Combination Of Cytarabine Research Articles

Characteristics and outcomes of older patients with secondary acute myeloid leukemia according to treatment approach.

The development of newer strategies to improve outcomes for older patients with secondary acute myeloid leukemia (s-AML) is a critical unmet need. Establishing baseline metrics for evaluating newer approaches is important. s-AML was defined as 1 or more of the following: a history of an antecedent hematologic disorder (AHD), a diagnosis of therapy-related acute myeloid leukemia (AML), and AML with karyotype abnormalities characteristic of myelodysplastic syndrome. Newly diagnosed s-AML patients aged 60 to 75 years were grouped into 5 treatment cohorts: 1) patients receiving high- or intermediate-dose cytarabine-based intensive chemotherapy (IC), 2) patients receiving a hypomethylating agent (HMA) or HMA combinations, 3) patients receiving low-dose cytarabine (LDAC) combinations, 4) patients receiving CPX-351, and 5) patients receiving investigational (INV) agents. Nine hundred thirty-one patients met the age and s-AML criteria. Complete remission rates were statistically lower in the HMA group (36%) versus the IC (46%), CPX-351 (45%), and LDAC groups (43%). Patients receiving less intensive regimens (the HMA and LDAC groups combined) had superior overall survival (OS) in comparison with patients receiving IC-based regimens (median 6.9 vs 5.4 months; P = .048). Only 4.3% of the IC patients proceeded to transplantation, whereas 10.3% of the patients on lower intensity regimens did (P = .001). There was no difference in median survival between patients treated with CPX-351 and patients treated with conventional lower intensity approaches (P = .75). Age > 70 years, an adverse karyotype, and a prior AHD were associated with decreased OS in a multivariate analysis. Lower intensity approaches are associated with lower early mortality rates and improved OS in comparison with intensive regimens. OS is poor with currently available therapies with a median OS of 6 months (5.4-7.6 months across regimens). Unsatisfactory outcomes with other INV agents underscore the need for more effective therapies. Cancer 2017;123:3050-60. © 2017 American Cancer Society.

Carboplatin instead of cisplatin in combination with dexamethasone, high-dose cytarabine with or without rituximab (DHAC+/-R) is an effective treatment with low toxicity in Hodgkin's and non-Hodgkin's lymphomas.

The DHAP regimen (high-dose cytarabine in combination with dexamethasone and cisplatin) with or without rituximab (DHAP+/-R) is one of the most common regimens in daily practice. It is considered the standard treatment for relapse or refractory Hodgkin's and non-Hodgkin's lymphoma (NHL). Cisplatin nephrotoxicity is a major concern, and other platinum compounds are being tried. We performed a monocentric retrospective analysis to evaluate the use of carboplatin, so-called DHAC+/-R regimen. The purpose was to assess the toxicity of the DHAC+/-R regimen in real-life. The Dexamethasone, Cytarabine, Carboplatin (DHAC) regimen consisted of carboplatin AUC=5mg/ml/min (targeted area under the curve with Calvert's formula) on day 1, cytarabine 2g/m2 twice a day on day 2 and IV dexamethasone 40mg from days 1 to 4. Rituximab was administrated at 375mg/m2 on day 1 for CD20+ NHL. The interval between courses was 21days. During the period considered, 199 patients received DHAC+/-R. For the entire cohort, median follow-up is 24months (range, 2-82), median OS is not reached (NR), estimated 2-year OS is 75% (95% CI, 69-83) and median progression-free survival (PFS) is 46months (95% CI, 22-NA). Of 144 patients scheduled for autologous stem cell transplantation (ASCT), 102 (71%, NA=2) were in response after DHAC+/-R and all except 4 underwent ASCT. Grade≥3 haematological toxicities were mainly thrombocytopenia (n=101) and anaemia (n=95). Grade≥3 neutropenia occurred in 10 patients. No grade≥3 renal and one grade 3 neurological toxicity were reported. DHAC+/-R is feasible in daily practice, provides good response rates and jeopardises neither stem cell collection nor ASCT.

Antiproliferative effect of ZSTK474 alone or in combination with chemotherapeutic drugs on HL60 and HL60/ADR cells.

While chemotherapy remains to be one of the main approaches in the clinical treatment of acute myeloid leukemia (AML), multidrug resistance (MDR) has become a serious problem which limits the therapeutic efficacy. The important roles of the PI3K/Akt pathway in modulating cell proliferation and MDR suggest that PI3K inhibitor might be effective for treatment of AML. In the present study, the antiproliferative effects of PI3K inhibitor ZSTK474 on AML cell HL60 and the adriamycin (ADR)-resistant HL60/ADR cells were investigated. Our data indicated that ZSTK474 exhibited potent antiproliferative activity, induced G1 cell cycle arrest, but no obvious apoptosis in both cell lines. Moreover, ZSTK474 affected the protein levels of cell-cycle-related molecules including increased p27, decreased cyclin D1 and phosphorylated Rb in dose-dependent manner. The proteins downstream of PI3K including phosphorylated PDK1, Akt and GSK-3β were reduced in a dose-dependent manner after ZSTK474 treatment. ZSTK474 reversed ADR resistance, increased the intracellular accumulation of ADR, and reduced the expression and function of multidrug resistance (MDR) proteins including both P-gp and MRP1 in HL60/ADR cells. The combination of ZSTK474 and chemotherapeutic drugs cytarabine or vincristine led to a synergistic effect in HL60 and HL60/ADR cells. In conclusion, ZSTK474 showed potent antiproliferative effect on HL60 and HL60/ADR cells; combination with cytarabine or vincristine resulted in synergistic effect. Our results suggest ZSTK474 has the potential to be applied in the treatment of AML patients, while further evidences particularly those about in vivo efficacy are needed.

What are the most promising new agents in acute myeloid leukemia?

Although the treatment paradigm for acute myeloid leukemia (AML) had been largely unchanged for many years, in-depth molecular characterization has revolutionized our understanding of mutations that drive the disease, subsequently serving to guide current clinical investigation. Furthermore, recent advances in the field have highlighted the importance of optimizing known efficacious agents by improving drug delivery or bypassing resistance mechanisms. The current status of novel agents which are shaping the clinical management of AML patients are summarized in this review. Practice changing findings over the past year include improved overall survival (OS) in a molecularly defined AML subgroup as well as in elderly patients with secondary AML (sAML). Specifically, synergistic combination of daunorubicin and cytarabine (i.e., CPX-351) was found to improve OS in sAML patients. Furthermore, although multiple mutation specific inhibitors have been developed, optimal combination with additional agents appears critical, as monotherapies have not resulted in durable remissions or improved outcomes. Improved OS via the addition of midostaurin to intensive chemotherapy in FLT3 mutant AML supports this concept. For the first time in AML, personalized therapy has become possible through improved understanding of the molecular architecture and survival pathways of an individual's disease. The landscape of AML treatment is encouraging, with multiple novel agents likely to gain approval over the next 5 years.

