatment with subcutaneous LDARAC (2x 10 mg/m2/d sc., d1-10, qd29) until progression or were followed by best supportive care, including symptomatic treatment, transfusions or treatment of clinical infections- but without chemotherapy.Results: After first-line AZA 48/75 (64%) achieved a partial hematologic response (n=23), stable disease (n=14) or clinical benefit (n=7). The median overall survival (OS) of all 48 patients with response or clinical benefit to AZA was 27 months. Median duration of response was 13 (4-56) months. Cytogenetic risk at diagnosis was a significant prognostic factor for OS (P<0.001), but not age or ECOG-PS (P =0.17 and P =0.68, respectively). After a median follow-up of 24 months, 31 patients had a loss of hematologic response. Fifteen of 31 relapsed patients were treated with a second-line therapy with LDARAC until progression. Two of those 15 patients received an initial re-induction therapy with intermediate dose cytarabine plus daunorubicine ("5+2"). 16 patients were followed by BSC. Four of 15 patients who were treated with LDARAC achieved a partial hematologic response and 6/15 had stable disease with a median response duration of 4 months. In the BSC group no objective responses were observed. The median overall survival from the time of progression on AZA (OS-2) was 7.2 months in patients treated with LDARAC versus 2.9 months in patients who received BSC care only (P<0.01). In a multivariate analysis response to LDARAC was the only significant prognostic factor for OS-2 (P =0.02, HR: 3.16), while age, ECOG-PS or cytogenetic risk did not reach statistical significance.Conclusions: Our analysis shows that second-line treatment with LDARAC may add a survival benefit of approximately 3 months compared to BSC alone. The second overall survival (OS-2) of 7.2 months is within the range achieved with LDARAC as primary treatment for this patient population. Our data indicate that LDARAC can be considered as a reasonable therapeutic option after failure of first-line treatment with demethylating agents like AZA. This clinical observation is supported by recent pre-clinical data, showing that epigenetic modifications in AML cells can have a sensitizing effect for the subsequent administration of cytarabine. DisclosuresNo relevant conflicts of interest to declare.

Persistence of Minimal Residual Disease Assessed By Multi-Parameter Flow Cytometry Is a Strong Predictor of Outcome in Younger Patients with Acute Myeloid Leukemia

Background - Minimal Residual Disease (MRD) assessed by Multi-parameter Flow Cytometry (MFC) has not been extensively evaluated as a predictor of outcome in younger patients with acute myeloid leukemia (AML) receiving ara-C plus anthracycline inductionMethods - We examined the predictive value of MRD assessment by MFC in mainly younger patients with newly diagnosed AML who were treated with intermediate dose cytarabine (total of ≥ 6 g/m2) and idarubicin based induction chemotherapy. Among 280 patients treated with clofarabine, idarubicin plus ara-C (CIA), fludarabine, idarubicin plus ara-C (FIA), fludarabine, ara-C, GCSF plus idarubicin (FLAG-Ida), cladribine, idarubicin, plus ara-C (CLIA) who achieved complete remission (CR), CR without platelet recovery (CRp), or CR with incomplete count recovery (CRi) 186 had at least one available MRD data and are the subject of this analysis. MRD by MFC was assessed using an 8-color panel containing 19 distinct markers, on bone marrow specimens obtained at the time of achievement of CR/CRi/CRp (approximately 1-2 months post induction), during consolidation (approximately 3-7 months post-induction) and at completion of therapy (≥ 8 months post induction). Residual leukemic blasts were identified based on phenotypic differences from normal myelomonocytic precursors. Sensitivity was estimated at 0.1% in most cases, with maximum achievable sensitivity of 0.01%, depending on the leukemic phenotype.Results - Median age of the patients was 51 years (Range, 17 - 77 years). 6 patients were older than 65 (all with ELN favorable disease). Median WBC at presentation was 4.7 x 109/L (Range, 0.5 - 103 x 109/L). Cytogenetics was favorable risk in 34 (18%), intermediate risk in 115 (62%) and adverse in 27 (15%) and was not available in 10 (5%) Treatment included CIA in 102 (55%), FIA in 34 (18%), FLAG-Ida in 34 (18%) and CLIA in 16 (9%). 166 patients had available samples at 1-2 months post induction and 131 (79%) became MRD negative. Achieving MRD negative status at response was associated with a statistically significant improvement in relapse free survival (RFS) (p= 0.001) and overall survival (OS) (p= 0.003) (Figure 1). 116 patients were evaluated for MRD status during consolidation and 100 (86%) became negative. Achieving a negative MRD status during consolidation was associated with a significant improvement in RFS (p˂0.001) and OS (p˂0.001)(Figure 2). 69 patients were evaluated for MRD status after completion of all therapy and 58 (84%) became negative. Achieving a negative MRD status at completion of therapy was associated with improvement in RFS (P˂0.001) and OS (P˂0.001) (Figure 3). On multivariate analysis including age ˂40 years vs. ≥ 40, WBC at presentation ˂or ≥ 10 x 109/L, cytogenetics (favorable, intermediate, adverse), achieving CR vs. CRp/CRi, and treatment with CIA, FIA, CLIA, or FLAG-Ida, achieving MRD negative status was the only independent predictor of RFS and OS at response (P=0.03 and P=0.005, respectively), during consolidation (p˂0.001 for both), or at completion of therapy (p˂0.001 for both).Conclusion - Achieving MRD negative status by MFC at response, during consolidation therapy and after completion of therapy is associated with a highly significant improvement in the outcome of younger patients with AML receiving ara-C plus idarubicin-based regimens. [Display omitted] [Display omitted] [Display omitted] DisclosuresJabbour:Pfizer: Consultancy, Research Funding. Faderl:Astellas: Research Funding; Celator: Research Funding; JW Pharma: Consultancy; Seattle Genetics, Inc.: Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Speakers Bureau; Ambit: Research Funding; BMS: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Prognostic Markers in Core-Binding Factor Acute Myeloid Leukaemia

