Idarubicin and Cytarabine Combined with Clofarabine or Fludarabine for the Treatment of Newly Diagnosed Acute Myeloid Leukemia: Interim Result of a Phase II Clinical Trial

Abstract Background: The combination of 7+3 with a purine nucleoside analogue improved overall survival (OS) in patients with acute myeloid leukemia (AML). We randomized patients to receive either clofarabine (CIA) or fludarabine (FIA) combined with idarubicin and cytarabine. Methods: Patients who were diagnosed with non-CBF AML or non-APL AML were eligible and were randomized using a Bayesian design to one of the following two induction chemotherapy regimens: CIA (clofarabine 15 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily for 5 days) or FIA (fludarabine 30 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily x 5 days). Patients could proceed to up to 6 cycles of consolidation with the same drugs according to an attenuated schedule. Results: One-hundred-fifty-eight patients (97 patients, CIA; 61 patients, FIA) were treated so far. Patient characteristics and outcome are summarized in Table 1. Median age is 53 years (range, 20-66) in CIA and 49 years (range, 18-66) in FIA. All patients were evaluable for response. Responses are summarized in Table 1. MRD negativity was observed in 43 (74%) patients treated with CIA and in 19 (35%) patients treated with FIA (p=0.049). Median follow up is 21 months and 16 months for patients treated with CIA and FIA, respectively. Treatment was well tolerated with 8-week mortality rates of 1% and 2%, for patients treated with CIA and FIA respectively. The overall median EFS and OS for the whole population were 12 months and 25 months, respectively. Median EFS for patients treated with CIA and FIA was 14 months and 11 months, respectively (p=0.81). No difference in OS between CIA and FIA was observed: the 2-year OS rates were 48% and 53% (p=0.45), respectively. Furthermore, there was no difference in survival whether patients were censored or not at the time of transplantation. Compared to IA regimen in similar patients population, the triplet (FIA and CIA) showed an improvement in 2-year EFS (60% vs 34%; p=0.05) and a trend for better survival (40% vs 32%; p=0.5) in younger patients (40 years and younger). Conclusions: The combination of clofarabine or fludarabine to idarubicin and cytarabine is safe and effective with high CR and negative MRD rates in patients with newly diagnosed AML. Particularly in younger patients, CIA or FIA can lead to a superior outcome compared to 3+7. Table 1. Patient characteristic and outcome CIA N= 97 (61%) FIA N= 61 (39%) P Median age, y 53 [20-66] 49 [18-66] NS PS ≥ 1 79 (81) 48 (79) NS Hemoglobin, g/dL 9.4 [7.3-13.1] 9.2 [7.8-11.4] NS Platelets x 109/L 37 [1-1069] 40 [5-399] NS WBC x 109/L 3.6 [0.6-103.0] 4.1 [0.5-59.4] NS blast (PB) 11 [0-92] 10 [0-94] NS blast (BM) 52 [1-96] 50 [11-96] NS Creatinine, mg/dL 0.79 [0.34-1.35] 0.79 [0.49-1.72] NS LDH, IU/L 819 [325-11952] 684 [231-12042] NS Bilirubin, mg/dL 0.6 [0.2-1.9] 0.5 [0.2-1.5] 0.03 Cytogenetic # evaluable 97 61 NS Diploid 46 (47) 26 (43) -5/-7 or complex 25 (26) 19 (31) Misc 26 (27) 16 (26) FLT3-ITD, # evaluable 94 61 NS Mutated 20 (21) 11 (18) NPM1, # evaluable 90 55 0.05 Mutated 28 (31) 9 (16) Response # evaluable 97 61 0.347 ORR 82 (85) 48 (79) CR 70 (72) 41 (67) CRp 9 (10) 6 (10) PR 1 (1) 1 (2) MRD Negativity 43/58 (74) 19/35 (54) 0.049 Overall MRD Negativity 54/64 (84) 24/37 (65) 0.024 CR/CRp > SCT 33/79 (42) 23/47 (49) 0.435 Death (on study) 2 (2) 1 (2) NS 4-week mortality 0 (0) 1 (2) NS 8-week mortality 1 (1) 1 (2) NS Median F/U (m) 21.3 [0.9-44.7] 16.3 [4.3-42.0] NS Events, # evaluable 97 61 NS Events 51 (53) 31 (51) Primary failure 15 (15) 13 (21) Relapse 26/82 (32) 13/48 (27) Death in CR 6 (9) 4 (7) Disclosures O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:LFB: Consultancy, Honoraria; Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Chahoud:American Society of Hematology (ASH): Other: 2015 HONORS Award recipient.