FLAG Regimen with or without Idarubicin in Children with Relapsed/Refractory Acute Leukemia: Experience from a Turkish Pediatric Hematology Center.

Objective:The optimal therapy to achieve higher rates of survival in pediatric relapsed/refractory acute leukemia (AL) is still unknown. In developing countries, it is difficult to obtain some of the recent drugs for optimal therapy and mostly well-known drugs proven to be effective are used. We assessed the efficacy of the combination of fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG regimen) with or without idarubicin (IDA) in children with relapsed/refractory acute lymphoblastic leukemia and acute myeloid leukemia.Materials and Methods:Between September 2007 and May 2015, 18 children with refractory/relapsed AL attending our center, treated with a FLAG regimen with or without IDA, were included. The primary end point was the remission status of the bone marrow sampled after the first/second course of chemotherapy. The second end point was the duration of survival after hematopoietic stem cell transplantation (HSCT).Results:Complete remission (CR) was achieved in 7 patients (38.8%) after the first cycle, and at the end of the second cycle the total number of patients in CR was 8 (42.1%). All patients in CR underwent HSCT. The CR rate in patients who had IDA in combination therapy was 28.6%, and it was 50% in patients treated without IDA (p=0.36). Mean survival duration in transplanted patients was 24.7±20.8 months (minimum-maximum: 2-70, median: 25 months), and it was 2.7±1.64 months (minimum-maximum: 0-5, median: 3 months) in nontransplanted patients. Five of them (27.7%) were still alive at the end of the study and in CR. The median time of follow-up for these patients was 33 months (minimum-maximum: 25-70 months).Conclusion:FLAG regimens with or without IDA produced a CR of >24 months in 27.7% of children with relapsed/refractory AL and can be recommended as therapeutic options prior to HSCT in developing countries.

Comparison of efficacy between high-dose CAG regimen and standard-dose cytarabine regimen for acute myeloid leukemia patients with partial remission after the first course of standard induction chemotherapy

Objective To compare the efficacy of high-dose CAG (HD-CAG) regimen by increasing the dose of aclarubicin in conventional CAG regimen and standard-dose cytarabine (SDAC) combination regimen in acute myeloid leukemia (AML) patients with partial remission (PR) after standard induction regimen. Methods This study retrospectively analyzed 49 PR AML patients after 3 days of daunorubicin or idarubicin and 7 days of cytarabine regimen (namely 3+7 ) in the First Affiliated Hospital of Soochow University and Haikou Municipal People's Hospital from October 2006 to September 2015. Based on different reinduction regimen, these patients were divided into 2 groups: HD-CAG (23 cases) and SDAC (26 cases). The clinical characteristics, efficacy, toxicity and survival rate were further evaluated between 2 groups. Results The complete remission (CR) rate in HD-CAG group was higher than that in SDAC group [91.3% (21/23) vs. 65.4% (17/26), P=0.030], while the overall response (OR) rate between 2 groups was not statically different [95.7% (22/23) vs. 84.6% (22/26), P=0.423]. Meanwhile, myelosuppression and infection rate of HD-CAG regimen were similar with SDAC regimen. There were no statistically significant differences in overall survival (OS) and disease free survival (DFS) rates at 12 months between 2 groups (P=0.287, P=0.816). Conclusion The HD-CAG regimen could obtain a better efficacy than SDAC regimen for these AML patients with PR after the first course of standard induction chemotherapy. Key words: Leukemia, myeloid, acute; High-dose CAG regimen; Standard-dose cytarabine; Induction chemotherapy

Carmustine replacement in intensive chemotherapy preceding reinjection of autologous HSCs in Hodgkin and non-Hodgkin lymphoma: a review.

High-dose chemotherapy preceding autologous hematopoietic stem cell transplantation (auto-HSCT) is one treatment option for patients with Hodgkin (HL) or non-Hodgkin lymphoma (NHL). The most frequently used intensive chemotherapy is a combination of carmustine (BCNU), etoposide, cytarabine and melphalan (BEAM). However, BCNU is consistently in short supply, and there has been a recent dramatic increase in its cost, necessitating the utilization of conditioning alternatives. The busulfan-based conditioning regimen known as the busulfan-cyclophosphamide-etoposide (BuCyE) combination is the second most-studied conditioning regimen worldwide after BEAM, and it exhibits a benefit/risk ratio that is comparable to that of BEAM. In addition to these two combinations, the present manuscript also summarizes data reported for other conditioning combinations. Owing to the lack of prospective and comparative studies, a comparison of the toxicities and medicoeconomical profiles of these treatments is warranted to identify effective replacements for BCNU-based conditioning.

Southwestern Oncology Group pretreatment risk criteria as predictive or prognostic factors in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a clonal hematological malignant condition and the implications of pretreatment risk criteria as predictive or prognostic factors are constantly under evaluation. With this study, the authors' intent was to characterize AML patients and to evaluate the clinical outcome associated with Southwestern Oncology Group (SWOG) coding pretreatment risk criteria/cytogenetic score. Between 2002 and 2010, 225 patients were diagnosed with AML at the Portuguese Institute of Oncology (Porto, Portugal). From this patient group, 128 patients aged <65 years were selected. The patients were treated using a combination of cytarabine and anthracycline, with the addition of cyclosporine when bone marrow dysplasia was observed. A median survival of 24 months was observed in this group. The patients were divided in subgroups according to the SWOG pretreatment risk criteria. We observed a statistically significant association of non-favorable SWOG coding with female gender [P=0.025; risk ratio (RR)=3.632, 95% confidence interval (CI): 1.113-11.852], indication for allogeneic bone marrow transplantation (P=0.023, RR=1.317, 95% CI: 1.184-1.465), complete response achievement (P=0.013, RR=1.385, 95% CI: 11.232-1.556) and relapse (P=0.048, RR=3.181, 95% CI: 10.966-10.478). Furthermore, SWOG pretreatment risk criteria also significantly affected global overall survival (OS; P=0.003) and OS at 5 years (P=0.001). A multivariate Cox regression analysis supported response to induction therapy (3-year OS: P=0.011, RR=0.385, 95% CI: 10.184-0.806; 5-year OS: P=0.012, RR=0.388, 95% CI: 10.597-1.994), consolidation (3-year OS: P=0.005, RR=0.328, 95% CI: 0.150-0.720; 5-year OS: P=0.002, RR=0.308, 95% CI: 0.144-0.657) and the diagnosis of therapy-related aml (3-year OS: P=0.016, RR=2.756, 95% CI: 0.486-1.281; 5-year OS: P=0.031, RR=2.369, 95% CI: 1.081-5.189) as prognostic factors, but this was not confirmed for SWOG pretreatment risk criteria. Therefore, we concluded that the reproducibility of the application of the SWOG pretreatment risk criteria may not be available as a prognostic factor in every acute leukemia population. However, its application as a predictive factor of response has been confirmed in our population.

