ALBERT

Description: Introduction With standard intensive induction regimens, up to 80% of Acute Myeloid leukemia (AML) patients can achieve complete remission (CR). Several evidences demonstrated that the persistence of detectable disease (MRD) assessed with highly sensitive techniques such as Multicolor-Flow-Cytometry (MFC) and PCR based molecular analysis, retains a prognostic value among patients achieving morphological remission (Walter RB, 2015; Araki D et al, 2016, Zhou Y et al, 2016). The aim of the present study was to retrospectively evaluate the prognostic impact of MRD in a cohort of uniformly treated AML patients. One hundred and ten consecutive AML patients who had been treated in our center between January 2004 and December 2014 were retrospectively analyzed. All patients had received a fludarabine-containing induction (FLAI-5) and received second cycle and further consolidation therapy according to our published strategy (Guolo F, 2016). Median age was 47 years (range 17-61). Median follow up was 59 months. Patients features are summarized in Table I. MRD assessment was performed through 4-colour MFC analysis (MFC-MRD)and through WT1-gene expression analysis, as previously described (Guolo F, 2016). Three different MRD time-points (TP)were considered: TP1, after induction I; TP2, after induction II; TP3, after consolidation therapy for patients who did not undergo HSCT and at HSCT for patients who underwent HSCT. Relapse-free survival (RFS) was calculated from the time of diagnosis until last follow-up or documented leukemic relapse. CR rate after 1st and 2ndinduction was 82.7 and 85.5%, respectively, whereas 30 and 60 days mortality was 6.4% and 8.2%, respectively. Overall, patients showed MRD reduction from TP1 to TP2. Detailed MRD negativity rates are provided in table II. MRD clearance probability was significantly influenced only by ELN risk group and Karyotype (p

Description: Backgrounds and aims Prevention and prompt treatment of invasive fungal infections (IFI) in acute myeloid leukemia (AML) patients can improve overall survival not only by reducing infection-related mortality but also allowing to comply induction regimens on time. The aim of the study was to estimate efficacy and feasibility of primary antifungal prophylaxis with posaconazole (PSZ) in patients affected by acute myeloid leukemia receiving front-line chemotherapy and to optimize our clinical practice. Materials and methods From January 2013 to May 2014, 28 AML patients undergoing intensive chemotherapy and potentially eligible for bone marrow transplantation in our institute received PSZ prophylaxis for IFI. All patients received a fludarabine, cytarabine and idarubicin containing regimen as first line treatment. We performed a retrospective analysis to evaluate the efficacy and feasibility of PSZ prophylaxis; to detect factors affecting drug exposure we analyzed each period of hospitalization as a single independent event. PSZ was given at the standard dose of 200 mg for 3 times/day, concurrently with a fat snack or with at least 100 ml of an acidic drink. Because of unpredictable absorption rates PSZ serum levels (TDM) were assessed routinely according to a validated high-performance liquid chromato-graphic (HPLC) method as described. A comparison with an historical cohort with similar features who had received fluconazole (FLC) prophylaxis was made. The use of empirical or targeted antifungal therapies and the incidence of IFI were compared. Results and discussion PSZ showed a good tolerability profile with no serious adverse events clearly related to prophylaxis occurring. A median number of 2 TDM for each period of hospitalization was performed (range 2-5). The achievement of a plasmatic PSZ concentration 〉 0,7 mcg/mL is considered optimal for prophylaxis efficacy; in 30/47 (64%) episodes of hospitalization and treatment, with at least two TDM, the threshold PSZ serum concentration was reached, with stable plasmatic levels. Median PSZ plasmatic value at first assessment was 0.89 mcg/mL (range 0.1-3.3). Table 1 summarizes patients features and factors that might affect PSZ plasma concentrations. The