IntroductionWhile core-binding factor acute myeloid leukaemia (CBF AML) as defined by t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) has a favourable prognosis, 30-40% of patients still relapse after chemotherapy. Risk factors predictive for relapse include increasing age and white cell count (WCC), poor performance status and adverse-risk cytogenetics. Rising minimal residual disease (MRD) by molecular monitoring and receptor tyrosine kinase (RTK) mutations also predict higher risk of relapse (Yin et. al., Blood 2012; Jourdan et. al., Blood 2013).Aims1. Identify prognostic markers for CBF AML2. Determine significance of persistent molecular positivity in complete remission (CR) post-treatmentMethodsWe undertook a retrospective audit from 2001-2012 at 4 tertiary-level hospitals. The inclusion criteria were adult patients >18 years with de novo CBF AML treated with at least intermediate dose cytarabine. Co-variates included in univariate analysis and then multivariate analysis if predictive of overall survival (OS) and relapse-free survival (RFS) included age, WCC, sex, cytogenetics, RTK mutations (KIT and FLT3) and MRD (RUNX1-RUNX1T1 or CBFB-MYH11 bone marrow (BM) qPCR post-induction (MRD1). Univariate analysis was also performed for BM MRD after each consolidation cycle 1-4 (MRD2-5 respectively).Results70 patients were identified (Male=39, Female=31; inv(16)=30, t(8:21)=40). The median age at diagnosis was 43 years (range 17-73). There were 2 induction deaths and 68 achieved morphological CR. OS was 70.7% and RFS was 59.1% at a median follow-up of 31.4 months. There were 16 deaths (inv(16)=9, t(8;21)=7; median OS 14.8 months; 9 from relapsed AML, 4 treatment-related complications, 2 graft-versus-host disease (GVHD) and 1 unrelated). 24 relapses (22 morphological, 2 molecular) occurred with a median RFS of 9 months (inv(16)=17, t(8;21)=7). RFS was significantly worse for inv(16) vs t(8;21) (39% vs 75%; p=0.0004). The inv(16) cohort had significantly higher median WCC of 33x109/L vs 10.5x109/L t(8;21). Univariate analysis identified age (p=0.032) and WCC>40 (p=0.002) as significant for inferior OS and RFS respectively. The impact of KIT (n=34, Pos=14, p=0.158) and FLT3 (n=27, Pos=2, p=0.152) mutations on OS/RFS were non-significant independent of CBF AML subtype. However, there were systematic differences in KIT and FLT3 data availability in the relapse vs non-relapse cohorts (Absent data: KIT 17/24(71%) vs 19/46(41%); FLT3 17/24(71%) vs 26/46(57%)). MRD analysis by qPCR at the different timepoints (MRD1=37, MRD2=24, MRD3=28, MRD4=23, MRD5=12) by < or ≥3 log reduction in comparison to pre-treatment values was not predictive of OS/RFS. On multivariate analysis excluding RTK mutations, age was the only significant predictor for OS (p=0.032) and WCC>40 for relapse (p=0.025). Standard vs intermediate/high-dose cytarabine in induction had no impact on OS/RFS but ≥3 consolidation cycles of intermediate-dose cytarabine improved OS vs ≤2 cycles (p=0.035). There was no significant difference in the median age of the cohorts receiving consolidation chemotherapy (≤2: n=37, 47 years, ≥3: n=30, 35.5 years).Median BM qPCR values increased from 0 to 11% at relapse for inv(16) at a median duration of 4.3 months (range 1-8) and 0.05 to 178% for t(8;21) at 6 months (range 5-35) respectively. Of the 43 with durable CR, 28 maintained PB or BM qPCR values of 0-0.1% or <10 copy numbers throughout follow-up for 2 years post-completion of consolidation treatment. 6 had qPCR values >0.1% or >50 copy numbers; 5 were t(8;21) achieving PCR negativity at a range of 9-24 months post-completion of consolidation. Of the 24 who relapsed, 15 proceeded to stem cell transplant (13 allograft: inv(16)=8, t(8;21)=5; 2 autograft: inv(16)). There were 6 deaths in the allograft group (inv(16)=3, t(8;21)=3) and none in the autograft group. 3 deaths were related to relapsed disease post-allograft, 2 GVHD and 1 from non-GVHD complications.ConclusionsAge is a significant predictor of OS in our CBF AML cohort while WCC is more predictive of relapse risk. The significance of RTK mutations and MRD is limited by data availability. ≥3 consolidation cycles of intermediate-dose cytarabine improved OS in comparison to fewer cycles. Stable low level MRD did not predict relapse. Regular monitoring of PB and BM qPCR values post-completion of treatment is necessary for prediction of subsequent relapse. [Display omitted] DisclosuresGrigg:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Szer:Alexion Pharmaceuticals Australasia Pty Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Addition of Sorafenib to Chemotherapy Improves the Overall Survival of Older Adults with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) (Alliance C11001)

