Geriatric 8 can predict treatment outcomes of elderly patients with de novo AML who received low-dose chemotherapy
Abstract Abstract 3612 The incidence of Acute Myeloid Leukaemia increases with age and advanced age is a major adverse prognostic marker. Elderly patients treated with intensive chemotherapy experience high treatment-related mortality, low rates of remission and early relapse. Elderly patients are often unsuitable for intensive chemotherapy due to multiple medical comorbidities and poor risk disease, so have limited treatment options. Our centre is using a novel treatment strategy of prolonged low-dose cytarabine and thioguanine in combination with peg-filgrastim administered in the outpatient setting. Preliminary findings demonstrate a surpising efficacy for this regimen. This is an updated report on our experience. Method: A retrospective single-centre study was performed at Royal North Shore Hospital, NSW, Australia. The study includes patients who were diagnosed with AML between April 2009 and April 2012 and treated using the low-dose chemotherapy protocol. The group includes de novo AML patients as well as patients refractory to other therapies. The analysis included an oncology pharmacy audit as well as review of medical records and pathology results. Treatment consists of daily subcutaneous cytarabine 20mg/m2 and oral thioguanine 80mg for 14 to 21 day periods on monthly cycles with continued treatment for a period of 2 years. Peg-filgrastim is given concomittently with chemotherapy when patients become neutropenic. Response is assessed by bone marrow aspiration after treatment cycles. Routine supportive care is provided. Results: Between March 2009 and May 2012, a total of 21 patients (13 with de novo AML and 9 with refractory/relapsed AML) received the low dose protocol. The median patient age was 75 (range 52 to 89 years). 12 (57%) patients had treatment-related or MDS-related AML. 7 (33%) patients had poor risk cytogenetics. A CR or CRi was achieved in 13 (62%) patients. The median follow-up time is 11.9 months. Of those that achieved CR or CRi, 9 patients (43%) have remained in remission with Kaplan-Meier estimated mean leukamia-free survival of 23.3 months (14–32.5, 95%CI). The Kaplan-Meier estimated mean overall survival for the group is 22.4 months (14.3–30.5, 95%CI). 6 patients have crossed over to other treatment modalities. 5 of 7 patients with poor cytogenetics achieved CR/CRi. 3 patients with abnormal cytogenetics achieved both morphologic and cytogenetic remission. The treatment was generally well tolerated. Outpatient administration of cytarabine is managed well with assistance from community nursing. Conclusion: The results reported here provide longer follow-up time and a larger number of patients as further evidence for the efficacy of the low-dose chemotherapy protocol and its feasibility in the outpatient setting. The remission rates acheived are comparable to those reported for intensive therapy with potential benefits of reduced toxicity, lower cost, fewer hospital admissions and improved quality of life. We suggest that this low-dose protocol may be a consideration for elderly patients deemed unsuitable or ineligible for intensive chemotherapy or azacitidine. A prospective study is underway to further evaluate this protocol. Disclosures: No relevant conflicts of interest to declare.
Abstract Background : A substantial proportion of older patients with AML are considered unlikely to benefit from an intensive treatment approach. They often receive either best supportive care (BSC), low dose treatment such as Low Dose Ara-C (LDAC), or clinical trials of novel agents. In one of the few randomised studies where patients were prospectively considered likely to be unfit for intensive therapy, LDAC was superior to BSC with 18% v 1% patients achieving CR. No patients with high risk cytogenetics (Grimwade 1998), achieved CR (Burnett 2007). Laromustine (Cloretazine®) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Laromustine has previously shown clinical activity in patients with de novo AML and high risk MDS (Giles et al. JCO 2007). A confirmatory phase II study of single agent laromustine was conducted in previously untreated patients ≥ 60 years old with de novo AML, prospectively considered likely to be unfit for intensive chemotherapy. Patients had at least one poor risk factor, defined by age ≥70, performance status 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Eighty-five patients received induction therapy with 600 mg/m2 laromustine. Second induction cycles were administered in 14 patients after partial response or hematologic improvement. Eighteen patients received at least one consolidation cycle of cytarabine 400 mg/m2/day CIV for 5 days. Methods: A retrospective non-randomised comparison was performed between the 85 patients treated with laromustine, and 121 patients satisfying the same entry criteria, treated in the AML 14 trial with either BSC or LDAC. Outcomes were compared using Mantel-Haenszel and logrank methods for unadjusted comparisons, and regression methods for adjusted analyses. Results : Patients in AML14 were slightly older than those treated with laromustine (median age 75 v 73), and tended to have higher white blood cell counts; by contrast, there were significantly fewer cardiac or respiratory comorbidities reported in the AML14 population. Other important