5-Azacitidine Therapy in Patients with Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia: a Single Institution Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4963-4963
Author(s):  
Alessandra Freyrie ◽  
Gianluigi Reda ◽  
Daniele Vincenti ◽  
Mariarita Sciumé ◽  
Francesca Binda ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Median Number ◽  
Observation Time ◽  
Chronic Myelomonocytic Leukemia ◽  
Female Ratio ◽  
Number Of Cycles ◽  
Male To Female ◽  
Myelomonocytic Leukemia

Abstract 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.

scholarly journals Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1831-1831 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Guillermo Montalban-Bravo ◽  
Koji Sasaki ◽  
Naval G. Daver ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Immune Checkpoint Inhibitor ◽  
Overall Response Rate ◽  
Response Rate ◽  
Checkpoint Inhibitor ◽  
Median Number ◽  
Front Line ◽  
Genetics Research ◽  
Number Of Cycles

Abstract Introduction: Myeloid cells express PD1 and CTLA-4. Expression of these molecules is enhanced by azacitidine (AZA). Treatment of patients (pts) with nivolumab (Nivo) and anti-PD1 antibody or ipilimumab (Ipi) and anti-CTLA-4 antibody results in the upregulation of CTLA-4 in patients treated with Nivo and reversely of PD1 in patients treated with Ipi, potentially as a mechanism of evasion. In view of the activity of Nivo and Ipi in MDS (Garcia-Manero, ASH 2016), we hypothesized that dual combination of Nivo + Ipi with AZA could have significant activity in high risk MDS. Methods: To study this, we designed a basket exploratory phase 2 trial of ICPI in MDS. Patients with MDS age 18 or older with adequate renal and hepatic function without history of autoimmune disorders were eligible. Patients were divided into front-line and HMA-failure cohorts. Front-line patients were treated with AZA 75mg/m2 iv daily days 1-5 of a 28 day cycle with Nivo 3 mg/kg iv on days 6 and 20 + Ipi 3 mg/kg iv on day 6. Patients with HMA failure where treated with Nivo 3 mg/kg iv on days 1 and 15 + Ipi 3 mg/kg iv on day 1 of a 28 day cycle. The study design allowed for AZA add-back after 6 cycles of therapy if there was no response or progression. The maximum size per cohort was 20 pts. The primary endpoint was to determine the safety of Nivo or Ipi as single agents or in combination with AZA. Secondary objectives included overall response rate (ORR) and assessment of biological activity. Responses were evaluated following the revised 2006 IWG criteria. The study included stopping rules for response and toxicity. Results: The median follow up was 4.7 months [range 0-10 months]. From January 2017 to April 2018, 14 patients were treated, 6 pts on front-line cohort and 8 on HMA failure. The median age was 69 years [range 52-80]. A total of 4 (29%) pts had Int-1 risk, 6 (43%) had Int-2 and 4 (29%) had High risk by IPSS. Next generation sequencing on whole bone marrow extracted DNA was performed using a 28 gene panel in 5 pts and an 81-gene panel in 9 pts. Cytogenetic abnormalities and identified mutations are shown in Table 1. Median number of marrow blasts was 10 [range 1-16]. Median Hgb was 9.5g/dL [range 7.3-10.9 g/dL], median WBC was 1.5x109/L [range 0.9-4.7] and platelets was 29x109/L [range 8-117]. A total of 13 pts are evaluable for response at the time of analysis. A total of 3 (38%) pts in the HMA failure cohort received AZA after 6 cycles of therapy. The median number of cycles was 4 [range 1-10] with a median number of cycles to response of 3 [range 1-4]. The overall response rate was 50% (3/6) in the frontline cohort, all of them complete responses, and 29% (2/7) in the HMA failure cohort, including 1 complete response and 1 hematological improvement. Adverse events are shown in Table 2. Treatment with Ipi or NIvo had to be held due to rash in 2 pts, due to elevation of creatinine in 2 pts. Early mortality was observed in 1 patient and this was due to pneumonia complicated with respiratory failure and renal failure. The median overall survival is NR in the frontline cohort and is 8.4 months in the HMA failure cohort (Figure 1). Conclusion: Preliminary results suggest double immune checkpoint inhibitor blockade with Ipi and Nivo in combination with AZA in the frontline setting, or in pts with HMA failure is associated with a tolerable safety profile and clinical activity. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Daver:Incyte: Research Funding; Novartis: Consultancy; Alexion: Consultancy; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; Otsuka: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Sunesis: Research Funding; Karyopharm: Consultancy; BMS: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Karyopharm: Research Funding; Kiromic: Research Funding; ImmunoGen: Consultancy. DiNardo:Abbvie: Honoraria; Celgene: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Medimmune: Honoraria; Bayer: Honoraria. Ravandi:Xencor: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Bose:Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Blueprint Medicines Corporation: Research Funding. Pemmaraju:plexxikon: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; abbvie: Research Funding; SagerStrong Foundation: Research Funding; Affymetrix: Research Funding. Cortes:novartis: Research Funding. Kadia:Jazz: Consultancy, Research Funding; BMS: Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; BMS: Research Funding; Celgene: Research Funding; Takeda: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding.

