ALBERT

Description: Aims: In elderly patients with acute myeloid leukemia (AML), complete remission (CR) rate following intensive chemotherapy is approximately 45%, considerably lower than in younger patients, with a shorter duration of remission and high treatment-related mortality (30-50%). Median survival is about 12 months. Intensive chemotherapy is indicated in a small proportion of "fit" elderly patients. In a phase III, prospective, randomized, open-label, multicenter trial designed to assess the efficacy of post-remission treatment with 5-Azacitidine versus best supportive care (BSC) in patients 〉 60 years of age with AML in CR after conventional induction ("3+7") and consolidation chemotherapy, quality of life (QoL) was assessed from diagnosis. We present interim results of changes of QoL. Methods: Patients with newly diagnosed AML with 〉 30% myeloid marrow blasts, either "de novo" or evolving from myelodysplastic syndrome without contraindications for intensive chemotherapy and with an ECOG performance status 〈 3 are included. Induction chemotherapy consists of two courses of "3+7": Daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily continuous IV infusion days 1-7. Patients in CR receive consolidation (cytarabine 800 mg/m2 3 hour infusion bid days 1-3) and are randomized 1:1 to receive BSC or 5-Azacitidine maintenance therapy up to 4 years and six months until AML recurrence. QoL assessment was performed using the EORTC QLQ-C30 and the QOL-E v.3 questionaires. Results: QoL results assessed at 3 time points are reported: 1) baseline; 2) at hematological recovery immediately after the first "3+7" course; and 3) after consolidation at randomization. Ninety-nine patients (male/female 50/49) of median age 70 (IQR 65-74) years have been enrolled. At diagnosis, mean hemoglobin was 9.2 (SD ± 2.4) g/dL, leukocytes were 7.9 (2.3-29.6)/µL, platelet count was 54 (IQR 29-85) Gi/L and bone marrow blasts were 70 (IQR 50-85)%. Seventy-five patients had "de novo" AML. Twenty-three patients had comorbidities. Forty-three patients had an ECOG PS 1 and 28 had ECOG PS 2. Baseline median QOL-E scores were poor (≤60) in all dimensions, except for fatigue (76, IQR 52-85). EORTC QLQ-C30 confirmed that fatigue was not prevalent at diagnosis (median 33, IQR 22-56). Median baseline EORTC QLQ-C30 scores were good in all domains except for global health status (GHS, median 50, IQR 33-67). Gender, comorbidities, bone marrow blasts and secondary AML were not related to QoL. Baseline Hb levels correlated with QOL-E functional (r=0.0216, p=0.14), fatigue (r=0.256, p=0.002) and disease-specific (r=0.247, p=0.010) scores and with EORTC QLQ-C30 GHS (r=0.270, p=0.001), physical (r=0.304, p

Description: Background: In elderly patients with acute myeloid leukemia (AML), complete remission (CR) rate following intensive chemotherapy is approximately 45%, considerably lower than in younger patients, with a shorter duration of remission and high treatment-related mortality (30-50%), which partially explains a median survival of 7 to 12 months. Several studies have suggested that maintenance therapy may improve CR duration and long-term, disease-free survival (DFS). Grovdal et al (2010) treated 60 elderly patients with high-risk myelodysplastic syndrome (MDS) or AML with cytarabine-based induction therapy resulting in CR in 24 patients who continued on to 5-Azacitidine (5-Aza) maintenance therapy. The median duration of CR was 13.5 months. The median OS for the 5-Azacitidine-treated group was 20 