risk factors such as performance status and cytogenetics were similar between the groups. Responses overall (CR/CRp) were seen in 33% (28/85) of patients treated with laromustine, compared with 2% (1/60) and 23% (14/61) in patients treated with BSC and LDAC (p<0.0001, p=0.2, respectively). In particular, 1 patient with −5/del(5q), and 3 patients with −7/del(7q) cytogenetics experienced a CR with laromustine; patients in AML 14 with adverse cytogenetics saw no remissions. Survival was significantly improved in the laromustine group compared to BSC (1 year survival 20% v 8%, unadjusted HR 0.58 [0.40–0.84] p=0.004), and roughly comparable to that of LDAC (1 year survival 20% v 25%, HR 1.04 [0.73–1.49] p=0.8). Analyses adjusted for differences in baseline demographics, and using propensity scores gave consistent figures. Conclusions: Retrospective comparison of unrandomised data has significant limitations even though care has been taken to match for factors known to be predictive for survival. Laromustine was able to achieve a higher CR rate than LDAC or BSC, and produced remissions in groups where no remissions have previously been seen with LDAC or BSC. Laromustine gave significantly better survival than BSC, and demonstrated similar survival to LDAC.
Abstract Abstract 2157 Background: Secondary acute myeloid leukmia (AML; sAML) is a distinct disease entity among AMLs. It usually includes AMLs with previous history of myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN), and therapy-related AMLs (tAMLs) developed after exposure to leukemogenic chemotherapy or radiation therapy. It has been known that its prognosis is very poor with median survival of less than 1 year, and that allogeniec hematopoietic stem cell transplantation (HSCT) is the only curative treatment modality with improving clinical outcomes. The current study evaluated clinical characteristics, treatment outcomes in patients with sAML, the impact of cytogenetic risk group or functional activity of p-glycoprotein, related to multidrug resistance 1 (MDR1), on the treatment outcomes in sAML compared to those in de novo AML (dAML). Methods: A total of 441 consecutive AML patients diagnosed at the Samsung Medical Center, Seoul, Korea between Jan 2002 and Jun 2010 were included in this retrospective study. Out of them, 76 patients (17.2%) were sAML, among whom 39 patients (8.8%) had previous history of MDS or MPN and 37 patients (8.4%) were tAML. The overall survival (OS) and event free survival (EFS) were evaluated according to the cytogenetic risk group and the performance of HSCT, in addition to other clinical risk factors. Furthermore, P-glycoprotein assay for multidrug resistance 1 (MDR1) functional activity was performed. MDR1 functional activity was calculated by verapamil-inhibited rhodamine-123 efflux activity minus uninhibited rhodamine-123 efflux activity, and positivity was determined as equal to or over 5% MDR activity. Results: In sAML, a trend of higher frequency of unfavorable cytogenetic group was noted (23.7% in sAML vs 13.7% in dAML). The OS and EFS were significantly shorter in sAML than in dAML. Median OS duration was 12.8 months in sAML, but not reached in dAML (p<0.001), while that of EFS was 8.5 months in sAML, vs. 28.1 months in dAML (p<0.001). Confined to intermediate cytogenetic risk group, sAML group showed shorter OS than dAML group (8.0 months vs 55.1 months; p<0.001). However, no difference of OS was noted between sAML vs dAML in favorable (not reached vs not reached; p=0.4) or unfavorable cytogenetic risk groups (16.5 months vs 11.2 months; p=0.7), respectively. With respect to EFS, when confined to intermediate cytogenetic risk group, sAML group showed shorter EFS than dAML group (5.7 months vs 19.9 months; p<0.001). No difference of EFS was noted between sAML vs dAML in unfavorable cytogenetic risk groups (12.6 months vs 7.9 months; p=0.9). Of interest, in favorable cytogenetic risk group, adverse impact of sAML over dAML on EFS was suggested (15.4 months vs not reached, p=0.1). The patients receiving HSCT for sAML showed better survival compared to those not receiving HSCT for sAML (p<0.001). Among patients receiving HSCTs, OS of sAML patients was still shorter than that of dAML patients (28.3 months vs not reached, p=0.01). Even more, among patients without receiving HSCT, OS of sAML patients was significantly shorter than that of dAML patients (4.4 month vs 28.3month, p<0.001), thus still requiring further improvement of HSCT outcomes in sAML. In terms of MDR1 activity, no difference of MDR1 positivity was noted between sAML (60.6% [n=20/33]) and dAML (61.9% [n=117/189]; p=0.8). Also, mean MDR1 activity was indifferent between in sAML and dAML groups (12.5±2.9% in sAML, 13.4±1.8% in dAML, p=0.8). This finding suggested that MDR1 may not be resopnsbile for drug resistance in patients with sAML, thus other mechanism needs to be investigated for unfavorable characteristics of sAML. Conclusion: The current study suggested that 1) the patients with sAML showed a poorer outcome especially in intermediate cytogenetic risk group; 2) HSCT could improve treatment outcomes of sAML patients, but transplant outcome in sAML patients is still inferior to that in dAML patients receiving HSCT; 3) MDR1, one of important resistance mechanism of AML, may not be the case for resistance in sAML. Disclosures: No relevant conflicts of interest to declare.
