ALBERT

Description: Despite advances in treatment and supportive therapies, outcome of acute myeloid leukemia (AML) remains dismal with approximately 40% of younger and less than 20% of elderly patients becoming long-term survivors. Stem cell transplantation (SCT) is a well-established post-remission therapeutic option, and in both its variants, autologous (AuSCT) and allogeneic (ASCT), it is often incorporated in modern treatment programs for it may reliably improve long-term prognosis. Ten years ago we demonstrated that the levels of minimal residual disease (MRD) before autologous stem cell transplant (AuSCT), assessed at the post-consolidation time point by multiparametric flow cytometry (MFC), affected outcome (1). Moreover, we have preliminarily observed that in MRD positive (MRDpos) patients, allogeneic stem cell transplant (ASCT) attenuates the negative prognostic impact of pre-transplant MRD positivity by conferring a significant survival advantage in terms of either overall (OS) or disease free survival (DFS) (2). At variance with this, others have shown that even in the setting of ASCT, pre-transplant MRD positivity is associated with a poor prognosis regardless of the graft-versus-leukemia (GVL) effect (3). The aim of the present analysis was to evaluate, in 81 MRDpos patients submitted to ASCT (45) or AuSCT (36), the impact on clinical outcome of different MRD levels. As previously reported, counting 3.5x10-4 (0.035%) residual leukemic cells (RLCs) or more in the bone marrow (BM) upon full hematological recovery after consolidation cycle, was regarded as a condition of MRD positivity. Patients with or above 3.5x10-4 RLC were arbitrarily divided into 3 different cohorts: 1) ≥0.035%≤0.1% (13 patients, 6 ASCT and 7 AuSCT); 2) 〉0.1%≤1% (52 patients, 31 ASCT and 21 AuSCT); 3) 〉1% (16 patients, 8 ASCT and 8 AuSCT). In the category no. 2, ASCT gave a significant 5-years OS (64,9% vs 17,9%, p

Description: Multiparametric flow cytometry (MPFC) detection of minimal residual disease (MRD) represents a robust surrogate for the quality of complete remission (CR) and reliably predicts clinical outcome. In our experience, MRD detection provides prognostically relevant information when assessed at the post-consolidation time point. Ten years ago we demonstrated that the amount of MRD before autologous stem cell transplant (AuSCT) affected outcome. More recently, other authors have extended this observation to allogeneic stem cell transplant (ASCT) showing that pre-transplant MRD is a major determinant of prognosis regardless of graft-versus-leukemia (GVL) effect. The aim of our study was to evaluate, in an extended series of patients submitted to AuSCT or ASCT, the impact of a pre-transplantation MRD positive (MRDpos) or negative (MRDneg) status on overall survival (OS) and disease free survival (DFS). We analyzed 173 MRDpos and 53 MRDneg patients of whom 67 were submitted to AuSCT and 51 to ASCT. Eighty-two patients received no transplant because of age, poor performance status or insufficient stem cell harvest whereas 26, all in the MRDpos group, relapsed before transplant delivery. In the AuSCT group, before transplant, 32/67 (48%) were MRDneg and 35/67 (52%) MRDpos, with MRDneg group showing a superior OS (55% vs 20%, p=0.007). In the ASCT group, before transplant, 45/51 (88%) were MRDpos and 6/51 (12%) MRDneg. For 21 out of 51 (41%) sources of stem cells were matched unrelated donors (12) or haploidentical donors (9). In this subgroup, MRDpos and MRDneg patients shared a comparable 5-years OS (60% vs 56%, p=NS), with a 36% survival gain for those MRDpos who received ASCT as compared to AuSCT. Among MRDneg patients, no survival differences were demonstrated between those submitted to AuSCT or ASCT (55% vs 60%, p=NS). Such a lack of difference is likely due to the higher treatment related mortality (ASCT 3/6, 50% vs AuSCT 2/32, 6%, p=0.003) which counterbalanced the lower relapse rate in the ASCT group (ASCT 0/6, 0% vs AuSCT 11/32, 34%, p=NS). In conclusion, ASCT confers a significant survival advantage to MRDpos patients, attenuating the negative prognostic impact of pre-transplant MRD positivity. ASCT may expose MRDneg patients to an excess of toxicity suggesting that in these patients the allogeneic option should be postponed after a second remission. In MRDpos patients, AuSCT does not represent a valid therapeutic choice and ASCT, which should be timely delivered, also considering alternative sources of stem cells. Disclosures No relevant conflicts of interest to declare.