A multi-institutional analysis of peritransplantation radiotherapy in patients with relapsed/refractory Hodgkin lymphoma undergoing autologous stem cell transplantation.

No consensus exists regarding the use of radiotherapy (RT) in conjunction with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) for patients with relapsed/refractory classical Hodgkin lymphoma (HL). The objectives of the current study were to characterize practice patterns and assess the efficacy and toxicity of RT at 2 major transplantation centers. Eligible patients underwent HDC/ASCT from 2006 through 2015 using the combination of either carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) or cyclophosphamide, BCNU, and etoposide (CBV). For the cohort of 189 patients, the 4-year overall survival rate was 80%, the progression-free survival rate was 67%, and the local control (LC) rate was 68%. RT was used within 4 months of ASCT for 22 patients (12%) and was given more often for disease that was early stage, primary refractory, or [18 F]fluorodeoxyglucose (FDG)-avid at the time of HDC/ASCT. Disease recurrence occurring after HDC/ASCT was associated with primary refractory disease and FDG-avidity at the time of HDC/ASCT. RT was not found to be associated with LC, progression-free survival, or overall survival on univariate analysis. In a model incorporating primary refractory HL and FDG-avid disease at the time of HDC/ASCT, RT was found to be associated with a decreased risk of local disease recurrence (hazard ratio, 0.3; P = .02). In patients with primary refractory HL and/or FDG-avid disease at the time of HDC/ASCT, the 4-year LC rate was 81% with RT versus 49% without RT (P = .03). There was one case of Common Terminology Criteria for Adverse Events grade ≥ 3 RT-related toxicity (acute grade 3 pancytopenia). In patients undergoing ASCT for relapsed/refractory HL, peritransplantation RT was used more often for disease that was early stage, primary refractory, or FDG-avid after salvage conventional-dose chemotherapy. RT was associated with improved LC of high-risk localized disease and was well tolerated with modern techniques. Cancer 2017;123:1363-1371. © 2016 American Cancer Society.

Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia.

In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo. Low EZH2 levels resulted in derepression of HOX genes, and knockdown of HOXB7 and HOXA9 in the resistant cells was sufficient to improve sensitivity to TKIs and cytotoxic drugs. The endogenous loss of EZH2 expression in resistant cells and primary blasts from a subset of relapsed AML patients resulted from enhanced CDK1-dependent phosphorylation of EZH2 at Thr487. This interaction was stabilized by heat shock protein 90 (HSP90) and followed by proteasomal degradation of EZH2 in drug-resistant cells. Accordingly, inhibitors of HSP90, CDK1 and the proteasome prevented EZH2 degradation, decreased HOX gene expression and restored drug sensitivity. Finally, patients with reduced EZH2 levels at progression to standard therapy responded to the combination of bortezomib and cytarabine, concomitant with the re-establishment of EZH2 expression and blast clearance. These data suggest restoration of EZH2 protein as a viable approach to overcome treatment resistance in this AML patient population.

Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi

The combination of rituximab, bendamustine, and cytarabine (R-BAC) was highly active in a pilot trial of mantle cell lymphoma, but its use was restricted by high haematological toxicity. We aimed to assess the efficacy and safety of an R-BAC regimen with low-dose cytarabine (RBAC500). In this multicentre, phase 2 trial, we recruited previously untreated patients with an established histological diagnosis of mantle cell lymphoma from 29 Fondazione Italiana Linfomi centres in Italy. Patients had to be older than 65 years and fit according to the comprehensive geriatric assessment, or aged 60-65 years if they were ineligible for high-dose chemotherapy plus autologous stem-cell transplantation and were fit or unfit. All patients received RBAC500 (rituximab 375 mg/m2 on day 1, bendamustine 70 mg/m2 on days 2 and 3, and cytarabine 500 mg/m2 on days 2-4; all administered intravenously) every 4 weeks for up to six cycles. Primary endpoints were the proportion of patients achieving complete response at the end of treatment and toxicity, defined as the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity. All patients who started at least one cycle of RBAC500 were included in the primary and safety analyses. Using efficacy and toxicity as a composite primary endpoint, we considered the final conclusion positive if more than 28 of 57 patients achieve complete response and fewer than 18 of 57 patients report toxicities. This study is registered with EudraCT, number 2011-005739-23, and ClinicalTrials.gov, number NCT01662050, and is completed. Between May 2, 2012, and Feb 25, 2014, we enrolled 57 patients (median age 71 years, IQR 67-75). 54 (95%) patients received at least four RBAC500 cycles (three discontinued because of toxicity), and 38 (67%) completed six cycles. Two (4%) had disease progression (one after the fourth cycle and one after the sixth cycle). All 52 (91%, lower limit of one-sided 95% CI 85%) remaining patients achieved complete response at the end of treatment. 23 (40%, upper limit of one-sided 95% CI 53%) of 57 patients had at least one episode of relevant toxicity. The most frequent grade 3-4 haematological toxicities were neutropenia (149 [49%] of 304 cycles) and thrombocytopenia (158 [52%]). Most treatment-related non-haematological adverse events were of grade 1-2, with the most frequent ones being fatigue (14 [25%] patients), nausea or vomiting (12 [21%]), and infusion-related reactions or tumour lysis syndrome (12 [21%]). 41 (72%) patients required a dose reduction. 12 patients died during the study, but no deaths were related to treatment. RBAC500 is an effective treatment for elderly patients with mantle cell lymphoma and, despite not meeting our prespecified safety boundary, haematological toxicity was manageable with appropriate supportive care and dose reduction. Since maintenance therapy is not required, RBAC500 could be considered an option and should be studied in phase 3 trials. Fondazione Italiana Linfomi and Mundipharma.