strongest negative factors affecting PSZ absorption are the discontinuation of prophylaxis and the concomitant assumption of proton pump inhibitors since their negative impact is shown both in univariate and multivariate analysis. No proven IFI were observed in our cohort with only one probable IFI occurring in a patient with refractory disease who did not reach adequate serum PSZ concentration. Table 2 summarizes the comparison with our historical cohort. The risk of experiencing IFI (proven or probable) during AML treatment is significantly higher in the FLC cohort (HR: 9.488, CI: 1,404 - 64,122). Moreover, the use of targeted or empirical antifungal therapies had been significantly higher in FLC cohort (HR: 2.7, CI: 1,212 - 6,050). Our clinical experience confirms the utility and cost-effectiveness of primary prophylaxis with PSZ in AML patients receiving intensive treatment. Table 1: Factors affecting PSZ serum concentration Reached plasmatic concentration threshold (%) p(univariate) p(multivariate) All Hospitalizations 30/47 (64) - - Sex Male 17/23 (74) 0.227 - Female 13/24 (54) Disease Status Active Disease 13/27 (57) 0.014 0.156 Complete Response 17/20 (85) Mucositis None or Grade 1 25/32 (78) 0.008 0.228 Grade 〉=2 5/15 (33) Age 45 years 18/26 (69) Concomitant PPI No 28/36 (78) 0.001 0.000 Yes 2/11 (18) Concomitant Ranitidine No 26/42 (62) 0.640 - No 4/5 (80) Concomitant Levofloxacine prophylaxis Yes 27/39 (69) 0.118 0.042 No 3/8 (38) Prophylaxis Discontinuation Never 27/36 (75) 0.009 0.003 At least for 2 dd 3/11 (27) Infectious Complications None 8/11 (73) 0.722 - At least one episode 22/36 (61) PSZ Assumption with Fat snack 5/11 (46) 0.153 0.150 Acidic drink 25/35 (71) Table 2: Historical comparison FCZ PSZ p All hospitalizations 54 47 - Median age (range) 47 (17-72) 47 (19-68) 0.560 Median ANC

Description: Background: Allogeneic bone marrow transplantation (BMT) offers the greatest chance of cure for most patients affected by acute myeloid leukemia (AML). Persistence of disease or high levels of pre BMT minimal residual disease (MRD) have been reported to predict disease relapse after BMT. WT1 expression levels and multicolor flow cytometry (MFC) are widely used as markers of MRD. We recently reported that combined evaluation of MRD by WT1 and MFC after induction therapy can predict relapse risk in AML patients. Aims: The aim of the present study was to apply the same MRD assessment in pre BMT setting to evaluate its reliability in predicting relapse. Methods: We retrospectively analyzed BMT outcome of 66 AML patients with both WT1-based and MFC-based MRD evaluation on bone marrow samples before transplant. Median age at transplant was 44 years. Forty-one were transplanted in first and twenty-five in second or subsequent complete remission. Induction therapies included fludarabine-containing regimens or standard ara-C and daunorubicin schedule (3+7). Median follow-up was 44 months (range 0-119 months); pre-transplantation evaluations were performed at a median of one month before transplant (range 1-3). Disease-free survival (DFS) was calculated from the time of transplantation until last follow-up or documented leukemic relapse. Overall survival was calculated from the time of transplantation to the last follow-up or death for any cause. All causes of death not directly due to relapse or progression of leukemia were considered as non-relapse mortality. A positive MFC MRD was defined by the presence of no less than 25 clustered leukemic cells /105 total events (threshold of 2.5x10-4 residual leukemic cells) at four-color flow-cytometry. Real-time PCR for WT1 was performed on DNA Engine 2 (Opticon®, MJResearch®). WT1 copy number/Abl copy number 500x104 was used as cut-off value for high WT1 expression. Results: Twenty-five relapses (37.9%) were observed. Median DFS was 31 months. Our analysis shows that the probability of relapse was significantly influenced only by disease status (first or subsequent CR) and MRD status at transplantation. Specifically, MFC-MRD was the strongest predictor of longer disease free survival (p

