Lower c-D-Index in Acute Myeloid Leukemia with Febrile Neutropenia during Chemotherapy

Background: The D-index is a clinical tool used to assess the total severity of a patient's neutropenia. The D-index was originally proposed by Portugal et al. as a quantitative evaluation of the severity of a patient's neutropenia. The utility of the D-index has been validated in various clinical settings. The D-index has recently been investigated as a potential predictor of febrile neutropenia (FN) and infections resulting from neutropenia. The D-index varies according to the ending period for the calculation. If the period until the onset of FN is included, this is called the cumulative D-index (c-D-index) and reflects an accumulation of neutropenia until FN. The c-D-index is thought to represent more accurate and ongoing severity of patient's neutropenia. Purpose: To examine whether the D-index/c-D-index are a useful predictor of the onset of FN or various infections in acute myeloid leukemia (AML) patients treated with chemotherapy. Methods: This study included consecutive AML patients treated in our hospital between November 1998 and December 2018, retrospectively. The inclusion criteria were age 18-74 years at the onset, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2, hematologic diagnosis of AML, and treatment with Japan Adult Leukemia Study Group (JALSG) 97 or JALSG 201 protocol regimens. We used the JALSG disease risk as the risk factors at the onset of AML. We extracted the cases that fulfilled all the above criteria. We collected all FN events from the start of a patient's induction chemotherapy to the end of the final consolidation therapy. We collected complete FN events during chemotherapy and evaluated associations with the severity of FN and infectious events. FN was defined as a fever ≥38°C with a neutrophil count <500 cells/μL. If a fever ≥38°C was observed again after the body temperature had decreased to <37.5°C for over 48 h, it was defined as a new febrile episode. Results: A total of 51 patients (25 women, 26 men; median age 53 years, range 18-74 years) met the eligibility criteria. These patients experienced 171 FN events (68 induction and 103 consolidation chemotherapy episodes). The JALSG prognosis score indicated good risk in 16 subjects, intermediate risk in 19, poor risk in 14, and unknown in 2. The response rate to induction chemotherapy was 56.8% (29/51), and 80.4% (41/51) of patients were alive at the end of follow-up. In the univariate analysis of the risk factors for the onset of FN, the D-index, the c-D-index, PS, remission status, diabetes mellitus, and neutrophil count at the start of chemotherapy were identified. Multivariate analysis showed the c-D-index, but not the D-index, as a risk factor for the onset of FN (P = 0.00903). The statistically significant explanatory factors for microbiologically proven infections were high-dose Ara-C (P = 0.00103) and diabetes mellitus (P = 0.0251). The most prolonged period of FN was observed in subjects in whom the site of infection was respiratory comparing to other sites; blood stream infection (P = 0.0018), oral cavity (P = 0.0026), and gastro-intestine (P = 0.047), respectively. The D-index was significantly higher in patients with FN (P = 0.0028). Conversely, the c-D-index was significantly lower in patients with FN (P = 0.0016). The mean c-D-index in patients with FN was 3842 ± 1811 (the 75% tile range is 5517), and the mean c-D-index in patients without FN was 5597 ± 4289. The median day of the onset of FN was day 14 ± 5. Among the patients with FN, c-D-index were lower in patients with documented infection compared to those whom without it (2681 vs 4295, P = 0.0006). Conclusion: The D-index did not predict the onset of infection. However, the c-D-index can predict the onset of FN. The c-D-index depict the onset of FN within the mean value of 3842 at the median day 14. Among FN events, the onset of microbiologically proven infections were significantly associated to high-dose Ara-C and diabetes mellitus. Among FN patients, the documented infection occurred in significantly lower c-D-index patients. This may suggest documented infection will be diagnosed in the earlier stage of febrile episode among patients with AML during chemotherapy. Respiratory symptoms on the onset of FN are a risk factor for the prolonged duration of FN. Future research should focus on whether comorbidity at diagnosis and the value of the D-index at the onset of FN are associated with poor treatment outcomes in AML. Disclosures Kadowaki: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Daiichi Sankyo Company Ltd.: Honoraria, Research Funding; Eisai Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Asahi Kasei Pharma Corporation: Honoraria, Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria, Research Funding; Taiho Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria, Research Funding; Novartis AG: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Merck & Co., Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Company Ltd.: Honoraria, Research Funding.

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Dose-related mucositis with hydroxyurea for cytoreduction in acute myeloid leukemia

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155218758499 ◽

2018 ◽

Vol 25 (4) ◽

pp. 801-805 ◽

Cited By ~ 1

Author(s):

