scholarly journals Prospective Phase II Single-Center Study of the Safety of a Single Very High Dose of Liposomal Amphotericin B for Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia

2013 ◽  
Vol 57 (6) ◽  
pp. 2596-2602 ◽  
Author(s):  
Luciana Annino ◽  
Anna Chierichini ◽  
Barbara Anaclerico ◽  
Erica Finolezzi ◽  
Marianna Norata ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Amphotericin B ◽  
Myeloid Leukemia ◽  
Liposomal Amphotericin ◽  
Antifungal Prophylaxis ◽  
High Dose ◽  
Mean Values ◽  
The Mean ◽  
Grade 3 ◽  
Acute Myeloid

ABSTRACTSome preclinical and pharmacokinetic studies suggested the variable safety and the potential efficacy of an antifungal prophylaxis with a single high dose of liposomal amphotericin B (L-AmB) in high-risk patients. An open-label, prospective study was conducted with 48 adults receiving induction chemotherapy for acute myeloid leukemia (AML). Patients received a single infusion of 15 mg/kg of body weight L-AmB and, eventually, a second dose after 15 days of persistent neutropenia. The primary objective was tolerability and safety. Efficacy was also evaluated as a secondary endpoint. A pharmacokinetic study was performed with 34 patients in order to evaluate any association of plasma L-AmB levels with toxicity and efficacy. Overall, only 6 patients (12.5%) reported Common Toxicity Criteria (CTC) grade 3 hypokalemia, which was corrected with potassium supplementation in all cases, and no patient developed clinically relevant nephrotoxicity. Mild infusion-related adverse events occurred after 6 of 53 (11.3%) total infusions, with permanent drug discontinuation in only one case. Proven invasive fungal disease (IFD) was diagnosed in 4 (8.3%) patients. The mean AmB plasma levels at 6 h, 24 h, and 7 days after L-AmB administration were 160, 49.5, and 1 mg/liter, respectively. The plasma AmB levels were higher than the mean values of the overall population in 3 patients who developed CTC grade 3 hypokalemia and did not significantly differ from the mean values of the overall population in 3 patients who developed IFD. Our experience demonstrates the feasibility and safety of a single 15-mg/kg L-AmB dose as antifungal prophylaxis in AML patients undergoing induction chemotherapy.

Mucormycosis in a Patient with Acute Myeloid Leukemia Successfully Treated with Liposomal Amphotericin B Associated with Deferasirox and Hyperbaric Oxygen

2013 ◽  
Vol 175 (3-4) ◽  
pp. 295-300 ◽  
Author(s):  
Eduardo Flavio Oliveira Ribeiro ◽  
Vitorino Modesto dos Santos ◽  
Guilherme Teixeira Guimarães Paixão ◽  
Leonardo Rodrigues Cruz ◽  
Milena Zamian Danilow ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Amphotericin B ◽  
Hyperbaric Oxygen ◽  
Myeloid Leukemia ◽  
Liposomal Amphotericin ◽  
Liposomal Amphotericin B ◽  
Acute Myeloid

Limited Phase I Trial of Sequential High Dose Cytarabine and Clofarabine (HiDAC→CLOF) in Relapsed or Refractory Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4565-4565
Author(s):  
Bayard L. Powell ◽  
James Lovato ◽  
Claire Kimbrough ◽  
Susan Lyerly ◽  
Sonya Galloway-Daniels ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Skin Toxicity ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