Sorafenib is an oral multikinase inhibitor that blocks the autophosphorylation and activation of a number of kinases including the FLT3 tyrosine kinase with an internal tandem duplication mutation (FLT3-ITD). Sorafenib has activity against AML with FLT3-ITD mutations as a single agent in the setting of post-transplant relapse and in combination with chemotherapy for newly diagnosed AML. Historical Cancer and Leukemia Group B results using standard chemotherapy for older patients (pts) with FLT3-ITD have demonstrated a complete remission (CR) rate of 67%, median survival of 0.8 yrs, and 1-yr overall survival (OS) of 30% (Whitman et al., Blood 2010). More recently, sorafenib was demonstrated to significantly prolong event-free (EFS) and disease-free survival (DFS) of younger adults irrespective of FLT3 mutation status (Rollig, et al., ASH 2014). We hypothesized that the addition of sorafenib to induction and post-remission therapy would improve the overall survival of older pts with FLT3-mutated AML.The Alliance for Clinical Trials in Oncology conducted a multicenter, single-arm phase 2 study in pts ≥ 60 years old with AML and either a FLT3-ITD or a point mutation in the activation loop of the kinase domain (FLT3-TKD). Subjects with PML-RARA, core-binding factor AML or who had received prior treatment for AML were excluded. Induction chemotherapy consisted of cytarabine 100 mg/m2 CIVI on days 1-7 and daunorubicin 60 mg/m2 IV on days 1-3 (7+3) with oral sorafenib 400 mg bid on days 1-7. Those not achieving a hypoplastic bone marrow on day 14 were to receive a second cycle of cytarabine and daunorubicin (5+2) plus sorafenib 400 mg bid on days 1-7. Post-remission therapy consisted of intermediate-dose cytarabine 2 g/m2 on days 1-5 with sorafenib 400 mg bid on days 1-28 for 2 cycles followed by maintenance sorafenib 400 mg bid for 12 28-day cycles. The primary endpoint of the study was 1-yr OS. With a sample size of 39 FLT3-ITD patients and type I error rate of 10%, this design provided 90% power to distinguish between true 1-yr OS rate of 50% compared to our historical rate of 30% for the FLT3-ITD pts.A total of 474 pts were screened for FLT3 mutations though a central laboratory. FLT3 mutations were identified in 83 subjects (17.5%). Fifty-four pts with a median age of 67 years (60.3-82.7) were enrolled, including 39 with FLT3-ITD (71%) and 15 with FLT3-TKD (29%). All pts have now completed protocol treatment. Of the 54 pts, 37 achieved a CR or CRi (69%). The 30-day induction mortality was 9% with no additional deaths occurring between days 30-60. With a median follow up of 28.3 months, the observed 1-yr OS (95% CI) was 62% (45-78) for the FLT3-ITD pts and 71% (42-92) for the FLT3-TKD pts. The median DFS and OS was 12.5 mo (7.7-17.4) and 15.0 mo (10.4-20.1) respectively in the FLT3-ITD group and 9.0 (1.6-NA) and 16.2 mo (5.0-NA) for the FLT3-TKD group. For all subjects, the 2-yr OS was 28% (17-43) and DFS was 27% (15-46). There were no treatment-related deaths during consolidation or maintenance. For pts receiving sorafenib maintenance, the most commonly reported related adverse events were Grade 1 diarrhea, fatigue, transaminitis, and Grade 2 palmar-plantar erythodyesthesia. The mean plasma inhibitory activity (PIA) for FLT3 was 94% (n=25) on day 6 of induction, 93% (n=15) on day 15 of consolidation and 99.2% (n=6) on day 15 of maintenance demonstrating robust inhibition of FLT3 in vivo.This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the US cooperative group setting. The study met the primary endpoint demonstrating that the addition of sorafenib to chemotherapy for FLT3-ITD AML improves the survival of older adults more than doubling the 1-yr OS compared to historical controls (62% vs 30%, p <0.0001). DisclosuresUy:Novartis: Research Funding. Off Label Use: Sorafenib for AML. DeAngelo:Novartis: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Agios: Consultancy; Celgene: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Byrd:Acerta Pharma BV: Research Funding. Stone:Celator: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy; AROG: Consultancy; Merck: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Juno: Consultancy; Agios: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Increased efficacy of intermediate-dose cytarabine + G-CSF compared to DHAP + G-CSF for stem cell mobilization in patients with lymphoma: an analysis by the polish lymphoma research group.