Morgan L Trepte ◽

Jessica J Auten ◽

Stephen M Clark ◽

Hendrik W van Deventer

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Medical Center ◽

Prescribing Patterns ◽

High Dose ◽

Dosing Strategies ◽

Safety And Toxicity ◽

Dosing Strategy ◽

Acute Myeloid

Hyperleukocytosis occurs in 15–20% of all newly diagnosed acute myeloid leukemia patients and requires emergent treatment with leukapheresis or hydroxyurea when accompanied by signs or symptoms of leukostasis. Currently, there is no standardized hydroxyurea dosing strategy, although usual dosing ranges from 50 to 150 mg/kg/day, and prescribing patterns vary significantly among oncologists and institutions. In addition to other hematologic and dermatologic toxicities, the use of hydroxyurea may be associated with significant mucositis and mucositis-related pain. The purpose of this study was to compare mucositis-related pain between two different hydroxyurea dosing strategies in patients who received hydroxyurea for cytoreduction during induction. A retrospective chart review of adult patients with acute myeloid leukemia treated with chemotherapy at UNC Medical Center from April 2014 to April 2016 who received at least one dose of hydroxyurea for cytoreduction was conducted. This study compared the safety and toxicity profiles of hydroxyurea in patients who received high-dose hydroxyurea (≥75 mg/kg/day) versus low-dose hydroxyurea (<75 mg/kg/day). Safety and toxicity were evaluated based on indicators of mucositis and cumulative intravenous narcotic requirements following induction chemotherapy. Data collection included baseline demographics, mucositis risk factors, baseline laboratory values, hydroxyurea dosing, mucositis indicators, and pain indicators. A total of 55 patients were included in the study, 21 patients (38.2%) received the high-dose hydroxyurea dosing strategy. The high-dose hydroxyurea dosing strategy had a significantly higher white blood cell count at diagnosis, increased duration of hydroxyurea, and received a higher cumulative dose of hydroxyurea. Additionally, the high-dose hydroxyurea dosing strategy patients were associated with significantly more grade 3 or 4 mucositis requiring a formulation change (0% versus 28.6%, p = 0.002) and significantly higher cumulative intravenous narcotic requirements during induction (p = 0.019). No significant differences in baseline demographics or mucositis risk factors between dosing strategies were identified. The high-dose hydroxyurea dosing strategy patients had a significant increase in cumulative intravenous narcotic requirements and formulation changes, both common interventions made for the treatment of mucositis. Additional studies are needed to further elucidate the safety and toxicity profiles of hydroxyurea dosing strategies and to explore the correlation between total cumulative hydroxyurea dose and total cumulative narcotic requirements.

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Acute Myeloid Leukemia: Longterm Outcome Predicted by Age and Genetic Groups

Blood ◽

10.1182/blood.v120.21.1509.1509 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1509-1509

Author(s):

Thomas Buchner ◽

Wolfgang E. Berdel ◽

Utz Krug ◽

Claudia Haferlach ◽

Susanne Schnittger ◽

...

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Standard Dose ◽

Multivariable Analysis ◽

High Dose ◽

Genetic Groups ◽

Longterm Outcome ◽

Acute Myeloid

Abstract Abstract 1509 Introduction: Both, patients' age and genetic groups are important predictors of outcome in AML while their influence remains poorly quantified and compared. Methods: In the AMLCG (Acute Myeloid Leukemia Cooperative Group) 1999 trial 1470 patients (pts) were 16–59y and 1747 pts were 60–85y of age. 95% of pts could be classified according to genetic risk groups as standardized on behalf of the ELN (Blood 2010;115:453-74). Their treatment was randomized between TAD-HAM versus HAM-HAM induction (TAD, standard dose thioguanine, cytarabine, daunorubicin 60mg/m2 × 3; HAM, high-dose cytarabine 3g/m2 × 6, mitoxantrone 10mg/m2 × 3), TAD consolidation and monthly maintenance vs TAD and autologous SCT, any chemotherapy + vs – G-CSF priming. All assignment was done upfront. Pts of <60y received routine double induction and full dose HAM while pts of 60+y preferentially received only 1 course induction and HAM at 1g instead of 3g cytarabine/m2 × 6. Results: With little difference according to randomizations, pts <60y and 60+y achieved a complete remission (CR) rate of 65% and 51% (p<.001), a 5y overall survival (OS) of 41% and 14% (p<.001), and a 5y ongoing remission duration (RD) of 47% and 21% (p<.001). We particularly focussed on pts around 60y of age and compared the 231 pts of 57–59y with the 315 pts of 60–62y. Corresponding to their similar age the two groups showed similar baseline characteristics. In contrast and due to the cutoff point for age adaption at 60y they differed considerably in treatment. Expressed by the cumulative dosage of cytarabine in induction and early consolidation, the difference between the two groups was by factor 3.9. This difference, however, did not translate into a different outcome being 60% vs 57% CR (p=0.59), 28% vs 25% 5y OS (p=0.40) and 32% vs 29% RD at 5y (p=0.46). Through focussing on patients around 60y a relevant influence of chemotherapy intensity and age adaption could thus be excluded. A multivariable analysis in the complete patients between 16 and 85y of age identified genetic groups and age (as a continuous variable) to be the only risk factors predicting CR, OS as well as RD whereas other risk factors such as secondary AML, WBC, and LDH were predictive only for subsets of endpoints. Among all treatment variables only HAM-HAM induction was associated with a slightly superior RD (p= 0.0715). Grouping by age resulted in 4 age categories (16–46y:n=683, 47–59y: n=787, 60–66y: n=815, and 67+y: n=932) with significantly different OS as well as RD. Subdividing by genetic groups (favorable: n=593, intermediate I: n=1169, intermediate II: n=526, adverse: n=780) distinguished 3 significantly different categories (favorable, intermediate, adverse), a pattern observed in all age groups. Conclusion: In a defined representative population of pts with AML the longterm outcome was mainly determined by age and genetic groups but not by treatment intensity or variables, nor by other prognostic factors. Both, age and genetic groups should thus contribute to a reliable prediction of outcome in AML. Disclosures: No relevant conflicts of interest to declare.

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Comparison of Pegfilgrastim and Filgrastim to Prevent Neutropenic Fever during Consolidation with High Dose Cytarabine for Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-118336 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1404-1404

Author(s):

Evan Field ◽

Paolo F Caimi ◽

Brenda Cooper ◽

Jane Little ◽

Ehsan Malek ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Solid Tumors ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Neutropenic Fever ◽

