Low-dose Ara-C Research Articles

An Oral Combination Study of Novel Nucleoside Analogue Sapacitabine and BCL2 Inhibitor Venetoclax to Treat Patients with Relapsed or Refractory AML or MDS

An Oral Combination Study of Novel Nucleoside Analogue Sapacitabine and BCL2 Inhibitor Venetoclax to Treat Patients with Relapsed or Refractory AML or MDS

Outcomes of Relapsed or Refractory Acute Myeloid Leukemia after Frontline Hypomethylating Agent with Venetoclax Regimens

Outcomes of Relapsed or Refractory Acute Myeloid Leukemia after Frontline Hypomethylating Agent with Venetoclax Regimens

The Efficacy and Safety of Cladribine in Combination with Cytarabine ,ATRA, G-CSF and Mitoxantrone(Claag-M Regimen)in Relapsed/Refractory AML : A Phase 1/2, Prospective, Single-Arm, Multicenter Study

Background. Relapsed/refractory(R/R) AML has poor prognosis and lacks of standard treatment, while clinical trial has been recommended for these patients. It is necessary to find innovation and effective chemotherapy regimens for R/R AML. Cladribine-based regimens have been proved to be effective in R/R AML. As low-dose cytarabine (Ara-C) could reduce marrow myeloblasts and ATRA may sensitize leukemic cells to Ara-C, we performed the phase 1/2, single-arm, multicenter study of cladribine in combination with Ara-C,ATRA,G-CSF and mitoxantrone (CLAAG-M Regimen) in R/R AML (ChiCTR-OIC-16008110). Methods. R/R AML patients aged 18-70 years were eligible to enroll in this study. The objective was to assess the responses and safety of this therapy. All patients received continuous infusion cladribine 5mg/m2 on days 1-5 or 1-3 and mitoxantrone 6mg/m2 on days 1,3,5 or 1,3. ATRA was taken orally at 45mg/m2 on day 4-6 and 15mg/m2 on days 7-20. Subcutaneous injection of cytarabine 15mg/m2 every 12 hours on days 1-10 and G-CSF 300ug/d on day 0 until disease remission or absolute neutrophils count ≥ 0.5×109/L were administered. All patents received one or two courses of induction treatments. Consolidation chemotherapy consisted of cladribine, low-dose Ara-C and G-CSF with or without mitoxatrone or ATRA according to the choice of study site. Results. Between April 2014 and July 2019, a total of 52 patients from five centers were screened,data of 7 patients who did not meet the enrollment criteria and 3 patients did not follow the established treatment were excluded. Therefore, 42 patients were enrolled in this study with 22 females and 20 males (Table 1). Median follow-up duration is 202.0 days(range 12.0-1560.0) from enrollment. The median age was 46 yr (range 25-68 ) . 27 out of 42 patients were refractory AML, with 15 patients in relapsed disease.One patient did not evaluate curative effect owing to personal reason,thus among 41 estimated patients, the overall response rate (ORR= CR+PR) was 70.7%, with complete remission rate (CRR = CR + CRi) of 68.3%, while early death rate and non-remission rate were 7.3% and 22.0% respectively (Table 2). For patients achieved CR, 10 of them (24.4%) received hematopoietic stem cell transplantation (HSCT) and more patients (36.6%) were only treated with consolidation therapy. The median overall survival (OS) of all patients was 306.0 days (95%CI 150.0-462.5) and the rate of 1-year and 2-year OS were 38% and 32% (Figure A). The median disease-free survival(DFS)was 183.0 days (95%CI 16.7-349.2) with half-year survival rate of 37% and 1-year survival rate of 32% (Figure B). Hematological toxicity was the most prominent toxicity of the CLAAG-M regimens since the median duration of neutrophils<0.5×109/L and platelets<20×109/L were 22 days (range8-42) and 17 days (range5-112),respectively. WHO>2 extra-hematological toxicities were infection (21/51) and bleeding (2/51). Three patients (7.3%) died early,with one from infection and two from organ hemorrhage. In multivariate analysis, transplantation would prolong the OS (P=0.013,95%CI of HR 0.010-0.578) . Conclusion.CLAAG-M regimen is effective and tolerated in patients with R/R AML and could be as a bridging therapy regimen followed by HSCT. To confirm the clinical benefit, a randomized study will be further carried out. Disclosures No relevant conflicts of interest to declare.

DNA Damage Repair Interference By WEE1 Inhibition with AZD1775 Overcomes Combined Azacitidine and Venetoclax Resistance in Acute Myeloid Leukmeia (AML)

Acute myeloid leukemia (AML) has remained one of the most treatment resistant and deadliest cancers. The survival of AML blast cells is controlled by the balance of anti- and pro-apoptotic proteins. Recently approved Bcl-2 targeted therapy of AML with the Bcl-2 specific inhibitor Venetoclax in combinations has improved patients outcomes. However, a priori and developing resistance to venetoclax combinations with hypomethylating agents (HMA) azacitidine and decitabine challenge this treatment. As such, novel therapies to overcome venetoclax-HMA resistance are urgently needed. We have identified a combination of DNA damage repair interference by WEE1 inhibition with AZD1775, combined with low dose cytarabine (AraC) as an effective strategy to overcome combined venetoclax-azacitidine resistance (VAR). AZD1775 with low dose AraC induced massive apoptosis (by Annexin V and cleaved caspase-3) and almost completely reduced viability and clonogenic growth of primary AML cells. To delineate the molecular mechanism of the synergistic effect of AZD1775/AraC we performed RNAseq analysis of single agent or the combination of AZD1775+AraC in AML cell lines and primary CD34+ selected AML patient cells with the goal to identify deferentially regulated genes indicating a mechanistic underpinning of the potent activity. Only 2 genes were deferentially regulated across cell lines and CD34+ selected cells under AZD1775+AraC treatment: one of these is NR4A1, an orphan nuclear receptor, which we went on to validate as a potential downstream target of Wee1 inhibition. The inactivation of NR4A1 in mice was previously shown to induce AML and to maintain leukemia stem cells. Using qPCR we confirmed that the expression of NR4A1 is upregulated after AZD1775/AraC combo treatment in human leukemic cells. We then demonstrated that activators of NR4A1 (cytosporone B and pPhOCH3) reduce viability of leukemic cells, while NR4A1 inhibitor pPhOH was able to abolish the effect of AZD1775/AraC combo treatment increasing leukemic cell viability]. To investigate the involvement of mitochondria in the effect of AZD1775/AraC treatment we performed the expression of mitochondrial genes and pathway analyses in RNAseq data and found that mitochondrial gene expression, including many genes involved in apoptosis, has most dramatic changes in the combo treatment if compared to the single agents. Subsequently, we have examined the expression of the main BCL-2 family apoptotic genes by qPCR and western blot analysis. We found that AZD1775/AraC induces the expression of Bim isoforms, whereas Bcl-2, Mcl-1 and Bcl-Xl were largely unaffected. NR4A1 was previously shown to translocate to mitochondria, release Bim from Bcl-2 protein binding, as well as convert Bcl-2 to an extreme potent pro-apoptotic form. Finally, we generated several additional VAR cell lines and cells with subclones and demonstrated that AZD1775/AraC combination treatment is able to overcome VAR in almost every clone. Our results show that DNA damage repair interference with Wee1 inhibition has the potential to overcome VAR through a novel mechanisms of AZD1775 increasing NR4A1, freeing pro-apoptotic Bim irrespective of anti-apoptotic Bcl-2 proteins leading to massive apoptotic cell death in AML cells. The precise molecular mechanisms and the involvement of NR4A1 in this phenomenon will be presented at the meeting. Our findings will help to develop new therapeutic strategies in AML treatment and a trial of AZD1775 + AraC in AML is currently ongoing. Disclosures No relevant conflicts of interest to declare.