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WT1 Monitoring of Minimal Residual Disease (MRD) in Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.3695.3695 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3695-3695 ◽

Cited By ~ 1

Author(s):

Michele Malagola ◽

Crisitina Skert ◽

Enrico Morello ◽

Francesca Antoniazzi ◽

Erika Borlenghi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Newly Diagnosed ◽

End Of Treatment ◽

Minimal Residual ◽

Acute Myeloid

Abstract Background: Although a complete remission (CR) can be achieved in 70-80% of newly diagnosed acute myeloid leukemia (AML) patients, relapses occur in up to the 50% of cases. Thus, minimal residual disease (MRD) monitoring is a major issue for early detection of patients at high-risk of treatment failure and relapse. Aim: to dynamically evaluate WT1 pan-leukemic molecular marker of MRD in patients with AML. Matherial and methods: 107 newly diagnosed AML patients consecutively treated between 2010 and 2013 were monitored with quantitative WT-1 from bone marrow (BM) and peripheral blood (PB) at baseline, after induction, after the first consolidation course, before allogeneic stem cell transplantation (allo-SCT), at the 3rd and the 6th month after transplantation Results: At diagnosis, 104/107 (97%) had increased PB and BM WT1 levels assessed according to the ELN assay. Eighty-eight out of 107 patients (82%) achieved a complete remission (CR) after induction, 30/88 (34%) relapsed during follow up and 24/107 (22%) were addressed to allogeneic stem cell transplantation (allo-SCT). By univariate analysis, PB-WT > 50x10^4/ABL and BM-WT1 > 250x10^4/ABL after induction (PB: p=0.02; BM: p=0.04), after consolidation (PB: p=0.003), at the end of treatment (PB and BM: p=0.001), at 3rd month of follow up (PB and BM: p=0.005) and at 6th month of follow up (PB: p=0.005) were associated with a reduced overall survival (OS). By multivariate analysis, a BM-WT1 > 250 x 10^4/ABL at the end of treatment was significantly associated with a reduced OS. In order to adapt the cut-off of WT1 in our series of patients, we considered WT1 levels as continuous variables and categorized them at approximately the 25th, 50th, and 75th percentile. A cut-off of PB-WT1 > 25x10^4/ABL and BM-WT1 > 125x10^4/ABL at the end of the treatment program was identified as correlated with reduced leukemia-free survival (LFS) and OS (p=0.001). Similarly, and restricting the analysis on the 24 patients allo-transplanted in CR, 8/11 (73%) with pre-transplant PB-WT1 ≥ 5 and 4/13 (31%) with PB-WT1 < 5 relapsed, respectively (p=0.04). The incidence of relapse was higher in AML patients with PB-WT1 ≥ 5 measured at 3rd (56% vs 38%; p=0.43) and 6th month (71% vs 20%; p=0.03) after allo-SCT. Interestingly, 5/5 (100%) patients with pre-transplant PB-WT1 ≥ 5 who never reduced this level at 3rd or 6th month after allo-SCT experienced a disease recurrence. Conclusions: our data, although retrospectively collected, show that WT1 monitoring may be useful to predict the relapse in AML patients. Acknowledgments: This work was supported in part by Banca di Credito Cooperativo di Pompiano e Franciacorta and Lions Club Bassa Bresciana Association. Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy.

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Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-130379 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3895-3895

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Group ◽

Newly Diagnosed ◽

Advisory Committees ◽

Acute Myeloid

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3. Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: 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; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.

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Updated Results of a Randomized Phase II Trial of Idarubicin and Cytarabine with Clofarabine or Fludarabine in Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.1067.1067 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1067-1067

Author(s):

Nicholas J. Short ◽

Farhad Ravandi ◽

Xuelin Huang ◽

Jorge E. Cortes ◽

Naveen Pemmaraju ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Cell Transplant ◽