Description: BACKGROUND AND AIMS In patients with myelodysplastic syndromes (MDS) several validated prognostic scores, such as IPSS and R-IPSS, are available to assess the risk of AML progression and predict overall survival (OS) as well as leukemia-free survival (LFS). A number of molecular aberrations can be identified in MDS. However, differently from AML, none of the current prognostic indexes takes into account molecular profile at diagnosis. WT1 expression has often been evaluated in acute leukemias and MDS. High WT1 expression levels on bone marrow at diagnosis have been reported to identify MDS patients who are at high risk of progression to AML. BAALC (Brain And Acute Leukemia Cytoplasmic) hyper-expression has been associated with a poor prognosis in AML patients, whereas its prognostic value in MDS is not yet clearly defined. The aim of our study was to determine if combined assessment of WT1 and BAALC expression levels at diagnosis could be predictive of leukemic evolution. MATERIALS AND METHODS We selected 86 patients with available WT1 and BAALC expression levels on BM samples at diagnosis. According to IPSS score, 22 patient were considered low-risk, 27 intermediate-1 and 28 intermediate-2 or high risk. Patients underwent different treatment schedules including supportive care, erythropoietin, hypomethylating and immunomodulating agents, according to their risk group. Median follow-up was 36 months (range 4 -121 months). Leukemia-free survival (LFS) was calculated from the diagnosis until last follow-up or documented leukemic progression as defined in literature. LFS was estimated using the Kaplan–Meier method. All Real-Time PCR were performed on DNA Engine 2 (Opticon®, MJ Research®). WT1 copy number/Abl copy number 1000x104 was used as cut-off value for high WT1 expression, a level of 1000x104 BAALC copy number/Abl copy number was set as cut-off for BAALC hyper-expression. RESULTS After a median time of 32 months, 43 patients died. The main cause of death was leukemic evolution (accounting for 31/43 deaths, 72%), other causes were cardiovascular events and infections (data not shown). The risk of death by any cause was significantly affected by leukemic evolution, diagnosis according to WHO classification and molecular expression profile at diagnosis. Multivariate analysis showed that leukemic evolution was an independent predictor of death (p

Description: Background The use of 5-azacytidine (AZA) as front line therapy in elderly, frail patients with acute myeloid leukaemia (AML) has entered in clinical practice. Our retrospective therapeutic experience with AZA in 52 AML patients is presented and compared with intensive chemotherapy (FLAI-GO). Materials and methods We retrospectively analysed the outcome of 52 elderly AML patients treated with AZA as front line therapy from June 2010 to June 2016. We compared the outcome with that of a cohort of a 55 partially matched AML patients who had received FLAI-GO from September 2004 to January 2010. The two populations were comparable for sex, karyotype, FLT3 mutational status, LDH levels, WT1 and BAALC expression levels. The two cohorts significantly differed for median age (76.5 and 71 years for AZA and FLAI go, respectively), percentage of patients older than 70 years (77% vs 58%), secondary disease (75% vs 31%), mean leukocytes count (8850/mmc vs 2800/mmc ). Relevant comorbidities were present in both arms. AZA was administrated monthly (75 mg/mq5+2 schedule) until disease progression or toxicity (mean 7 courses range 1-27). FLAI-GO consisted inFludarabine30 mg/mq,Cytarabine1000 mg/mq,Idarubicin5 mg/mq(day 1-2-3) andGemtuzumabozogamicin(3 mg /mq) on day 4. Those achieving CR after induction received an identical consolidation cycle, those not in CR were treated with salvage therapy (MEC, MEA, MINI ICE or low dose chemotherapy). Results Early death rate was comparable between the two arms (5/52 for AZA 3/55 for FLAI-GO). CR rate was lower in patients treated with AZA (12,8 %) compared with those receiving FLAI-GO (52%). No factors influenced theprobability of achieving CR in AZA arm (sex, disease onset, karyotype, WBC count, age, blasts, LDH, WT1 and BAALC levels) although none of the 3 patients with