Abstract Abstract 2624 The incidence of acute myeloid leukemia (AML) increases with age and outcomes for elderly patients remain poor. Furthermore, intensive induction chemotherapy is often unsuitable for elderly patients and can result in significant periods of inpatient care. Recent understanding of leukemia stem cell cycling suggests that prolonged cytotoxic exposure, e.g. >14–21 days, could provide a more effective anti-leukemic effect than the typical 5–7 days schedules during which time very few leukemic stem cells would be likely to undergo cell division. We have been using prolonged low-dose cytarabine schedules as reported 20 years ago (Hellstrom-Lindberg, Brit J Haem,1992;81:503), however we have combined this with oral thioguanine, a purine analogue that may synergize with cytarabine. Concomitant filgrastim or pegfilgrastim was given to minimize neutropenia and for its possible synergizing anti-leukemic effect when combined with cytotoxic agents. Encouraging experience with this schedule in a few relapsed/refractory elderly AML patients prompted us to use this strategy in elderly de-novo patients unsuitable for standard induction. Surprisingly good results prompted us to report our preliminary experience with this novel strategy. This report is a retrospective, single-center analysis of outcomes in elderly patients with AML managed as outpatients in an ambulatory care day unit. Between April 2009 and March 2011, 14 patients with either relapsed/refractory AML (n=5) or de novo AML (n=9) unsuitable for intensive therapy were treated using prolonged, low-dose cytarabine 20mg/m2/day subcutaneously and thioguanine 80mg/day orally. Treatment was given for 21 days followed by a 14 day break after which the schedule was repeated until remission. After obtaining remission, patients received a maintenance schedule consisting of 14 days on treatment with rest periods increasing from 14 to 28 days according to tolerance and time on therapy, with an intention to continue maintenance for 2 years. All patients received the treatment in an ambulatory care unit with supportive care including filgrastim or pegfilgrastim, blood and platelet transfusion as required, regular clinical review and prophylactic antibiotics and antifungal agents. Patient age ranged from 52 to 89 years (median 75y). All patients had intermediate or poor risk cytogenetics. A morphologic remission according to bone marrow aspirate was obtained in 8 patients (57.1%), with relapse seen in 1 patient at 2.6 months follow-up. Remission was maintained in 7 patients (50%) with follow-up ranging from 4.7 to 26.6 months (median 9.7 months), including 1 patient who was refractory to standard first and second-line induction chemotherapy. Refractoriness to treatment occurred in 5 patients (35.7%). Mortality relating to disease progression occurred in 3 patients (21.4%) and 1 patient died secondary to infection. All patients developed grade 3/4 neutropenia and thrombocytopenia but severe mucositis was not seen. The infection rate was low and hospital admission was uncommon. Nausea was common but manageable and significant liver toxicity was not observed. This study demonstrates that effective management of AML in elderly patients can be achieved in the outpatient setting. The data suggests a surprising efficacy for this strategy, with a remission rate comparable to that reported using standard induction chemotherapy but with a potentially favorable toxicity profile. A prospective study is now underway to further evaluate this protocol. Disclosures: Arthur: AMGEN: Honoraria.