Newly Diagnosed ◽

Historical Cohort ◽

To Receive ◽

Acute Myeloid

Abstract Background: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in acute myeloid leukemia (AML). We sought to evaluate the relative safety and efficacy of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FAI) in adult patients (pts) with newly diagnosed AML. Methods: Adult pts ≤60 years of age with newly diagnosed non-APL AML were randomized using a Bayesian adaptive design to receive either CIA or FAI. All pts received induction with idarubicin 10 mg/m2 IV daily on days 1-3 and cytarabine 1000 mg/m2 IV daily for on days 1-5. Pts in the CIA arm also received clofarabine 15 mg/m2 IV daily on days 1-5; pts in the FAI arm received fludarabine 30 mg/m2 IV daily on days 1-5. Responding pts could receive up to 6 cycles of consolidation with attenuated doses of the same drug combination. The primary endpoint was to compare the event-free survival (EFS) of CIA and FAI. Secondary endpoints included the CR/CRp rates, overall survival (OS) and the safety of the regimens. Results: Between 8/2011 and 6/2016, 182 pts have been randomized to receive either CIA (n=106) or FAI (n=76). Baseline characteristics of the 2 arms were well-balanced and are summarized in Table 1. Response rates are summarized in Table 2. Of the 180 pts evaluable for response, the CR/CRp rate was similar in the CIA and FAI arms (80% and 81%, respectively). However, the rate of MRD negativity by multiparameter flow cytometry at the time of CR/CRp was significantly higher in pts who received CIA than in those who received FAI (80% vs. 64%, respectively, P<0.05). Rates of stem cell transplant (SCT) in first remission were similar in the two arms (35% vs. 38%, respectively). The median duration of follow-up was 27 months. The median EFS and OS for the entire cohort were 12 months and 39 months, respectively. The median EFS was similar in the CIA and FAI arms (13 months and 12 months, respectively, P=0.91). The imbalance in sample size between these two arms was caused by better performance of the CIA arm during the initial period of the trial, although the difference largely disappeared after further follow-up. There was also no difference in OS between the two regimens; the 2-year OS rates were 51% and 57%, respectively (P=0.24). No difference in survival was observed if pts were censored at the time of SCT. Overall, treatment was safe with 8-week mortality rates of 4% in the CIA arm and 1% in the FAI arm. When compared to a historical cohort of pts treated with idarubicin and cytarabine (IA) alone, the triplet regimen (pooled population of CIA + FAI) resulted in improved EFS and OS among a subgroup of patients <40 years of age. In this group of younger patients, the median EFS for CIA/FAI (n=38) and IA (n=16) were 25 months and 9 months, with a 2-year EFS rate of 52% and 33% respectively (P=0.27). There was also a strong trend towards superior OS in the CIA/FAI compared to the IA groups (median OS: not reached vs. 20 months; 2-year OS rate 68% vs. 47%; P=0.08). Conclusions: In adult pts with newly diagnosed AML, CIA and FAI resulted in similar rates of CR/CRp and had similar EFS and OS. Compared to a historical cohort of pts treated with IA alone, the addition of a nucleoside analogue appears to result in superior EFS and OS in younger pts. Disclosures Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Daver:Ariad: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Jain:Novimmune: Consultancy, Honoraria; Infinity: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. Wierda:Acerta: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding. DiNardo:Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

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Longer Follow-Up Of The Combination Of Clofarabine, Idarubicin, and Cytarabine (CIA) As Frontline Therapy For Patients Younger Than 61 Years With Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v122.21.1451.1451 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1451-1451

Author(s):

Aziz Nazha ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

Huang Xuelin ◽

Sangbum Choi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Historical Cohort ◽

Free Survival ◽

Ecog Ps ◽

Acute Myeloid

Abstract Background Clofarabine is a second generation nucleoside analogue with activity in adults with AML. In a phase II trial of clofarabine in combination with idarubicin and cytarabine in newly diagnosed patients (pts) with acute myeloid leukemia (AML) </= 60 years old, the overall response rate (ORR) was 79%. The combination was well tolerated with low induction mortality. Compared to historical pts who were treated with idarubicin and cyarabine (IA), the overall survival (OS) and event-free survival (EFS) were significantly longer for CIA treated pts and mainly for pts </= 40 years old. Aim To report a longer follow up of this study. Patients and Methods Eligible were adults between 18-60 years old with newly diagnosed AML with adequate renal (creatinine </= 1.0 mg/dL) and hepatic (bilirubin </= 1.5 x upper limit of normal, [SGPT and/or SGOT] </= 2.5 x ULN) functions. Ptswere excluded for ECOG PS > 2, cardiac ejection fraction < 45%, or active and uncontrolled infection. For the first 30 pts, induction therapy consisted of Clofarabine 22.5 mg/m2 iv daily (days 1-5), Idarubicin 6 mg/m2 daily (days 1-3), and Cytarabine 0.75 g/m2 daily (days 1-5). From pt 31 onward, induction doses were amended to Clofarabine 20 mg/m2 x 5, Idarubicin 10 mg/m2 x 3, and Cytarabine 1 g/m2 x 5. Pts who did not achieve a complete remission (CR) following induction could receive one re-induction course. Pts in CR/CRp continued with up to 6 consolidation cycles with Clofarabine 22.5 mg/m2 x 3, Idarubicin 6 mg/m2 X 2, and Cytarabine 0.75 g/m2 x 3, subsequently amended to Clofarabine 15 mg/m2 x 3, Idarubicin 8 mg/m2 x 2, and Cytarabine 0.75 g/m2x 3. Results From April 2010 until February 2012, 57 pts were evaluable. With median follow up of 21.5 months (1.5-33.4), the median OS was 27.4 months, median relapse-free survival was not reached, and median EFS was 11.5 months. Patients </= 40 years who received CIA had a better OS (HR 0.43, CI 0.24-0.75, P = 0.007), and better EFS (HR 0.43, CI 0.24-0.75, P = 0.007) compared to pts > 40 years. Compared to a historical cohort of pts treated with IA, CIA continued to show superior OS (HR 0.8, CI 0.51-1.27, P = 0.043). In multivariate analysis, CIA retained its prognostic value on OS even when transplant was added as time dependent covariate (HR 0.84, CI 0.53-1.33, P = 0.04). Pts </= 40 years had superior OS (HR 0.15, CI 0.03-0.65, P= 0.039) when they were treated with CIA compared to IA. Conclusion A longer follow up of the CIA combination in newly diagnosed pts with AML </= 60 continues to show OS benefit compared to IA alone. Patients </=40 years continue to benefit the most from this combination regardless of transplant. A randomized trial to compare this combination to standard therapy in AML is needed to further investigate the role of this combination in AML. Disclosures: Off Label Use: Clofarabine use in AML. Kantarjian:Sanofi-Aventis: Research Funding. Ravandi:Sanofi-Aventis: Research Funding. Faderl:Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Mini- Vs. Regular-Dose CLAG-M (Cladribine, Cytarabine, G-CSF, and Mitoxantrone) in Medically Less Fit Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms

Blood ◽

10.1182/blood-2019-123542 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1364-1364 ◽

Cited By ~ 1

Author(s):

Anna B. Halpern ◽

Megan Othus ◽

Kelda Gardner ◽

Genevieve Alcorn ◽

Mary-Elizabeth M. Percival ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Intensive Therapy ◽

Treatment Intensity ◽

High Grade ◽

Intensive Chemotherapy ◽

Myeloid Neoplasms ◽

Acute Myeloid

Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a >10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight </≥76kg in both arms (days 0-5), and mitoxantrone 6 or 18 mg/m2/day (days 1-3). CLAG at identical doses was used for post-remission therapy for up to 4 (regular-dose CLAG) or 12 (mini-CLAG) cycles. The primary endpoint was feasibility of randomization, defined as ≥26/50 of patient-physician pairs agreeing to randomization. Secondary outcomes included rate of complete remission (CR) negative for measurable ("minimal") residual disease (MRD), rate of CR plus CR with incomplete hematologic recovery (CR+CRi), and overall survival (OS). Results: This trial enrolled 33 patients. Only 3 (9%) patient/physician pairs agreed to randomization and thus randomization was deemed infeasible (primary endpoint). Eighteen pairs chose mini-CLAG-M and 12 regular-dose CLAG-M for a total of 19 subjects in the lower dose and 14 subjects in the higher dose arms. The decision favoring lower dose treatment was made largely by the physician in 5/18 (28%) cases, the patient in 11/18 (61%) cases and both in 2/18 (11%). The decision favoring the higher dose arm was made by the patient in most cases 9/12 (75%), both physician and patient in 2/12 (16%) and the physician in only 1/12 (8%) cases. Despite the limitations of lack of randomization, patients' baseline characteristics were well balanced with regard to age, performance status, TRM score, lab values and cytogenetic/mutational risk categories (Table 1). One patient was not yet evaluable for response or TRM at data cutoff. Rates of MRDneg CR were comparable: 6/19 (32%) in the lower and 3/14 (21%) in the higher dose groups (p=0.70). CR+CRi rates were also similar in both arms (43% vs. 56% in lower vs. higher dose arms; p=0.47). Three (16%) patients experienced early death in the lower dose arm vs. 1 (7%) in the higher dose arm (p=0.43). With a median follow up of 4.2 months, there was no survival difference between the two groups (median OS of 6.1 months in the lower vs. 4.7 months in the higher dose arm; p=0.81; Figure 1). Conclusions: Randomization of medically unfit patients to lower- vs. higher-intensity therapy was not feasible, and physicians rarely chose higher intensity therapy in this patient group. Acknowledging the limitation of short follow-up time and small sample size, our trial did not identify significant differences in outcomes between intensive and non-intensive chemotherapy. Analysis of differences in QOL and healthcare resource utilization between groups is ongoing. Disclosures Halpern: Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Othus:Celgene: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Percival:Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding. Scott:Incyte: Consultancy; Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy. Walter:BioLineRx: Consultancy; Astellas: Consultancy; Argenx BVBA: Consultancy; BiVictriX: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Cladribine is FDA-approved for Hairy Cell Leukemia. Here we describe its use for AML, where is is also widely used with prior publications supporting its use