months. Aims: The present phase III, prospective, randomized, open-label, multicenter trial is designed to assess the efficacy of post-remission treatment with 5-Aza versus best supportive care (BSC) in 54 patients 〉 60 years of age with AML in CR after conventional induction (3+7) and consolidation chemotherapy. Primary endpoint is the difference in DFS at 2 and 5 years between; secondary endpoints are the difference in overall survival (OS) at 2 and 5 years, the number and length of hospitalizations and quality of life in the 2 arms in the 2-year post-remission period. Methods: Patients with newly diagnosed AML with 〉 30% myeloid marrow blasts, either "de novo" or evolving from myelodysplastic syndrome without contraindications for intensive chemotherapy and with a performance status 〈 3 are included. Standard induction chemotherapy consists of two courses of "3+7" (Daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily continuous IV infusion days 1-7). Patients in CR receive consolidation with cytarabine 800 mg/m2 3 hour infusion bid days 1-3. Patients in CR are randomized 1:1 to recieve best supportive care (BSC) or 5-Aza according to the following schema: 50 mg/m2 s.c. or i.v. for 7 days (5 + weekend off + 2) every 28 days and increase dosing after 1st cycle, if well tolerated, to 75 mg/ m2 for further 5 cycles, followed by cycles every 56 days for 4 years and six months post-remission. Results: At the time of the present interim analysis 88 patients have been included in the study. Median age at diagnosis was 71, interquartile range (IQR) 66-75 years, male/female 45/43. During induction-consolidation chemotherapy, 31 patients were relapsed/refractory, 14 died, 5 refused to continue, 3 were excluded for protocol violation, 1 was lost to follow-up and 6 have not yet reached consolidation treatment. Twenty-eight patients have been randomized and 9 have more than 1 year follow-up (7 5-Aza patients, 2 BSC patients). The characteristics of randomized patients are shown in the table. The median observation time is 42.3 weeks and 12 patients are still in CR. Twelve patients in the BSC arm have experienced AML recurrence versus 4 patients in the 5-Aza arm at 9,17,42,56 weeks, respectively. Median DFS in the BSC arm is shorter (14 weeks, IQR 9-50 weeks) compared to that observed in the 5-Aza arm (median not reached at 2 years, P=0.008; Figure 1). At 2 years post-randomization 10 patients have died: 4 in 5-Aza arm versus 6 in BSC arm. All deaths occurred after AML recurrence. Median OS in 5-Aza arm is not reached at 2 years, versus 57 weeks, IQR 25-NA weeks in the BSC arm (P= 0.219, Figure 2). Grade 3-4 adverse events in the 5-Aza arm included neutropenia in 3 cases and one hospitalization for pericarditis, concomitant to AML recurrence. No serious adverse events were experienced in the BSC arm. Conclusions: Preliminary results indicate that in elderly AML patients receiving standard induction-consolidation chemotherapy, 5-Aza post-CR is well-tolerated and significantly prolongs DFS. The trial is ongoing and may provide further insight on the impact of post-remission 5-Aza treatment on OS in this elderly population. Figure 1 Figure 1. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Oliva: Celgene: Consultancy, Honoraria; Novartis: Consultancy, Speakers Bureau. Off Label Use: Azacitidine is indicated for treatment of patients with the following French-American-British myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.. Musto:Celgene: Advisory Board Other, Honoraria.