Abstract VNP40101M (Cloretazine®) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Data from a previously reported phase II multi-center single agent study (CLI-033) in patients ≥60 years old with newly diagnosed AML or high risk MDS showed an overall response rate of 31% after VNP40101M induction (Giles, 2007). Subgroup analysis showed significant activity in 54 elderly patients with de novo AML with 24 patients (45%) achieving a complete response (CR) or CRp (CI: 30.9;58.6). Subsequently a confirmatory phase II study of single agent VNP40101M was conducted in elderly patients with poor risk de novo AML (CLI-043). Patients received induction therapy with 600 mg/m2 VNP40101M as a 60-minute infusion on day 1. A second induction cycle could be administered to patients with a partial response or hematologic improvement. Patients with CR or CRp received consolidation with cytarabine 400mg/m2/day CIV for 5 days. Patients were eligible if they were ≥60 yrs and had one of the following poor risk factors: age ≥70 yrs, ECOG PS 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Patients with a prior diagnosis of MDS or favorable cytogenetics were excluded. A 2-stage optimal minimax design was employed with a target response rate of 35%. The study proceeded to the 2nd stage when >8 responses were confirmed. At least 22 responses in 77 patients are required to accept the hypothesis of a 35% target response rate. Eighty-five patients were treated as of August 14, 2007. Median age (range): 73 yrs (61– 86 y); male: 59%. The majority of patients (79%) had 2 or more risk factors. The most common risk factors were age ≥70 (78%), unfavorable cytogenetics (45%, half with complex karyotype), ECOG PS 2 (41%) and cardiac dysfunction (38%). Thirty VNP40101M-related serious adverse events (SAE) have been reported to date in 22 of 85 patients. The most common SAEs are myelosuppression or complications thereof (pancytopenia (10%), infection (47%)). Non-hematologic SAEs consist of the following gr.3 events: left ventricular dysfunction (1), transaminitis (1), confusion (1), seizure (1), rash (1), hypokalemia (1), weakness (1) and hypoxia/pleural effusion (2). Seventy-nine patients are currently evaluable for early death analysis. Of these, 12 patients (15%) and 16 patients (20%) died at ≤30 days and ≤42 days from first induction therapy, respectively. The most common causes of induction death were progression of disease (6) and infection (6). Other causes were tumor lysis syndrome (1), acute renal failure (1), and respiratory failure (2). A confirmatory Phase II single-agent study of VNP40101M shows anti-leukemia activity in elderly patients with de novo AML and multiple poor-risk features. Major toxicities include myelosuppression. Severe drug-related non-hematological toxicity is uncommon. Patients continue in follow up, and additional safety and response data is pending.
Abstract The aim was to determine the predictive value of karyotype in 132 patients ≥65 years in a series of 404 cases with de novo AML. 61 females and 71 males with median age 71 years (65–91). FAB subtype were: 14 (10.6%) M0, 21 M1, 37 M2, 14 (10.6%) M3, 16 M4 (only one M4Eo), 21 M5, 8 M6, 1 M7 (vs 4% M0, 25,7% M3 in <65 years p=0.004). The prognostic value of clinical, pathologic and cytogenetic factors was evaluated by Kaplan-Meier estimate and compared by log-rank, Breslow and Tarone test, for overall survival (OS) and continuous complete remission (CCR). Chi-square analysis for comparisons of remission rates were. The impact of prognostic factors was studied using Cox regression model. p≤0.01, M=median, m=months. Cytogenetic abnormalities were seen in 62.1% of cases including: 32 (24,2%) complex abnormalities, 18 of them with >5 aberrations (vs 7,3% in <65 years p<0.001), twelve (9,1%) t(15;17), 7 trisomy 8, 3 trisomy 21, 3 trisomy 11, 3 del(7q), 2 t(8;21), 2 t(9;22), 2 del(5q), two 3q21q26 rearrangement, one inv h (16), one 11q rearrangement, one monosomy 7 and 8 with other abnormalities. One normal karyotype had FLT3 and NPM1 mutations. Karyotype was classified by SWOG and MRC classification. 21.2% showed trilineage myelodysplasia (TMDS) (vs 10% in <65 years p=0.003). 