ENHANCING EXPRESSION OF PRO-APOPTOTIC FACTORS THROUGH INHIBITION OF HDACS DRIVES P53-INDEPENDENT SYNERGY WITH VENETOCLAX FOR THE TREATMENT OF AML

Targeting BCL-2 with the BH3-mimetic venetoclax (VEN) has emerged as a highly efficacious treatment for elderly patients with acute myeloid leukaemia (AML), in combination with either low-dose Ara-C (Wei, JCO 2019) or hypomethylating agents (Di Nardo, Lancet Oncol 2018). Long-term survival outcomes remain poor among patients with adverse risk karyotype, who often harbour mutations in the TP53 gene. Therefore, identification of effective treatment options, with TP53 independent activity, represents an area of high unmet therapeutic need. We generated TP53-null AML cell lines using CRISPR-Cas9 gene editing and screened these cell lines against 48 compounds. The histone deacetylase inhibitors (HDACi) had substantial efficacy. Additional studies performed in factor dependent myeloid (FDM) cells demonstrated cell death from HDACi to be Bax/Bak dependent, but Bim and p53 independent. RNA-sequencing, following HDACi treatment, revealed a rapid upregulation of pro-apoptotic factors, including PMAIP1 (NOXA) and BBC3 (PUMA). These results indicate that treatment with HDACi upregulates pro-apoptotic factors, independently of P53, and led to our hypothesis that HDACi could sensitise tumor cells to BH3-mimetics. We then tested the activity of HDACi in combination with BH3-mimetics targeting BCL-2 against 61 primary AML patient samples. Overall, LC50 at 48h was reduced by >2 logs in 60% of cases. Importantly, TP53 mutant cases were sensitive to this combination. Patient-derived xenograft models confirmed that this combination was tolerable and able to suppress bone marrow AML in vivo. Our data supports the clinical use of combined HDAC and BCL-2 targeting for AML and represents a promising treatment option for patients with adverse risk genomic characteristics; in particular, those who have failed VEN treatment in combination with low dose chemotherapy, and cases defective in P53.

S880 A PHASE II STUDY OF SELINEXOR PLUS CYTARABINE AND IDARUBICIN IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (AML)

Background: G is a next generation hypomethylating agent (HMA) given subcutaneously (SC) which provides prolonged in vivo exposure to its active metabolite decitabine, thus offering potential clinical advantages over current HMAs. A multicenter phase 2 study reported a 38% CR rate, and a 54% composite CR (CR+CRp+CRi) rate using 5-day regimen at 60 mg/m2/d SC Q28 days in TN-AML not eligible for IC (Kantarjian et al, Lancet Oncology 2017). This led to ASTRAL-1 study, an international phase 3 randomized trial comparing G to TC of azacitidine (AZA), decitabine (DEC) or Low Dose Ara-C (LDAC). Aims: To report ASTRAL-1 study primary analyses results. Methods: TN-AML not eligible for IC due to age ≥ 75 y or comorbidities including ECOG PS 3 were randomized 1:1 to either G (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at standard regimens. AML diagnosis and response status were assessed by an independent central pathologist blinded to randomization assignment. CR and Overall Survival (OS) were co-primary endpoints. Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were balanced across the 2 arms. Median age 76 y for both arms, patients ≥75 y were 62% vs 62.4%, PS 2–3 in 50.5% vs 50.4% (including 10.8% vs 8.8% PS 3), poor risk cytogenetics 34.3% vs 34.6%, secondary AML 36.3% vs 36.9%, WBCs ≥20x109/L 15.2% vs 14.3%, and median BM blasts 56% vs 53% for G vs TC respectively. Median follow up was 25.5 m and median number of treatment cycles was 5 for both arms. Many patients (41.6%) received ≤ 3 cycles mainly due to early death or progression with no difference between the 2 arms (42.4% on G, and 40.8% on TC). The co-primary endpoints ITT analyses showed a CR rate of 19.4% vs 17.4% for G vs TC (p = 0.48). The median, 1-y, and 2-y survival were 7.1 m, 37%, and 18% for G, and 8.4 m, 36%, and 14% for TC (Figure 1). OS HR was 0.91, 0.98, and 0.96 for G vs AZA, DEC, and LDAC respectively. Landmark survival analyses showed potential benefit of G vs TC in patients who received >3 cycles (median, 1-y, and 2-y OS 15.6 m, 60% and 29% on G vs 13 m, 52%, and 20% on TC; log-rank p value = 0.02, HR 0.78, 95% CI 0.64–0.96), and those who achieved any CR (CR, CRp, or CRi): OS HR 0.72, 95% CI 0.50–1.05. Analyses of predefined clinical, cytogenetics, and molecular genetics variables assessed by PCR (Flt-3 ITD, CEBPA, NPM1, and TP53) did not show significant differences of primary outcomes between G and TC in any subgroup except for TP53. Patients with identified baseline TP53 mutations did worse on G vs TC while those without identified TP53 mutations had a more favorable outcome on G vs TC. Both treatment arms showed overall similar safety profiles with slightly higher but not significant serious AEs incidence (81% vs 75.5%) and Grade ≥ 3 AEs (91.5% vs 87.5%) on G vs TC respectively. There was no difference in AEs leading to death (28.7% for G vs 29.8% for TC).Summary/Conclusion: The trial did not achieve its primary endpoints of statistically significant superiority of G vs TC for CR or OS. However due to the large sample size and narrow 95% CI for OS difference, the trial suggests that G is an active drug with an overall similar efficacy and safety profiles to standard therapy. Potential benefit of G vs TC was observed in patients who were able to receive adequate treatment (>3 cycles), and those who achieved any CR. The significance of TP53 mutations needs to be further explored.