FLT3-ITD mutation showed any kind of response. In FLAI-GO arm the only factor which impacted on response rate was sex (CR rate was 69.2% and 34.6% in women and male, respectively, p=0,025). We observed a lower probability of CR in patients with higher bone marrow blast burden (CR rate of 80% with blasts 30%) and in patients with elevated BAALC (75% CR with BAALC 1000). The 1 and 2 years OS were 46 and 21 % in all patients (median 11 months),with no differences in AZA (45,9% and 26,2% ) and FLAI-GO arm ( 46,3% and 17,8%). In AZA group karyotype, FLT3 mutational status, WT1 expression significantly impacted on OS. In multivariate analysis only FLT3-ITD mutation retained its prognostic impact on OS (p = 0.02) . Achieving CR after AZA induction did not deeply modify OS probability, as there was no significant difference between patients in CR or not after AZA (even with a trend in favour of patients with CR). Non responders (NR) had a 1 year OS of 40% (median 9 months); patients with CR had a 1 year OS of 83.3% (median 47 months). Patients with an haematological improvement (HI) had a 1 year OS of 48% . In FLAI-GO arm the variables significantly influencing OS were: type of response (NR patients had a 2 years OS of 0% whereas CR patients had a 2 yeas OS of 38%), sex, WBC; neither karyotype, expression of BAALC , disease status, FLT3-ITD, WT1 expression, NPM1 mutation, blasts , age over 70 or LDH had a prognostic impact on OS. In multivariate analysis the only factor which impacted the survival was the achievement of CR to induction chemotherapy (p=0,000). Infection rate was 28/52 in AZA arm and 40/55 in FLAI-GO arm. The hospitalization rate was significantly lower in AZA arm compared to FLAI-GO (8.5 days vs 27 days in the first 30 days; 11.3 vs 51 in the first 90 days; 15 vs 64.5 in the first 180 days). Conclusions In our study AZA has shown to be well tolerated in a group of elderly frail patients until recently eligible only for best supportive care or low dose chemotherapy. AZA is less effective than FLAI-GO in inducing CR in all subgroups of patients but this doesn't translate into a lower OS. In the AZA arm the achievement of CR (or PR) is not fundamental for the duration of survival, unlike what has been observed in the FLAI-GO treated cohort. Our study suggests that some subgroups of patients may benefit more from AZA and others more from aggressive approaches; patients with low BAALC levels and with FLT3 mutation seem to benefit from FLAI-GO. Larger prospective trials evaluating clinical, cytogenetic and molecular risk factors in patients receiving AZA or chemotherapy will help to tailor the best therapy for each patient. Disclosures Gobbi: Novartis: Consultancy, Research Funding; Gilead: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Takeda: Consultancy; Roche: Honoraria.

Description: Background Conventional induction therapy of acute myeloid leukemia (AML) is still largely based on the combination of cytarabine (ARA-C) and daunorubicin. In the last two decades alternative drug combinations have been tested in order to improve complete remission (CR) rate and quality of remission. Fludarabine has been shown to enhance ara-CTP accumulation in leukemic blasts and to inhibit DNA repair mechanisms, thus providing a rationale for combination with DNA damaging agents. In our institution a fludarabine containing induction regimen (FLAI-5) is being used since more than 15 years. Patients and methods Eighty-four consecutive non M3 AML patients (age 17-72 years) treated in our center between 2006 and 2013 were retrospectively analyzed. Median follow-up was 42 months. Induction regimen included fludarabine 30 mg/sqm and ARA-C 2g/sqm on days 1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5, with or without gemtuzumab ozogamicin (3mg/sqm) on day 6. Patients achieving complete remission received a second course including ARA-C 2g/sqm on days 1 to 5 and IDA at an increased dose of 12 mg/sqm on days 1-3-5. Patients were stratified in prognostic risk groups according to a comprehensive score based on karyotype, de-novo or secondary disease, NPM and FLT3 status. High-risk and selected intermediate-risk