80 patients received intensive chemotherapy (11 with AML-M3 also received ATRA). Only 53.8%(43/80) achieved CR(vs 78 % in <65 years p<0.001) and this was lowest in complex karyotype (13.3%).The 5-year OS and CCR probability was: 6,2% (M=2.9 m) and 13,8% (M=1.5 m).The longest OS was for t(15;17) with 41,7% surviving at 5 years (M=10.0 m); normal karyotypes survive 2,28% and other abnormalities had very short survival (p<0.0001). Patients with complex karyotypes survive 0% at 17 months and all had relapsed at 5,3. Probability of relapse in t (15;17) was 51.31 % at 5 years (M 12,30), and this was higher in normal karyotype (93,4%), trisomy 8 (100%) and other abnormalities (100%) (p=0.0008). A longer OS was seen in patients with leucocytes ≤ 10×109/L (p=0.0006), subtype M3 (p=0.009)/t(15;17) (p<0.0001) who received ATRA (p=0.0001) and without TMDS (p=0.0043). FAB subtypes distinct of M3 (p=0.0046), age adapted chemotherapy treatment (p=0.0004) and complex karyotypes (p=0.0007) were unfavourable prognostic factors for CCR. The survival of cytogenetic groups according SWOG and MCR was significantly different (p=0.0005, p =0.0021 for OS; p<0.0001, p=0.0001 for CCR). Multivariate analysis showed that karyotype, TMDS and leucocytes are independent factor for OS. The higher risk of dead is for unfavourable (OR 2.94 p=0,008) and unknown (OR 2,52 p=0,03) cytogenetic SWOG groups. Only unfavourable SWOG karyotypes and chemotherapy without ATRA are independent factor for relapse risk. The elderly novo AML has a similar clinical-biological profile that the secondary AML, because of high frequency in undifferentiated subtypes, frequent TMDS, high percentage of complex abnormalities and poor CR, CCR and OS. This matter suggest that their aetiology is probably a lengthy exposure to environmental toxins. That’s the reason because it’s essential the cytogenetic study to decide induction chemotherapy or palliative support. Elderly patients with de novo AML which shown unfavourable SWOG abnormalities, failure to achieve CR, relapse promptly and have short survival. In this age group, today, only therapy designed to target specific molecular rearrangements has good prognostic.
Abstract Abstract 4341 Aim Acute myeloid leukemia (AML) incidence increases with age, yet treatment of elderly patients has reduced efficacy compared with younger patients and is often poorly tolerated. We aimed to determine the outcome of elderly patients with de novo AML treated with intensive chemotherapy with or without allogeneic stem cell transplantation. Methods All patients with de novo AML (excluding APML) aged ≥ 60 years treated with induction chemotherapy at our institutions between February 1999 and July 2011 were retrospectively identified from institutional databases. Information on cytogenetic risk, chemotherapy protocols, response to therapy, disease-free survival (DFS), and overall survival (OS) were then determined retrospectively by review of individual medical records. Survival analyses were calculated by the Kaplan-Meier method and compared using the log-rank test. Results Intensive induction chemotherapy was received by 128 patients (57.7% of elderly patients diagnosed with de novo AML), including 105 patients (82.0%) treated with standard-dose cytarabine (SDAC) (100mg/m2 days 1–7) and 14 patients (10.9%) treated with high-dose cytarabine (HiDAC) (≥ 2000mg/m2/day for at least 4 days). The median age of this cohort was 67 years (range 60–83 years). Based on cytogenetic profile, 3.1% of patients had favourable, 54.7% had intermediate, and 27.3% had adverse-risk disease. Responses to 1–2 cycles of induction chemotherapy were complete remission (CR1) in 73.4% of patients, refractory disease in 14.8%, and induction death in 11.7%. 83.0% of patients who achieved CR1 received consolidation chemotherapy, incorporating SDAC in 74.4% and HiDAC in 23.1%. At a median follow-up of 22 months for survivors, intensive induction chemotherapy resulted in a median DFS of 11 months, and median OS of 13 months (Figure 1); 3 year OS for the entire cohort was 27.9%, with favourable, intermediate, and adverse risk groups having 50.0%, 31.6%, and 12.6% 3 year OS, respectively. Thirteen patients (10.2%) proceeded to allogeneic transplantation in CR1; median age was 63 years (range 60–66 years). These patients did not reach median DFS or OS; 11 (84.6%) remain alive and disease-free at a median follow-up of 27 months post-transplant (Figure 2). The elderly patients were compared to the cohort of younger patients (15–59 years) with de novo AML treated over the same time period. This analysis found that the older patients had a higher rate of adverse-risk cytogenetics (27.3% vs 16.1%, respectively; P = 0.02), refractory disease (14.8% vs 3.3%, respectively; P = 0.0002) and induction death (11.7% vs 4.7%, respectively; P = 0.03), and lower CR1 rate (73.4% vs 91.9%, respectively; P < 0.0001), DFS (median DFS 11 months vs 25 months, respectively; P = 0.0009) and OS (median OS 13 months vs 78 months, respectively; P < 0.0001). Conclusions Despite intensive chemotherapy, the majority of patients ≥ 60 years with AML have poor outcomes, with high rates of induction death, refractory disease, and relapsed AML. However, a proportion of these patients experience long-term survival. While patients selected for allogeneic transplantation in CR1 have high DFS and OS, only a minority of patients receive this therapy. Disclosures: No relevant conflicts of interest to declare.
