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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 102-102 ◽  
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.

Phase II trial to assess the safety and efficacy of clofarabine in combination with low-dose cytarabine in elderly patients with acute myeloid leukemia

2013 ◽  
Vol 93 (1) ◽  
pp. 43-46 ◽  
Author(s):  
David Martínez-Cuadrón ◽  
Pau Montesinos ◽  
Albert Oriol ◽  
Olga Salamero ◽  
Belén Vidriales ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Safety And Efficacy ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

scholarly journals Off-Label Use of Venetoclax Combination Therapy in Relapsed/Refractory Acute Myeloid Leukemia: A Single Institution Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5133-5133 ◽  
Author(s):  
Daria Gaut ◽  
Aaron Burkenroad ◽  
Tuyen Duong ◽  
Jesse Feammelli ◽  
Joshua Sasine ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Combination Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Cell Transplant ◽  
Grade 3 ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Introduction Venetoclax (VEN) is a selective BCL-2 inhibitor that has demonstrated activity against acute myeloid leukemia (AML) and has been shown to be effective when used in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) for treatment-naïve, elderly AML patients unfit for intensive chemotherapy. Data on its use in the relapsed/refractory setting is limited. Methods A retrospective analysis was performed among 12 relapsed or refractory AML patients treated with VEN combination therapy at the University of California Los Angeles from 2018-2019. Seven patients received VEN in combination with azacitidine (75 mg/m2 x 7 days), 4 patients with decitabine (20 mg/m2 x 5 days), and 1 patient with low-dose cytarabine (20 mg/m2 x 10 days). Results The median patient age at time of VEN therapy was 58 years (range 41-79). Four patients (33.3%) had secondary AML. The majority (9 patients, 75.0%) had adverse cytogenetics. Three patients (25.0%) had received an allogeneic stem cell transplant prior to VEN therapy, and 5 patients (41.7%) had failed HMA therapy prior. Notable molecular mutations present were TP53 (4 patients, 33.3%), FLT3 (3 patients, 25.0%), and IDH2 (1 patient, 8.3%). Eight patients (66.7%) had grade 3 or greater neutropenia at time of VEN initiation, and 9 patients (75.0%) had grade 3 or greater thrombocytopenia. Four patients (33.3%) had a grade 3 or greater infection prior to VEN therapy. Dosing of VEN was by physician discretion with a median starting dose of 150 mg (range 100-800) and a median maintenance dose of 450 mg (range 200-800). The median number of cycles of VEN combination therapy was 2 (range 1-5). Seven patients (58.3%) had decreased VEN dosage due to concomitant azole for antifungal prophylaxis. Four patients (33.3%) were on an additional small molecular inhibitor while receiving VEN therapy (sorafenib in 3 patients, ruxolitinib in 1 patient). The majority (10 patients, 83.3%) had an interruption in VEN dosing for the following reasons: bone marrow functional delay (7 patients), inability to tolerate oral pills (4 patients), infection (3 patients), and bleeding (2 patients). The objective response rate (ORR) was 41.7% with 3 patients (25.0%) achieving complete remission with incomplete hematologic recovery (CRi) and 2 patients (16.7%) achieving partial remission (PR) (Table 1). Three patients (25.0%) experienced early death within 30 days due to the following: pneumonia (1 patient), multi-organ failure from infection and graft-versus-host disease (1 patient), and intracranial hemorrhage (1 patient). The median time to first and best response was 56 days (range 27-101) or after approximately 2 cycles of VEN combination therapy. During VEN therapy, all patients (100%) had grade 3 or greater neutropenia and thrombocytopenia, and 10 patients (83.3%) had grade 3 or greater anemia. The nadir of most cytopenias occurred during cycle 1. Six patients (50.0%) developed a grade 3 or greater infection following VEN therapy, and 2 patients (16.7%) developed a grade 3 or greater intracranial hemorrhage. The only other notable grade 3 or greater side effects noted during VEN therapy were dizziness (1 patient, 8.3%) and diarrhea (1 patient, 8.3%). After a median follow-up time of 3.14 months (range 1.22-13.48), 2 patients (16.7%) progressed, and the 1-year progression-free survival (PFS) rate was 71.11% (95% CI 43.40-100.00) (Figure 1). Eight out of 12 patients died as a result of infection (6 patients, 50.0%), disease progression (1 patient, 8.3%), and bleeding (1 patient, 8.3%). The median overall survival (OS) was 4.74 months (range 1.18-9.15), and the 1-year OS rate was 14.60% (95% CI 2.54-83.80) (Figure 2). VEN was discontinued in all patients because of no response (5 patients, 41.7%), adverse effects (4 patients, 33.3%), transition to donor lymphocyte infusion (1 patient, 8.3%), or transition to allogeneic stem cell transplant (2 patients, 16.7%). Conclusions We present our institutional experience with VEN combination therapy for the treatment of relapsed/refractory AML with a particularly high-risk patient cohort, predominantly characterized by adverse genetic features and grade 3 cytopenias prior to start of therapy. Overall, the response rate was modest, but not inferior to that with conventional salvage chemotherapy. Adverse events were primarily due to pre-existing bone marrow failure, likely exacerbated by treatment. Disclosures Schiller: Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor approved for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. It does not currently have an approved use for the treatment of acute myeloid leukemia in the relapsed/refractory setting.

scholarly journals Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

2021 ◽  
Author(s):  
Michael Heuser ◽  
B. Douglas Smith ◽  
Walter Fiedler ◽  
Mikkael A. Sekeres ◽  
Pau Montesinos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
De Novo ◽  
Secondary Acute Myeloid Leukemia ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

AbstractThis analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

scholarly journals Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome

Leukemia ◽  
2018 ◽  
Vol 33 (2) ◽  
pp. 379-389 ◽  
Author(s):  
Jorge E. Cortes ◽  
Florian H. Heidel ◽  
Andrzej Hellmann ◽  
Walter Fiedler ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Newly Diagnosed ◽  
Low Dose Cytarabine ◽  
Acute Myeloid
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