Description: Abstract 4963 Overall survival (OS) is significantly improved by 5-azacitidine in intermediate-2 (int-2) and high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) with 10–29% marrow blasts, and acute myeloid leukemia (AML) with 20–30% marrow blasts, compared with conventional treatments, and currently appears as the standard of care, at least in patients who are not candidates to allogeneic stem cell transplantation (alloSCT). We retrospectively evaluated the efficacy and tolerability of 5-azacitidine in 25 patients treated at our institution from 2009 to 2012, outside of clinical trial. Our series was composed by 17 cases of MDS with IPSS risk int-2 or high, 6 AML with marrow blasts between 20% and 30% and 2 CMML. Patients were treated with 5-azacitidine at a dosage of 75 mg/m2/d subcutaneously for 7 days every 28 days (schedule 5 day on, 2 day off and 2 day on). Median age of our cohort was 72 years (range 37–81 y), male to female ratio was 0. 6 and the median number of cycles received was 7 (range 1–26). According to the MDS-specific comorbidity index 9 pts (53%) were classified as low-risk, 7 pts (41%) as intermediate risk and 1 pt (6%) as high risk. Seventeen (68%) patients (13 MDS, 3 AML, 1 CMML) who had received at least 4 cycles of therapy were evaluable. Median age of these 17 patients was 71 years (range 37–81 y), male to female ratio was 0. 8 and median number of cycles administered was 8 (range 4–26). The overall response rate (ORR) was 59% (10/17 patients). According to International Working Group (IWG) 2006 criteria, five patients (29%) reached complete remission (CR) after a median of 5 cycles of therapy (range 4–6), two patients (12%) obtained hematologic improvement with bone marrow complete remission (marrow CR) after 6 and 11 cycles of therapy respectively, three patients (18%) showed hematologic improvement (HI) after 5 cycles (range 4–6), while stable disease (SD) and progressive disease (PD) were observed in 4 (23%) and in 3 patients (18%) respectively after 5 cycles (range 4–7). Median duration of response was 12 months (range 6–26 mo); median overall survival from the beginning of 5-azacitidine, for all patients treated, was 14. 4 months (range 7–33 mo). We did not observe any differences in response rate according to age, bone marrow fibrosis, cytogenetics and transfusion requirements. In the responder group (10 patients) we did not observe grade 3 or 4 non-hematologic toxicity after a median observation time of 10 months (range 5–33 mo). Among non-responding patients, four (57%) recurred to hospitalization due to infectious or hemorrhagic complications (median observation time 15 months, range 7–33). 5-azacitidine confirmed to be an active therapy for patients with int-2 and high risk MDS and AML with low marrow blast counts not candidate to high intensity treatment for age and or comorbidities, showing high response rate and good tolerability. The low rate of serious adverse events and need of hospitalization improved patient's quality of life and reduced the utilization of medical resources. Disclosures: No relevant conflicts of interest to declare.

Description: Background The incidence of acute myeloid leukemia (AML) increases with age. In elderly AML patients, intensive chemotherapy has been associated with complete remission (CR) rates of approximately 45%, considerably lower than in younger patients; the duration of remission is shorter and the early treatment-related mortality is high, 30% to 50%, which partially explains a median survival of 7 to 12 months. Several studies have suggested that maintenance therapy may improve CR duration and long-term, disease-free survival (DFS). Grovdal et al (2010) treated 60 elderly patients with high-risk myelodysplastic syndrome (MDS) or AML with cytarabine-based induction therapy resulting in CR in 24 patients who continued on to 5-Azacitidine (5-Aza) maintenance therapy. The median duration of complete response was 13.5 months. The median OS for the 5-Azacitidine-treated group was 20 months. Aims The present phase III, prospective, randomized, open-label, multicenter trial is designed to assess the efficacy of post-remission treatment with 5-Aza versus best supportive care in a cohort of subjects of 〉 60 years of age with AML, and in CR after conventional induction (“3+7”) and consolidation chemotherapy. Primary objectives are to evaluate overall survival overall survival and DFS at 2 years; secondary objectives are to evaluate the number and length of hospitalizations in the 2 arms in the 2-year post-remission period. Methods Approximately 95 patients with the following criteria: newly diagnosed AML with 〉 30% myeloid marrow blasts, either “de novo” or evolving from a MDS not previously treated with chemotherapeutic agents; no contraindications for intensive chemotherapy and performance status