Abstract Backgrounds: Acute myeloid leukemia (AML) is a heterogeneous disease whose onset involves a variety of chromosomal abnormalities and genetic mutations. To improve the outcome of AML treatment, it is very important to establish a prognosis from cytogenetic and genetic analysis and provide accordingly differentiated treatment. However, the treatment strategy has not been clear in elderly patients with AML due to intolerance of treatment and its adverse characteristics such as concomitant comorbidity and poor performance status. To clarify the prognostic impact of genetic abnormalities in elderly AML, we conducted a comprehensive analysis of recurrently mutated 28 genes in AML. Method: We retrospectively analyzed newly diagnosed 128 AML patients excluding M3 who were more than 65 years old at Nippon Medical School Hospital or its associated facilities between 1990 and 2014. Mutation analyses were performed by direct sequence analysis, Mutation Biased PCR, direct sequence analysis, and the next-generation sequencer Ion PGMTM. Results: Average age was 70.5 years (65-91years). The patients from 65 years old to 74 years old (early elderly) were 92 (71.9%)cases, the patients 75 years or older (late elderly) were 36 (28.1%)cases. Chromosomal analysis according to the prognostic risk classification of the Eastern Cooperative Oncology Group (ECOG) classified into 14 of the favorable cytogenetic risk group (10.9%), 80 of the intermediate cytogenetic risk group (62.5%), and 24 of the poor cytogenetic risk group (18.8%). Gene mutations were observed in 112 cases (87.5%). The most frequent gene mutations were NPM1 (89 cases/28.9%), FLT3/ITD (25 cases/19.5%), TET2 (20 cases/15.6%), and DNMT3A (19 cases/14.8%). CEBPA double mutation was detected at low frequency in elderly patients (younger patients: 15/311 (4.8%) vs elderly patients: 1/128 (0.8%)). There were no significant differences in gene mutations between early elderly and late elderly patients). Of 102 patients who received induction therapy, 52 patients (51.0%) achieved first hematological complete remission (CR), but primary refractory and early death were observed in 50 patients (49.0%). There was no significant difference in CR rate between the two groups in the early elderly patients and late elderly patients (early elderly: 53.8% vs late elderly: 41.7%. p= 0.354). In addition, there was no difference in CR rate in the standard chemotherapy and low dose chemotherapy group (standard chemotherapy: 48.7% vs low dose chemotherapy: 38.9%. p= 0.601). Median overall survival (OS) was 287days, OS at 3years was 35.9%. Prognostic stratification was possible for CR rate on the chromosomal classification (favorable cytogenetic risk 92.9%, intermediate cytogenetic risk 50.0%, poor cytogenetic risk 12.5%, p< 0.001). For total cohort of patients, rates of relapse free survival (RFS) at 3 years are significantly lower in patients with FLT3ITD (p=0.006) and TP53 abnormality (p< 0.001) compared to without it. Rates of overall survival (OS) at 3 years are significantly lower in patients with DNMT3A mutation (p=0.004), FLT3ITD (p=0.003), and TP53 abnormality compared to without it. Also late elderly patients (p=0.010) and high white blood cell count (≥ 20,000/μl) (p=0.023) were powerful factors for unfavorable prognosis. In stratified analysis of FLT3ITD-negative cases aged below 75 years with intermediate cytogenetic prognosis, TP53 abnormality was associated with unfavorable prognosis (RFS: p=0.062, OS: p< 0.001). Finally multivariate analysis demonstrated that FLT3ITD (p=0.014) and TP53 abnormality (p=0.015) were an independent poor prognostic factor for RFS, and poor cytogenetic risk (p=0.002), Flt3ITD (p=0.014), TP53 abnormality (p=0.015), and DNMT3A mutation (p=0.001) were an independent poor prognostic factor for OS. Conclusions: Our results suggest that the genetic abnormalities have a prognostic importance in elderly patients, as well as younger patients with AML. FLT3ITD mutation is an important factor for unfavorable prognosis, but going forward TP53 mutation may also serve as a clinically important gene mutation marker in elderly patients with AML. Disclosures No relevant conflicts of interest to declare.