Salvage regimens, like DHAP (dexamethasone, cytarabine, and cisplatin) are frequently used for stem cell mobilization in lymphoma. The aim of this study was to compare the efficacy of DHAP + G-CSF with intermediate-dose cytarabine (ID-AraC) + G-CSF, recently proposed as an alternative schedule. Consecutive patients with Hodgkin's or non-Hodgkin lymphoma who had received at least 2 lines of chemotherapy, mobilized with either DHAP (n = 51) or ID-AraC (n = 50) + G-CSF were included in the analysis. AraC was administered at the dose of 400mg/m [1] bid intravenously for 2days followed by filgrastim starting from day 5. In the AraC group, 96% of patients collected at least 2 × 10 [2] CD34(+) cells/kg compared to 71% in the DHAP group (p = 0.0006). The CD34(+) cell yield was 9.3 (0-30.3) × 10 [2]/kg vs. 5.6 (0-24.8) × 10 [2]/kg, respectively (p = 0.006). A single apheresis was sufficient to achieve the threshold number of CD34(+) cells in 82% of the cases after AraC compared to 45% after DHAP (p = 0.001). We conclude that stem cell mobilization using ID-AraC is associated with a significantly higher efficacy than DHAP, allowing for collection of the transplant material in almost all patients with lymphoma. Our observation suggests that ID-AraC + G-CSF may be a preferable mobilization regimen in this setting.

Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study.

Cytarabine is a pyrimidine analogue used to treat a variety of haematological malignancies. There are few data regarding the pharmacodynamics of cytarabine. The only publications regarding this issue cite a biphasic pattern of decline in white blood cell (WBC) counts following low and intermediate doses, in patients with various malignancies, most of them non-haematological. Our purpose was to establish the pharmacodynamics of cytarabine induced leucopenia in acute myeloid leukaemia (AML) patients treated with contemporary cytarabine containing protocols. We conducted a retrospective cohort study, including 56 patients with AML in complete remission who had received 89 cycles of intermediate or high dose cytarabine. Daily counts for WBCs and neutrophils (ANC) were collected during the first 15 days after the initiation of cytarabine administration and pharmacodynamics were analyzed. Further analysis was carried out to correlate between WBC and ANC pharmacodynamics and different cytarabine protocols [high dose cytarabine (HiDAC) vs. intermediate dose cytarabine (IDAC)]. Analysis of blood counts demonstrated a monophasic decline of WBCs and ANCs, unlike a previous depiction of a biphasic pattern. HiDAC was associated with a significantly sharper decline of WBCs than IDAC. Our data support a monophasic decline pattern of WBCs and ANCs following contemporary cytarabine protocols. The decline rate is steeper for patients receiving HiDAC than for those receiving IDAC. These results might help form evidence based guidelines regarding patient monitoring intensity, timing of prophylactic antibacterial and antifungal treatment as well as growth factors' support following cytarabine based consolidation for AML.

Feasibility and efficacy of outpatient therapy with intermediate dose cytarabine, fludarabine and idarubicin for patients with acute myeloid leukaemia aged 70 or older.

A multicentre prospective non-randomised study of de novo acute myeloid leukaemia (AML) in patients aged ≥70yr was designed to reduce toxicity and achieve acceptable complete remission (CR) rates. The outpatient treatment included induction with oral fludarabine, subcutaneous cytarabine and subcutaneous filgrastim (FAG). The patients received more induction cycles according to the response achieved. If there was no response to induction with FAG, the following induction cycle included oral idarubicin, subcutaneous cytarabine and subcutaneous filgrastim (IAG). Patients achieving CR received one intensification (FAG on response to previous FAG or alternatively IAG) and one consolidation cycle (IAG). Thirty patients were enrolled from April 2004 to June 2007. The median age was 73yr (range 70-77). Fifteen patients (50%) achieved CR. The 2-yr DFS was 29% (95% CI, 5-47%), and the 2-yr OS was 23% (95% CI, 12-35%). Twenty-five of 69 cycles (36%) were managed on a completely outpatient basis. The median hospital stay per cycle was 10d (95% CI, 3-25). This study demonstrates the tolerability and efficacy of a semi-intensive treatment in elderly de novo patients with AML managed on an outpatient basis, without substantial toxicity.