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Clinical Outcomes Following Treatment with Gilteritinib or Quizartinib in Patients with Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-136118 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Alexander E. Perl ◽

Qiaoyang Lu ◽

Alan Fan ◽

Nahla Hasabou ◽

Erhan Berrak ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase 3 ◽

Hematopoietic Stem ◽

Travel Costs ◽

Baseline Characteristics ◽

Acute Myeloid

Background: Gilteritinib is approved for patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on findings from the phase 3 ADMIRAL trial (Perl AE, et al. N Engl J Med. 2019). A phase 3 trial, QuANTUM-R, demonstrated the benefit of quizartinib in pts with R/R AML with FLT3 internal tandem duplication (FLT3-ITD) mutations (Cortes JE, et al. Lancet Oncol. 2019). Although eligibility criteria across both studies were similar, QuANTUM-R was more stringent as to prior therapy intensity and remission duration, which potentially enriched for higher-risk pts. We sought to describe outcomes from ADMIRAL among pts who otherwise met eligibility for QuANTUM-R. Methods: In this post-hoc analysis, a subset of pts from ADMIRAL were matched with R/R FLT3-ITD+ AML pts from QuANTUM-R on the basis of baseline characteristics and prior treatment criteria. Matched pts were either refractory to initial anthracycline-based chemotherapy or had relapsed ≤6 mos after achieving composite complete remission (CRc) with an anthracycline-based regimen. Results: Overall, 218 pts with R/R FLT3-ITD+ AML in the ADMIRAL trial (gilteritinib, n=140; salvage chemotherapy [SC], n=78) were matched with the QuANTUM-R intention-to treat (ITT) population (N=367; quizartinib, n=245; SC, n=122). Proportions of pts preselected for high-intensity SC were 66% (n=143/218) in the matched ADMIRAL ITT population and 77% (n=281/367) in the QuANTUM-R ITT populations. Demographic and baseline characteristics of the matched ADMIRAL ITT population and QuANTUM-R ITT population were similar. Median durations of exposure to gilteritinib and quizartinib were 3.8 mos and 3.2 mos, respectively, and median number of treatment cycles received were five and four, respectively. Rates of hematopoietic stem cell transplantation (HSCT) were similar in pts treated with gilteritinib (35%; n=49/140) or quizartinib (32%; n=78/245), as were the proportions of pts who resumed gilteritinib (23%; n=32/140) or quizartinib (20%; n=48/245) therapy post-HSCT. Median overall survival (OS) in pts treated with gilteritinib or quizartinib was longer than that observed with SC. After a median follow-up of 17.4 mos, median OS was 10.2 mos with gilteritinib versus 5.6 mos with SC (hazard ratio [HR]=0.573 [95% CI: 0.403, 0.814]; one-sided nominal P=0.0008). After a median follow-up of 23.5 mos, median OS with quizartinib was 6.2 mos versus 4.7 mos with SC (HR=0.76 [95% CI: 0.58-0.98]; one-sided P=0.02). After censoring for HSCT, median OS was 9.3 mos with gilteritinib versus 5.5 mos with SC (HR=0.525 [95% CI: 0.356-0.775]; nominal one-sided P=0.0005), and 5.7 mos versus 4.6 mos with quizartinib versus SC, respectively (HR=0.79 [95% CI: 0.59, 1.05]; one-sided P=0.05). In both QuANTUM-R and matched ADMIRAL populations, the survival benefits of quizartinib and gilteritinib compared with SC were maintained across multiple subgroups, including high FLT3-ITD allelic ratio subsets. Compared with SC, high CRc rates were observed in pts treated with either gilteritinib (57%; n=80/140) or quizartinib (48%; n=118/245). The complete remission (CR) rate with gilteritinib was 23% (n=32/140), whereas the CR rate with quizartinib was 4% (n=10/245) (Table). Median time to achieve CRc was 1.8 mos with gilteritinib and 1.1 mos with quizartinib, median duration of CRc was 5.5 mos with gilteritinib and 2.8 mos with quizartinib. The safety profiles of gilteritinib and quizartinib were generally similar, though aspartate or alanine aminotransferase elevations (any grade) were more frequent with gilteritinib (41-44%) than quizartinib (≤13%), whereas neutropenia (14% vs 34%, respectively), fatigue (24% vs 39%, respectively), and prolonged QT intervals (9% vs 27%, respectively) were more frequent with quizartinib. Conclusions: In pts with R/R FLT3-ITD+ AML and similar baseline characteristics, both gilteritinib and quizartinib were generally well tolerated and associated with improved survival and treatment response compared with SC. Responses to gilteritinib and quizartinib, as measured by CRc, were similar; blood count recovery varied between the two FLT3 inhibitors. Although cross-study comparisons have substantial limitations, the findings suggest that while remission is achieved faster with quizartinib, response may be more durable and survival potentially longer with gilteritinib. Disclosures Perl: Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; New Link Genetics: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Takeda: Honoraria, Other: Travel costs for meeting; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other. Lu:Astellas: Current Employment. Fan:Astellas Pharma: Current Employment. Hasabou:Astellas Pharma: Current Employment. Berrak:Astellas: Current Employment. Tiu:Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas Pharma Global Development: Current Employment.