S879 RESULTS OF ASTRAL‐1 STUDY, A PHASE 3 RANDOMIZED TRIAL OF GUADECITABINE (G) VS TREATMENT CHOICE (TC) IN TREATMENT NAÏVE ACUTE MYELOID LEUKEMIA (TN‐AML) NOT ELIGIBLE FOR INTENSIVE CHEMOTHERAPY (IC)

Background:G is a next generation hypomethylating agent (HMA) given subcutaneously (SC) which provides prolonged in vivo exposure to its active metabolite decitabine, thus offering potential clinical advantages over current HMAs. A multicenter phase 2 study reported a 38% CR rate, and a 54% composite CR (CR+CRp+CRi) rate using 5‐day regimen at 60 mg/m2/d SC Q28 days in TN‐AML not eligible for IC (Kantarjian et al, Lancet Oncology 2017). This led to ASTRAL‐1 study, an international phase 3 randomized trial comparing G to TC of azacitidine (AZA), decitabine (DEC) or Low Dose Ara‐C (LDAC).Aims:To report ASTRAL‐1 study primary analyses results.Methods:TN‐AML not eligible for IC due to age ≥ 75 y or comorbidities including ECOG PS 3 were randomized 1:1 to either G (60 mg/m2/d SC for 5‐days Q28 days) or a preselected TC of AZA, DEC, or LDAC at standard regimens. AML diagnosis and response status were assessed by an independent central pathologist blinded to randomization assignment. CR and Overall Survival (OS) were co‐primary endpoints.Results:815 patients were randomized to G (408) or TC (407). Preselected TCs were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were balanced across the 2 arms. Median age 76 y for both arms, patients ≥75 y were 62% vs 62.4%, PS 2–3 in 50.5% vs 50.4% (including 10.8% vs 8.8% PS 3), poor risk cytogenetics 34.3% vs 34.6%, secondary AML 36.3% vs 36.9%, WBCs ≥20x109/L 15.2% vs 14.3%, and median BM blasts 56% vs 53% for G vs TC respectively. Median follow up was 25.5 m and median number of treatment cycles was 5 for both arms. Many patients (41.6%) received ≤ 3 cycles mainly due to early death or progression with no difference between the 2 arms (42.4% on G, and 40.8% on TC). The co‐primary endpoints ITT analyses showed a CR rate of 19.4% vs 17.4% for G vs TC (p = 0.48). The median, 1‐y, and 2‐y survival were 7.1 m, 37%, and 18% for G, and 8.4 m, 36%, and 14% for TC (Figure 1). OS HR was 0.91, 0.98, and 0.96 for G vs AZA, DEC, and LDAC respectively. Landmark survival analyses showed potential benefit of G vs TC in patients who received >3 cycles (median, 1‐y, and 2‐y OS 15.6 m, 60% and 29% on G vs 13 m, 52%, and 20% on TC; log‐rank p value = 0.02, HR 0.78, 95% CI 0.64–0.96), and those who achieved any CR (CR, CRp, or CRi): OS HR 0.72, 95% CI 0.50–1.05. Analyses of predefined clinical, cytogenetics, and molecular genetics variables assessed by PCR (Flt‐3 ITD, CEBPA, NPM1, and TP53) did not show significant differences of primary outcomes between G and TC in any subgroup except for TP53. Patients with identified baseline TP53 mutations did worse on G vs TC while those without identified TP53 mutations had a more favorable outcome on G vs TC. Both treatment arms showed overall similar safety profiles with slightly higher but not significant serious AEs incidence (81% vs 75.5%) and Grade ≥ 3 AEs (91.5% vs 87.5%) on G vs TC respectively. There was no difference in AEs leading to death (28.7% for G vs 29.8% for TC).Summary/Conclusion:The trial did not achieve its primary endpoints of statistically significant superiority of G vs TC for CR or OS. However due to the large sample size and narrow 95% CI for OS difference, the trial suggests that G is an active drug with an overall similar efficacy and safety profiles to standard therapy. Potential benefit of G vs TC was observed in patients who were able to receive adequate treatment (>3 cycles), and those who achieved any CR. The significance of TP53 mutations needs to be further explored.image

S840 IMPACT OF 1ST LINE TREATMENT ON OVERALL SURVIVAL IN 1.633 PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA – A MULTINATIONAL COLLABORATIVE EFFORT COORDINATED BY THE AGMT STUDY GROUP

Background:Chronic myelomonocytic leukemia (CMML) is a rare myeloid stem cell disorder, defined by the presence of absolute monocytosis (≥1.0x109/μl), with dysplastic (MD) and proliferative (MP) features (Orazi A, IARC Press Lyon 2017, pp82–86). The only curative treatment option is allogeneic stem cell transplantation (allo‐SCT), from which most patients are excluded (Symeonidis A, BJH 2015, pp239–246). Other options including hypomethylating agents (HMA), are not curative. Only one matched‐pair analyses (Pleyer L, Leuk Res 2014, pp475–843) and one randomized clinical trial exclusively recruiting CMML patients (Wattel E, Blood 1996, pp2480–2487) have been published, with another one being underway (NCT02214407). We do not currently know whether active treatments provide overall survival (OS) benefit compared to best supportive care (BSC).Aims:To evaluate the impact of 1stline and cumulative treatment on OS.Methods:Data was collected from 7 European study groups and 2 US MDS Centers of Excellence. Data from 1633 patients was received; 67 patients were excluded (missing data); data cut‐off 10.02.19; ML and LP performed data cleaning. Assign Data Management and Statistics GmbH performed statistical analyses with SAS 9.3.Results: Median age (range) was 73 (18–104) years, male (68%), splenomegaly (25%), B‐symptoms (17%), elevated serum LDH (55%), ECOG PS 0–1 (49%), t‐CMML (7%), MP‐CMML (49%), transfusion dependent (TD) (33%), IPSS cytogenetic good risk (57%), CMML‐0 (39%), CMML‐1 (29%), CMML‐2 (19%); 33% were diagnosed in the pre‐HMA era; 71% had died at data cut‐off. In total, 42, 32, 16 and 10% of patients received 0, 1, 2, or ≥3 treatment lines, respectively; 24, 23, 6, 5 and <1% received hydroxyurea (HU), HMA, low‐dose AraC (LDAC)/ImiDs/other drugs, intensive chemotherapy (IC) or allo‐SCT as 1st line treatment, respectively.Patients receiving BSC only had significantly less adverse risk factors, as compared to patients receiving treatment: Splenomegaly (8 vs 38%, p < 0.001), B‐symptoms (4 vs 27%, p < 0.001), elevated LDH (30 vs 70%, p < 0.001), MP‐CMML (31 vs 56%, p < 0.001), ECOG PS 32 (11 vs 16%, p = 0.008), RBC‐TD (12 vs 45%, p < 0.001), PLT‐TD (3 vs 12%, p < 0.001), poor IPSS cytogenetic risk (4 vs 9%, p < 0.001), trisomy 8 (0 vs 11%, p < 0.001), complex karyotype 0 vs 5%, p < 0.001), CMML‐2 (14 vs 22%, p < 0.001).Median OS [95% CI] was 27.9 [25.6, 26.9] months as of initial diagnosis for the total cohort, and 18.9 [17.1, 20.8] months for all patients with 1stline treatment, respectively. The impact of 1st line treatment, number of treatment lines, FAB subtype and initial diagnosis timepoint on OS are summarized in Fig1. Median OS [95% CI] for patients receiving BSC only was 29.3 [24.7, 34.5] months, and median OS from diagnosis (treatment start) was 24.1 (17.6), 32.2 (21.1), 31.8 (26.5), 19.1 (11.5) and 42.0 (38.2) months for patients receiving HU, HMA, others, IC or Allo‐SCT as 1st line treatment, respectively. Patients with MP‐CMML had significantly worse OS as compared to MD‐CMML (median OS 18.7 vs 37.0 (p < 0.001) and 16.1 vs 24.5 months (p < 0.001) from diagnosis and treatment start, respectively). Patients diagnosed after approval of HMA had significantly longer OS from diagnosis as compared to those diagnosed in the pre‐HMA era (29.9 vs 24.5 months, p < 0.001).Summary/Conclusion:Allo‐SCT as 1st line treatment remains the most effective treatment approach. Patients treated with HU or IC 1st line seem to fare worst. Multiple therapy lines are not indicative of poor outcome but may help maintain OS. Biologic selection may play a role.image