Abstract High dose cytarabine (HiDAC) is the most effective single agent for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. We conducted a two step limited phase I trial of sequential HiDAC (2g/m2 over 3 hours) followed by CLOF (30 or 40 mg/m2 infused over 2 hours), each given daily for 5 days, in adults with AML in first or second relapse or refractory to initial induction chemotherapy. Patients with persistent leukemia on day 12–14 received a second course of HiDAC→CLOF; phase I toxicity evaluation was based on cycle 1 data only. Nine patients (6 men and 3 women) were treated. The median age was 55.5 years (range 29.2 – 68.1). All had relapsed AML; two had prior autologous stem cell transplant. The initial cohort of 3 patients received clofarabine 30 mg/m2 with one dose limiting toxicity (DLT); an additional 3 patients were treated in cohort 1. The second cohort was treated with CLOF 40 mg/m2, the target dose for a planned phase II trial of HiDAC→CLOF. Hematologic toxicities and infections were not considered DLT. In the first cohort (30 mg/m2; n = 6) there was 1 DLT - grade 4 skin rash in a patient who subsequently died on day 17 with sepsis-related multi-organ failure; 3 patients had reversible grade 3 elevations in AST/ALT, 1 had grade 3 skin toxicity. In cohort 2 (40 mg/m2 ; n = 3) there was no DLT; 1 patient had grade 3 AST/ALT; 2 had grade 3 skin. Three of nine patients received a second course of induction HiDACCLOF. Two of six patients in cohort 1 achieved complete remission (CR), 1/3 patients in cohort 2 achieved CRi(CRp). Two of three CR/CRi patients received one course and one received two courses of HiDAC→CLOF induction. Conclusion: HiDAC→CLOF was associated with transient elevation in AST/ALT (4/9) and skin rash (3/9; primarily extensive palmar/plantar); skin toxicity appeared especially prominent in patients with palmar/plantar toxicity during prior therapy with HiDAC. Toxicities (other than skin) were comparable to other salvage regimens for relapsed and refractory AML. This combination is active in relapsed AML with 3/9 CR/CRp. A phase II trial of HiDAC→CLOF is underway; prophylactic intravenous hydrocortisone has been incorporated in an attempt to decrease skin toxicity.

Randomized Study of Decitabine Versus Observation or Continued Cytotoxic Chemotherapy in Patients with Intermediate and Poor Risk Acute Myeloid Leukemia in First or Subsequent Complete Remission.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2859-2859 ◽  
Author(s):  
Farhad Ravandi ◽  
Jean-Pierre Issa ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Mary Hood ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Clin Oncol ◽  
Myeloid Leukemia ◽  
Cytotoxic Chemotherapy ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Poor Risk ◽  
Grade 3 ◽  
Acute Myeloid

Abstract The role of maintenance therapy in acute myeloid leukemia (AML) remains unclear. Continued therapy with cytotoxic agents similar to those used for induction and consolidation is associated with toxicity but can improve disease free survival (DFS). (Buchner T, J Clin Oncol. 2006;24:2480 and Lowenberg B, J Clin Oncol. 1998;16:872) Immune modulation in this setting may also be effective in prolonging DFS.(Brune M, Blood2006;108:88). Methylation status of tumor suppressor genes in clinical remission predicts the relapse risk in AML with earlier relapse in patients with increased DNA promotor methylation.(Agrawal S, Cancer Res. 2007;67:1370) Therefore, hypomethylating therapy may be effective in maintaining remission and prolonging survival in these patients. We are conducting a clinical trial comparing decitabine to cytotoxic chemotherapy or observation in patients with AML in their first or subsequent complete remission (CR). Patients with non-favorable risk AML (including intermediate and poor risk) receive induction therapy with idarubicin and high dose cytarabine followed by at least 2 cycles of cytarabine based consolidation. They are then stratified by age (≤ 60 vs. > 60) and cytogenetics (intermediate vs. poor risk) and randomized to receive decitabine 20 mg/m2 IV daily × 5 every 4 to 8 weeks for 12 cycles, or to continue chemotherapy/observation. Patients in > first CR are randomized after completion of salvage therapy. Serial samples for methylation studies and determination of minimal residual disease by flow cytometry are collected. To date, 19 (8 M, 11 F) patients with AML (including 14 in first CR and 5 in subsequent CR) have been enrolled onto the study. Median age of the patients is 56 years (range 31 – 74). Fourteen patients are ≤ 60 years. Cytogenetics at diagnosis was intermediate in 10 patients, poor-risk in 8 patients, and favorable [inv(16)] in one relapsed patient. Eight patients were randomized to decitabine and have received a median of 3 cycles (range 1 – 6). Eleven patients were randomized to observation/continued therapy and all, except 2 patients, have received further cytarabine based therapy after consolidation. With a median duration of follow up for the entire group of 5 months (range 1 – 9), 7/8 patients on the decitabine arm and 9/11 patients on the other arm have remained in remission. Toxicity in the decitabine treated patients was limited to 4 episodes of grade 3 neutropenia, 2 episode of grade 3 thrombocytopenia, and 1 episodes of grade 3 anemia. All of these cytopenias were short in duration and reversed without any associated adverse events. We conclude that administration of decitabine in CR at the above schedule/dose is safe and well tolerated.