High Dose ◽

Consolidation Chemotherapy ◽

High Dose Cytarabine ◽

Acute Myeloid

Abstract Background: Granulocyte colony stimulating factor (G-CSF) to prevent neutropenic fever is a well-accepted standard of care to minimize the risk of neutropenic fever during consolidation chemotherapy for acute myeloid leukemia (AML). Although prospective, randomized clinical trials of filgrastim versus depot pegfilgrastim demonstrated biologic equivalency, retrospective studies in patients with solid tumors suggest the use of pegfilgrastim results in reduced rates of admission for neutropenic fever. Patients undergoing AML consolidation may be at higher risk for admission, as with solid tumors. Biosimilars for filgrastim (filgrastim-sndz and tbo-filgrastim) and pegfilgrastim (pegfilgrastim-jmdb) are creating market forces that may make daily administered agents an attractive alternative to pegfilgrastim, and therefore additional observational studies to clarify of the safety of daily administered G-CSF vs depot injections. We hypothesize that the use filgrastim over pegfilgrastim may result in higher hospital admission rates in AML patients undergoing consolidation chemotherapy outside the setting of prospective trials. Methods: Patient charts from the year 2004 through early 2017 diagnosed with AML at the Seidman Cancer Center of University Hospitals Cleveland Medical Center (UHCMC) were reviewed as a retrospective cohort study. Patient were included who received at least one cycle of high dose cytarabine during 1st complete remission, and received filgrastim or pegfilgrastim were considered available for analysis. Individual cycles of chemotherapy were assessed for potential adverse outcomes with the use of different forms of GCSF. The primary outcome of interest is hospitalization during consolidation chemotherapy. The incidence of hospitalization was analyzed using longitudinal logistic regression with generalized estimating equations for statistical inference assuming exchangeable variance-covariance structure of multiple hospitalizations from the same patients. Results 436 patient charts were reviewed identifying 165 patients receiving at least one cycle of HiDAC chemotherapy. Of these, 156 patients received either filgrastim or pegfilgrastim, representing 256 cycles of high dose cytarabine chemotherapy supported with GCSF. Patients receiving filgrastims vs pegfilgrastim differed in the number of HiDAC cycles received (1.64 vs 1.97, p = 0.046), the distribution of favorable risk AML (11.9% vs 32.7%, p = 0.035). Groups did not differ based on age, sex, race, initial response to therapy, and proportion of secondary AML. After controlling the effects of age, sex, race and initial clinical response, treatment (filgrastim vs. pegfilgrastim) was significantly associated with hospitalization during consolidation therapy (p = 0.005). Specifically, the odds of having hospitalization for patients treated with Filgrastim is estimated to be 2.31 times the odds of having hospitalization for patients treated Pegfilgrastim with 95% CI (1.28, 4.17). Also, the estimated probability of having hospitalization for patients treated with filgrastim was 0.59 (95% CI: 0.43- 0.73) vs. 0.38 (95% CI: 0.27 - 0.51) for patients treated with pegfilgrastim. Conclusions: The use of filgrastim was found to be statistically significantly associated with and increased risk of hospitalization. Disclosures Caimi: Kite Pharma: Other: Advisory Board Participation; Celgene: Speakers Bureau; Genentech: Other: Advisory Board PArticipation, Research Funding; Kite Pharma: Other: Advisory Board Participation. Little:PCORI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding; NHLBI: Research Funding. Malek:Sanofi: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau.

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Condensed Versus Standard Schedule of High-Dose Cytarabine Consolidation Therapy with Pegfilgrastim Growth Factor Support in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.337.337 ◽

2016 ◽

Vol 128 (22) ◽

pp. 337-337

Author(s):

Sonia Jaramillo ◽

Axel Benner ◽

Jurgen Krauter ◽

Hans Martin ◽

Thomas Kindler ◽

...

Keyword(s):

Valproic Acid ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Growth Factor ◽

Myeloid Leukemia ◽

Research Funding ◽

High Dose ◽

Consolidation Therapy ◽

High Dose Cytarabine ◽

Acute Myeloid

Abstract Background: The concept of intensive post-remission chemotherapy in acute myeloid leukemia (AML) is based on the observation that despite achievement of a first complete remission (CR) after intensive induction therapy virtually all patients relapse in the absence of further treatment. Moreover, randomized studies showed that intensive post-remission consolidation chemotherapy was superior to prolonged low-dose maintenance therapy in younger patients. With regard to consolidation therapy, the landmark study conducted by the Cancer and Leukemia Group B established the current standard for patients aged 60 years and younger with high-dose cytarabine (HDAC) 3g/m² bidaily on days days 1, 3, and 5. Aims: to compare a compressed schedule of high-dose cytarabine (HDAC) on days 1, 2, and 3 with the standard HDAC given on days 1, 3, and 5 as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in patients in first CR receiving repetitive consolidation cycles for acute myeloid leukemia. Methods: Patients (18 to 60 years) were accrued between 2004 and 2009. They were randomized up-front 1:10 between the standard German intergroup-arm (Büchner et al. J Clin Oncol. 2012;30:3604-10) and the AMLSG 07-04 study (NCT00151242). Induction therapy in the AMLSG 07-04 study consisted of two cycles of idarubicin, cytarabine and etoposide +/- all-trans retionoic acid (ATRA) and +/- valproic acid (VPA) in a 2 by 2 factorial design. After recruitment of 392 patients the randomization for VPA was stopped due to toxicity. For consolidation therapy, patients with high-risk AML, defined either by high-risk cytogenetics or induction failure, were assigned to receive allogeneic hematopoietic cell transplantation from a matched related or unrelated donor. All other patients were assigned to 3 cycles of HDAC from 2004 to November 2006 with cytarabine 3g/m² bidaily, on days 1, 3, 5 and pegfilgrastim on day 10 (HDAC-135) and from December 2006 to 2009 patients were treated with a condensed schedule with cytarabine 3g/m², bidaily, on days 1,2,3 and pegfilgrastim on day 8 (HDAC-123). Patients randomized into the German AML intergroup arm were treated for consolidation therapy with cytarabine 3g/m² bid on days 1, 3, 5 (HDAC-135) without prophylactic growth-factor support. Results:Overall 568 patients receiving 1376 consolidation cycles were included into the study. According to up-front randomization 41 were treated with HDAC-135 without prophylactic growth factor support in the German AML Intergroup protocol, 135 with HDAC-135 and 392 with HDAC-123 with intended prophylactic pegfilgrastim at day 10 and 8, respectively, in the AMLSG 07-04 protocol. Time from start to chemotherapy until hematological recovery with leukocytes >1.0G/l and neutrophils >0.5G/l was significantly (p<0.0001, each) and in median 4 days shorter in patients receiving HDAC-123 compared to HDAC-135, and further reduced by 2 days (p<0.0001) by the addition of pegfilgrastim. Treatment with ATRA and VPA according to initial randomization had no impac on hematological recovery times. Rates of infections were significantly reduced by HDAC-123 compared to HDAC-135 (p<0.0001) and pegfilgrastim yes versus no (p=0.002). Days in hospital and platelet transfusions were also significantly reduced in patients receiving HDAC-123 compared to HDAC-135. Relapse-free and overall survival were similar with HDAC-123 and HDAC-135 (p=0.48, p=0.90, respectively). Conclusion: Data from our study suggest that consolidation therapy with a condensed schedule of HDAC-123 is superior to that of standard HDAC-135 in terms of faster hematological recovery, lower infection rate and fever days in hospital. In addition, the administration of one dose of pegfilgrastim after chemotherapy further shortened hematological recovery and reduced infection rate. Importantly, similar efficacy in terms of relapse-free and overall survival rates after HDAC-123 and HDAC-135 were observed. Disclosures Lübbert: Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding. Fiedler:GSO: Other: Travel; Pfizer: Research Funding; Teva: Other: Travel; Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.