Activity of venetoclax-based therapy in TP53-mutated acute myeloid leukemia.

7034 Background: Mutations in TP53 are associated with low response rates to standard therapy and poor outcomes in patients (pts) with acute myeloid leukemia (AML). Combination therapy with the BCL2 inhibitor venetoclax (VEN) has emerged as an effective treatment option for pts with AML. Methods: We reviewed pts with TP53-mutated AML treated with VEN-based therapy between 2014-2018. Mutation testing was performed using a whole-exome next-generation sequencing panel. We analyzed the characteristics of these pts, responses to therapy, and outcomes. Results: Sixty nine pts with TP53-mutated AML treated with VEN were identified, 36 (52%) in frontline & 33 (48%) in the salvage (R/R) setting (Table). The median follow up was 4.5 [0.5 - 48.5] and 8 [1 - 46.5] months for frontline & R/R pts, respectively. Karyotype was complex in 32 (88%) and 29 (88%) pts in the frontline & R/R cohorts, respectively. In the R/R cohort, the number of median prior treatments was 2 [0 – 8]. VEN was given in combination with: 1) Hypomethylating agents (HMA) (87%), 2) FLAG-Ida (3%), 3) Low dose Ara-C (4%), or 4) CPX-351 (6%). The overall response rate (ORR) was 47% & 24% in frontline and R/R pts, respectively. All 6 pts with negative minimal residual disease (MRD) achieved complete cytogenetic response after taking VEN % remain in complete remission (CR) with a median of 3.4 [1.7-4.7] months. Two pts (both R/R) underwent allogeneic stem cell transplantation. Conclusions: VEN based therapy was associated with similar ORR, but higher CR rates in TP53 mutated AML compared with HMAs alone. Larger studies with longer follow up are needed to determine the role of VEN-based therapy in this difficult subset. Patient characteristics and outcome. [Table: see text]

New FDA Approved Therapies for AML & Impact on the Older Population

New FDA Approved Therapies for AML & Impact on the Older Population

The Achievement of Complete Remission Is Associated with Improved Quality of Life in Non-Intensively Treated Patients with Acute Myeloid Leukemia: Results of the UK NCRI LI-1 Tria

Introduction: With a median age of diagnosis in the late 60s, many patients with Acute Myeloid Leukemia (AML) are deemed unsuitable for conventional curative therapy (typically anthracycline and ara-C). The decision may be based upon a patient's age, cytogenetic profile, fitness, comorbidities, or indeed a preference for less-intensive therapy. Survival in these patients has traditionally been poor with <20% typically surviving at 2 years, whether treated with regimens such as low-dose ara-C (LDAC) or hypomethylating agents. There is a clear unmet clinical need in these patients both to improve survival and also to maximise quality of life (QoL) in that period. The UK NCRI LI-1 trial has evaluated a number of novel agents, either as monotherapy or in combination with LDAC. While some agents have improved remission rates, none has so far demonstrated improved survival. However, achievement of remission may itself represent an improvement for the patient. We therefore evaluated the impact of remission on patient QoL.Methods: Within the LI-1 trial, QoL using EORTC, QLQ30C and EQ-5D3L was collected at baseline, 3, 6 and 12 months. Summary scores were calculated according to the scoring manuals for these instruments with QLQ30C summarised using the summary score obtained from the 13 individual dimensions. QLQ30C and EQ5D Visual Analogue Score (VAS) were scored from 0-100; the EQ5D utility score had a maximum of 1 (equating to perfect health). For the purposes of this analysis data from all trial arms were combined. Comparisons at individual timepoints were performed using Student's t-test, with Mixed Models Repeated Measures analysis performed to give overall differences across timepoints.Results: A total of 1653 questionnaires (baseline n=827; 3 month n=402; 6 month n=280, 12 month n=143) were received from 833 patients. On all measures, QoL was lower in patients not surviving to the next assessment point (Figure); using repeated measures analysis, patients who died before the next QoL assessment point had QLQ30C summary score 8.65 (6.68-10.61) points lower, EQ5D utility score 0.11 (0.08-0.14) points lower, and EQ5D VAS 7.73 (5.13-10.34) lower (all p<.0001). After early deaths had been excluded, there were no significant differences in baseline quality of life between those patients who entered remission and those who did not on any measure. In an analysis where patients who died within 90 days of the assessment were excluded to allow for the effect of impending mortality on QoL, patients who were in remission at a post-baseline timepoint had significantly improved QLQ30C summary score (difference 4.27 (0.06-8.48), p=0.05), and EQ5D utility score (difference 0.08 (0.02-0.14) p=0.008), but EQ5D VAS was not significantly different by remission status (-1.32 (-7.57-4.93) p=0.7). When individual timepoints were considered, point estimates favoured remission for QLQ30C summary score, and EQ5D utility score at all time points, reaching significance at 3 months on both scores, and at 6 months on the EQ5D utility score.Conclusion: This is the largest study to date of quality of life in this population. Patients who died demonstrated a downturn in QoL, measured either using QLQ30C, EQ5D Utility Score or EQ5D VAS at the assessment immediately prior to their death. In particular, early mortality was associated with lower QoL at baseline, although there was considerable overlap meaning it is unlikely that QoL alone can be used to guide treatment. Additionally, in patients achieving complete remission, both the QLQ30C and EQ5D Utility Score were significantly higher at timepoints when the patient was in remission, although differences were modest. The EQ5D VAS was not however significantly different. These data indicate that even without prolonging survival, an increase in complete remission rates may be associated with patient benefit. Clinical trials in this population should include QoL measures as a matter of course, as treatments which improve remission rates may deliver meaningful benefit in terms of QoL and health utility. Further work is required to determine whether, in light of the lack of benefit on the patient's own summary measure of their QoL, these potential improvements are perceived by patients as being worthwhile.Figure caption: Quality of Life scores at each timepoint - open boxes represent patients who die before the next assessment is due (or 18 months in the case of the 12 month assessment). [Display omitted] DisclosuresHills:Daiichi Sankyo: Consultancy, Honoraria. Russell:Jazz Pharma: Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy.