Response Rates of Phase 2 and Phase 3 Trials of Decitabine (DAC) in Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2515-2515 ◽  
Author(s):  
Hussain I. Saba ◽  
Michael Lübbert ◽  
P.W. Wijermans
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Median Duration ◽  
Response Rate ◽  
Response Rates ◽  
Median Number ◽  
Phase 2 ◽  
Phase 3 ◽  
Overall Response ◽  
Number Of Cycles

Abstract Background: MDS is characterized by ineffective hematopoiesis, resulting in cytopenias with dysplastic morphology of peripheral blood cells and bone marrow. Decitabine (Dacogen™ DAC) is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. Due to the requirement for DNA synthesis and subsequent demethylation, decitabine may require prolonged administration to achieve maximum benefit. Overall response rates (ORR) (CR+PR) from 1 pivotal Phase 3 (D-0007) and 3 supportive Phase 2 trials (91–01, 95–11 and 97–19) in patients with intermediate and high risk MDS receiving DAC are being presented. Methods: The Phase 2 trials were open-label and single-arm, with a minimum of 4 treatment cycles and a maximum of 8 cycles, while the D-0007 was a 1:1 randomized comparison of DAC plus supportive care (SC) vs. SC alone, with a maximum of 10 cycles of therapy. The D-0007 study design dictated that patients be removed from therapy following 8 cycles of decitabine if CR was not achieved, and 6 cycles in the absence of PR. Patients who maintained a CR for 2 cycles were removed from therapy. Results: A total of 271 unique patients were exposed to DAC in the studies (n= 89 in D-0007, n=29 in 91–01, n = 66 in 95–11, n = 87 in 97–19). Patients receiving DAC had similar demographics and disease characteristics in all trials. Responses were observed in all IPSS and FAB subgroups. The percent of patients classified as intermediate-2 and high risk (according to the International Prognostic Scoring System) in the Phase 3 trial was 69% vs. 72% in the Phase 2 trials. By intent-to-treat analysis, the ORRs were 45%, 26%, and 26% respectively, for the Phase 2 trials. These results were corroborated in the Phase 3 trial, where the response rates were evaluated according to the more robust International Working Group MDS criteria, following a blinded, centralized bone marrow review. The D-0007 overall response rate was 17% for DAC (9% CR, 8% PR) vs. 0% for SC (p<0.001). Responses were durable, lasting a median of 266 days. The 95–11 and 97–19 response rates were also centrally reviewed, while 91–01 responses were investigator-assessed. In the 91–01 trial, the ORR was 45% (28% CR, 17% PR) with a median duration of response of 217 days, the 95–11 ORR was 26% (21% CR, 5% PR) with a median duration of 250 days, and the 97–19 ORR was 26% (22% CR, 5% PR) with a median duration of 146 days. Hematologic improvement (HI) was also evaluated according to varied criteria in conjunction with the response rates in all 4 studies; 12 patients (13%) had HI in D-0007, 2 patients (7%) in 91–01, 8 patients (12%) in 95–11, and 13 patients (15%) in 97–19. The D-0007 trial design dictated that patients who maintained a CR for 2 cycles be removed from therapy. As a result, the median number of cycles delivered was 3, with only 48% of patients receiving ≥4 cycles. In the Phase 2 studies, the median number of cycles is clearly higher (median 4), with the majority of patients receiving at least 4 cycles and approximately one-third of patients receiving ≥6 cycles. Conclusion: While response rates of ≥17% were demonstrated in these trials, the optimization of hypomethylating agents for maximum efficacy is very likely to include prolonged therapy, which may correlate with increases in response rate and duration.

Efficacy of Azacitidine In the Treatment of Chronic Myelomonocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4017-4017
Author(s):  
Melissa L. Teichman ◽  
Gene A. Wetzstein ◽  
Viet Q. Ho ◽  
Jeffrey E. Lancet ◽  
Alan F. List ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Research Funding ◽  
Response Rate ◽  
Response Rates ◽  
Chronic Myelomonocytic Leukemia ◽  
Low Risk ◽  
Randomized Clinical Study ◽  
Baseline Characteristics ◽  
Myelomonocytic Leukemia