Description: Azacitidine (AZA) is effective in high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia type 2 (CMML-2) and low blast count acute myeloid leukemia (AML) patients not suitable for more intensive treatment. Factors that may influence response to AZA are still under investigation. Bone marrow fibrosis is a potentially negative prognostic marker on overall survival (OS), but its clinical significance in this setting of patients remains to be clarified. We evaluated clinical predictors of OS and overall response rate (ORR; complete/partial response CR/PR; stable/progressive disease SD/PD) to AZA in a real life cohort. We studied 94 consecutive patients, treated at two Institutions from June 2009 till February 2016 with AZA subcutaneously (5+2+2 schedule) every 28 days, outside clinical trials. We analyzed data from routine laboratory analysis, bone marrow histology, morphology and cytogenetics at diagnosis. OS was measured from the starting of AZA treatment. Table 1 shows the clinical characteristics pre- and post-AZA: most patients (68%) were AREB1 or AREB2, 13% RCUD/RCMD or MDS NOS according to WHO 2008 classification, 17% AML, 2% CMML. At the onset of AZA therapy the majority of MDS cases (68%) showed an intermediate-2 risk, according to the International Prognostic Scoring System (IPSS) and high/very high risk (78%) according to IPSS-revised. Secondary and de novo cases, as well as cytogenetics risk groups, were equally represented; 50% of patients were transfusion dependant and moderate to severe neutropenia or thrombocytopenia were present in roughly 50/70% of cases respectively. As expected, bone marrow biopsies pre-AZA showed hypercellularity in most patients (65%). Remarkably, 47,5% of cases showed bone marrow fibrosis of ≥1 grade before AZA initiation. These findings were mostly unchanged at post-AZA evaluation. On the whole, 93 patients receiving 〉 4 cycles of therapy were available for response evaluation according to International Working Group 2006 criteria. After a median of 6 cycles (4-44), ORR was 41.9% (CR 18.3%, PR 11.8%, SD with hematologic improvement HI 11.8%), SD was 21.5%, PD 10.7% and 25.8% failed to achieve a response. Thirteen percent of patients reached at least partial cytogenetic response and 50% a HI. ORR was not influenced by monocytosis, neutropenia or IPSS cytogenetic risk category. Interestingly, pre-AZA marrow blast percentage, cytogenetic risk, time from diagnosis to AZA and the interval from 1st to 6th cycle had no impact on response. As regards marrow characteristics, patients with MF-0 pre-AZA displayed significantly lower PD rate and higher ORR, SD and HI than those with any grade of fibrosis (21.4% vs 51.4% and 78.6% vs 48,6%, respectively p=0.006, Fig1). This observation was also confirmed at marrow evaluation after AZA (22% versus 48% for PD and 78% versus 52% for ORR/SD/HI, p=0.05, Fig1). Regarding cellularity pre- and post-AZA, higher ORR,SD and HI and lower PD were observed for patients with normo/hypo compared to those with hyper-cellularity (Fig1) although not significantly. Forty-one percent of cases presented a hematologic toxicity (33% neutropenia and 18% thrombocytopenia of any grade) occurring after a median of 2 (1-18) AZA cycles. Moreover 28.6% of patients had an infection during AZA treatment, not related to neutropenia degree. Of note, toxicities did not affect median time from the 1st to the 6th AZA cycle (170,115-240 days), nor ORR. Median OS from the beginning of therapy was 18.5 months (12.7-24.4, 95% CI). IPSS high category [HR 2.24 (1.19-4.20) p=0.01], poor cytogenetics [2.19 (1.27-3.78) p=0.005], and lower ORR [0.46 (0.26-0.80) p=0.006] significantly affected OS. Unexpectedly, a response obtained after less than 4 cycles negatively impact OS [HR 0.86 (0.80-0.92) p