Decitabine Is Superior to Cytotoxic Chemotherapy in Elderly Acute Myeloid Leukemia Patients in Terms of Medical Source Utilization and Cost-Effectiveness without Negatively Impacting Survival Outcomes

IntroductionDecitabine is a drug commonly used drug in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The efficacy of decitabine compared to best supportive care or low dose cytarabine has been shown in previous studies. However, no comparison has been made between decitabine and intensive chemotherapy in fit elderly patients. Hence, in this study, we tried to uncover the cost-effectiveness of decitabine compared to cytotoxic chemotherapy in elderly AML patients using a big database, called the Korean National Health Insurance (KNHI) Claims Database.MethodsRecords from elderly (>=65 years) patients with AML who received chemotherapy were retrieved from the KNHI claims database between July 1st, 2010 and December 31st, 2014. We investigated survival outcome within 1 year after the administration of the first line chemotherapy, utilization of the emergency room, utilization of the intensive care unit (ICU), visit to out-patient clinics and in-patient units, and total medical cost (1USD=1,000KRW) within 6 months after the initial chemotherapy. Overall survival (OS) following chemotherapy was calculated using the Kaplan-Meier method. The log-rank test was carried out to compare survival curves.ResultsA total of 1,151 records from elderly patients who received chemotherapy for AML were retrieved from the database. Decitabine was administered as the first line therapy in 239 patients, while low dose cytarabine and cytarabine combination chemotherapy were given as the first line therapy in 258 and 654 patients, respectively.In older patients (age 65-74 years, n=821), the majority of patients received cytarabine combination chemotherapy (n=560), while 130 patients received decitabine as the first line therapy. In these patients, OS was not different between decitabine group (median OS 43.0 weeks) and cytarabine combination group (median OS 46.2 weeks). Patients who received cytarabine single agent showed significantly poorer survival with a median OS of 7.7 weeks compared to patients receiving other treatments (decitabine or cytarabine combination) (p<0.0001).In elderly patients (age over 75 years, n=330), one-third of patients received decitabine (n=109), and 127 patients received cytarabine single treatment as the first line therapy. In these patients, OS was not different between decitabine group (median OS 37.9 weeks) and cytarabine combination group (median OS 47.9 weeks). Patients who received cytarabine single agent showed significantly poorer survival with median OS of 6.3 weeks compared to patients receiving other treatments (decitabine or cytarabine combination) (p=0.0002).Although a similar survival outcome was observed between decitabine treatment and cytarabine combination treatment, decitabine treatment was associated with less need for intravenous antibiotic treatment (p=0.01) and less utilization of the ICU (p=0.02).The total medical cost per person was similar to decitabine arm (40,568 USD/person) and cytarabine combination arm (44,506 USD/person) (p=0.26).Decitabine treatment, however, was related to more frequent outpatient clinic visits (p<0.0001). Blood transfusion requirements (p=0.09), need for in-patient care (p=0.12), and utilization of the emergency room (p=0.22) were similar between the two groups.ConclusionIn conclusion, in elderly AML patients decitabine is a reasonable first line treatment regimen with less medical source utilization and better cost-effectiveness without negatively impacting survival outcomes.This study is funded by Janssen Korea Ltd. DisclosuresYun:Janssen: Research Funding.

Clofarabine Plus Low-Dose Cytarabine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome (MDS) Who Have Been Relapsing after, or Are Refractory to, Hypomethylating Agent (HMA) Therapy

▪Background: HMA therapy is standard of care for patients with MDS. Outcome post HMA failure is poor with a median survival of 4-6 months. Clofarabine is a second generation nucleoside analog with single agent activity in MDS. The objective of this phase II trial is to evaluate the safety and activity of the combination of clofarabine and low dose cytarabine in the treatment of patients with high risk MDS who failed prior HMA therapy.Methods: Eligible patients were adults older than 18 years with MDS intermediate-1 and higher by the IPSS, who have had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine. Patients were required to have an Eastern Cooperative Oncology Group performance status of </=2 at the time of study entry. Responses were defined according to International Working Group 2006 criteria. Induction therapy consisted of clofarabine 10-15 mg/m2 IV daily X 5 days (days 1-5) and cytarabine 20 mg SC twice daily X 7 days (days 1-7). Patients could receive up to 3 induction cycles as long as they tolerated the therapy and had stable disease. Responding patients proceeded with consolidation therapy with clofarabine 10-15 mg/m2IV daily X 3 days (days 1-3) and cytarabine 20 mg SC twice daily X 5 days (days 1-5) for a maximum of 12 cycles. Cycles were repeated every 4 to 8 weeks depending on hematopoietic recovery and resolution of toxicities.Results: From January 2012 to August 2015, 80 eligible patients were enrolled in this prospective study (NCT01444742) and received a median of 2 cycles (range, 1-12) (Table 1). The overall response rate (ORR) was 46% (16 [20%] achieved complete remission (CR), 17 [21%] marrow CR, 1 [1%] partial response (PR), 3 [4%] hematological improvement (HI)) with a median response duration of 7 months. The median time to response was 42 days (range, 9-191). By multivariate analysis, complex karyotype was the only independent factor predicting for response (hazard ratio [HR] 0.13; 95% confidence interval [CI]: 0.03- 0.62; p=0.01). Of the 37 patients with diploid karyotype, the overall response was 68% (7 [19%] achieved CR, 15 [41%] marrow CR, 1 [3%] PR, 3 [4%] HI). Nine of the responding patients received subsequent allogeneic stem cell transplant (ASCT). With a median follow-up of 24 months (range: 1-51 months), the median event-free survival (EFS) and overall survival (OS) times were 5 months (95% CI: 2.7-6.3) and 11 months (95% CI: 6.5-14.9), respectively (Figure 1). The median OS for responding and non-responding patients was 24 months (95% CI: 11.7-35.6) and 5 months (95% CI: 2.8-6.2), respectively (p<0.001). There was no difference in OS whether patients were censored or not at the time of ASCT (p=0.463). At last follow-up, 22 patients (28%) remained alive: 1 is receiving low-dose clofarabine and cytarabine, 5 are alive in response after ASCT, 9 are receiving salvage therapy, 1 went to hospice, and 6 were lost to follow-up. By multivariate analyses, complex karyotype, platelet count less than 30 x 109/L, and poor performance status were independently associated with poor survival. In addition, the response to the combination of low-dose clofarabine and cytarabine was independently associated with better OS (HR 0.17; 95% CI 0.09-0.36; p<0.001). Grade ≥ 3 therapy-related toxicity included infections (34%), increased liver functional tests (8%), acute renal failure (3%), skin rash (3%), syncope (1%), and rectal bleeding (1%). Twenty-two (28%) patients had clofarabine dose reduction after a median of 2 courses. After 47 patients were enrolled and several patients experienced infections during induction, the protocol was amended to reduce the dose of clofarabine to 10 mg/m2 per day for 5 and 3 days during the induction and consolidation phases, respectively. There was no difference in responses before and after the modification to the protocol’s dosing schedule (p=0.314).Conclusion: The combination of low-dose clofarabine and cytarabine in patients with higher-risk MDS after HMA failure resulted in an ORR of 46% and median OS of 11 months and may be particularly effective in patients with diploid karyotype. Our results also indicate that the combination of low-dose clofarabine and cytarabine may be useful as a bridge to ASCT in eligible patients. [Display omitted] [Display omitted] DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jain:Abbvie: Research Funding; Infinity: Research Funding; Servier: Consultancy, Honoraria; Incyte: Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Novimmune: Consultancy, Honoraria; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