Abstract Abstract 3621 Acute myeloid leukemia (AML) has a dismal prognosis in elderly population because of intrinsic chemoresistance and frailty of patients. High-dose Cytarabine (HiDAC) in induction therapy did not improve the CR in younger AML patients and recent guidelines discourage this approach in elderly because of high extrahematological toxicity. Amifostine showed to selectively protect normal Hemopoietic progenitors from chemotherapy and we previously successfully tested the feasibility of an induction schedule including HiDAC (3 g/m2 days 1,2,3,4,5), Idarubicin 40mg/m2 on day 3 preceeded by Amifostine (740 mg/m2). We designed a prospective observational study including the same induction schedule, aimed to evaluate the outcome (CR rate, OS and EFS) of a larger population of fit AML elderly patients. Fit patients, selected according the Multidimensional Geriatric Assessment, received 1–2 courses and underwent PBSC mobilization after consolidation. Patients who collected ≥3×10e6CD34+/kg received ASCT, while poor mobilizers were considered for alternative regimen including Allogeneic transplantation from an HLA-matched sibling, chemotherapy (CHT) or Gemtuzumab-Ozogamicin (GO). We registered 156 consecutive patients, aged >59 yrs; 56 were unfit for intensive induction chemotherapy and received only palliative care; 100 (64%) fulfilled the inclusion criteria of our protocol: 91 received the scheduled induction regimen, while 9 received a Fludarabine regimen because of reduced cardiac function. These patients were not included in the response evaluation, but were considered for the outcome (according to the ITT criteria). Patients' characteristics are shown in table 1. CR was achieved in 73.6% of patients; multivariate analysis showed secondary disease as predictive of poor response, with a 65% CR rate (RR = 2.54; 95% CI: 1–6.45; p= 0.05) vs 83% in primary disease. Induction death rate was 5% and not influenced by any prognostic factors. The median time to achieve neutrophil>500× 106/L and platelet>20,000×106/L, were 17 and 19 days (ranges of 9–29 and 3–47 respectively). The main extrahematological toxicity were grade 3–4 mucositis (13%) and hepatic toxicity (9%). We also observed 66 grade III-IV febrile neutropenia/infectious episodes. Overall 65 patients received a first consolidation course and mobilization for PBSC harvest; we observed 6 TRD, a 3% of grade 3–4 hepatic and neurological toxicity and 6% of grade 3–4 cardiac toxicity; in 4 patients we observed rapid early leukemia relapse; overall 55 patients were eligible for post-consolidation therapy. Only 24 patients achieved a succesfull PBSC mobilization and ASCT was performed in 21 (2 relapsed and died before ASCT and 1 received Allogeneic Transplant). Thirty-one patients were poor mobilizers: 3 received Allogeneic Transplant, 3 CHT, 5 stopped treatment because of persistent aplasia and 20 received low-dose GO (3 mg/m2 monthly for 3 times and every 3 months after; median: 3, range 3–6 courses). With a median follow-up of 70 months (range 24–124) 21 patients are alive (19 in continuous CR), 6 after ASCT, 13 after GO, 1 after CHT. The 8 yrs Overall Survival (OS), Disease Free Survival (DFS) and Event Free Survival (EFS) are respectively 20.4% (median: 11.4 months), 24,3% (median 8.8 months) and 17,7% (median: 8.8 months). Secondary AML and hyperleukocytosis are factors predictive of OS at the multivariate analysis. Patients with secondary disease have a 1.59 RR to die with a 9.9% 8 yrs OS vs 27.1% of patients with primary AML. Patients with WBC ≥50,000/mcl had a 2.2 RR to die with a 0% OS at 33 months vs 23.2% 8 yrs OS in patients with WBC<50,000/mcl. In conclusion our novel intensive induction regimen for fit AML patients is safe and effective both in term of CR rate and outcome. The ASCT feasibility was confirmed to be poor in this setting (21%) while GO low-dose seems to be feasible and promising. Finally our prospective study in 156 elderly AML patients describes the real-life outcome of this setting, suggesting that two thirds of AML elderly patients are fit for intensive treatment and that long term OS can be achieved in a relevant proportion of patient with de novo AML. Table 1: Patients' characteristics N (%) Gender: Male 58 Female 42 Karyotype: Favorable 5 (5.7) Intermediate 49 (56.3) Unfavorable 33 (38) De novo AML 61 Secondary AML 39 Age: <70 yrs 55 >69 yrs 45 WBC count: <50,000/mcl 89 ≥50,000/mcl 11 PS: 0–2 96 3 4 FDI 0 60 >0 40 Sorror 0–2 62 (74.7) >2 21 (25.3) Disclosures: No relevant conflicts of interest to declare.