Description: Introduction. In a modern context of improved management of acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement at diagnosis remains an obstacle towards long-term cure. We have previously reported that flow cytometry (FCM) is better than conventional cytology (CC) in demonstrating the presence of leukemic cells in patients' (pts) cerebrospinal fluid (CSF), especially in samples with low cell counts. In the framework of the national Campus ALL program aimed at improving the management of adult ALL patients enrolled in the GIMEMA protocols, we retrospectively evaluated the incidence of occult CNS positivity and its impact on outcome in 221 adult pts with newly diagnosed ALL from 11 centers. Methods. Ninety-four patients (42%) were females and 127 (58%) males, with a median age of 44 years (range 17-80), a median white blood cell (WBC) count of 10.6x109/L (range 0.1-457). One hundred and seventy pts (77%) had B-lineage ALL. Cytogenetic/genetic data were available in 167 (75%) pts: 58 (35%) had a BCR/ABL rearrangement, 14 (8%) a complex karyotype and 11 (6%) a MLL rearrangement. Pts were treated according to the GIMEMA/NILG ALL protocols or with the Hyper-CVAD program. Ninety-eight pts underwent an allogeneic stem cell transplant (ASCT). Median follow up was 26.8 months (range 1-136.6). All CSF samples were evaluated both by CC and FCM. The presence of ≥10 clonally restricted or phenotypically abnormal events was regarded as a FCM positivity. Based on the results of CSF examination, three different categories were recognized: manifest CNS+ (CC+FCM+), occult CNS+ (CC-FCM+) and CNS- (CC-FCM-). Results. Overall, 16 (7%) pts had manifest CNS+, 39 (17%) occult CNS+ and 166 (75%) were CNS-Median age, WBC count, B/T lineage, cytogenetic/genetic features did not differ significantly between the three categories. A complete remission (CR) was achieved in 178 (80%) pts, 9 (4%) died early in induction and 104/178 (58%) experienced a relapse. The frequency of CR rate did not vary significantly across the three identified categories. In univariate analysis, the CNS status correlated significantly with the incidence of relapse (p=.004) and with censor (45 years (RR:1.45, 95% CI 1.47-2.43, p=0.04)were independently associated with a lower OS. Conclusions. Our large, multicenter CAMPUS ALL study showed that i) in ALL adult pts, FCM allows to detect occult CNS disease, even in conditions of low spinal fluid leukemic count; ii) the presence of occult CNS disease is associated with an unfavorable outcome. Further prospective studies on larger series are needed to confirm these data. Figure. Figure. Disclosures Del Principe: Gilead: Membership on an entity's Board of Directors or advisory committees. Fracchiolla:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Foà:NOVARTIS: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau.

Description: Although the therapy of acute myeloid leukemia (AML) has remarkably improved over the last 2-3 decades, two thirds of young adults still die of their disease. In elderly adults, who represent the majority of patients with AML, the results are even more unsatisfactory with less than 10% of patients being long-term survivors. Based on this, age is universally recognized as a critical prognosticator affecting outcome and therefore treatment choice. In consecutive series of adult patients with de novo AML, we have repeatedly demonstrated the prognostic role of minimal residual disease (MRD) as detected by flow cytometry. In particular, we have found that a level of MRD ≥ 3.5x10e-4 residual leukemic cells (RLC) at the end of consolidation is associated with a relapse rate of 70-80%. In the present study we evaluated whether the prognostic impact of MRD assessment after consolidation remained unaltered even in age-stratified (〈 60 and 〉 60 years) populations of adult patients with de novo AML. To this end, we analyzed 149 young (median age 46, range 18-60) and 61 elderly adults (median age 67, range 61-78). All patients under study achieved complete remission after an induction therapy of the EORTC/GIMEMA protocols AML10, LAM99P and AML12 (for patients 〈 60 years) or AML13, AML15A and AML17 (for patients 〉 60 years). The two cohorts were well balanced in terms of frequency of FLT3-ITD and NPM1 mutated cases. A lower frequency of favorable-risk karyotypes was observed in elderly versus young patients (4% vs 19%, p=0.024). Of 149 younger patients, 105 (70%) underwent stem cell transplantation (SCT) (45 allogeneic, 60 autologous) as compared to 7 (11%) in the older age group (1 allogeneic, 6 autologous), (p=