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Racial Variations in Mutational Profile in Newly Diagnosed Acute Myeloid Leukemia Patients

Blood ◽

10.1182/blood-2020-143329 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 40-41

Author(s):

Tahsin Anwar ◽

Mohammed Mian ◽

Mahran Shoukier ◽

Achuta K Guddati ◽

Moinul Hossain ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Tumor Suppressors ◽

Myeloid Leukemia ◽

Research Funding ◽

Cohesin Complex ◽

Newly Diagnosed ◽

Mutational Burden ◽

Epigenetic Modifiers ◽

Kinase Pathway ◽

Acute Myeloid

Background: Increasing evidence shows the impact of mutational burden in acute myeloid leukemia (AML) and impact on clinical response. Classifying these mutations into exclusive sub-types that are mutually exclusive was recently attempted. We sought to identify differences in mutational burden in AML patients based on race. Methods: We retrospectively reviewed the patient charts to distinguish the mutational markers of AML that substantially impact the outcome of AML. We categorized the mutations in seven functional groups with mutually exclusive mutations Signaling and kinase pathway (FLT3, KRAS, NRAS, KIT, PNPN1, JAK2, CBL), Epigenetic modifiers (DNMT3A, IDH1, IDH2, TET2, ASXL1, EZH2, and MLL/KMT2A), Nucleophosmin (NPM1), Transcription factors (CEBPA, RUNX1, and GATA2), Tumor suppressors (TP53), Spliceosome complex (SRSF2, U2AF1, SF3B1, and ZRSR2), and Cohesin complex (RAD21, STAG1, STAG2, SMC1A, and SMC3). For estimating racial distribution, we included only Whites and African Americans (AA) in the study as they represent 95% of the total population at our Cancer Center. Remission and relapse were defined per standard guidelines. We compiled data of all newly diagnosed AML patients treated at our institution between 2016 to the end of 2019. Both next generation sequencing (NGS) and Polymerase Chain Reaction (PCR) methods of genetic marker recognition techniques were included in the study. Results: 159 patients with AML were included in the analysis. We excluded seven patients of different race, including Asian (n=2), Hispanic (n=3), and unknown (n=2). The median age of the patients at diagnosis were 47 years (range 14 - 84 years), 73.3 % were white Caucasian, and 52.8% were female. The median age for white and African American (AA) patients was similar (47 vs 42 year respectively, p=0.55659), however, AAs have more female than Whites (65.9% vs. 47.8%, p=0.04164). In descriptive analysis of genetic marker mutation distributions between Whites and AA we observed signaling and kinase pathway 26.9% vs 25%, p=0.80231; epigenetic modifiers 14.8% vs 25%, p=0.13144; nucleophosmin 14.8% vs 13.6%, p=85460; transcription factors 5.2% vs 6.82%, p=0.69686; tumor suppressors 7.8% vs 0%; spliceosome complex 6.1% vs 2.3%, p=0.32647 and cohesin complex 1% vs 0%, respectively. Overall, 32.2% achieved complete remission (CR), 21.5% complete remission with incomplete hematologic recovery (CRi) and 45.6% Refractory. The CR + CRi rates of Whites and AA were not statistically significant (54.8% vs 52.3% respectively, p=0.77699). The median number of induction required for CR in both races was the same (2 and 2, respectively). We did not find any differences in number of induction for achieving CR by race. However, the rate of relapse was higher in white patients than in AA (49.1% vs 31.8%, respectively) (p=0.05039). Conclusion: This analysis suggests that there might be variations in functional categories of mutations markers in AML patients by race, tumor suppressors (TP53) found more frequently in whites and epigenetic modifiers in AA. This might be at least in part the reason for a higher relapse rate among whites. Additional studies and larger cohorts are needed to further explore the correlation between race, molecular markers and outcomes for AML. Figure Disclosures Cortes: Daiichi Sankyo:Consultancy, Research Funding;Astellas:Research Funding;BioPath Holdings:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda:Consultancy, Research Funding;Pfizer:Consultancy, Research Funding;Telios:Research Funding;Jazz Pharmaceuticals:Consultancy, Research Funding;Merus:Research Funding;Immunogen:Research Funding;BiolineRx:Consultancy, Research Funding;Bristol-Myers Squibb:Research Funding;Arog:Research Funding;Amphivena Therapeutics:Research Funding;Novartis:Consultancy, Research Funding;Sun Pharma:Research Funding.Kota:Novartis:Consultancy;Pfizer:Consultancy.