Inhibition of the Enzyme Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

BackgroundThe prognosis for adults diagnosed with acute myeloid leukemia (AML) remains poor, with a five-year survival of 25%. This prognosis is even more dismal in older patients, and those who are not well enough to receive standard induction chemotherapy. Speaking to the need for new therapies is the fact that our therapeutic backbone - a combination of cytarabine and an anthracycline - remains unchanged for 40 years.Differentiation therapy (e.g. ATRA and Arsenic trioxide) revolutionized care for the small subset of patients diagnosed with acute promyelocytic leukemia (APL). Where APL was once the worst form of myeloid leukemia, it now carries the best prognosis, with a five-year survival exceeding 85%. Replicating the success of differentiation therapy in the remaining 90% of patients with AML has remained elusive, and was the motivation behind our studies.HypothesisAML comprises disparate genetic sub-types, but one shared hallmark is that the leukemic blasts are frozen at an immature and self-renewing stage of development. Despite AML's heterogeneity, 70% of cases overexpress HoxA9, a gene that must be downregulated in the process of normal myeloid cell differentiation. We hypothesized that the process through which HoxA9 maintains the undifferentiated state represented a commonly dysregulated node, and that therapies that bypass this node would be useful in the treatment of AML. Thus, we asked the question: 'can we identify small molecules that overcome myeloid differentiation arrest?'A Phenotypic Differentiation ScreenWe established a HoxA9-based AML screening system that permitted an unbiased flow cytometry phenotypic differentiation screen. We screened 330,000 small molecules for those with myeloid differentiation activity. Target identification of our lead compounds led to the unexpected discovery that inhibitors of dihydroorotate dehydrogenase (DHODH) can overcome myeloid differentiation arrest. DHODH is a mitochondrial enzyme involved in the endogenous synthesis of pyrimidines. The modulation of DHODH had not previously been shown to affect myeloid differentiation.DHODH Inhibitors in the Treatment of LeukemiaThe small molecule brequinar is a potent DHODH inhibitor (Panel A). Brequinar triggered myeloid differentiation in vitro (Panel B) and in vivo. Brequinar was highly active in vivo, as demonstrated in syngeneic murine AML models (HoxA9+Meis1 and MLL/AF9) as well as xenotransplant AML models (THP1, HL60, MOLM13, OCI/AML3).In an aggressive MLL/AF9 model of AML, treatment of mice with brequinar caused myeloid differentiation (Panel D), reduced leukemic cell burden, and improved overall survival (Panel C). Furthermore, treatment with brequinar reduced the number of leukemia stem cells, reduced colony-formation activity, and depleted the number of leukemia initiating cell activity (Panel E). These findings support the hypothesis that the myeloid differentiation resulting from DHODH inhibition is both phenotypic and functional, such that the matured leukemia cells lose their self-renewing capability.DHODH Inhibitors and Normal HematopoiesisTreatment with brequinar was better-tolerated and more effective than treatment with cytotoxic chemotherapy. Unlike cytarabine and doxorubicin, brequinar could be given for many weeks without cumulative toxicity. To assay the effect of DHODH inhibition on normal cells, we performed competitive bone marrow transplantation assays. Mice were treated with brequinar, 5-fluorouracil or induction chemotherapy. Their bone marrow was transplanted in competition (1:1) with normal (untreated) bone marrow, to gauge the effect of therapy on hematopoietic stem cell (HSC) function. Treatment with 5-FU and induction chemotherapy led to a dramatic loss of HSC fitness. In contrast, HSCs from mice treated with brequinar were functionally equivalent to those of untreated mice (Panel F) supporting the notion that DHODH inhibition does not lead to detrimental differentiation of the HSC compartment.DiscussionThe mechanism for the selective vulnerability of leukemia cells to DHODH inhibition remains under investigation. Our studies point towards DHODH as a new metabolic target; DHODH inhibitors may provide differentiation therapy for patients with AML. [Display omitted] DisclosuresSykes:Bayer Pharma AG: Research Funding. Meyer:Bayer Pharma AG: Employment. Stoeckigt:Bayer Pharma AG: Employment. Janzer:Bayer Pharma AG: Employment. Scadden:GlaxoSmithKline: Research Funding; Dr. Reddy’s: Consultancy; Fate Therapeutics: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties; Teva: Consultancy; Apotex: Consultancy; Bone Therapeutics: Consultancy; Magenta Therapeutics: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties.

Intensive Versus Non-Intensive Induction Therapy for Patients (Pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) Using Two Different Novel Prognostic Models

Background: Induction therapy for newly diagnosed AML pts can be classified as intensive or non-intensive. Non-intensive therapies are increasingly used in pts aged >65 years due to concerns about their ability to tolerate intensive chemotherapy. However, the relative benefit-risk ratios associated with intensive versus non-intensive therapies in AML pts is likely affected by age, comorbidities, and disease-related characteristics, such as cytogenetic and molecular features. Here, we examine these relationships.Methods: Data from 1295 newly diagnosed AML patients, given induction therapy between 2008 and 2012 at six participating academic centers, were retrospectively collected. We used two previously validated models to define distinct prognostic groups, and within each, compared 2-year mortality rates according to whether pts received intensive or non-intensive therapy. Non-intensive therapy principally included azacitidine, decitabine, or low-dose cytarabine, while intensive therapies primarily included the standard 7+3 regimen or "high-dose" cytarabine combinations with anthracyclines or purine analogs. The first model (Blood 2015; 126:532) was a composite of the prognostic effects of age, comorbidity index, and cytogenetic/genetics risks per European Leukemia Net (ELN) classification. The second (JCO 2011; 29(33): 4417) was a treatment related mortality (TRM) index including 8 pt- and AML-specific risk factors.Results: Age distribution of the pts were ≤49 (23%), 50-59 (20%), 60-69 (33%), and ≥70 (24%) years old. Median follow-up for currently alive pts was 41 (range, 0-99) months. Cytogenetic-molecular risks per ELN classification were favorable (18%), intermediate I and II (39%), or unfavorable (43%). Induction treatments were intensive in 77% and non-intensive in 23% of pts. The proportion of patients receiving non-intensive therapy increased with increasing age (Table 1).Almost all pts (99%) with the lowest composite scores (1-3) received intensive therapies and were therefore omitted from the comparisons with either model. Per the composite model grouping, pts had better survival rates if they received intensive therapy, although the differences were not statistically significant in pts with composite scores ≥10 (Table 2). Pts with TRM scores of 0-4 and ≥5, with a score of 5 corresponding to the median score, statistically significantly benefitted from intensive therapies (Table 2). Among all pts aged 70-79 years old (n=242), 41% received intensive therapy, while 59% received non-intensive therapy. The intensively treated pts in this age range had statistically significantly higher survival rates at 2 years (26% versus 13%, HR: 0.73, 95% CI: 0.54-0.98, P=0.04, Figure).Conclusion: After accounting for underlying prognosis using 2 validated models, we found pts with newly diagnosed AML generally had better survival if they received intensive therapy. This survival benefit was not statistically proven for pts with the highest composite scores (≥10). Early mortality was not increased in older pts given intensive versus non-intensive therapy (Figure), likely due to improvements in supportive care which allowed the greater anti AML effect of intensive therapy to become manifest over time. While we cannot exclude the effects of selection bias, absent a randomized trial our results suggest intensive therapy could be considered for most pts, up to the age of 80 years, regardless of their comorbidity burden. Although results seem better with intensive therapy, less than 50% of patients with composite scores >3 given such therapies were predicted to be alive at 2 years, suggesting the need for randomized clinical trials between novel intensive and non-intensive therapies to achieve better survival. [Display omitted] [Display omitted] [Display omitted] DisclosuresFathi:Bexalata: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Research Funding. Shami:JSK Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Optimization of IA Regimen with Homoharringtonine for Induction in Younger AML Based on Peripheral Blast Clearance Rate: First Result of the RJ-AML 2014 Trial