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A Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in the Induction Chemotherapy for Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.2535.2535 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2535-2535 ◽

Cited By ~ 1

Author(s):

Je-Hwan Lee ◽

Hawk Kim ◽

Young-Don Joo ◽

Won Sik Lee ◽

Sung Hwa Bae ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Research Funding ◽

High Dose ◽

Event Free Survival ◽

Consolidation Chemotherapy ◽

Free Survival ◽

Acute Myeloid

Abstract Introduction: We conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with acute myeloid leukemia (AML) and showed intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d x 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d x 3d) (Lee JH et al. Blood 2011;118:3832). As it is necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin, we performed another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin (ClinicalTrials.gov #NCT01145846). Here, we present final results of the study. Methods: Between May 2010 and March 2014, a total of 316 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study. Seventeen patients were removed from the study (change of diagnosis in 11, patient's refusal to be randomized in 3 and other in 3) and the remaining 299 patients were analyzed. After random assignments, 149 patients received idarubicin (AI, 12 mg/m2/d x 3d) and 150 patients received high-dose daunorubicin (AD, 90 mg/m2/d x 3d) in addition to cytarabine (200 mg/m2/d x 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d x 2d) or daunorubicin (AD, 45 mg/m2/d x 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 x 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 x 6d) plus etoposide (150 mg/m2 x 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion after one or two cycles of consolidation chemotherapy in most transplant cases. Results: CR was induced in 232 (77.6%) of 299 patients. Reasons for induction failure were resistant disease in 50, hypoplastic death in 5, and indeterminate cause in 12. As postremission therapy, 3 patients received no further treatment, 71 received consolidation chemotherapy without HCT, 137 underwent allogeneic HCT, and 21 underwent autologous HCT. The CR rates were not significantly different between two arms: 80.5% (120 of 149, AI) vs. 74.7% (112 of 150, AD) (P=0.224). With a median follow-up of 1046 days, overall survival probabilities at 4 years were 51.1% in AI vs. 54.7% in AD (P=0.756). The probabilities at 4 years for relapse-free survival were 63.5% in AI vs. 74.2% in AD (P=0.181) and those for event-free survival were 44.8% in AI vs. 50.7% in AD (P=0.738). Toxicity profiles were similar between two arms. Interestingly, overall and event-free survivals of 44 patients with FLT-ITD mutants (27 in AI and 17 in AD) were significantly different according to the induction regimens (AI vs AD; overall survival, 30.8% vs. 61.9%, P=0.030; event-free survival, 31.4% vs. 61.9%, P=0.025). Conclusions: The results of this phase 3 trial, which compared idarubicin (12 mg/m2/d x 3d) with high-dose daunorubicin (90 mg/m2/d x 3d), did not show significant differences between two arms in the outcomes of patients in terms of CR rates and overall, relapse-free or event-free survivals. In subset analysis, high-dose daunorubicin seems to be more effective than idarubicin in patients with FLT-ITD mutants. Disclosures Kim: Celgene: Research Funding; Alexion Pharmaceuticals: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding.

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Targeting MAPK Signaling Pathway with Cobimetinib (GDC-0973) Enhances Anti-Leukemia Efficacy of Venetoclax (ABT-199/GDC-0199) in Acute Myeloid Leukemia Models

Blood ◽

10.1182/blood.v128.22.97.97 ◽

2016 ◽

Vol 128 (22) ◽

pp. 97-97 ◽

Cited By ~ 3

Author(s):

Lina Han ◽

Qi Zhang ◽

Ce Shi ◽

Antonio Cavazos ◽

Vivian Ruvolo ◽

...