FLAG-Idarubicin Is Superior to Cytarabine Plus Idarubicin (7+3) for Initial Treatment of Acute Myeloid Leukemia (AML): A Multivariable Analysis of Patients Treated at a Single Center

IntroductionCombination chemotherapy with a seven-day continuous infusion of cytarabine (100-200mg/m2/d) plus 3 days of an anthracycline (7+3 ) is considered standard of care for remission induction in newly diagnosed patients with acute myeloid leukemia (AML) However, the MRC AML 15 trial (Burnett et al. J Clin Oncol 2013, 31:3360) suggested that in younger AML patients, a combination regimen containing fludarabine plus intermediate dose cytarabine x 5 days with granulocyte colony-stimulating factor (GCSF) and idarubicin x 3 days (FLAG-Ida) may produce higher CR rates after one course and reduced relapse rates than a combination of cytarabine and daunorubicin given for 3+8 days. The schedule of cytarabine given during DA in the MRC AML 15 trial was not the same as the continuous infusion cytarabine given as standard of care for 3+7 regimens in the United States. We compared standard continuous infusion cytarabine (100mg-200mg/m2/d x 7 days) plus idarubicin (12 mg/m2 /d x 3 days) (AI) administered at our center to FLAG-Ida (fludarabine 25-30mg/m2/d followed 4 hours later by cytarabine (2g/m2/d) x 5 days with granulocyte colony-stimulating factor beginning day 1 until count recovery and idarubicin 10 mg/m2/d x 3 d with respect to safety and efficacy in the initial induction therapy of newly diagnosed AMLMethodsPatients with newly diagnosed AML who received remission induction therapy with FLAG-Ida or AI were identified from January 1 2008 through May 2014. Patients with M3 FAB subtype and those with relapsed or refractory AML were excluded. Supportive care measures were standardized and identical between the two groups. Primary endpoints included complete remission rate post induction therapy, overall survival (OS) and disease free survival (DFS). Remission status was categorized into complete remission (CR), incomplete remission (CRi), and primary induction failure (PIF). Secondary endpoints included non-relapse related mortality (NRM), time to neutrophil recovery >1000 and time to platelet recovery > 100K. CR, CRi and PIF were defined according to the International Working Group recommendations (Cheson B et al. J Clin Oncol 2003 Dec; 21 (24) 4624-49). NRM was defined as death by any cause through day 30 of induction therapy. OS was defined as time from start of therapy to death and DFS was time from diagnosis to relapse or non-relapse death. Subgroups analysis for the primary endpoints were completed based on age (≥60 and <60), and risk status (favorable, intermediate, and poor). Risk status was assessed using molecular and cytogenetic abnormalities defined in the 2014 NCCN guidelines. Cox proportional hazards and logistic regression models were developed for the endpoints using regimen and the other parameters as covariatesResultsWe identified 112 patients who received FLAG-Ida and 56 patients who received AI. Cytogenetic risk and previous antecedent hematologic disorder/secondary leukemia were similar between the two groups. FLAG-Ida achieved faster neutrophil recovery higher overall CR and CR+CRi rate with lower NRM (Table 2). In patients ≥60 years old, CR rates were 75% and 45% for FLAG-Ida vs. AI respectively (p=0.021). OS and DFS between the two regimens did not significantly differ in the subgroup analysis for age or cytogenetic risk group except that intermediate risk patients had better overall survival with FLAG-Ida (p=0.008, log rank test). In a multivariate logistic regression model on achievement of remission (CR+Cri), the use of AI had an odds ratio of 0.38 (p=0.012) compared to FLAG-Ida. In Cox analysis, AI vs FLAG-Ida was a factor of borderline statistical significance for NRM (HR 1.91, p=0.052) and overall survival (HR 1.62, p=0.062)ConclusionsThese data demonstrate faster hematopoietic recovery, superior remission (CR+CR1) and NRM rates for FLAG-Ida when compared to AI. Overall survival rates are confounded by subsequent therapies but also appear to be improved for patients in the intermediate risk group who received FLAG-Ida. Of particular interest was the improvement in CR rates for FLAG-Ida in patients ≥ 60 years of age. These data suggest that FLAG-Ida should be considered a valid option for the initial therapy of AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Maintenance Lenalidomide for Adults Aged 18-65 Years with AML in First Complete Remission after Intensive Chemotherapy: A Phase Ib Dose-Escalation Study of the Australasian Leukemia and Lymphoma Group (ALLG)