patients underwent allogeneic bone marrow transplantation (BMT) in first complete remission if a donor was available. The other patients were scheduled to receive at least 2 and up to 4 courses of consolidation therapy with 4 days of ARA-C (2g/sqm, daily). Patients features, CR rate and overall survival (OS)analysis are summarized in Table 1. Results and Discussion Six patients (7%) died during first induction mainly because of infective or hemorrhagic events. Of the remaining 78 patients, 63 patients achieved CR (81%) and 15 did not respond (19%). FLAI-5 was generally well tolerated, with negligible non-hematological toxicity; median time to neutrophil and platelet recovery was 18 and 17 days, respectively. Most patients were able to receive subsequent therapy at full dose and in a timely manner; 33/63 CR patients underwent BMT whereas 21/30 (70%) non-transplanted patients received the full programmed therapy. In the whole cohort, 3 years OS was 50.9% (median 38 months). Factors affecting CR rates and OS are summarized in Tab.1. In a large randomized trial Burnett et al showed that FLAG-Ida favorably compared with other induction schedule. However the longer disease free survival and the lower relapse rate observed in the FLAG-Ida arm did not translate in a higher OS mostly due to the severe hematological toxicities following the second course. Our results are comparable to those recently published and show that the administration of fludarabine only in the first course may significantly reduce hematological toxicity therefore allowing patients to proceed along the consolidation program or undergo allo-BMT in a good performance status. Besides, we were able to increase IDA dose (10 and 12mg/sqm in first and second course, respectively, compared to 8 mg/sqm used in the FLAG-Ida combination). Our results show that FLAI-5 induction regimen followed by a second ARA-C and IDA containing course is an effective and well tolerated therapy for younger AML patients and confirm that CR rate and OS are mainly affected by comprehensive risk group, WBC count at diagnosis and NPM status. Abstract 2266. Table 1: Patients features and CR/OS analysis CR after 1st cycle/Tot.(%) p(univ.) p(multiv.) Median OS(months) OS 36 months (%) p(univ.) P(multiv.) All Patients 63/78 (81) - - 38 50.9 - - Age 〈 45 yrs 28/34 (82) 1.000 - NR 53.4 0.121 0.105 〉 45 yrs 35/44 (80) 15 49.2 Karyotype Favorable 3/3 (100) 0.093 0.248 NR 100 0.003 0.775 Intermediate 52/61 (85) NR 60.9 Sfavorable 8/13 (62) 7 0 NPM Wild type 36/50 (72) 0.003 0.001 32 45.1 0.270 0.541 Mutated 26/26 (100) 65 66 FLT3 Wild type 48/60 (80) 0.721 - 65 56.3 0.249 0.658 FLT3 ITD 14/16 (88) 14 35 Disease Onset De novo 57/67 (85) 0.031 0.213 65 56.1 0.001 0.809 Secondary 6/11 (55) 7 21.4 WBC at diagnosis 30.000/mmc 22/31 (71) 14 39.4 Comprehensive Risk Group Good 17/17 (100) 0.009 0.983 NR 81.2 0.000 0.001 Intermediate 31/37 (84) NR 63.5 Poor 15/24 (63) 9 14.4 Mylotarg FLAI 44/54 (82) 1.000 - 34 49.1 0.676 - MY-FLAi 19/24 (79) 65 52 Figure 1: OS according to risk group Figure 1:. OS according to risk group Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND AND AIMS Non high risk acute promyelocytic leukemia (APL) patients, as defined by WBC count at diagnosis, have nowadays a very good prognosis when treated with ATRA plus chemotherapy based protocols, with high rate of complete molecular remission after consolidation therapy. However, a small proportion of patients (roughly 10-15%) will eventually relapse, despite the achievement of molecular CR. In the past years, some groups showed that relapse risk could be predicted by testing for some gene alterations, such as FLT3-ITD, or by break point cluster region (BCR) analysis. However, those results were not confirmed in prospective trials. We retrospectively applied a simple 3 gene based molecular panel to low-intermediate risk acute promyelocytic patients, alongside with BCR analysis, in order to develop a risk score. MATERIALS AND METHODS Fifty-nine low/intermediate risk APL patients, treated with the Italian age-adapted AIDA protocol from January 1st 2004 to December 31st 2014 in our center were retrospectively