Keyword(s):

Cell Death ◽

Acute Myeloid Leukemia ◽

Cell Lines ◽

Myeloid Leukemia ◽

Research Funding ◽

Combination Group ◽

High Dose ◽

Response Patterns ◽

Acute Myeloid

Abstract Despite advances in understanding of the biology of acute myeloid leukemia (AML), cure remains elusive for the majority of patients. Pro-survival molecules of BCL-2 family play critical roles in leukemia transformation and chemoresistance. The anti-leukemia potency of selective BCL-2 inhibitor venetoclax (ABT-199/GDC-0199) has been demonstrated in AML models (Pan et al. Cancer Discovery 2014). However, venetoclax is often associated with resistance due to its poor inhibition of MCL-1. RAF/MEK/ERK (MAPK) pathway is commonly activated in AML, and can stabilize anti-apoptotic MCL-1 and inactivate the pro-apoptotic BIM. In this study, we evaluated the anti-leukemia effects of concomitant BCL-2 and MAPK blockade by venetoclax in combination with MEK1/2 inhibitor GDC-0973 (cobimetinib). First, anti-leukemia activity of cobimetinib and venetoclax was examined in 18 primary AML samples with diverse genetic alterations. The combination significantly enhanced cell death, as compared to the single agent treatment (Fig 1A). Cobimetinib inhibited cell proliferation in the majority of AML cases (34.2 ± 23.7%) and the cell growth suppression was more profound in the combination group (60.2 ± 28.8%, p<0.001) (Fig 1A). The clonogenic potential of myeloid progenitors was significantly suppressed by the combination (82.5 ± 20.0%), as compared to cobimetinib (38.3 ± 14.6%, p=0.01) or venetoclax (41.9 ± 18.6%, p<0.05). The normal progenitor function was minimally affected. We next investigated signaling patterns and BCL-2 family protein expression in AML stem/progenitor cells using a 34-antibody panel for CyTOF. In AML 4400240, we identified 10 distinct subpopulations based on cell surface marker expression that were used to build the SPADE tree. BCL-2 and MCL-1 were both enriched in progenitor populations phenotypically positive for CD34, CD38, CD123 and HLA-DR (A2-5 and A9-10, Fig 1B and 1C). G-CSF-induced p-ERK and SCF-induced p-S6 signaling pathways were efficiently suppressed by cobimetinib (Fig 1D). The inhibition of p-S6 may reflect the sensitivity to cobimetinib of this sample (IC50=1.68 nM); consistent with previous study that suppression of TORC1 predicted response to MEK inhibitor (Corcoran et al. Sci Transl Med 2013). We have previously reported activity of venetoclax/cobimetinib combination in a panel of myeloid leukemia cell lines and revealed distinct response patterns to single agents and combination (Han et al. ASH 2015). Functional proteomics RPPA data indicated that p-ERK, p-S6 and p-RSK pathways were significantly down-regulated in response to the combination in cells showing synergy. Western blotting was performed to validate the RPPA data in 4 cell lines representing different response patterns. Cobimetinib inhibited p-ERK when used at high dose (1 _M) in all cell lines. In turn, inhibition of p-S6 at both ser235/236 and ser240/244 sites occurred at low dose of cobimetinib in sensitive cell lines (OCI-AML3 and MV4-11) and required high dose in resistant lines. In OCI-AML3 cells that showed synergy to combination, elevated levels of cleaved PARP was observed in the combination group, which was likely due to suppression of both BCL2:BIM and MCL-1:BIM complex, followed by release of free BIM to induce cell death. To test the efficacy in vivo, we injected NSGS mice with genetically engineered MOLM3/Luc/GFP cells. Bioluminescent imaging demonstrated significantly reduced leukemia burden in treated groups compared to controls, more prominently in the venetoclax (100 mg/kg/d) group and in venetoclax plus cobimetinib (10 mg/kg/d) co-treated mice (Fig 1E and 1F). Human CD45 engraftment and cell counts in both bone marrow and spleen demonstrated a trend towards decreased tumor burden when venetoclax was combined with cobimetinib in vivo (Fig 1G and 1H). In summary, combinatorial blockade of MAPK and BCL-2 pathways promotes cell death and suppresses proliferation in the majority of primary AML cells. The anti-leukemia efficacy of combined blockade of signaling and pro-survival pathways is associated with downregulation of MCL-1, release of pro-death BIM and suppression of p-S6. Additional novel transcriptional biomarkers of response are now being analyzed and will be presented. Combined efficacy of these agents is under clinical investigation in a Phase I trial in elderly relapsed/refractory AML (NCT02670044). Figure 1. Figure 1. Disclosures Leverson: AbbVie: Employment, Other: Shareholder in AbbVie. Monique:Genentech: Employment. Phillips:AbbVie Inc.: Employment. Chen:AbbVie: Employment. Jin:AbbVie Inc.: Employment. Daver:Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Otsuka: Consultancy, Honoraria; Karyopharm: Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Sampath:Genentech: Employment. Konopleva:AbbVie: Research Funding; Genentech: Research Funding.

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Risk factors for high-dose cytarabine neurotoxicity: an analysis of a cancer and leukemia group B trial in patients with acute myeloid leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.1992.10.6.948 ◽

1992 ◽

Vol 10 (6) ◽

pp. 948-953 ◽

Cited By ~ 72

Author(s):

E H Rubin ◽

J W Andersen ◽

D T Berg ◽

C A Schiffer ◽

R J Mayer ◽

...

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Elevated Serum ◽

High Dose ◽

Increased Risk ◽

High Dose Cytarabine ◽

Group B ◽

Leukemia Group ◽

Acute Myeloid

PURPOSE We analyzed pretreatment characteristics of patients with postremission acute myeloid leukemia (AML) treated with high-dose cytarabine (HIDAC) during a recent Cancer and Leukemia Group B (CALGB) trial to determine risk factors associated with HIDAC neurotoxicity. PATIENTS AND METHODS One hundred seventy-six patients received at least one course of HIDAC as part of a CALGB protocol designed to determine the optimal dose of cytarabine (ara-C) for postremission treatment of AML. HIDAC consisted of 3 g/m2 ara-C infused over 3 hours at 12-hour intervals on days 1, 3, and 5. The pretreatment characteristics of 170 patients were available for risk analyses. RESULTS Eighteen patients (10%) experienced neurotoxicity. Univariate analyses demonstrated associations between the occurrence of neurotoxicity and elevated serum creatinine, age, and alkaline phosphatase (AP). Multivariate analysis showed that these variables were independent risk factors. These findings were used to construct a risk model with the following parameters: creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40 years, and AP greater than or equal to 3 x normal. Seventeen of 46 (37%) patients with two or more of these criteria developed neurotoxicity compared with one of 124 (1%) patients with one or none. The sensitivity and specificity of this model were 94% and 81%, respectively. CONCLUSION We conclude that patients with two or more of the following parameters may be at increased risk for HIDAC neurotoxicity: (creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40, and AP greater than or equal to 3 x normal). However, this model should be confirmed by analysis of additional groups of patients treated with HIDAC.