Relapse risk in the first 12 months after achieving complete remission (CR) is approximately 40% in the adult acute myeloid leukemia (AML) population (Bradstock, Blood 2005; Burnett, JCO 2013). In this phase 1b study conducted by the ALLG, patients with AML in first CR or CR with incomplete count recovery (CRi) after intensive chemotherapy were allocated to escalating dose cohorts of lenalidomide maintenance; 10 mg (n=8), 20 mg (n=9), 30 mg (n=9) or 40 mg (n=4) administered daily for two continuous 28-day cycles, followed by lenalidomide 10 mg daily for a total lenalidomide duration of 12 months. To date, 28 patients have been enrolled from 8 centers. The median age is 54 (range 18-65) years, ECOG performance status was 0 in 82% and 1 in 18%. Preceding chemotherapy for patients 18-55 years was HiDAC-3 induction (cytarabine 3 g/m2 bd D1, 3, 5, 7 + idarubicin 12 mg/m2 D1-3) and IcE (idarubicin 12 mg/m2 D1-2, cytarabine 100 mg/m2 D1-5 and etoposide 75 mg/m2 D1-5) consolidation. Patients aged 56-65 years received 7+3 induction (cytarabine 100 mg/m2 CIVI D1-7 + idarubicin 12 mg/m2 D1-3) and IDAC-2 (intermediate dose cytarabine 1 g/m2 bd D1, 3, 5 + idarubicin 12 mg/m2 D1-2) consolidation. Patients with core binding factor subtypes were consolidated with 3-4 cycles of HiDAC (cytarabine 3g/m2 bd D1,3,5). Patients received either one (3%), two (79%) or three-four (18%) cycles of consolidation chemotherapy prior to study entry. Cytogenetic risk at diagnosis was favorable (29%), intermediate (67%) or adverse (4%) by MRC criteria (Grimwade, Blood 2010). Molecular features included FLT3-ITD in 33% and NPMc mutation in 26%. During cycles 1-2 the frequency of grade 3-4 neutropenia/thrombocytopenia for each lenalidomide cohort was: 10 mg (13/13%), 20 mg (11/0%), 30 mg (50/12%), 40 mg (75/25%). Four patients have developed grade 3 skin rash on study. Two patients experienced grade 3 febrile neutropenia but there were no treatment-related deaths. The maximum tolerated dose has not been reached and recruitment is continuing at the 50mg dose level. With a median follow-up of 23 months, actuarial incidence of relapse in the first 12 months after commencing lenalidomide was 18% and 26% in the second year (Figure 1A). Overall survival (OS) after starting lenalidomide maintenance was 97% at 12 and 91% at 24 months (Figure 1B). Relapse-free survival (RFS) 24 months after starting lenalidomide maintenance according to cytogenetic or molecular factors was 78% (favorable karyotype), 48% (intermediate karyotype), 75% (NPMc mutation), 31% (FLT3-ITD) and 53% (FLT3-ITD and NPMc double negative). In conclusion, lenalidomide maintenance in an adult AML population has acceptable tolerance, even after prior HiDAC. Relapse risk in the first year during lenalidomide maintenance is lower than historically observed, but later relapses continue to be seen suggesting that future studies could investigate extended duration schedules of lenalidomide maintenance. [Display omitted] [Display omitted] DisclosuresWei:Celgene: Consultancy, Honoraria, Research Funding. Off Label Use: Lenalidomide as maintenance therapy for AML. Hertzberg:Celgene: Consultancy, Honoraria. Seymour:Celgene: advisory board Other, Consultancy, Honoraria.

High Event-Free Survival Rate with Minimum-Dose-Anthracycline Treatment in Childhood Acute Promyelocytic Leukemia: A Nationwide Prospective Study By the Japanese Pediatric Leukemia / Lymphoma Study Group (JPLSG)