Background: Combination of idarubicin and cytarabine (IA) is now the basis of induction treatment for acute myeloid leukemia (AML) while the complete remission (CR) rate is only 60-75%. Homoharringtonine (HHT) based regimen was proved to be an option for AML and may improve long-term survival [1]. As previously reported, we established an effective evaluation of early treatment response by monitoring peripheral blast through flow cytometry, and concluded that patient with Day 5 peripheral blast clearance rate < 99.55% (D5-PBCR +) carries poor prognosis [2]. Thus we designed clinical trial to testify if HHT addition can reverse the unfavorable outcome of these D5-PRCR (+) patients. And here we report the latest response and survival results for this study.Patients and Methods: This clinical trial was designed using single arm Simon stage II model. We hypothesized the CR rate may increase 15% by addition of HHT, and then sample size of D5-PRCR (+) patients who need to combine HHT should be 55. Between 2014 and 2016, 148 patients (pts) aged 18-59 years old with newly diagnosed de-novo AML were enrolled in the RJ-AML 2014 trial (Fig.1). All patients received induction with standard IA regimen (idarubicin 10mg/M², d1-3; cytarabine 100mg/M², d1-7). Peripheral blood samples were collected before and on day 5 of induction. D5-PRCR was calculated as previously reported. Pts with D5-PRCR (+) were assigned for additional chemotherapy (HHT 2mg/M²£¬d6-10). Pts in CR were offered four cycles of intermediate-dose cytarabine (cytarabine 2g/M², every 12 hours, d1-3) for consolidation. And pts with NCCN unfavorable cytogenetic/molecular risk were recommended for allo-HSCT. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-OPC-15006085.Result: Baseline characteristic including age, white blood-cell count and bone marrow blast were similar between D5-PRCR (+) and D5-PRCR (-) groups. And patients with intermediate-unfavorable risk were more likely to be D5-PRCR (+). 68 pts were D5-PRCR (+), and 12 pts were unfit for HHT addition due to severe infection or unstable haemodynamics. Thus, 56 pts received HHT for induction. The CR rate among all pts was 86.03% (CR1: 117/136) after one course of induction. The CR1 rate for D5-PBCR (-) group was 90% (favorable: 96.0%, intermediate: 96.8%, unfavorable: 77.3%) and D5-PBCR (+) group was 80.36% (favorable: 100%, intermediate: 96.7%, unfavorable: 41.18%). And the CR rate of all pts was 90.44% after two courses of induction [D5-PBCR (-): 92.5% vs. D5-PBCR (+): 87.5%, P=0.329]. Compared to our previous results, CR rate was significantly increased for D5-PBCR (+) patients by HHT addition (87.5% vs. 56.14%, P=0.006) [2]. For the 12 pts with D5-PBCR (+) and were unfit for HHT addition, CR rate was only 66.67% after one courses of induction which is similar to our previous (P=0.502). 60-day early mortality rate was 2.5% for IA and 1.8% for IA+HHT. (Table. 1) The duration of neutropenia and thrombocytopenia were similar (P>0.05) and the incidences of non-hematologic toxicities including hepatic, renal, cardiac and gastrointestinal were not significantly different (P>0.05). Estimated overall survival of all pts at 1 year was 84.2% and relapse free survival was 80.4%, no statistical difference were found between two groups (Fig.2).Conclusion: This study was the first proposed trial of early induction intervention based on residual peripheral blast level in AML. Our current results indicated that IA+HHT is a well-tolerated regimen for younger AML pts. And the addition of HHT may benefit intermediate risk patients, reverse the insensitivity to traditional IA regimen and improve long-term survival. It still require longer follow-up to conclude more detailed and reliable result.1. Jin J, et al. The Lancet Oncology. 2013; 14(7):599-608.2. Yu C, et al. Journal of Hematology & Oncology. 2015; 8(1). [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Rituximab, Bendamustine and Cytarabine (RBAC500) As Induction Therapy in Elderly Patients with Mantle Cell Lymphoma: Final Results of a Phase 2 Study from the Fondazione Italiana Linfomi