included in this study. Median age was 47 years (range 19-88), 16 patients were older than 60 years (27%). BCR analysis was available in all patients, 41 patients showed BCR1/2, whereas 18 patients had BCR3 (30%). Molecular profile included determination of FLT3-ITD mutation, WT1 and BAALC gene expression levels and was available in 38/59 patients (64%); bone marrow sample of diagnosis is available for all other 21 patients for further analysis. Cut-off values for WT1 (20000/abl x 104) and BAALC (450/abl x 104) were arbitrarily chosen after pre-analysis and comparison with our published data. Five patients had FLT3-ITD mutation (13%), 18 (45%) patients had higher WT1 expression levels and BAALC was overexpressed in 9 (24%) patients. Pre-analysis showed that FLT3-ITD, low WT1 levels, high BAALC levels but not the presence of BCR3 were associated with higher relapse risk. A molecular score including those 3 genes was built: 16 patients had no risk factors (42%), 17 patients had one risk factor (45%), 5 had two risk factors (13%). RESULTS Fifty-four patients survived induction, all of them achieved CR, in 52 PML/RARα transcript was undetectable after last consolidation therapy. The two patients with molecular persistence of disease received further therapy and then achieved molecular CR. Nine patients (15%) relapsed after a median follow-up of 56 months, 45 patients are alive at the time of analysis (76%). Relapse risk was influenced only by the presence of at least one molecular risk factor (p

Description: Background, methods and aims of the study. It is widely established that the prognosis of patients with acute myeloid leukemia (AML) is related to clinical (age, denovo or secondary leukemia, presence of comorbidities), cytogenetic and molecular (e.g. FLT3-ITD, NPM1 gene mutation.) factors. We have developed a Comprehensive Risk Score (CRS) identifying three prognostic subgroups with favorable (low risk karyotype or intermediate karyotype + mutations of NPM1 gene without FLT3-ITD), unfavorable (high risk cytogenetics or FLT3-ITD without NPM1 mutation or secondary AML) and intermediate (including all the other patients not belonging to previous groups) prognosis. The clinical utility of CRS was tested on a cohort of 292 AML patients included in the REGAL registry, a regional Italian registry that was established in October 2010 at the University of Genoa. Results. Analysis of age distribution confirmed the increased incidence of AML in patients older than 60 years (n. 182, 62.4%). Patients with de novo or secondary AML were 210 (71.9%) and 82, (28.1%) respectively. Patients with significant and often multiple comorbidities at diagnosis were 131 (44.8%). Seventeen patients (6%) received only supportive therapy, 217 (74.3%) intensive induction regimens (mainly FLAG-Ida and 3+7), including 96% of patients with age below 60 years and 61% of those over the age of 60 years. Therapy with hypomethylating agents (azacitidine and decitabine) was given to 31 patients (10.6%). In the whole cohort of patients 24 months projected survival (OS) was 66% among 62 patients defined as low risk according CRS (median not reached), 37,9% among 118 intermediate risk patients (median 13.8 months) and 12,7% in 112 patients included in the unfavorable risk group (median survival 4.8 months) (p =0.000, Fig. 1). In patients aged younger than 60 years, OS of favorable and intermediate risk groups were similar (77% and 72% in 39 low risk and in 44 intermediate risk patients, respectively), whereas the outcome of 27 high risk patients was worse (OS 28.2%, median survival of 10,3 months, p 0.0001). In the group of elderly patients (〉 60 years) the outcome of the intermediate group was rather similar to that observed in the poor risk group (OS 16% and 7% in 74 intermediate and in 85 poor risk patients, respectively, p n.s). On the contrary OS of 23 favorable risk patients was good (49%, p = 0.0015).Twenty-nine patients have actually received an allogeneic bone marrow transplant (BMT) during first CR (66% of 44 with indication) and 14 in second or third CR. The sources of stem cells have been HLA-identical and haploidentical sibling