Treatment of Elderly and Unfit AML Patients with Prolonged Administration of Low Dose Cytarabine and Thioguanine Achieves High Complete Remission Rates in an Outpatient Setting

Background: The treatment of elderly or unfit patients with AML is disappointing with little improvement in the past 30 years. Studies in the 1960s (Clarkson, Cancer 1972) explored the use of prolonged low dose cytarabine (Ara-C) with frequent bone marrow monitoring until marrow hypoplasia. Treatment was given as long as needed with up to 6 weeks continuous therapy with some studies combining with synergistic thioguanine (TG). We developed a modification of the prolonged therapy concept using a 21 day course of low dose subcutaneous Ara-C with TG. Maintenance therapy with the same drugs was given for 2 yrs.Aim: To assess the safety and efficacy of low-dose sc cytarabine in combination with TG in patients with AML.Methods: Patients included (i) de novo AML, aged > 65, or unfit for intensive chemotherapy or (ii) patients >18 yrs with relapsed/refractory (R/R) AML. Patients received repeated administration of cycles of Ara-C 20mg/m2 s/c once daily with TG 40 mg/m2 PO once daily for 21 days. Bone marrow biopsy was performed within 4-7 days of completing the 21-day cycle and if blasts > 5% the next cycle was started immediately.There was no specified limit to the induction cycles which was at the investigators discretion considering patient tolerability. Once remission was achieved cycles were reduced to 14 days every 4-6 weeks for 2 years. Supportive care mandated posaconazole, ciprofloxacin, amoxycillin and pegfilgrastim 6 mg every 14 days continued until remission. Treatment was administered in an outpatient setting and Ara-C was given in the home by community nurses or local medical practitioners. The study was approved by the local hospital Human Ethics Committee and registered on the ANZ Clinical Trials Registry (ACTRN12617000231347).Results: Sixty patients were treated, Median age was 75 (range 72-94), 42 (70%) had de-novo AML and 18 (30%) R/R AML. Presenting WCC ranged from 0.8 to 185. Adverse cytogenetics were present in 40 (66%). In de-novo patients, 17 (40%) had prior haematologic disorders and 4 (10%) were treatment related. Response rates were: complete remission 40% or CR with incomplete count recovery (CRi) 28.5% in the entire cohort giving a response rate of CR+CRi of 68.5%. In the newly diagnosed group CR/CRi was 74%. Responses were also seen in the relapsed/refractory group with 5 of 18 (30%) achieving CR/CRi. The median number of cycles to achieve remission was 2 but some patients required up to 4 cycles. There were 9 (15%) deaths during induction. The median overall survival is 15 months in the de-novo group and 5 months in the relapsed/refractory group. A proportion of patients, 20-25% remain alive and in remission at 3 years post treatment. The main toxicity was as expected in this group of patients with infections predominating. No cases of severe liver toxicity were seen despite the prolonged use of thioguanine.Conclusion: Prolonged therapy with low dose Ara-C and TG can be given as an outpatient in elderly AML patients. Complete remission rates appear equal to or better than other commonly used protocols. Anthracyclines are not used. Toxicity was manageable and mainly neutropenia related but some patients never developed serious infections or required hospitalisation. We suggest that this concept of prolonged low dose cytotoxics with individual patient adjusted therapy based on bone marrow response has been overlooked since it was first proposed 40-50 years ago. Further studies are required to independently confirm these results. DisclosuresNo relevant conflicts of interest to declare.

Outcomes in Relapsed/Refractory Patients with FLT3-ITD Mutated AML Are Poor When Treated with Non-Targeted Therapy with a Potential Role for Stem Cell Transplantation: Results from the NCRI AML Trials

Introduction: Patients with Acute Myeloid Leukaemia (AML) who harbour a FLT3-ITD mutation have a worse prognosis characterised by increased early relapse. Outcomes following relapse in such patients are typically poor, not only because of earlier relapse, but also because of worse performance post-relapse than those who have the same remission duration but are FLT3-ITD WT. In a single centre retrospective study among relapsed patients, Ravandi et al [1] found a remission rate of 24% and median survival of only 13 weeks. There are therefore twin challenges in this population: first to reduce the early relapse rate, and also to develop more effective treatments post relapse. In the recent QUANTUM-R trial [2] for patients with relapsed or refractory disease, single agent quizartinib (AC220) was found to significantly improve median survival from 20.4 weeks to 27 weeks when compared to “doctor's choice” treatment (low-dose ara-C, MEC or FLAG-Ida). There is however, no directly comparable data for the population in the QUANTUM-R trial. To contextualise these results, especially given the potentially different outcomes by control treatment, we looked at outcomes in the UK NCRI AML15,16,17 trials in patients satisfying the eligibility criteria of QUANTUM-R.Methods: Patients aged 18+ in the UK NCRI AML15,16,17 trials were identified who harboured a FLT3 ITD mutation, were treated with intensive chemotherapy, and were either refractory to two courses of induction therapy, or relapsed within six months of transplant, or did not receive a prior transplant and had a remission duration of 6 months or less. Patients were grouped hierarchically as refractory, relapsed post transplant, or relapsed without prior transplant. Eligibility was established at the point a patient first became eligible for analysis. The primary outcome was overall survival (OS), measured from point of eligibility, with subsequent remission with or without count recovery as secondary outcome. A sensitivity analysis was performed excluding those who died within 21 days of eligibility to eliminate patients who might be thought of as too unwell to enter a post-relapse trial. Cox regression was used to identify prognostic factors for survival.Results: A total of 264 patients were identified (refractory n=58, relapsed post SCT n=49, relapsed without SCT n=157). The median age was 51 (range 18-84); 25% of patients were aged 60 or older; 44% were male, 95% had intermediate cytogenetics; 11% had secondary disease. Split by age, among those under 60 45 were refractory, 44 relapsed post SCT and 110 relapsed without SCT; for ages 60+ the figures were 13 vs 5 vs 47. Overall 17% of patients experienced a subsequent remission; with median survival of 86 days and 1 year OS of 13%. If deaths within 21 days were excluded, the remission rate improved to 21%; with a median survival of 133 days and 1 year OS of 16%.In multivariable Cox regression, age group HR for age>60 1.81 (1.33-2.47) p=0.0002) and route to eligibility (HR refractory vs relapsed no SCT 0.77 (0.55-1.07); relapsed post SCT vs no SCT 1.58 (1.11-2.25) p=0.003) were the only factors affecting survival - in particular sex, secondary disease, and ITD allelic burden were not significant. In the sensitivity analyses, only age was significant (HR 1.77 (1.24-2.53) p=0.001); with route to eligibility not significant (p=0.14).Among patients with post-relapse treatment information, 65% were treated intensively, 8% non-intensively, and 20% with palliation - other patients received experimental therapies. When restricting attention to those treated intensively, median survival was 130 days with 17% 1 year OS. Figures were not materially changed if early death was excluded.Of 215 patients who had not relapsed post transplant, 53 (25%) received a transplant post-eligibility. In these 56 patients, median survival was 301 days with 42% alive at one year.Conclusions: In relapsed/refractory AML, outcomes for FLT3-ITD mutated patients are generally poor and worse for older patients. Applying the eligibility criteria of QUANTUM-R and excluding early deaths gives outcomes comparable to the control group of the QUANTUM-R study. In the 25% of patients who proceeded to transplant survival was extended indicating that a treatment which can deliver patients to transplant has the potential to improve patient outcomes.