Introduction: Anthracyclines (Atc) are the key drugs in the treatment of acute promyelocytic leukemia (APL) combined with all-trans retinoic acid (ATRA), however, dose-dependent risk of long-term cardiac toxicity is sometimes problematic especially in pediatric patients. To evaluate efficacy of the treatment with reduced cumulative doses of Atc in childhood APL, we conducted a nationwide non-randomized prospective study, AML-P05, in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).Patients & Methods: Between April 2006 and March 2011, forty-six children with newly diagnosed APL were enrolled in this study. All patients received at least 3-day precedence of ATRA monotherapy (45mg/m2/d for 35 days in total), followed by chemotherapeutic agents consisted of cytarabine (200mg/m2/d for 7 days) and daunorubicin (DNR, 45mg/m2/d for 3 days) as the first induction therapy. The second induction therapy and subsequent 3 courses of consolidation therapy consisted of ATRA, either high- or intermediate-dose of cytarabine, triple intrathecal injection, and single dose of Atc; 10mg/m2 of mitoxantrone (MIT) in the first 2 courses and 45mg/m2 of pirarubicin (THP) in the last 2 courses. Finally, patients received one-year maintenance therapy with ATRA for 15 days every 3 months.Results: Among the 46 patients registered in this study, 3 were excluded because of PML/RARA negativity, and the remaining 43 patients including 2 with molecular variants were evaluated. The median age at diagnosis was 9 years (range, 11 months to 15 years old). The median follow up period was 4.47 years (0.00-7.45 years). FLT3-ITD was positive in 6 out of 40 patients examined. Two patients died during induction therapies; one of coagulopathy in first course and the other of infection in second course. Two patients developed differentiation syndrome but resolved with temporary cessation of ATRA and supportive therapies. Three patients did not achieve complete remission (CR) after 2 courses of induction therapy, and overall CR rate was 85.7% (36/42, 95%CI: 71.5-94.6%). Neither cardiac adverse events nor treatment-related death were observed during consolidation and maintenance therapies. Three patients exhibited relapse during or after maintenance therapy, and another one developed secondary acute myeloid leukemia. Consequently, the 3-year event-free (EFS) and overall survival rate were 83.6% (95%CI: 68.6-91.8%) and 90.7% (95%CI: 77.1-96.4%), respectively. Age less than 4 years old at diagnosis and non-M1 marrow after first induction therapy were associated with lower EFS. High WBC count (>10,000/μL), low platelet count (<40,000/μL), FLT3-ITD positivity, and additional chromosomal abnormality did not influence the risk of events.Conclusions: According to the JPLSG criteria of Atc equivalents, cumulative Atc dose in this study was converted to 246mg/m2 of doxorubicin (for 1:0.83 for DNR, 1:4 for MIT, and 1:0.6 for THP). The dose was much lower than that in recent US or European protocols, especially in those designed primarily for adult APL patients where more than 600mg/m2 of Atc were used. Comparing with these studies, we have achieved equivalent good results with minimum does of Atc. Therefore, single administration of Atc in each consolidation phases seems sufficient in the treatment of childhood APL.This trial is registered with UMIN Clinical Trials Registry (UMIN-CTR, URL: http://www.umin.ac.jp/ctr/index.htm), number UMIN000000645 DisclosuresNo relevant conflicts of interest to declare.

A Randomized Phase II Study of Tosedostat in Combination with Either Cytarabine or Decitabine in Newly Diagnosed Older Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Background: Tosedostat is an oral aminopeptidase inhibitor that has anti-neoplastic activity in a variety of malignancies. Pre-clinical assays have demonstrated synergy between tosedostat and both cytarabine and hypomethylating agents. We performed a randomized, open-label Phase II trial to determine the rates of complete remission (CR) and 4 month overall survival using tosedostat in combination with intermediate-dose cytarabine or decitabine in patients with untreated AML or high-risk MDS.Methods: Patients ≥60 years old were randomized in a 1:1 fashion to receive tosedostat 120 mg daily by mouth days 1-21 with either 5 days of intravenous cytarabine 1 g/m2/day or decitabine 20 mg/m2/day delivered every 35 days for up to three cycles. Eight patients received 180 mg tosedostat daily continuously. Patients who obtained a CR or CR with incomplete blood count recovery (CRi) after 3 cycles of therapy were eligible to receive up to 2 additional cycles (maximum of 5).Results: Thirty-four patients with a median age of 70 (range, 60-83) years were treated, with 17 each receiving either tosedostat/cytarabine or tosedostat/decitabine. Twenty-nine patients (85%) had AML and 5 (15%) had MDS RAEB-2. Nineteen patients (56%) had cytogenetics with intermediate-risk, 14 (41%) adverse-risk, and 1 (3%) favorable-risk by European Leukemia Net criteria. Seven patients had FLT3/ITD mutations with normal cytogenetics. Fifteen patients (44%) had secondary AML/MDS or antecedent hematologic disorder. The median duration of treatment was 3 months. The overall CR/CRi rate was 53% (9 in each arm), with 14 patients (41%) achieving a CR and 4 patients (12%) a CRi. CR/CRi was attained in 6 patients with adverse cytogenetics and 4 additional patients with FLT3 mutations. Fourteen patients (41%) were taken off study after a median of 2 cycles due to lack of response or disease progression. With a median follow-up of 11.2 months (range, 0.5-22.3 months), the median overall survival was 11.5 months (95% CI, 5.2-16.7). Twenty-three patients (67.6%) were treated as outpatients and 10 of these patients (44%) required hospitalization during treatment for febrile neutropenia. There were no Grade 3-4 non-hematologic toxicities requiring withdrawal from the study.Conclusions: Tosedostat in combination with cytarabine or decitabine likely provides a CR/CRi rate of >50% with acceptable toxicity in older patients with untreated AML/ MDS. This approach delivered predominantly as outpatient therapy suggests that further study in a larger, controlled trial may be warranted. DisclosuresOff Label Use: Pravastatin is not FDA approved for treatment of AML. Wang:CTI Biopharma: Employment. Singer:CTI BioPharma, Corp: Employment, Equity Ownership.