in 45% and 50% of patients, respectively. Discussion and conclusions. Our study suggests that the predictive value of CRS is clearly affected by the therapeutic strategy. Whereas the score allows the stratification of the whole cohort of patients in three groups with different outcome, in younger fit patients a more intensive therapeutic approach, such as the FLAG-IDA regimen and a wider use of allogeneic bone marrow transplantation made possible by the use of haploidentical donors, results in the super-imposable prognosis between favorable risk and intermediate risk patients. However, the same intensive approach cannot overcome the unfavorable features of the majority of high risk patients. In the elderly group median age and comorbidities prevent patients from receiving intensive induction therapy. Therefore, intermediate and unfavorable risk patients show a similar poor outcome. In elderly patients the achievement of a good outcome is related to disease status (denovo AML), favorable cytogenetic and molecular features, good performance status and administration of intensive induction and consolidation treatment, including BMT in selected cases. Disclosures Carella: Seattle Genetics Inc.: Research Funding.

Description: BACKGROUND AND AIMS The prognosis of Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) patients has improved since the introduction of tyrosine kinase inhibitors (TKI). The inclusion of TKIs in standard ALL protocols allows a great increase in complete molecular responses, but at the price of non negligible toxicities and high rates of toxic deaths. On the other and TKI monotherapy as induction treatment allows to rapidly achieve complete hematologic remission (CR) but only a minority of patients achieve a complete molecular response with high risk of relapse. On the other hand, In the last years we tested a combination of Fludarabine, Cytarabine, Daunoxome (FLAD) with or without TKIs (mainly Dasatinib) as salvage regimen in relapsed-refractory ALL, with acceptable toxicity and good efficacy. We decided to apply the same schedule in newly diagnosed Ph+ ALL as consolidation treatment after a two months TKI (Dasatinib) monotherapy induction on a minimal residual disease condition. MATERIALS AND METHODS FLAD regimen consisted with a three-days administration of Fludarabine 30 mg/sqm followed four hours later by Cytarabine 2000 mg/sqm and Daunoxome 100 mg/sqm. TKI were suspended during chemotherapy administration and were re-administrated starting from day 5. G-CSF was given to all patients from day 4 to complete hematological recovery. FLAD was administrated for up to two cycles; all patients with available donor proceeded to allogeneic bone marrow transplantation (allo-BMT) after FLAD. Minimal residual disease (MRD) was evaluated in all patients after each FLAD either by RQ-PCR for VDJ rearrangements, multicolor flow cytometry (MFC) and RQ-PCR for BCR/Abl. Ten Ph+ ALL have been treated with FLAD + TKIs from January 2008 to December 2014: six patients received FLAD as salvage regimen, two of them in post allo-BMT setting, whereas four patients were treated frontline, after hematological CR was obtained with Dasatinib + steroids induction. All frontline patients proceeded to allo-BMT after two FLAD. Median age for frontline patients was 50 years (range 29-58), median follow-up was 20 months. RESULTS As salvage regimen, 5/6 patients achieved hematological CR after FLAD, with three patients achieving also MFC MRD negativity and clearance of VDJ and BCR/Abl transcript. All patients who did not receive subsequent BMT relapsed, whereas of the two transplanted patients one is still in CR after a follow-up of 38 months. In the frontline setting, all patients received 70 days induction of Dasatinib + Steroids and achieved CR with complete hematological recovery. BCR/Abl transcript could be detected in all patients on BM samples on day 33 and on day 70 (Fig. 1), two patientshad MFC MRD positivity both on day 33 and on day 70, whereas two patients achieved MFC MRD negativity on day 33. FLAD was very well tolerated, with negligible non hematological toxicity, with a median duration of ANC