Combined BCL-2 and HDAC Targeting Has Potent and TP53 Independent Activity in AML

Background:Acute myeloid leukaemia (AML) arises from the transformation of hematopoietic stem and progenitor cells. Targeting BCL-2 with the BH3-mimetic venetoclax (VEN) has emerged as a highly efficacious treatment option for elderly patients with AML, in combination with either low-dose ara-C (LDAC) (Wei, ASH 2017) or hypomethylating agents (HMA) (Di Nardo, Lancet Oncol 2018). Long-term survival outcomes, however, remain poor among patients with adverse risk karyotype, who often harbour mutations in the TP53 gene. Identification of more effective treatment options with TP53 independent activity represents an area of high unmet therapeutic need in AML.Methods:Panobinostat (histone deacetylase inhibitor; HDACi) was obtained from Novartis, S55746 (BCL-2 inhibitor) was obtained from Servier, and venetoclax (BCL-2 inhibitor) was obtained from Selleck Chemicals. Primary AML samples were obtained from patients providing informed consent. For in vivo experiments, NOD/Rag-/-/Il2rgtm1Wjl Tg(IL3, CSF2, KITLG) (NRG-SG3) mice were used. Dosing for S55746 was 100mg/kg daily Mon-Fri and panobinostat 10mg/kg on Mon/ Wed/ Fri.Results:A panel of 22 drugs were screened for enhanced anti-leukaemic activity in combination with BH3-mimetics targeting either BCL-2 or MCL1 against 45 primary AML patient samples. This revealed the histone deacetylase inhibitor (HDACi) panobinostat to have substantially enhanced efficacy: LC50 at 48h was reduced by >2 logs when combined with VEN to target BCL-2 in 13/21 (62%) or S55746 in 19/24 (79%) cases. Targeted exome sequencing revealed adverse-risk AML, including TP53 mutant cases, to be sensitive to this combination. Studies performed in factor dependent myeloid (FDM) cells, derived from gene knockout mice, demonstrated cell death from panobinostat to be Bax/Bak dependent. CRISPR/Cas9 BIM (MV4;11) and TP53 (OCI-AML3) deleted AML cell lines confirmed panobinostat-VEN activity to be independent of these pathways. Comparison of panobinostat in combination with BCL-2 targeting showed the combination to be less affected by p53 deficiency than cytotoxic (idarubicin, ara-C) + BCL2 inhibitor combinations. Patient-derived xenograft (PDX) models confirmed that this combination was tolerable and able to rapidly suppress bone marrow AML in vivo. Exploratory CyTOF and Western blot studies in MV4;11 cells showed that panobinostat +/- BCL-2 targeting markedly suppressed levels of MYC, pSTAT5 and pERK.Conclusions:Combined targeting of HDAC and BCL-2 represents a promising, chemotherapy-free, treatment option for patients with AML, including sub-groups with adverse risk genomic characteristics. The combination may have particular relevance for patients with adverse risk AML, including cases defective in functioning TP53. [Display omitted] DisclosuresTeh:The Walter and Eliza Hall Institute of Medical Research: Other: Institutional funding for venetoclax including milestone and royalty payments.. Kraus-Berthier:servier: Employment. Kloos:Servier: Employment; Novartis: Other: Partnership. Schoumacher:Servier: Employment. Gray:The Walter and Eliza Hall Institute of Medical Research: Other: Institutional funding for venetoclax including milestone and royalty payments.. Wei:Celgene: Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Amgen: Honoraria, Other: Advisory committee, Research Funding; Pfizer: Honoraria, Other: Advisory committee; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

Clinical Responses of Glasdegibplus Low-Dose Ara-C, Azacitidine, and Decitabine Among Acute Myeloid Leukemia (AML) Patients Ineligible to Receive Intensive Chemotherapy: Comparative Effectiveness Using Indirect Treatment Comparison (ITC) Methods