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Impact of Sars-Cov-2 Infection in Acute Myeloid Leukemia Patients: Experience of the Pethema Registry

Blood ◽

10.1182/blood-2020-138471 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Pilar Martínez ◽

Tomás Palanques Pastor ◽

Jose Luiz Lopez Lorenzo ◽

Javier Cornago Navascués ◽

Gabriela Rodriguez-Macías ◽

...

Keyword(s):

Clinical Trial ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Genetic Material ◽

Specific Treatment ◽

Duration Of Symptoms ◽

The Mean ◽

Active Disease ◽

Acute Myeloid

SARS-CoV-2 infection can impact survival of patients with acute myeloid leukemia (AML). International experts recommend considering delaying or stopping AML treatment, test patients who need intensive induction and s prioritizing outpatient treatment. However there is little published evidence in AML. Objective To analyze the clinical futures and outcome of SARS-CoV-2 infection in AML patients. Methods and patients Observational multicenter study between March and May 2020; 117 patients reported from 47 Spanish centers, but 13 had no PCR or antibody test documented, finally including 104 patients from 45 hospitals. Results The median age was 68 years, men (56.7% vs 43.3%), and the median time from AML diagnosis to SARS-CoV-2 was 4 months. The mean of comorbidities was 1.2, high blood pressure (40.4%), heart disease (17.3%), diabetes (13.5%), smoking (8.8%), chronic obstructive pulmonary disease or emphysema (7.7%), renal failure (6.7%) and liver dysfunction (1.9%). Cytogenetic risk was low in 16.9%, intermediate in 57.1% and high in 26.0%; 55.7% had active disease, 39.2% complete remission and 5.1% partial response. 29.4% were off-therapy and 70.6% under antileukemic treatment at the time of SARS-CoV-2: induction chemotherapy (25.3%), hypomethylating (19.3%), clinical trial (17.0%), consolidation chemotherapy (14.8%), venetoclax (3.4%), FLT3 inhibitors (3.4%) and/or maintenance (1.1%). Overall 3.7% were newly diagnosed (no prior therapy), 77.8% had received one line of treatment, 14.8% two and 3.7% four. 15.4% had prior allogeneic transplantation. Only 4.0% of the patients were asymptomatic, while the main signs and symptoms were fever (77.8%), pneumonia (75.0%), cough (65.3%), dyspnea (52.0%), diarrhea (20.4%), nausea and/or vomiting (12.2%), rhinorrhea (10.2%) and headache (7.4%). Analytical parameters were: neutrophils 3112 cells/µL (1900-7300), lymphocytes 1090 cells/µL (1000-3000), interleukin 6 118 pg/mL (0-100), ferritin 4505 ng/mL (15-150) and D-dimer 2823 ng/mL (20-500), with liver enzymes altered in 23.9% of cases. 84.2% received specific treatment for coronavirus infection: chloroquine or hydroxychloroquine (82.2%), lopinavir/ritonavir (54.0%), corticosteroids (39.6%), azithromycin (33.0%), tocilizumab (15.8%), plasma convalescent (3.0%), clinical trial medication (3.0%), remdesivir (2.0%) and/or anakinra (1.0%). The course was mild in 14.7% (no hospitalization), moderate in 32.0% and severe in 53.3%. The implementation of intensive measures was assessed in 48.2%(14.9% admitted to the ICU and the remaining 33.3% rejected). The mean time to negativization was 20.5 days, duration of symptoms 17.6 days and the hospital stay 11.1 days. In 48.1% of the cases treatment for AML was maintained, in 26.6% delayed and in 25.3% modified due to coronavirus disease.47.5% died, establishing an association between mortality and age over 60 years (58.3% vs 36.4%, p=0.043), ≥2 lines of treatment (72.7% vs 44.3%, p=0.020), active disease (62.5% vs 29.4%, p=0.002) and pneumonia (61.2% versus 22.7%, p=0.002). Overall 47.5% overcame the infection, and in 5.0% SARS-CoV-2 genetic material was still detected at the time of analysis. A non-significant lower mortality rate was observed among: previous transplantation (45.7% vs 64.3%, p=0.19), neutrophil >1900 cells/µL (41.1% vs 60.0%, p=0.09), lymphocyte >1000 cells/µL (42.9% vs 63.6%, p = 0.09) and hydroxychloroquine/chloroquine plus azithromycin (35.3% vs 60.0%, p=0.10). Conclusions SARS-CoV-2 infection produces high mortality among AML patients. Mortality was correlated with age, active disease and pneumonia. Disclosures Martinez-Lopez: Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Research Funding.