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Activity of venetoclax-based therapy in TP53-mutated acute myeloid leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7034 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7034-7034

Author(s):

Mahran Shoukier ◽

Marina Konopleva ◽

Courtney Denton Dinardo ◽

Farhad Ravandi ◽

Michael Andreeff ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Residual Disease ◽

Patient Characteristics ◽

Cytogenetic Response ◽

Effective Treatment Option ◽

Whole Exome ◽

Poor Outcomes ◽

Acute Myeloid

7034 Background: Mutations in TP53 are associated with low response rates to standard therapy and poor outcomes in patients (pts) with acute myeloid leukemia (AML). Combination therapy with the BCL2 inhibitor venetoclax (VEN) has emerged as an effective treatment option for pts with AML. Methods: We reviewed pts with TP53-mutated AML treated with VEN-based therapy between 2014-2018. Mutation testing was performed using a whole-exome next-generation sequencing panel. We analyzed the characteristics of these pts, responses to therapy, and outcomes. Results: Sixty nine pts with TP53-mutated AML treated with VEN were identified, 36 (52%) in frontline & 33 (48%) in the salvage (R/R) setting (Table). The median follow up was 4.5 [0.5 - 48.5] and 8 [1 - 46.5] months for frontline & R/R pts, respectively. Karyotype was complex in 32 (88%) and 29 (88%) pts in the frontline & R/R cohorts, respectively. In the R/R cohort, the number of median prior treatments was 2 [0 – 8]. VEN was given in combination with: 1) Hypomethylating agents (HMA) (87%), 2) FLAG-Ida (3%), 3) Low dose Ara-C (4%), or 4) CPX-351 (6%). The overall response rate (ORR) was 47% & 24% in frontline and R/R pts, respectively. All 6 pts with negative minimal residual disease (MRD) achieved complete cytogenetic response after taking VEN % remain in complete remission (CR) with a median of 3.4 [1.7-4.7] months. Two pts (both R/R) underwent allogeneic stem cell transplantation. Conclusions: VEN based therapy was associated with similar ORR, but higher CR rates in TP53 mutated AML compared with HMAs alone. Larger studies with longer follow up are needed to determine the role of VEN-based therapy in this difficult subset. Patient characteristics and outcome. [Table: see text]

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Optimizing Therapy for Acute Myeloid Leukemia

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2008.0076 ◽

2008 ◽

Vol 6 (10) ◽

pp. 1003-1016 ◽

Cited By ~ 8

Author(s):

Holbrook E. Kohrt ◽

Steven E. Coutre

Keyword(s):

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Cytotoxic Chemotherapy ◽

Newly Diagnosed ◽

Younger Patients ◽

The Past ◽

Diagnostic Technologies ◽

Disease Free ◽

Acute Myeloid

The 10-year overall survival for younger patients with newly diagnosed acute myeloid leukemia has improved threefold in the past 2 decades. This improvement has occurred in large part because of advances in supportive care and efforts to optimize standard induction and consolidation therapies applied in a stratified approach based on predictors of individual patient risk. Innovations in diagnostic technologies have broadened the understanding of key prognostic factors, including cytogenetic and molecular status, which define the extensive interpatient heterogeneity of this clonal disease. Despite this progress, only approximately 25% of patients who experience a complete remission with cytotoxic chemotherapy (50%–70% of patients with newly diagnosed disease) remain disease-free. Efforts to develop novel agents are actively ongoing, particularly for older patients (age ≥ 60), and targeted therapies, for specific subsets of patients are being based on a better understanding of the biology of the disease.