Abstract Introduction Azacitidine (AZA) is a promising agent for higher risk myelodysplastic syndrome (MDS), but it does not prevent disease progression as a single agent in most cases of AML. MDS is a heterogeneous disease not only pathologically but also clinically. Some cases have progressive clinical stages and disease-related symptoms (fever, edema and effusion), so called aggressive MDS (aMDS). Since some aMDS cases failed single agent AZA treatment, we considered combination chemotherapy with AZA for aMDS. Here we report the use of low dose of AraC followed by AZA for aggressive MDS in a pilot study. Method We evaluated eligible 37 MDS, CMML, overt AML and de novo AML patients from March, 2011 to June, 2013. All MDS and CMML patients had disease-related symptoms or disease progression in the previous 3 months. Twenty-two patients (median age 73 years, range 55-87) were treated with single agent AZA (sAZA) 75 mg/m2/day i.v. 1∼5, 8, 9 days every four weeks. For low dose AraC combination therapy, AraC 10mg/m2xtwice/day s.c. for 1∼5 days and Aclarubicin Hydrochloride (Aclacinon) 20 mg/m2/day i.v. for 1, 2days (CA therapy) was followed by AZA 75 mg/m2/day iv for 7 days (8∼12, 15, 16). Fifteen patients (median age 74 years, range 62∼85) received sAZA after 1 cycle of CA followed by AZA (CA-AZA). Responses were scored according to IWG 2006 criteria for MDS. Results Diagnosis was RCMD n=3, RAEB1 n=4, RAEB2 n=10, CMML n=1, overt AML n=3, de novo AML n=1 for sAZA-treated group and RCMD n=1, RAEB1 n=2, RAEB2 n=6, CMML n=2, overt AML n=4 for CA-AZA-treated group. IPSS-R risk category was intermediate n=6, high n=2, very high n=8 for sAZA-treated group and intermediate n=1, high n=1, very high n=7 for CA-AZA-treated group. Overall response rate was 27.2% and 80% for sAZA- and CA-AZA-treated groups, respectively. 50% of progressive disease and 9% (n=2) of failure (death) were observed in sAZA group at 1 to 3 courses of AZA. One year overall survival (1yOS) was 38.1% and 90.9% in sAZA- and CA-AZA-treated groups, respectively, without significant difference (P=0.11). In overt AML, CA-AZA treatment resulted in a significant difference in 1yOS (0% vs. 100%, P=0.02). In the higher risk groups (High, Very high and overt AML) and the poor and very poor karyotype groups, CA-AZA treatment showed a trend towards improved 1yOS (P=0.07, P=0.11) compared with sAZA. Adverse events were similar between two treatment groups. Conclusions For aMDS, sAZA therapy was not sufficient to control disease progression. To suppress disease progression and to improve the efficacy of AZA, we used CA prior to AZA maintenance therapy. In one case with overt AML and in two cases of aggressive type CMML, CA with AZA maintenance successfully prevented disease progression for almost two years. These three cases are now being treated every two or three months with sAZA as maintenance therapy. AZA combination therapy with AraC have been examined in in vitro and in vivo studies (R.L. Momparler Cancer Res. 1975;35, G.L. Neil Cancer Res. 1976;36). Our low dose and short term chemotherapy (CA) was safely and effectively combined with AZA for older aMDS patients. We are planning a clinical study to further evaluate CA-AZA therapy in a larger cohort of patients. Disclosures: Hirai: NIPPON SHINYAKU CO.,LTD: Speakers Bureau. Hino:NIPPON SHINYAKU CO.,LTD: Research Funding.