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Safety and Efficacy of Venetoclax Plus Low-Dose Cytarabine in Treatment-Naive Patients Aged ≥65 Years with Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.102.102 ◽

2016 ◽

Vol 128 (22) ◽

pp. 102-102 ◽

Cited By ~ 32

Author(s):

Andrew Wei ◽

Stephen A. Strickland ◽

Gail J. Roboz ◽

Jing-Zhou Hou ◽

Walter Fiedler ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Median Time ◽

Myeloid Leukemia ◽

Research Funding ◽

Low Dose ◽

Safety And Efficacy ◽

Treatment Naïve ◽

The Mean ◽

Low Dose Cytarabine ◽

Acute Myeloid

Abstract Background: Multiple studies have demonstrated the modest efficacy of low-dose cytarabine (LDAC) in older patients (≥65 years) with Acute Myeloid Leukemia(AML) who are unlikely to benefit from an anthracycline and cytarabine intensive induction [CR/CRi rates of 10 - 26%; (CRi = complete remission with incomplete marrow recovery)]. Venetoclax, a selective BCL-2 inhibitor has demonstrated single-agent activity in patients with relapsed and refractory AML [Konopleva et al., ASH 2014]. When administered with LDAC, the recommended phase 2 dose (RP2D) of venetoclax was 600 mg daily [Lin et al., ASCO 2016 (abstract 7007)]. Here we present the safety and efficacy data at RP2D of venetoclax from the dose escalation and expansion phases of the study (NCT02287233). Methods: Patients enrolled as of 15DEC2015 are included in this analysis with a data cut-off date of 31MAR2016. Patients were eligible if considered unfit for intensive chemotherapy, had an ECOG performance status of 0-2 and adequate renal and liver function. Patients treated with cytarabine for a pre-existing myeloid disorder, or those with acute promyelocytic leukemia or active CNS involvement with AML were excluded from the study. Venetoclax 600 mg was administered orally once daily on days 2 - 28 of Cycle 1 and days 1 - 28 of subsequent cycles. A 5-day dose ramp-up schedule was followed to reach the 600 mg dose. LDAC 20 mg/m2 was administered s.c. daily on days 1-10 in 28-day cycles. To mitigate the potential risk of tumor lysis syndrome (TLS), all patients were hospitalized and received prophylaxis commencing 48 hours prior to venetoclax during Cycle 1. Adverse events (AEs) were graded by NCI CTCAE Version 4.0. Results: Twenty patients were enrolled in the study (escalation, n=8; expansion, n=12). The median age was 74 years (range: 66 - 87). 8/20 (40%) patients had an antecedent hematologic disorder. Median time on venetoclax was 147.5 days (range: 8 - 455). Grade 3/4 AEs (≥10% patients) excluding cytopenias were febrile neutropenia (35%), hypertension (20%), hypophosphatemia (20%), decreased appetite, increased blood bilirubin, hyponatremia, hypoxia, hypotension, pneumonia, sepsis, syncope, urinary tract infection, and vomiting (10% each). No events of TLS occurred. Venetoclax exposures on Cycle 1 Day 10 (with LDAC) vs. Cycle 1 Day 18 (venetoclax alone) were comparable. The mean ± SD of maximum observed concentration (Cmax, µg/mL/mg) were 2.04 ± 1.45 vs. 2.92 ± 2.15, respectively. The mean ± SD of area under the curve (AUC24, µg*hr/mL) were 33.3 ± 27.5 vs. 46.1 ± 36.8, respectively. Similarly, co-administration of venetoclax did not markedly affect LDAC exposures. The mean ± SD of Cmax (ng/mL) of LDAC on Cycle 1 Day 1 (LDAC alone) vs. Cycle 1 Day 10 (with venetoclax) were 158.89 ± 79.08 vs 166.49 ± 32.06, respectively. Similarly, the mean ± SD of AUCinf (ng*hr/mL) were 170.64 ± 102.86 vs 246.51 ± 93.41, respectively. 15/20 (75%) patients achieved an objective response (CR+CRi+PR). Of them, 14/20 (70%) patients had a CR+CRi; all 14 patients belonged to a subset of 18 patients with no prior myeloproliferative neoplasm (MPN). 16/19 (84%) patients with available data had their bone marrow blast percentage reduced to below 5%. The 12-month overall survival (OS) estimate for all patients was 74.7% (95% CI=49.4 - 88.6) and that for the responders (n=15) was 86.7% (95% CI=56.4 - 96.5). The overall response rates and 12-month OS estimates for patients with or without prior hypomethylating agent (HMA) and with or without MPN are summarized in Table 1. A Kaplan-Meier curve showing OS for responders vs. non-responders is shown in Figure 1. The median time to best response was 30 days (range: 23 - 169). Only 2/14 patients who achieved CR/CRi have died [disease progression (n=1), acute hepatic failure (n=1)]. Conclusions: Venetoclax (600 mg RP2D) plus LDAC demonstrated an acceptable safety and pharmacokenitic profile in patients aged ≥65 years with treatment-naive AML who are not eligible for an intensive anthracycline-containing induction chemotherapy. Clinical remission was achieved in the majority of patients. The median OS has not been reached. A substantially better survival in responders as compared to non-responders suggests that the improvement is likely due to treatment with venetoclax plus LDAC. Updated responses and survival estimates for all patients, including those in dose expansion phase that were enrolled after the preliminary data cut, will be presented. Disclosures Wei: Novartis: Honoraria, Research Funding. Strickland:Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sanofi: Research Funding; Sunesis Pharmaceuticals: Consultancy, Research Funding; Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Fiedler:Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Kolltan: Research Funding; Novartis: Consultancy; Teva: Other: Travel; Ariad/Incyte: Consultancy; Gilead: Other: Travel; Pfizer: Research Funding; GSO: Other: Travel. Martinelli:MSD: Consultancy; Celgene: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; BMS: Speakers Bureau; Novartis: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Fakouhi:AbbVie Inc.: Employment, Other: may own stock. Darden:AbbVie Inc.: Employment, Other: may own stock. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Agarwal:AbbVie Inc.: Employment, Other: may own stock. Salem:AbbVie Inc.: Employment, Other: Stocks or options. Mabry:AbbVie Inc.: Employment, Other: May own stock. Hayslip:AbbVie Inc.: Employment, Other: May own stock.