▪Background: The combination of rituximab (R, 375 mg/m2 intravenously [IV], day 1), bendamustine (B, 70 mg/m2IV, days 2 and 3), and cytarabine (800 mg/m2, IV on days 2 to 4) was highly active in patients with mantle-cell lymphoma (MCL) in a phase 2 study [R-BAC; Visco et al, JCO 2013]. This regimen was well tolerated, but hematologic toxicity was quite relevant, especially in terms of transient grade 3 to 4 thrombocytopenia (76% of cycles). Aiming at reducing hematologic toxicity, the Fondazione Italiana Linfomi (FIL) designed a phase 2 trial adopting the R-BAC schedule, but lowering cytarabine dose to 500 mg/m2 (RBAC500).Materials and Methods: Patients with newly diagnosed MCL, aged 61 to 80 years, not eligible for autologous transplant and fit according to the comprehensive geriatric assessment, were enrolled. Patients presenting with non-nodal leukemic disease were excluded. The primary endpoints were complete remission rate (CR) measured by FDG-PET according to Cheson criteria 2007, and safety. Secondary endpoints included rate of molecular response (MR) by nested-PCR using patient specific IGH or BCL1 based targets, progression-free (PFS) and overall survival (OS). The study was conducted according to the Bryant and Day two-stage design.Results: From May 2012 to February 2014, 57 patients with MCL from 29 centers were recruited and treated. Central pathology revision was performed in 87% of cases. Median age was 71 years (range 61-79), 75% were males, and 91% had Ann Arbor stage III/IV disease. Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, high in 45%, Ki-67 was ≥30% in 31%, and 9% had the blastoid cytological variant. Overall, 53 patients (91%) received at least 4 cycles, while 36 (63%) had 6 cycles (median 5.3 cycles per patient). Fifteen patients (26%) discontinued treatment before reaching cycle 6 because of toxicity/adverse events, that mainly consisted of prolonged hemato-toxicity between cycles. Only one patient discontinued due to progressive disease. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 49% and 52% of administered cycles, respectively. Febrile neutropenia occurred in 6% of cycles. Extra-hematologic toxicity was mainly cardiac (5%). Overall response rate was 96%, and CR was 93%. The MR rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow (BM) samples. With a median follow-up of 34 months (28-52), the 2-years PFS (± confidence interval) was 81%±5% and the OS 85%±4%. Elevated Ki-67 (≥30%), and the blastoid variant were the strongest independent predictors of adverse PFS. Patients with either of these two features (33%), had a significantly inferior PFS (41% vs 97% after 34 months) compared to patients with classical/pleomorphic variants and low proliferative index (p<0.0001, Figure 1).Conclusions: The R-BAC500 regimen can be safely administered as first line therapy to elderly patients with MCL. Hematologic toxicity is substantially reduced compared to our previous experience. With 93% of FDG-PET negative CR, and a 2-years PFS of 81% without maintenance therapy, the R-BAC500 regimen is a highly effective treatment for patients with MCL, and compares favourably with previously reported regimens in this patient population, including R-bendamustine. [Display omitted] DisclosuresVisco:Gilead: Speakers Bureau; Lundbeck: Consultancy; Mundipharma: Research Funding; Celgene: Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Di Rocco:Celgene: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

A Phase 1b (OX1222) Dose-Finding Study of OXi4503 Combined with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

IntroductionThe vascular disrupting agent OXi4503, induces apoptosis in malignant myeloblasts, removes their endothelial cell protection, and sensitizes blasts to the cytotoxic effects of cytarabine. Cogle et al confirmed the safety and feasibility of intravenous (IV) OXi4503 up to doses of 7.81 mg/m2 (maximum tolerated dose [MTD] not reached) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (data on file). Based on these data, a Phase 1b dose-finding study was initiated to evaluate the safety and tolerability of combined therapy with OXi4503 and cytarabine for a similar patient population.MethodsThe primary objective of this ongoing study (NCT02576301) was to determine the MTD of OXi4503 in combination with intermediate-dose cytarabine in patients with relapsed/refractory AML or MDS. Pharmacokinetic/pharmacodynamic studies and a preliminary assessment of efficacy were secondary endpoints. Escalating doses of OXi4503 (based on a modified Fibonacci scheme and beginning at 3.75 mg/m2) were administered IV over 10 minutes on Days 1 and 4. Fixed dose cytarabine (1 g/m2) was administered IV over 2 hours on Days 1-5 and preceded infusion of OXi4503 on Days 1 and 4. Cycles were repeated every 28 days. Part 1 of the study was opened for patients with relapsed/refractory AML or MDS (following failure of at least 1 prior hypomethylating agent) who had good organ function, ECOG performance status of 0-2, and normal values for PT and INR (based on bleeding events observed with single-agent OXi4503). Key exclusion criteria included acute promyelocytic leukemia, absolute peripheral blood myeloblast count >20,000/mm3, uncontrolled hypertension, prolonged QTc, history of recent significant CV events, history of hemorrhagic stroke, and any requirement for full dose anti-coagulation.ResultsBetween December 2015 and May 2016, 7 patients with relapsed/refractory AML were enrolled (6 evaluable). Median age was 51.5 years (range 26-68), 50% were male, 83% and 17% had ECOG performance status scores of 1 or 2, respectively. Subjects had failed a median of 4.2 (range: 2-6) prior therapies and all patients had intermediate- or adverse-risk cytogenetics. Five of 6 patients (83%) received 1 cycle of therapy while 1 patient received 2 cycles. Four of 6 patients (67%) withdrew from the study for progressive disease (PD) and 1 patient withdrew with stable disease (SD). The final patient achieved a morphological complete remission (mCR) after 2 cycles and proceeded to donor lymphocyte infusion. One patient in the 3.75 mg/m2 cohort experienced a dose-limiting toxicity of hypofibrinogenemia, but no clinical evidence of bleeding. Following correction with cryoprecipitate, fibrinogen returned to normal and remained normal without further intervention. The most common (>10% incidence) Grade 3/4 treatment-emergent adverse events attributable to the combination of OXi4503 and cytarabine included neutropenic fever, anemia, platelet count decrease, neutrophil count decrease, fibrinogen decrease, AST increase, hypokalemia, and D-dimer increase.ConclusionsThe vascular disrupting agent OXi4503 (3.75 mg/m2) in combination with cytarabine (1 g/m2/day) is generally well tolerated with preliminary evidence of activity in heavily pretreated, refractory AML patients. This Phase 1b study continues to recruit patients into the second cohort, OXi4503 (4.68 mg/m2) plus cytarabine (1 g/m2/day), as the optimal dose combination has yet to be defined. DisclosuresNo relevant conflicts of interest to declare.