Description: Background: Elderly patients with acute myeloid leukemia (AML) experience a low complete remission (CR) rate following intensive chemotherapy, a short duration of CR and high treatment-related mortality. Median survival is 7-12 months. Several reports suggest that maintenance therapy may improve survival. In particular, a recent report (Huls G, et al. Blood 2019) has shown that azacitidine (Aza) maintenance treatment improves 1-year disease-free survival (DFS) when adjusted for cytogenetics at diagnosis and platelet (PLT) count at randomization. Aims: This phase III, randomized, multicenter trial assesses the efficacy of post-remission Aza treatment versus best supportive care (BSC) in 54 AML subjects 〉60 years of age in CR after homogeneous induction and consolidation chemotherapy. Primary endpoint is the difference in DFS at 2 and 5 years between arms; main secondary endpoints are the difference in overall survival (OS), the number and length of hospitalizations and quality of life (QoL). Methods: AML subjects with 〉30% blasts, "de novo" or evolving from myelodysplastic syndrome and fit for intensive chemotherapy, received 2 courses of "3+7" therapy (daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily IV infusion days 1-7). Subjects obtaining a CR received cytarabine 800 mg/m2 3 hour infusion bid days 1-3 and were randomized 1:1 to receive BSC or Aza at 50 mg/m2 s.c./i.v. for 7 days every 28 days and dose increase after 1st cycle to 75 mg/ m2 for further 5 cycles, followed by cycles every 56 days for 4.5 years or until relapse. QoL was assessed by QOL-E and EORTC QLQ-C30. Results: 149 subjects were included of median age 69, interquartile range (IQR) 65-74 years, and male/female 78/71. Amongst subjects not reaching randomization, 59 were relapsed/refractory, 22 died, 10 refused to continue, 3 were excluded for protocol violation, and 1 was lost to follow-up. Randomized patients (27 Aza, 27 BSC) were in study until relapse. Median follow-up was 9.9 months (IQR: 3.2-22.5). At 2 years post-randomization, no deaths occurred and 21 subjects in the BSC arm (median DFS 9 months, 95% CI 0-20) relapsed versus 18 subjects in the Aza arm (median DFS 11 months, 95% CI 1-21; P=0.33; Fig.1a). There was an effect modification by age on the effect of Aza versus BSC on relapse (P for effect modification=0.02) so that the effect of AZA was not significant for subjects 73 years (P=0.008, Fig.1b). Cytogenetic risk (P=0.84), minimal residual disease (P=0.97), and platelet (PLT) count (below/above 100 Gi/L, P=0.47) did not modify the effect of Aza on DFS. However, cytogenetic risk and PLT count were confounders: after data adjustment, the effect of Aza on DFS just failed to reach statistical significance [HR (Aza vs BSC): 0.53, 95% CI: 0.26-1.05, P=0.068] . At 5 years post-randomization, no subjects died; 2 subjects on Aza and 1 subject on BSC withdrew consent and 1 subject on Aza in CR withdrew for relapse of bladder cancer. In the BSC arm, 23 subjects relapsed (median DFS 9 months, 95% CI: 0-20) versus 20 Aza subjects (median 11 months, 95% CI: 1-21; P=0.31, Fig.1a).Similar to 2 years post-randomization, at 5 years post-randomization an effect modification by age on the effect of Aza versus BSC was confirmed (P for effect modification=0.01) and the effect of Aza was significant only in subjects 〉73 years of age (P=0.007, Fig.1b). Again, data adjustment for cytogenetic risk and PLT count strengthened the link between Aza and DFS [HR: 0.56, 95% CI: 0.29-1.07, P=0.08]. Grade 3-4 adverse events (mainly neutropenia) were more frequent in the Aza (41%) than in the BSC arm (4%, P=0.002). Two Aza subjects were hospitalized twice for adverse events for a total of 22 and 26 days, respectively, versus no hospitalization for BSC subjects. QOL-E scores were poor at diagnosis and improved significantly at randomization, with further improvement for physical well-being. EORTC QLQ-C30 symptoms improved progressively over time. In linear mixed model analyses, no significant effect of Aza versus BSC was found for any QoL domain, confirming safety of Aza versus BSC. Summary/Conclusion: With the limitation of a small trial, we conclude that post-remission Aza in elderly AML patients receiving standard induction-consolidation chemotherapy is safe and is well-tolerated. Noteworthy, in patients over 73 years of age, Aza significantly prolongs DFS up to 5 years. Figure Disclosures Oliva: Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Novartis: Consultancy, Speakers Bureau. Candoni:Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding. Musto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mannina:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Martino:Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol myers squibb: Membership on an entity's Board of Directors or advisory committees. Alati:Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Description: Chronic myelomonocytic leukemia (CMML) represents a diagnostic and therapeutic challenge characterized by highly heterogeneous clinical and laboratory aspects, contrasting from mainly dysplastic (MD) to predominantly proliferative (MP) in different patients. Although no specific cytogenetic or molecular aberration has been associated to CMML, next generation sequencing (NGS) has recently led to the discovery of at least one lesion in up to 90% of patients. Nonetheless, the role of the identified genetic aberrations in CMML onset and progression remains to be clarified. In a series of 40 consecutive patients we previously reported a higher frequency of RAS and JAK2 mutations and a shorter survival in those with MP- than in those with MD-disease. Furthermore, paired samples analysis showed RAS mutations acquisition in concomitance with progression from MD- to MP-CMML, suggesting these lesions as second hits that confer a proliferative advantage to the malignant clone, leading to poor outcome. In addition to these findings, a highly significant shorter life expectation in the MP-variant of CMML was more recently confirmed in an extended population of 74 patients (p=0.0005), further supporting the association of molecular acquisition of gene aberrations with disease progression. By comprehensive next generation sequencing (NGS) of selected genes, here we aimed to further investigate the spectrum of aberrations contributing to CMML development and progression and to examine whether MD- and MP-CMML may be also discriminated at the molecular level. We designed a NGS study (Oxford Gene Technology, Oxford UK) of 44 genes in DNA prepared from MNCs from 12 CMML patients after obtaining informed consent. Of the 21 samples analyzed, 17 were consecutively collected from 9 patients at the time of MD-CMML and later on during the disease course, showing either long lasting stable MD-CMML disease (median follow-up of 102 month), or progression to MP-CMML or AML, and 4 more were obtained from patients with MP-CMML (2 with previous MD-phase). In some patients, DNA prepared from purified CD3+ cells selected by FACS cell sorting was also analyzed. Candidate mutations were validated by Sanger sequencing. Deep sequencing analysis confirmed TET2 mutations as the most frequent (10/12 patients, 83%) and, the earliest known event in CMML, being present since time of referral in 100% of our cases with sequential samples, supporting their possible role of initiating lesions in CMML. Overall, 9 patients harbored frameshift/nonsense mutations and 1 had an essential splice site substitution. Non-synonymous variations of yet unknown origin were detected in 3 cases while in 1 case the substitution found in MNCs DNA was identified by direct sequencing also in DNA from buccal swab and thus annotated as a SNP. Other documented mutations in variable proportions involved ASXL1, SRSF2, SF3B1, EZH2, CBL, DNMT3A, MPL, NOTCH1, NOTCH2, N- and K-RAS. Among patients who were investigated with sequential samples collected at different time points and/or different disease phases, TET2, SRSF2 and ASXL1 mutations were documented from the first presentation in all cases, suggesting their acquisition as early events possibly driving molecular mechanisms of disease onset. In contrast, besides RAS mutations, which were detected at the time of disease progression from the MD- to the MP-variant in 2 patients, other aberrations possibly associated with disease evolution included EZH2 and CBL mutations, both detected in a small fraction of cells at diagnosis but significantly expanding after progression to MP-CMML. Of note, in one case harboring TET2, ASXL1, EZH2 and CBL concomitant mutations the sequencing of DNA from purified CD3+ cells unveiled the presence of TET2, ASLX1 and CBL mutations also in a significant fraction of T-lymphocytes, suggesting the aberration to possibly arise in a multipotent progenitor, whereas the EZH2 mutation appeared restricted to the myeloid lineage. A combined analysis of sequential samples and single-cell-derived colonies is currently ongoing to better elucidate clonal evolution in CMML, which in turn could help the improvement of disease classification as well as the early identification of patients at risk of disease evolution. Disclosures: No relevant conflicts of interest to declare.