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Gilteritinib Versus Salvage Chemotherapy for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: A Phase 3, Randomized, Multicenter, Open-Label Trial in Asia

Blood ◽

10.1182/blood-2021-145436 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 695-695

Author(s):

Jianxiang Wang ◽

Bin Jiang ◽

Jian Li ◽

Ligen Liu ◽

Xin Du ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Salvage Chemotherapy ◽

High Dose ◽

Efficacy And Safety ◽

Open Label ◽

Phase 3 ◽

Grade 3 ◽

Acute Myeloid

Abstract Background: Due to poor prognosis, treatment options for patients with FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) who are refractory to therapy or have relapsed (R/R) are needed globally. Gilteritinib is approved in multiple countries, including Japan, and has recently received conditional approval in China for the treatment of R/R FLT3mut+ AML; in the phase 3 ADMIRAL trial, superior survival benefit and a favorable safety profile were shown for patients receiving gilteritinib compared to those receiving salvage chemotherapy (SC) (HR 0.64 [95% CI: 0.49, 0.83]; P<0.001) in the R/R FLT3mut+ AML setting. While data from the Asian subpopulation of ADMIRAL have been evaluated, larger randomized, controlled trials of outcomes for treatments in a predominantly Asian population are lacking. Aim/Objective: To evaluate the efficacy and safety/tolerability of gilteritinib compared with SC in Asian patients with R/R FLT3mut+ AML after first-line therapy. Methods: In this phase 3, open-label, multicenter COMMODORE (NCT03182244) trial, adult patients in China, Russia, Singapore, Thailand, and Malaysia with R/R FLT3mut+ AML were randomized 1:1 to gilteritinib 120 mg orally per day or SC (low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine; or fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor) over continuous 28-day cycles. Patients must have had an ECOG performance status score ≤2; those with acute promyelocytic leukemia, BCR-ABL-positive leukemia, clinically active central nervous system disease, or secondary AML were excluded. The primary endpoint was overall survival (OS), and key secondary efficacy endpoints were event-free survival (EFS) and complete remission (CR). Additional secondary endpoints included duration of remission, composite CR (CRc), and safety/tolerability. OS and EFS were analyzed with stratified Cox proportional hazard models, and response rates were analyzed with the Cochran-Mantel-Haenszel test. Results of the interim analysis are presented here. Results: As of June 30, 2020, a total of 234 patients were randomized (gilteritinib, n=116; SC, n=118). Median age was 51.5 and 49.5 years in the gilteritinib and SC groups, respectively; most patients had not previously received FLT3 inhibitors (87.9% and 93.2%, respectively). Baseline FLT3 mutations in the gilteritinib vs SC groups were: FLT3-ITD (91.4% vs 83.1%), FLT3-TKD (6.0% vs 11.9%), and both FLT3-ITD and FLT3-TKD (2.6% vs 5.1%). Median follow-up duration for OS was 11.1 months for gilteritinib and 6.9 months for SC. Median OS was significantly longer in the gilteritinib group (9.0 months) compared with the SC group (4.7 months; HR 0.549 [95% CI: 0.379, 0.795]; P=0.00126; Figure); 1-year survival rates were 33.3% and 23.2%, respectively. Patients on gilteritinib had significantly longer EFS than those receiving SC (median EFS 2.8 vs 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; P=0.00004). A higher proportion of patients achieved CR on gilteritinib (16.4%) compared with SC (10.2%; P=0.17690); CRc rates were 50.0% and 20.3% (P<0.00001). Grade ≥3 adverse events (AEs) in the gilteritinib (97.3%) vs SC (94.2%) groups were comparable; rates for serious AEs were higher for gilteritinib (73.5%) vs SC (61.5%). When adjusted for treatment exposure, AE rates were lower with gilteritinib (grade ≥3, 55.56 events/patient-year [E/PY]; serious, 6.19 E/PY) than with SC (grade ≥3, 164.00 E/PY; serious, 12.40 E/PY). The most common AEs occurring in the gilteritinib group were anemia (76.1%), thrombocytopenia (46.9%), pyrexia (41.6%), and increased blood lactate dehydrogenase (41.6%); for SC, the most common AEs were anemia (64.4%), decreased white blood cell count (41.3%), and thrombocytopenia (38.5%). AEs leading to death occurred in 22 (19.5%) and 15 (14.4%) of patients receiving gilteritinib or SC, respectively. Conclusions: Gilteritinib significantly prolonged OS and EFS compared with SC in patients with R/R FLT3mut+ AML in Asia. When adjusted for treatment exposure, safety/tolerability was favorable for gilteritinib compared with SC. The results of the COMMODORE trial further validate and affirm the clinical efficacy and safety data from the ADMIRAL trial, reinforcing the significant benefit of gilteritinib in R/R FLT3mut+ AML. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Li: Astellas Pharma, Inc.: Research Funding. Liu: Astellas Pharma, Inc.: Research Funding. Du: Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Hu: Astellas Pharma, Inc.: Research Funding. Yuan: Astellas Pharma, Inc.: Current Employment. Sakatani: Astellas Pharma, Inc.: Current Employment, Current equity holder in publicly-traded company. Kadokura: Astellas Pharma, Inc.: Current Employment. Takeuchi: Astellas Pharma, Inc.: Current Employment. Izuka: Astellas Pharma, Inc.: Current Employment. Girshova: Astellas Pharma, Inc.: Research Funding. Tan: Astellas Pharma, Inc.: Research Funding. Wong: Astellas Pharma, INc.: Research Funding. Khuhapinant: Astellas Pharma, Inc.: Research Funding. Martynova: Astellas Pharma, Inc.: Research Funding. Hasabou: Astellas Pharma, Inc.: Current Employment. Tiu: Astellas Pharma, Inc.: Current Employment.

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