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Outcome of Newly Diagnosed Acute Myeloid Leukemia with Hyperleukocytosis: Retrospective Study of JALSG AML201

Blood ◽

10.1182/blood.v128.22.1616.1616 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1616-1616

Author(s):

Kenji Matsumoto ◽

Shin Fujisawa ◽

Maki Hagihara ◽

Sumihisa Honda ◽

Shigeki Ohtake ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Leukocyte Count ◽

Early Death ◽

Brain Hemorrhage ◽

Newly Diagnosed ◽

Chugai Pharmaceutical ◽

Pre Treatment ◽

Acute Myeloid

Abstract Introduction: Acute myeloid leukemia (AML) with hyperleukocytosis is considered to have a poor prognosis due to a high early death rate secondary to complications such as disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis. The usefulness of pre-treatment reduction of leukemic cells is controversial. We reviewed the clinical characteristics and outcome of adult patients with newly diagnosed AML with or without hyperleukocytosis registered to the Japan Adult Leukemia Study Group (JALSG) AML201study and examined whether early death in induction therapy for this AML subtype influenced the outcome. Methods: We retrospectively reviewed the records of 1,022 patients enrolled in the JALSG AML201 study, which was a phase 3 clinical trial for AML newly diagnosed from December 2001 to December 2005. The JALSG AML201 study administered cytarabine from day 1 to 7 as the induction therapy combined with idarubicin or daunorubicin (Ohtake S, et al. Blood. 2011, 24;117:2358-65.). None of the patients received pre-treatment with oral hydroxyurea or leukapheresis. Patients with performance status (PS) of 4 or severe comorbidities such as septic shock were excluded. Patients' characteristics and outcomes such as rate of early death (defined as death occurring within the first thirty days of treatment), achievement of complete remission (CR), overall survival (OS) rate and cumulative incidence of recurrence (CIR) were compared between patients with hyperleukocytosis and those without hyperleukocytosis. Result: We analyzed retrospectively the records of 1,057 patients with AML registered with the JALSG AML201 study and excluded 35 patients whose leukocyte count or outcome was not recorded. We found 113 AML patients with an initial leukocyte count greater than 100 × 109L−1 (HiLC group). There were 66 males and 47 females, and the median age was 45 years (range: 16-64). Median of leukocyte count before treatment was 160 × 109L−1 (range: 102-382 × 109L−1). According to the French-American-British (FAB) classification, there were four as M0, thirty-four as M1, fifty-six as M2, thirty as M4, and nineteen as M5. Cytogenetic analysis was performed in 107 patients. Eight patients had favorable karyotype, 90 had intermediate karyotype, and nine had unfavorable karyotype. Fifteen percent of patients with hyperleukocytosis had PS of two or greater. We compared the outcome of this AML subset with 909 patients with a leukocyte count lower than 100 × 109L−1 (median count: 10,900, range: 0.77-99.5× 109L−1) who received the same induction chemotherapy as the JALSG AML201 protocol (LoLC group). There was no significant difference between the two groups for age and sex; median age of the patients in LoLC group was 47 years (range: 15-64) with 542 males and 367 females. The frequency of the patients with a favorable karyotype or PS of 0 or 1 was lower in HiLC group than in LoLC group, whereas the rate of FAB M4 or M5 was higher in HiLC as compared to LoLC group. Eighty-two patients (72.5%) in HiLC group and 714 patients (78.5%) in LoLC group achieved CR. Sixty (53%) and twenty-two (19.5%) achieved CR after one and two cycles of treatment, respectively. In contrast, 577 (63%) and 137 (15%) in LoLC group achieved CR after one and two cycles of chemotherapy, respectively. The rate of CR was not significantly different between two groups (p=0.118). However, 5 year OS was significantly lower in HiLC as compared to LoLC group (26.9% vs. 49.4%, p < 0.001). Interestingly, the rate of early death was not different between the two groups (1.65% vs. 1.77%, p = 1.0), although the rate of severe complications, such as DIC, was higher in HiLC compared to LoLC group (32% vs. 10%, p < 0.001). The frequency of brain hemorrhage (1% vs. 1%, p = 1.0) and gastrointestinal hemorrhage (4% VS. 3%, p = 0.294) was not different between two groups. One patient died of brain hemorrhage and one of DIC in HiLC group, whereas five patients died of brain hemorrhage, four of sepsis, and three of pneumonia in LoLC within the first thirty days of treatment. CIR was higher in HiLC (64.7%) as compared to LoLC group (51.6%) (p = 0.0048). Conclusion: We conclude that hyperleukocytosis on presentation did not significantly affect the rate of early mortality during the induction phase of the treatment. It is considered that intensive chemotherapy without pre-treatment would be possible if appropriate supportive cares were given to manage fatal complications such as DIC. Disclosures Kiyoi: MSD K.K.: Research Funding; Alexion Pharmaceuticals: Research Funding; AlexionpharmaLLC.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Phizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding; Celgene Corporation: Consultancy; Chugai Pharmaceutical Co. LTD.: Research Funding. Naoe:Amgen Astellas BioPharma K.K.: Honoraria; CMIC Co., Ltd.: Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Bristol-Myers Squibb: Honoraria; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Celgene K.K.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties.

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