OBJECTIVESCurrently there is no standard treatment option for AML patients not fit for intensive chemotherapy. Further clinical challenges include poorer prognosis associated with advanced age. AML treatments among this population have not been directly compared in clinical trials. Furthermore, naïve comparisons of results across multiple trials are subject to bias related to not accounting for within-trial differences from control. Standard (unadjusted) ITC accounts for within-trial efficacy of treatment versus control, providing a valid and robust approach to compare effectiveness between trials. Additionally, simulated treatment comparison (STC) applies ITC methodology and adjusts for differences in population baseline characteristics. Previous ITC and STC of overall survival (OS) demonstrated superiority of combination glasdegib and low-dose ARA-C (GLAS+LDAC) over azacitidine (AZA) or decitabine (DEC). This present study applied ITC and STC of clinical response outcomes between GLAS+LDAC and AZA or DEC among older AML patients unfit for intensive chemotherapy. METHODSClinical outcomes for complete remission (CR) and CR plus CR with incomplete blood count recovery (CR+CRi) were indirectly compared between Phase II trial (n=116) GLAS+LDAC individual patient data (IPD) and published Phase III AZA results (n=488), and then between GLAS+LDAC IPD and published Phase III DEC results (n=457). Based on the Decision Support Unit STC guidelines from the National Institute for Health and Care Excellence, GLAS+LDAC IPD regression (which modelled response) was separately adjusted for AZA and DEC patient baseline characteristics. Stepwise models adjusted for key patient covariates and full models adjusted for all patient covariates mutually available between trials including age, sex, having denovo AML or not, bone marrow blast percentage, Eastern Cooperative Oncology Group performance status, cytogenetic risk factors, and hemoglobin level. Between trials, CR and CR+CRi were indirectly compared by standard ITC and STC using risk ratios (RR) with 95% confidence intervals (CIs). RESULTSNaïve comparisons of CR [GLAS+LDAC (17.95%), AZA (19.50%), and DEC (15.70%)] and CR+CRi [GLAS+LDAC (24.36%), AZA (27.80%), and DEC (25.62%)] favored AZA. However, based on each of the three modelling techniques (standard ITC, STC full covariate adjustment, STC stepwise adjustment), GLAS+LDAC showed superiority over AZA.Compared with AZA, standard ITC estimated that GLAS+LDAC patients were over seven and four times as likely to reach CR [RR=7.67 (1.02, 57.87)] and CR+CRi [RR=4.33 (1.02, 18.29)], respectively.Using STC full covariate adjustment, GLAS+LDAC patients compared with AZA were over nine times as likely to reach CR [RR=9.63 (0.81, 113.95)] and over four times as likely to reach CR+CRi [RR=4.45 (1.01, 19.59)]. In the stepwise STC approach, GLAS+LDAC versus AZA similarly improved the likelihood of CR [RR=8.76 (1.13, 68.21)] and CR+CRi [RR=4.42 (1.04, 18.87)].Comparing GLAS+LDAC to DEC, standard (unadjusted) ITC found numeric but not statistically significant improvement in CR [RR=3.43 (0.44, 27.00)] and CR+CRi [RR=1.94 (0.45, 8.43)]. STC methods for GLAS+LDAC versus DEC yielded trends similar to ITC. Non-significant trends in numeric favor of GLAS+LDAC were found using both full covariate adjustment [CR, RR=4.31 (0.36, 52.32); CR+Cri, RR=2.00 (0.46, 8.73)] and stepwise adjustment [CR, RR=3.41 (0.28, 41.94); CR+CRi, RR=1.97 (0.45, 8.65)]. CONCLUSIONSIn the absence of clinical trials directly testing less intensive AML treatments, indirect comparison methods apply statistically robust techniques versus naïve comparisons to measure comparative effectiveness. Regarding the likelihood of response to treatment, GLAS+LDAC showed improvement over AZA or DEC. As previously found when comparing OS, both ITC and STC estimated GLAS+LDAC superiority over AZA for both CR and CR+CRi. For GLAS+LDAC versus DEC, ITC and STC found numerical improvement in CR and CR+CRi; however, these treatments were not statistically significant for each of the two response outcomes.Figure 1. ITC and STC results for GLAS+LDAC versus AZA or DEC [Display omitted] DisclosuresForsythe:Novartis: Consultancy. Bell:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.

Personalized and Optimized Low-Dose and Intensive Chemotherapy Treatments for Patients with Acute Myeloid Leukemia (AML)

Patients with AML have heterogeneous features, including those specific to the patient as well as those specific to the disease, such as leukemic burden and dynamic sub-clonal populations. Outside of clinical trials, few of these components are used to determine treatment. In order to move towards precision medicine, we have developed πiChemo, a computational application based on a dynamic mathematical modelling framework, using patient-, leukemia- and treatment-specific data to predict outcomes and optimize chemotherapy regimens for patients with AML.The model consists of a pharmacokinetic and pharmacodynamic (PK/PD) module that calculates the concentration and effect of Cytarabine Arabinoside (Ara-C) and Daunorubicin (DNR) in bone marrow (BM); and a population balance models (PBMs) module that describes normal populations (stem cells, progenitors, precursors) and abnormal populations (leukemic sensitive blasts (LSB) and leukemic resistant blasts (LRB)) in BM. The PBMs module also determines mature cell numbers in three lineages found in BM and peripheral blood (PB): (1) red blood cells (RBC), (2) white blood cells (WBC) and (3) lymphocytes (L). Model structure was analysed by global sensitivity analysis, which identified the most significant parameters on outcome predictions, re-estimated for each patient. The final integrated PK/PD & PBMs model has 1,295 differential equations, 8,044 algebraic equations, 9,335 variables, 25 fixed parameters and 4 degrees of freedom or variables to be optimized (Ara-C dose, Ara-C injection duration, DNR dose and DNR injection duration).Model validation, predictions and optimizations were performed using anonymised retrospective data from 28 patients with AML. The model required: (i) patient features: height, weight, age and gender, (ii) patient status: initial BM differential and PB cell counts, (iii) leukemia data: cellularity, presence of dysplasia and initial blast percentage and, (iv) treatment data: type (low-dose (LD) or intensive (DA)), dose, administration route (SC vs IV), administration mode (bolus injection vs infusion), time between injections and between cycles.The model predicted the absolute numbers of stem cells, progenitors, precursors, WBC, RBC, L, LSB and LRB in BM, and WBC, RBC, L and neutrophil count in PB during treatment for all patients. Model simulations predicted outcomes for 18 patients who achieved complete remission (7 LD & 11 DA), 4 patients who entered partial remission (2 LD & 2 DA) and 6 patients who relapsed (2 LD & 4 DA). The most remarkable results are those of prediction for BM blast percentage after each chemotherapy cycle and the PB neutrophil count for all patients. The notable fit between model predictions and daily patient data demonstrate model robustness and accuracy in the capacity to track patient-specific restaging BM and daily PB count evolution before, during and after treatment.The same patient datasets were used to apply an optimization algorithm that could maximize normal cell number and reduce leukemia burden, to personalize chemotherapy dose and administration for best outcomes. The results show that doses and administration methods vary between patients and between chemotherapy cycles for the same patient, depending on the evolution of normal and abnormal populations in BM. Low-dose continuous Ara-C infusions were more effective than rapid bolus injections, due to reduced chemotherapy effects on normal cells and subsequent quicker recovery in the normal BM compartments. RBC progenitors and precursors recovered faster than WBC and L lineages, and the recovery of normal BM cells was faster than that of normal mature cells in PB.The πiChemo tool requires only patient- and leukemia-specific initial conditions at diagnosis, easily obtained in standard clinical practice, for outcome predictions and treatment optimizations. Real-time model-fit testing and comparison of model results against daily PB cell counts would enable the re-estimation of significant parameters, increasing model accuracy and treatment effectiveness whilst therapy is ongoing. The πiChemo precision therapy tool has the potential to personalize optimal standard and novel treatments for AML in real-time. DisclosuresNo relevant conflicts of interest to declare.