Description: Background Routine diagnostic lumbar puncture is not recommended in adult patients with acute myeloid leukemia (AML) without Central Nervous System (CNS) symptoms and little is known about the incidence of CNS involvement and its impact on survival in these patients. Furthermore, several studies have demonstrated that flow cytometry (FCM) is superior to conventional cytology (CC) for detection of CNS involvement in lymphoproliferative disorders but the role of this approach for the investigation of cerebrospinal fluid (CSF) in AML is unknown. Design and Methods The aims of our study were 1) to determine the incidence of occult/manifest CNS disease in a homogenous series of AML patients; 2) to correlate CNS disease with clinico-biologic parameters; 3) to examine the impact of CNS involvement on outcome. CSF samples were collected from 98 newly diagnosed AML patients, 62 males and 36 females, median age 53 years (range 18-75). Sixty-five and 33 patients aged 60 years, respectively.Seventy-one patients received standard and 22 high-dose-ARA-C-based regimens, 5 supportive care. All of 98 CSF samples were examined by CC whereas 90 (91%) also by FCM. CC positivity was defined as unequivocal morphologic evidence of leukemic blast in CSF and/or white blood cells count (WBCc) ≥ 5/µl with less than 10 erythrocytes/µl. A cluster of at least 10 phenotypically abnormal events was regarded as a proof of FCM positivity. Results Sixty-seven patients were CNS negative (CNS-) while thirty-one (31%) were CNS positive (CNS+). Among the last, 10 (10%) were positive on both CC and FCM (manifest CNS+) and 21 (21%) only on FCM (occult CNS+). There was an equal male/female distribution among CNS- and CNS+ patients, as well as median age (52 years, range, 20-71, vs 56 years, range, 18-75, p=NS) and WBCc(27.5 x109/L, range, 1,20-223 x109/L, vs. 11,6 x109/L, range, 0,70-315 x109/L, p= NS) were similar in both groups. Instead, higher levels of lactate dehydrogenase (LDH) were observed among CNS+ than CNS- patients (p=. 01). Forty-seven patients (48%) had monoblastic/monocytic or myelomonocytic AML and belonging to one of these categories was significantly associated with a condition of CNS positivity (55% vs 45%, P = 002). Cytogenetic/genetic data were available in 82/98 (84%). Twenty-for patients (29%), 33 (39%), 12 (14%) and 12 (14%), belonged to the category of favorable, intermediate-I, intermediate-II, and adverse karyotype, respectively. Cytogenetic/genetic characteristics did not differed significantly between CNS+ and CNS- patients. Overall, response rate was 70%, with complete remission rate being not statistically different between CNS+ and CNS- patients (69% vs 81% p= NS). Five-year DFS and OS were found to be significantly shorter in occult or manifest CNS+ patients than in those CNS- (23% vs 50% p= .03 and 19% vs 46%, p=.02, respectively)(Figure 1A and 1B). The prognostic variables achieving a statistical significance in univariate analysis (CNS status, age , WBCc, favorable vs adverse karyotype) were challenged in a multivariate model to determine to what extent they affected treatment outcome. In multivariate analysis, CNS positivity was found to be independently and significantly associated with a shorter duration of DFS.(p=.03 HR= 0.46). Age 〉50 years was found to be the only independent prognostic factor affecting OS (p=.01 HR= 2.26). Conclusion Our data suggest that incidence of CNS involvement in newly diagnosed AML pts is higher than expected. Regardless of neurologic symptoms, manifest and occult CNS positivity should always be sought at diagnosis since it may affect outcome and influence therapeutic decision. Further prospective studies on larger series are warranted to confirm this data. Figure 1 DFS and OS based on CNS status Figure 1. DFS and OS based on CNS status Disclosures Lo Coco: Teva: Consultancy, Honoraria, Speakers Bureau; Lundbeck: Honoraria, Speakers Bureau; Novartis: Consultancy; Baxalta: Consultancy; Pfizer: Consultancy.