Azacitidine Followed By Intensive Induction/Consolidation Chemotherapy in Older Patients with Acute Myeloid Leukemia (AML): Results from the Randomized AML-AZA Trial of the Study Alliance Leukemias (SAL)

▪IntroductionAberrant DNA methylation is a common feature of acute myeloid leukemia (AML) and increases with age. DNMT inhibitors such as Azacitidine (AZA) can induce meaningful responses and remissions in AML as monotherapy. The combination of AZA with standard chemotherapy (7+3) has not been tested in a randomized trial.Patients and study designThe AML-AZA trial compared AZA directly followed by standard induction therapy, AZA followed by standard consolidation, and further Azacitdine maintenance with standard induction and consolidation without AZA in older patients with AML. All patients received standard Cytarabine (100 mg/sqm) and Daunorubicin (60 mg/sqm) induction (“7+3”) and up to two cycles of intermediate dose Cytarabine (1 g/sqm q12hr days 1, 3, 5) as consolidation therapy. AZA (75 mg/sqm for 5 days) preceded each therapy cycle in the AZA arm. In addition, AZA maintenance for up to 1 year was also scheduled for patients in the AZA arm. 105 patients were randomized to receive AZA plus Cytarabine plus Daunorubicin as induction therapy (AZA + 7+3) and 109 patients to receive 7+3 only (control group). Median age was 70 years in both treatment arms. Patient cohorts were well balanced with regard to blast counts in bone marrow, secondary versus de novo AML and molecular genetics risk group. More patients in the AZA + 7+3 arm (39/105; 37.1%) than in the control group (25/109; 22.9%) showed high risk cytogenetics (p=0.057). Event free survival (EFS) was the primary end point. Secondary endpoints were overall survival (OS), complete remission (CR) rate, toxicity and different treatment response according to molecular markers.ResultsOverall, 214 of 216 planned patients were enrolled into the AML-AZA trial. Due to a higher number of severe adverse events (SAE), AZA administration was stopped after recruitment of 214 patients whereas chemotherapy was continued as planned. Percentages of patients in the AZA arm with AZA doses as initially planned were as follows: 99% for first induction cycle, 72% for the second induction cycle. AZA as maintenance therapy for at least one cycle was delivered to 18% of patients in the AZA group. At least one SAE occurred in 51% of AZA + 7+3 patients compared to 31% of 7+3 patients (p=0.005). Cardiac disorders with CTCAE grade 3-5 occurred more frequently in the AZA + 7+3 arm (n = 15) than in the 7+3 arm (n = 6) (not significant). Leukopenia was prolonged by one day (median 23 vs 22 days) in the AZA + 7+3 group (p=0.043), whereas time of thrombocytopenia was not different. The early death rates at 30, 60 and 90 days did not differ significantly between treatment groups. Efficacy analyses were performed on an intention-to-treat basis. Median EFS as the primary endpoint was 6 months in both treatment arms (p=0.96). Median OS was 16 months for patients treated with AZA + 7+3 and 21 months for 7+3 (p=0.35). Median relapse free survival was 12 months in both treatment arms (p=0.95). 48 of 100 patients (48%) in the AZA + 7+3 arm achieved complete remission (CR) after induction therapy versus 57 of 109 patients (52%) in the 7+3 arm (p=0.58). DNMT3A exon 23 mutations were detected in 30 out of 162 analyzed patients. Exploratory analyses were performed to detect a potential interaction between AZA + 7+3 response and DNMT3A mutation status. Trends for improved EFS and OS were noted for AZA + 7+3 treatment in DNMT3A mutated patients.ConclusionAZA as addition prior to standard induction and consolidation chemotherapy does not prolong EFS and OS in unselected older AML patients and it is more toxic. However, a trend towards better efficacy in patients with DNMT3A mutation was observed and should be further explored. DisclosuresMüller-Tidow:Celgene: Honoraria, Research Funding. Thiede:AgenDix GmbH: Equity Ownership, Research Funding; Illumina: Research Support, Research Support Other. Kiehl:Roche: Membership on an entity’s Board of Directors or advisory committees. Brümmendorf:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding. Ehninger:GEMoaB GmbH: Consultancy, Patents & Royalties.