scholarly journals Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

2015 ◽  
Vol 59 (4) ◽  
pp. 2078-2085 ◽  
Author(s):  
Oliver A. Cornely ◽  
Angelika Böhme ◽  
Anne Schmitt-Hoffmann ◽  
Andrew J. Ullmann
Keyword(s):  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
High Dose ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Dose Cohort ◽  
Acute Myeloid

ABSTRACTIsavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n= 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n= 12). The mean ± standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ± 22.3 μg · h/ml and 113.1 ± 19.6 μg · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n= 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.)

scholarly journals A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia

PLoS ONE ◽  
2016 ◽  
Vol 11 (10) ◽  
pp. e0164499 ◽  
Author(s):  
Christoph Schliemann ◽  
Joachim Gerss ◽  
Stefanie Wiebe ◽  
Jan-Henrik Mikesch ◽  
Nicola Knoblauch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Phase I ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Dose Escalation Study ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

scholarly journals Low-Dose Decitabine Plus Venetoclax Maintenance Therapy Can Decrease the Relapse after Allogeneic Stem Cell Transplantation for MRD Positive High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Yunxiong Wei ◽  
Yaqing Cao ◽  
Xin Jin ◽  
Xiaoyuan He ◽  
Rui Sun ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Post Transplantation ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) and myelodysplasia (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable option for patients suffering from high-risk AML/MDS. However, there were still many patients relapsed after allo-HSCT, especially for some patients are MRD positive before transplantation. Novel therapy to prevent replase is urgently needed. Both BCL-2 inhibitor, venetoclax (VEN) and hypomethylating agent, decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration DEC has been shown to ameliorate GVHD and boost GVL post-transplantation. Several clinical trials have also shown that venetoclax plus decitabine can be a safety and effective salvage treatment for patients with AML/MDS relapsing after allo-HSCT. We therefore conducted a prospective study (ChiCTR1900025374) to exam the tolerability and efficacy of a maintenance therapy low-dose decitabine (LDEC) plus VEN to prevent relapse after allo-HSCT for MRD positive high-risk AML/MDS patients. To our knowledge, this is the first report of venetoclax combined decitabine in this setting. Methods: Six patients with MRD positive high-risk AML (n=5) /MDS(n=1) post transplantation were recruited. Around day 100 post transplantation, all patients received LDEC (15mg/m2 for 3 days) followed by VEN (200mg) on day 1 to 21. Two months is a cycle. The primary end points of this study were rates of Overall survival (OS) and event-free survival (EFS). The secondary endpoints included adverse events (AEs), incidence of cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD) and incidences of viral infection after allo-HSCT. Survival outcomes were analyzed using Kaplan-Meier analysis Results: Two of the six patients were partial remission (PR) before transplantation, and the remaining 4 patients were MRD+ before transplantation. The median follow-up was 16 (11-26.5) months. Both 2-year OS and 2-year EFS were 83%. The median 2-year EFS time was 16(9-26.5) months, and five patients still EFS alive at the time of this writing. The 2-year cumulative incidence of relapse after LDEC+VEN was 17% and 2-year non-relapse mortality was 0%. No tumor lysis syndrome (TLS) was observed. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 adverse events were observed in 33% (2/6). No grade>3 AEs were observed. Acute (any grade) and chronic (limited or extensive) graft-versus-host disease occurred in 67% and 17% of patients, respectively. The 2-year cumulative incidence of CMV viremia and EBV viremia were 33.3% and 16.7%, respectively. Conclusion: We conclude LDEC+VEN can be administered safely after allo-HSCT, without evidence for increased incidence of GVHD, and this combination demonstrates decreased relapse for MRD positive high-risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent replase for MRD positive high-risk AML/MDS patients, and the clinical benefits need to be assessed in a comparative prospective trial. Figure Disclosures No relevant conflicts of interest to declare.

Dose Escalation Studies of Cytarabine, Daunorubicin, and Etoposide With and Without Multidrug Resistance Modulation With PSC-833 in Untreated Adults With Acute Myeloid Leukemia Younger Than 60 Years: Final Induction Results of Cancer and Leukemia Group B Study 9621

2004 ◽  
Vol 22 (21) ◽  
pp. 4290-4301 ◽  
Author(s):  
Jonathan E. Kolitz ◽  
Stephen L. George ◽  
Richard K. Dodge ◽  
David D. Hurd ◽  
Bayard L. Powell ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Phase Iii ◽  
Fixed Dose ◽  
Dose Escalation Study ◽  
Data Set ◽  
Psc 833 ◽  
Group B ◽  
Acute Myeloid

Purpose P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses. Patients and Methods A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833. Results Doses selected for phase III testing were DNR 90 mg/m2 and ETOP 100 mg/m2 in ADE, and DNR and ETOP each 40 mg/m2 in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients ≤ 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE. Conclusion A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients ≤ 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.

Results of a Phase 1/2a dose–escalation study of FF-10501-01, an IMPDH inhibitor, in patients with acute myeloid leukemia or myelodysplastic syndromes

2020 ◽  
Vol 61 (8) ◽  
pp. 1943-1953 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Naveen Pemmaraju ◽  
Yesid Alvarado ◽  
Kiran Naqvi ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Dose Escalation Study ◽  
Acute Myeloid

scholarly journals A Retrospective Observation of Treatment Outcomes Using Decitabine-Combined Standard Conditioning Regimens Before Transplantation in Patients With Relapsed or Refractory Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuhang Li ◽  
Longcan Cheng ◽  
Chen Xu ◽  
Jianlin Chen ◽  
Jiangwei Hu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Hematopoietic Reconstitution ◽  
Conditioning Regimens ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid ◽  
Refractory Aml

Hypomethylating agents, decitabine (DAC) and azacitidine, can act as prophylactic and pre-emptive approaches after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a non-intensive bridging approach before allo-HSCT. However, they are rarely used as a part of conditioning regimens in patients with relapsed or refractory acute myeloid leukemia (AML). This retrospectively study included a total of 65 patients (median, 37; range, 13–63) with relapsed or refractory AML who were treated by allo-HSCT after myeloablative conditioning regimens without or with DAC (high-dose DAC schedule, 75 mg/m2 on day −9 and 50 mg/m2 on day −8; low-dose DAC schedule, 25 mg/m2/day on day −10 to −8). DAC exerted no impact on hematopoietic reconstitution. However, patients who were treated with the high-dose DAC schedule had significantly higher incidence of overall survival (OS, 50.0%) and leukemia-free survival (LFS, 35.0%), and lower incidence of relapse (41.1%) and grade II–IV acute graft versus host disease (aGVHD, 10.0%) at 3 years, when compared with those treated with standard conditioning regimens or with the low-dose DAC schedule. In conclusion, high-dose DAC combined with standard conditioning regimens before allo-HSCT is feasible and efficient and might improve outcomes of patients with relapsed or refractory AML, which provides a potential approach to treat these patients.

scholarly journals Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome

2020 ◽  
Vol 4 (9) ◽  
pp. 2032-2043 ◽  
Author(s):  
Je-Hwan Lee ◽  
Stefan Faderl ◽  
John M. Pagel ◽  
Chul Won Jung ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Acute Myeloid

Abstract CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of β-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.

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