Effective Combination of CPX-351 with FLT3 Inhibitors in AML Blasts Harboring the FLT3-ITD Mutation

Introduction: CPX-351 (Vyxeos), a liposomal combination of cytarabine and daunorubicin co-encapsulated at a synergistic 5:1 molar ratio, has recently been shown to be significantly more efficacious than the standard of care, 7+3 administration regimen of free (non-liposomal) cytarabine + daunorubicin in treating elderly high-risk AML patients, including patients with the FLT3-ITD mutation. We previously exposed AML blasts from primary patient samples to CPX-351 ex vivo and found that samples harboring FLT3-ITD were significantly more sensitive to CPX-351 and also demonstrated enhanced drug uptake. We hypothesized that dysregulated FLT3 signaling results in upregulated liposome uptake pathways, leading to increased cell death and overall sensitivity to CPX-351. Furthermore, we wanted to examine the effect of combining CPX with existing FLT3 inhibitors (e.g. quizartinib or midostaurin).Methods: To examine drug uptake dynamics, we exposed AML cell lines (including MOLM-13 and MOLM14 that contain FLT3-ITD, and ME1 that contains mutant, activated FLT3) to varying concentrations of CPX-351, with or without pre-treatment of quizartinib and midostaurin. We measured cell viability and intracellular daunorubicin fluorescence, an indicator of drug uptake, by flow cytometry and using a fluorescent plate reader. Additionally, we performed synergy analyses on the cytotoxic activity in these cells, adding CPX-351 and FLT3 inhibitors in combination at different exposure sequences followed by measurement of cell viability and daunorubicin fluorescence.Results: We observed that cell lines containing FLT3-ITD or FLT3-activating mutation were more sensitive to CPX-351, and exhibited increased drug uptake, compared to cell lines with other genetic abnormalities. Interestingly, we observed that pre-treatment with quizartinib for 16 hrs produced a population of cells (approximately 50% of the total population) that exhibited decreased daunorubicin fluorescence, indicating that prolonged FLT3 inhibition may decrease CPX-351 uptake. Consistent with this, in synergy studies we observed robust synergy when combining CPX-351 with FLT3 inhibitors simultaneously or with CPX-351 exposure scheduled 24 hours prior to FLT3 inhibitor exposure. However, exposure to FLT3 inhibitors 24 hours prior to CPX-351 administration was less synergistic and even antagonistic at certain doses.Conclusions: These results provide additional supportive evidence that FLT3 activation results in increased uptake of CPX-351, which is consistent with results from the CPX-351 Phase III trial in which FLT3-ITD+ patients survived significantly longer when treated with CPX-351 compared to 7+3 chemotherapy. We also show that combining CPX-351 with existing FLT3 inhibitors can elicit a synergistic response when administered in dosing regimens where FLT3 inhibition does not precede CPX-351 treatment. Cumulatively, our data support further testing of CPX-351 in combination with FLT3 inhibitors for treating AML patients with genetic dysregulation of FLT3 signaling. DisclosuresTardi:Jazz Pharmaceuticals: Employment. Mayer:Jazz Pharmaceuticals: Employment.

Combination of Selinexor with High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in Acute Myeloid Leukemia (AML) Is Feasible and Tolerable

Background: Selinexor, an exportin 1 (XPO1) inhibitor, has demonstrated anti-leukemic effect as a single agent. There are also data demonstrating synergistic killing of leukemia cells with the combination of selinexor with anthracyclines and/or DNA damaging agents. The HiDAC/Mito combination is an effective induction regimen for relapsed/refractory (R/R) AML patients with a reported overall response rate (ORR) of 55% at our institution. We hypothesize that adding selinexor to HiDAC/Mito is feasible and has synergistic anti-leukemic effects.Methods: We performed a phase I dose escalation trial with cohort expansion in patients with AML that combined increasing doses of selinexor with age-adjusted HiDAC/Mito (NCT02573363). The primary endpoint was to determine the maximum tolerated dose of selinexor when given in combination with HiDAC/Mito. Selinexor was given orally on days 2, 4, 9, and 11 during the induction phase of the study. HiDAC (1.5 to 3 gm/m2 depending on age, IV over 3 hours) followed immediately by Mito (20 to 30 mg/m2 IV over 1 hour) was administered on day 1 and 5. Initial selinexor dose was 60mg (~35mg/m2) followed by a dose escalation to a target level of 80mg (~50mg/m2). Patients who entered remission proceeded to stem cell transplantation (SCT) or consolidation chemotherapy with HiDAC/selinexor followed by maintenance therapy with weekly selinexor alone for up to one year. Dose limiting toxicity (DLT) was defined as any grade 3 or greater non-hematologic toxicity, except transient (<48 hours) nausea/vomiting or liver function abnormalities, or by persistent bone marrow aplasia lasting >56 days in the absence of disease. Once a dose level was declared tolerable, more patients could be enrolled at that level to provide additional safety, tolerability, and efficacy data.Results: As of July 2016, 12 patients had enrolled. Selinexor dose levels were 60mg (n=3) and 80mg (n=9). Median age = 61 (range 44 - 74). De novo AML = 5 (42%); secondary AML = 3 (25%), R/R AML = 4 (33%). Eight (67%) patients were previously untreated, 1 (8%) was beyond the first relapse, and 3 (25%) had primary refractory disease. Prior therapies included combination cytarabine with anthracycline, HiDAC, decitabine, and clinical trial agents. Molecular/genetic subgroup profiles by European Leukemia Net (ELN) criteria included favorable = 1 (8%), intermediate I = 5 (42%), intermediate II = 1 (8%), and adverse = 5 (42%).Only 10 patients are evaluable for safety and efficacy at the time of analysis. Myelosuppression was the most common side effect and was universal. Median and average times to count recovery for responding patients from day 1 were 38 and 47 days, respectively. Febrile neutropenia was observed in 8 patients (80%), compared to our historical experience of 64% for HiDAC/Mito alone. Other significant adverse events included line-associated thromboses (n=3), cardiac toxicity (n=3), cerebellar toxicity (n=1), arm cellulitis (n=1), and syncope (n=1). No DLTs were observed. 30 and 60-day induction mortality was 10% (1 patient with R/R AML died from progressive disease).Ten patients are evaluable for response: complete remission (CR) = 4 (40%), CR with incomplete count recovery (CRi) = 1 (10%), partial remission (PR) = 1 (10%), and treatment failure (TF) = 4 (40%). Thus, the ORR is 60%. Of those who responded, 2 patients proceeded to consolidation, 1 underwent allo-SCT, and 3 are in preparation for allo-SCT. No response was achieved in patients with R/R AML.Bone marrow samples from screening and day 12 of treatment were used for biomarker analysis in three CR patients. A marked reduction in KI67, MYC, FLT3, KIT, and DNA damage response proteins was observed in the remaining tumor cells in the post-treatment samples. Staining for P53 showed an increase in nuclear staining intensity, which is consistent with the known effect of selinexor on tumor cells.Conclusions: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses up to 80mg/day or ~50 mg/m2/day twice weekly. It yields an ORR of 60% based on currently available data. The recommended phase II dose is 80mg of selinexor. Additional molecular correlative studies are evaluating patients' marrow and blood samples for markers that predict response and relapse. DisclosuresOdenike:Spectrum Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Geron: Research Funding; Incyte: Honoraria, Membership on an entity’s Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Stock:Sigma-Tau: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Gilead Sciences: Honoraria; Amgen: Honoraria; Royalties for a chapter in Up to Date: Patents & Royalties. Liu:Karyopharm: Research Funding; BMS: Research Funding.