Description: Abstract 3596 Intensive chemotherapy (IC) is associated with significant mortality and morbidity in elderly with acute myeloid leukemia (AML); particularly in patients aged ≥ 70 years, it is currently debated whether or not to deliver IC. Recent findings suggest that hypomethylating agents have encouraging clinical and biological activity in AML, with limited toxicity. Based on this background we wanted to evaluate retrospectively: 1) the efficacy of azacitidine (AZA) in elderly patients with untreated AML, diagnosed according to WHO criteria; 2) the impact of AZA on overall survival (OS) of this category of patients. For comparative purposes a historical group of matched patients who received IC was also analyzed. The AZA group included 57 patients, median age was 76 yrs (range 63–88) with 91% (52) of the patients being 70 yrs old or more, 32 were males and 25 females. Forty-two (78%) had a white blood cell count (WBCc) 〈 10×109/L, 17 (30%) a secondary AML supervening after an antecedent hematological disorder and 28 (49%) a bone marrow (BM) blast count 〈 30%. Karyotype was evaluable in 38 (67%) patients and, according to the refined Medical Research Council criteria, 27 (47%) had intermediate-risk abnormalities (25 normal karyotype) and 11 (20%) an unfavorable risk karyotype. A diagnosis of AML according to WHO classification, absence of uncontrolled infections, adequate renal and hepatic function, life expectancy longer than 4 months were the criteria to receive AZA. IC historical control group consisted in 83 patients enrolled sequentially in the AML13 and AML17 EORTC/GIMEMA protocols between 1995 and 2008. In these prospective trials patients aged 61–80 years received an induction course consisting in mitoxantrone, cytarabine (ARA-C), and etoposide (ICE) followed by 2 consolidation cycles including idarubicin, ARA-C, and etoposide (mini-ICE). In AML17 trial, the patients were also randomized to receive or not gemtuzumab ozogamicin, during induction and consolidation courses. Median age was 67 yrs (range 61–78) with 34% (28) of the patients being 70 years old or more, 47 were males and 36 females; 43 (52%) had a WBCc 〈 10×109/L and 79 (95%) a BM blast count ≥ 30%. Karyotype was evaluable in 65 (78%) patients: 52 (63%) belonged to the intermediate category (43 normal karyotype), 2 (2%) and 11 (13%) carried a favorable and unfavorable risk karyotype, respectively. Thirty-nine patients (68%) received AZA subcutaneously at the conventional dose of 75 mg/m2, the remaining 18 at a flat dose of 100 mg daily; all patients were given a schedule of 7 consecutive days per month. The median number of cycles delivered was 6 (range 1–39) and 77% of the patients received at least 4 cycles of therapy. Median follow up was 244 days (range 30–1281). Overall response rate, estimated according to the revised recommendation of the International Working Group in AML, was 17% and consisted in 11 (8%) complete remission (CR), 4 (3%) CR with incomplete blood count recovery (CRi) and 9 (6%) partial remission (PR). The chance of obtaining a response to AZA was significantly associated with a WBCc 〈 10×109/L (p=0.002). The median duration of response was 183 days (range 60–1067). Projected 2-years OS for patients on AZA treatment vs IC was 14% and 38%, respectively (p=0.008). Since the median age of the AZA group was 76 years, we broke down the analysis focusing on patients aged 70 years or more. By doing so, we observed that the projected 2-years OS for patients receiving AZA vs those receiving IC was 12% and 28%, respectively (p=0.11). Finally, among the category of patients aged ≥ 70 yrs, we extrapolated those who achieved a response with AZA (22 patients) or IC (22 patients); for these individuals, 2-years OS rate was 25% and 36%, respectively (p=0.46). In conclusion, our retrospective analysis suggests that in AML patients aged ≥ 70 yrs and with a WBCc 〈 10×109/L, AZA is as effective as IC and could be considered a valid therapeutic option. In this context, the manageable and limited toxicity of AZA will also allow for the quality of life objective to be accomplished. Patients aged 〈 70 yrs or those who, whatever the age, have a WBCc ≥ 10×109/L are likely to benefit more from IC than AZA. Controlled, randomized, clinical trials are warranted to further explore this matter and confirm our conclusions. Disclosures: No relevant conflicts of interest to declare.