An Analysis of Real Life Data Obtained from 30 Years Follow-up of Primary Myelodysplastic Syndromes (MDS) Patients Confirms a Leading Role of Stem Cell Transplantation (SCT) for Achievement of Prolonged Survival

AIM OF THE STUDY, PATIENTS AND METHODS : The data obtained from a long-term follow-up for a period of 30 years (1988-2017) were analyzed in a group of 529 patients with primary MDS and factors affecting prolonged survival were detected using different statistical methods including Kaplan Maier test and multivariate analysis. RESULTSThe results confirmed usefulness of both IPSS and IPSS-R (median survival in months for risk groups : very low - 73.7, low - 40.0, intermediate - 27.0, high - 9.0, very high - 3.5). In a subgroup of 249 patients with less advanced disease without excess of blasts, allogeneic SCT represented the most favouring treatment approach leading to estimated 10 years survival in 49.1% of patients. However, when compared to patients treated by supportive care only, a benefit in overall survival for SCT did not become significant before 5 years of follow-up (estimated 5 years survival /e5yS/: 43.3% for supportive care vs. 54.7 % for SCT). Only 2 (3.8%) out of 53 transplanted patients died later than after 5 years follow-up in comparison to 31 (20.8%) out of 149 patients on supportive care; 22 of them died on complications not directly related to MDS and a late disease progression (between 6 and 26 years after diagnosis of MDS) was observed in 9 patients. Transplantation related mortality was 30.2%, SCT at the time of disease progression (>5% of bone marrow /BM/ blasts) and prolonged (>3 months) administration of corticosteroids prior to SCT were independent adverse prognostic factors for SCT outcome (P<0.001). Special treatment approaches were effective in selected subgroups of patients : rHuEPO in patients with sEPO < 100 IU/l and ≤ 2 TU of RBC/month, lenalidomide in patients with isolated del(5q) and ATG in hypoplastic MDS with e5yS of 63.6%,75.0% and 83.3%, respectively. In 169 patients with advanced MDS ( ≥ 10% BM blasts), allogeneic SCT was the only treatment option leading to prolonged survival ( e5yS: 48,9%). The difference between efficiency of SCT and treatment with hypomethylating agents (HMA) became significant after 2 years of follow-up, estimated 3years survival was 53,2% for SCT and 26.9% for HMA, e5yS for HMA was only 3.8%. The differences were similar in a subset of patients older than 50 years of age (e5yS for SCT: 31.3%, for HMA: 3.2%). Reduction of BM blasts below 10% prior to SCT was an important factor affecting outcome of patients (median survival 62.3 months for those transplanted with < 10% BM blasts vs. 17.0 months for those with ≥ 10% BM blasts /P<0.001/). The type and intensity of conditioning did not affect outcome of SCT. Seven (14.9%) out of 47 transplanted patients relapsed, all of them within 3 years after SCT, 6 of them entered SCT with ≥ 10% BM blasts. Only 3 (6.4%) SCT patients died later than 5 years after SCT. Introduction of HMA improved short term outcome of patients not indicated for SCT ( estimated 1 year survival for HMA was 80.8% vs. 41.3% for combination chemotherapy and 52.9% for low dose ARA-C) but only minimum (4.1%) of non-transplanted patients survived 5 years. CONCLUSIONSThe analysis of long-term follow-up showed that younger patients with less advanced MDS without excess of blasts and adverse prognostic factors should be transplanted as soon as possible after diagnosis before disease progression. An advantage of more conservative approach to patients with early disease who are not indicated for SCT was confirmed by presence of a relatively high number of patients surviving 5 years with supportive care only. SCT represented the treatment of choice for advanced MDS and reduction of BM blasts prior to SCT siginficantly affected outcome of SCT. Administration of HMA significantly improved short term survival but did not affect long term outcome of patients. DisclosuresNo relevant conflicts of interest to declare.

PCN136 - Cost Effectiveness Analysis of Azacitidine in Patients with Acute Myeloid Leukemia With >30% Blasts and who are Not Candidate for Curative-Intend Chemotherapy

Azacitidine is a hypomethylating agent that has been adopted for the treatment of acute myeloid leukemia in patients who are not eligible for curative-intent chemotherapy because of their age or comorbidities. Patients with low bone marrow blast counts (<30%) seem to derive the greatest benefit from azacitidine compared to the patients with blasts > 30%. We present here a cost-effective analysis of azacitidine in patients with AML with > 30% blasts. A markow model with a 22 months time horizon divided in 35 days cycles was developed. Cost-utility of azacitidine was compared to that of conventional care regiment (CCR: which includes best supportive care, low-dose AraC and induction chemotherapy). A Canadian public health care system as a third party public payer perspective was selected. Overall survival and utilities values were derived from the AZA-AML- 001. In the case base, azacitidine has an incremental cost-effectiveness ratio of $142,932 per quality adjusted life year compared to CCR. The results were most sensitive to cost of azacitidine and then to survival with both azacitidine and CCR. The value of azacitidine for the treatment of azacitidine exceeds the commonly used willingness to pay in the Canadian health care system.

Combination therapy with azacitidine, etoposide, and cytarabine in the treatment of elderly acute myeloid leukemia patients: A single center experience.

The prognosis of acute myeloid leukemia (AML) in elderly patients is worse due to age and comorbidities. Lately, monotherapy with hypomethylating agents like azacitidine (Aza) has been used to prolong overall survival (OS) in AML patients. Herein, we present a retrospective study investigating treatment responses and OS of Aza in combination with etoposide (Eto) and cytarabine (ARA-C) in elderly. In this study, therapies and outcomes of 37 newly diagnosed AML patients, >60 years old, and ineligible for intensive chemotherapy were investigated retrospectively. Patients were grouped according to the treatments they received as follows - Group 1: low-dose conventional therapies as hydroxyurea, low-dose ARA-C, or best supportive care (n = 11); Group 2: Aza alone (n = 6); Group 3: Aza in combination with Eto and ARA-C (Aza + Eto + ARA-C, n = 20). It was found that an Aza + Eto + ARA-C combination therapy had significantly better overall response rates (P = 0.002). Combination group had significantly better OS than Group 1 (8 months vs. 1 month, P < 0.001), the difference between combination and monotherapy was not significant. The OS was also associated with age and performance status, but the difference was still statistically significant after adjustment for these factors, especially for patients with younger age and better performance. We concluded that combination therapy of Aza with Eto and ARA-C increases response rates, and prolong survival for this poor prognosed patient group. We believe that larger controlled studies investigating Aza combinations with other antileukemic drugs will contribute to the development of tolerable treatment protocols for elderly AML patients.

Experiment research of focused ultrasound combined with drug and microbubble for treatment of central nervous system leukemia

It has been shown that low frequency ultrasound in the presence of microbubble can effectively open the blood brain barrier (BBB) to allow the drugs to be delivered into the brain with an increased concentration. We aim to apply this method to increase the efficacy of Cytarabine (Ara-c) to treat central nervous system leukemia (CNSL). In the present study, we validated this ultrasound contrast agent Sonovue® targeting treatment via in vivo and in vitro experiments. The results showed that Sonovue® combined with Cytarabine could significantly inhibit K562 cell (chronic myeloid leukemia cell line) proliferation. In the animal experiments, it has been shown that high dose Ara-c chemotherapy could prevent and cure CNSL effectively and the drug concentration in the brain was much higher compared with low dose Ara-c chemotherapy group. We certified that under ultrasound exposure Sonovue® combined with low dose Cytarabine achieved an effective drug concentration in the rat brain, and brain tissue had no significant damage. Further animal experiments will be conducted to confirm these results in a leukemia animal model, considering the blood brain barrier is destroyed at different levels by leukemia cells. We hope this method will reduce the side effects of high-dose Cytarabine and improve the clinically high recurrence and poor prognosis of the central nervous system leukemia.