Abstract Abstract 4017 Background: Chronic myelomonocytic leukemia (CMML) is a heterogeneous disease sharing features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). FDA approved indications for azacitidine and decitabine include CMML as subset of MDS. Fewer than 10 patients with CMML, however, were treated in each of the original studies. In this study we report our institutional experience of azacitidine treatment of CMML patients. Methods: This was a retrospective review of CMML patients who received azacitidine at Moffitt Cancer Center. The primary endpoint was determining response rate to azacitidine utilizing International Working Group 2006 criteria (IWG 2006). Secondary objectives were to assess treatment tolerance and overall survival. Descriptive statistics were used for baseline characteristics and response rates. Kaplan-Meier estimates were used for evaluation of overall survival. Results: Between July 2004 and December 2009, 35 CMML patients treated with azacitidine were identified. Table-1 summarizes baseline characteristics of those patients. Based on Dusseldorf CMML risk criteria one patient (2.9%) was low risk, 17 (48.7%), intermediate, 7 (20%) high risk and 10 (28.6%) were unknown. According to MD Anderson CMML risk model, 11 (31.4%) were low risk, 12 (34.3%) int-1, 2 (5.7%) int-2, 1 (2.9%) high risk and 9(25.7%) unknown. The median number of azacitidine cycles was 6.0 (1-34) The best response rates by IWG 2006 criteria were complete response (CR) 5 (14.3%), marrow CR 4 (11.4%), partial response (PR) 1 (2.9%), and hematological improvement (HI) 7 (20%). The overall response rate was 48.6%. The median OS was 25 month (95%CI 13.8–36.1 mo). Conclusions: In this retrospective analysis, response to azacitidine in CMML was similar to response rates reported in other MDS patients on azacitidine studies. The median overall survival is comparable to AZA-001 randomized clinical study. Disclosures: Lancet: Celgene: Research Funding. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

scholarly journals Outcome After Azacitidine Treatment in Patients with High-Risk Myeolodysplastic Syndrome, Chronic Myelomonocytic Leukemia Type 2 and Acute Myeloid Leukemia – A Single Center Experience (Preliminary Data)

2020 ◽  
Vol 47 (4) ◽  
pp. 38-43
Author(s):  
V. Varbanova ◽  
A. Anastasova-Postadzhiyan ◽  
A. Nedeva ◽  
I. Nikolov ◽  
I. Kindekov ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Preliminary Data ◽  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Disease Assessment ◽  
Single Center ◽  
Platelet Response ◽  
Myelomonocytic Leukemia ◽  
Acute Myeloid

AbstractIntroduction: Hypomethylating agents have become a standard therapy for certain myeloid malignancies.Aim: The aim of this preliminary study was to assess efficacy and safety of azacitidine in patients with myelodysplas tic syndromes (MDS), chronic myelomonocytic leukemia with 10-29% blasts (CMML-2) and acute myeloid leukemia (AML) treated in a single center.Material and Methods: Twenty-six (69% male and 31% female, median age 67.8 years) patients (MDS, = 15; CMML-2, n = 2; AML, n = 9) treated with azacytidine in the period April 2017 to October 2018 year were included in the study. Disease assessment was performed after the 3rd cycle, 6th cycle, and at progression.Results: The median number of administered cycles was 6 (1-16). Erythroid response was achieved in 46.7% after 3rd cycle and 66.7% after 6th cycle. Platelet response was reached in 72.7% after 3rd cycle and 40% after 6th cycle and neutrophil hematological improvement in 27.3% and 50%, respectively. Only one patient (8.3%) progressed after the 6th cycle, stable disease or better marrow response was achieved in the others. The median progression free survival (PFS) and overall survival (OS) were 7.9 and 10.7 months in the MDS group and 9.7 and 11.5 months in the AML group, respectively. None of the patients with CMML-2 progressed at the end of the study. The only found factor to correlate with shortened PFS and OS was IPSS high risk MDS. The most frequent grade ≥ 3 adverse events was neutropenia 38.5%, followed by anemia 15.4% and thrombocytopenia 11.5%.Conclusion: The therapy with azacitidine is an option for elderly patients with high-risk MDS, AML and CMML-2 that provides PFS and OS for approximately one year irrespective of age or nosological subgroup. These are preliminary data and larger patient cohort and longer follow-up period are needed for clinical conclusions.

Feasibility of hypomethylating therapy in patients with renal insufficiency

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7089-7089
Author(s):  
G. Batty ◽  
H. Kantarjian ◽  
J. J. Issa ◽  
G. Garcia-Manero ◽  
S. Pierce ◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Response Rate ◽  
Objective Response ◽  
Standard Of Care ◽  
Complete Response ◽  
Median Number ◽  
Epigenetic Therapy ◽  
Myelomonocytic Leukemia

7089 Background: Epigenetic therapy with hypomethylating agents (HA) is the standard of care in patients (pts) with myelodysplastic syndrome (MDS). Although neither 5-azacytidine (5AZA) nor 2'-deoxy azacytidine (decitabine; DAC) are excreted by the kidneys, many studies exclude pts with a serum creatinine level (sCr) ≥ 1.5 mg/dL. Moreover, there are no reports of use of these agents in pts with renal insufficiency (RI) commonly seen in pts with MDS. Methods: We investigated the outcomes of pts with RI and MDS, chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML) receiving therapy with HA. RI was defined by a sCr ≥ 1.5 mg/dL. We examined the compliance, dose adjustments (DA), and complications of treatment with DAC and 5AZA given at standard doses. We used the International Working Group criteria to evaluate the response rates. Data for pts with sCr > 2 mg/dL were compared to pts with sCr ≤ 2 mg/dL (Kantarjian H, et al, Blood. 2007). Results: Forty-two pts with sCr ≥ 1.5 mg/dL (including 17 with MDS, 16 with AML, and 9 with CMML) were treated with DAC or 5AZA alone or in combination with other agents (primarily histone deacetylase inhibitors). 14 (33%) and 28 (67%) of the pts received 5AZA and DAC, respectively. The median number of courses was 4.5 (range 1–19). 9 pts (21%) required treatment delay or discontinuation, and 12 pts (28%) required dose reduction (DR). Overall, 25 (62%) had an objective response (OR), and 4 pts (9%) had complete response (CR). 15 (36%) and 7 (17%) of the pts experienced episodes of therapy-related infections and bleeding, respectively. Among 12 pts who had sCr > 2.0 mg/dL, 7 pts (58%) required DR due to myelosuppression (n = 3) and to worsening of renal function (n = 4). The incidence of complications, DA, and the response rate were not significantly different for pts with sCr > 2.0 mg/dL. Conclusions: The use of HA is well tolerated in pts with MDS and AML and RI who achieved comparable OR rates to those without RI. Dose adjustment might be required in some pts. [Table: see text] [Table: see text]

scholarly journals Impact of Bone Marrow Fibrosis and Early Response on Outcome after Azacitidine Therapy in 94 Patients with Myelodisplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3187-3187
Author(s):  
Gianluigi Reda ◽  
Marta Riva ◽  
Ramona Cassin ◽  
Bruno Fattizzo ◽  
Martina Pennisi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Severe Neutropenia ◽  
Bone Marrow Fibrosis ◽  
Myelomonocytic Leukemia ◽  
Marrow Fibrosis ◽  
Acute Myeloid

Abstract 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<0.0001]. Notably, cases with pre-AZA fibrosis ≥MF-1 showed lower OS [2.26 (1.28-3.99) p=0.005]. In conclusion we provide evidence of no relationship between neutropenia and infections and of no impact of toxicities on dose-density and ORR to AZA treatment. Moreover, high marrow fibrosis and hypercellularity may affect response to AZA therapy. Further studies are needed to disclose the clinical/biological significance of marrow fibrosis/cellularity in the era of hypomethylating agents. Disclosures Reda: Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding.

scholarly journals Asxl1 C-terminal mutation perturbs neutrophil differentiation in zebrafish

Leukemia ◽  
2021 ◽  
Author(s):  
Xiao Fang ◽  
Song’en Xu ◽  
Yiyue Zhang ◽  
Jin Xu ◽  
Zhibin Huang ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Nonsense Mutations ◽  
Myeloid Malignancies ◽  
A Subunit ◽  
Neutrophil Differentiation ◽  
Polycomb Repressive Complex 1 ◽  
Myelomonocytic Leukemia ◽  
Inhibitor Treatment ◽  
Acute Myeloid

AbstractASXL1 is one of the most frequently mutated genes in malignant myeloid diseases. In patients with myeloid malignancies, ASXL1 mutations are usually heterozygous frameshift or nonsense mutations leading to C-terminal truncation. Current disease models have predominantly total loss of ASXL1 or overexpressed C-terminal truncations. These models cannot fully recapitulate leukemogenesis and disease progression. We generated an endogenous C-terminal-truncated Asxl1 mutant in zebrafish that mimics human myeloid malignancies. At the embryonic stage, neutrophil differentiation was explicitly blocked. At 6 months, mutants initially exhibited a myelodysplastic syndrome-like phenotype with neutrophilic dysplasia. At 1 year, about 13% of mutants further acquired the phenotype of monocytosis, which mimics chronic myelomonocytic leukemia, or increased progenitors, which mimics acute myeloid leukemia. These features are comparable to myeloid malignancy progression in humans. Furthermore, transcriptome analysis, inhibitor treatment, and rescue assays indicated that asxl1-induced neutrophilic dysplasia was associated with reduced expression of bmi1a, a subunit of polycomb repressive complex 1 and a reported myeloid leukemia-associated gene. Our model demonstrated that neutrophilic dysplasia caused by asxl1 mutation is a foundation for the progression of myeloid malignancies, and illustrated a possible effect of the Asxl1-Bmi1a axis on regulating neutrophil development.

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