Efficacy of Mitoxantrone and Etoposide in Patients with Acute Myeloid Leukemia Refractory to Initial Standard Induction Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4385-4385 ◽  
Author(s):  
Rajesh Sehgal ◽  
Wassim McHayleh ◽  
James Natale ◽  
Anastasios Raptis ◽  
Mounzer Agha ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Infectious Complications ◽  
High Dose ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3 ◽  
Acute Myeloid

Abstract The most effective reinduction regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after one cycle of cytarabine combined with an anthracycline is not well established. In an effort to search for new synergistic and non-cross resistant antileukemic regimens different chemotherapeutic combinations have been investigated in refractory AML patients. Multiple regimens including high dose cytarabine, anthracyclines, fludarabine and etoposide have been used with CR rates up to 40%. Mitoxantrone and etoposide have activity in AML as induction agents but their role in reinduction in patients not responding to first line therapy has not been fully established. In the current retrospective study we evaluated the efficacy and toxicity of mitoxantrone and etoposide in AML patients treated at our institution who did not respond to first induction therapy with cytarabine and an anthracycline. A total of fifty seven AML patients were treated with mitoxantrone and etoposide (mean age 55 years, range 18–75 years). Twenty four patients were treated with mitoxantrone 10 mg/m2/d and etoposide 100 mg/m2/d both administered intravenously, days 1 to 5 (regimen 5+5) and thirty three patients were treated with mitoxantrone 10 mg/m2/d administered intravenously days 1 to 3 and etoposide 100 mg/m2/d administered intravenously, days 1 to 5 (regimen 3+5). Twenty six of fifty seven patients (46%) achieved CR. CR was achieved in 38% of patients (9/24) treated with the 5+5 regimen and 52% of patients (17/33) treated with the 3+5 regimen. Mean blast percentage before treatment with mitoxantrone and etoposide was 25% in patients who achieved CR vs 40% in patients who did not achieve CR (p < 0.03). Grade 3/4 hepatic toxicities were seen in 5% (3/57) of patients and there were no grade 3 or 4 renal toxicities. The median duration of neutropenia in patients achieving CR was 29 days after reinduction. 10% (6/57) of the patients died from infectious complications. Cytogenetic analyses were performed prior to first-line therapy in all patients. Patients with favorable cytogenetics treated with etoposide and mitoxantorne had 100% CR (3/3), patients with standard cytogenetics had 58% CR (19/33) and patients with unfavorable cytogenetics had 19% CR (4/21). Overall CR was achieved in 61% (22/36) of patients with favorable and standard cytogenetics. Our data suggest that the combination of etoposide and mitoxantorne is an active and well tolerated regimen, especially in patients with favorable and standard cytogenetics, and warrants further studies in prospective trials.

Phase 2 Trial of G-CSF Priming, Clofarabine, and High Dose Cytarabine (GCLAC) for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) or Advanced Myelodysplastic Syndrome or Advanced Myeloproliferative Neoplasm,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3617-3617
Author(s):  
Pamela S Becker ◽  
Bruno C. Medeiros ◽  
Frederick R. Appelbaum ◽  
Bart Lee Scott ◽  
Paul C. Hendrie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Pulmonary Toxicity ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasm ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 3617 Clofarabine and cytarabine combinations have been effective in the treatment of adult acute myeloid leukemia (AML) in both the relapsed/refractory and upfront settings. Based on our results with GCLAC (G-CSF priming, clofarabine, and high dose cytarabine) in a trial for relapsed/refractory AML (Becker et al. Br J Haematol in press), we are currently testing this regimen in newly diagnosed patients age < 65. The G-CSF dose is 5 mcg/kg/day by subcutaneous injection beginning the day prior to chemotherapy, clofarabine 30 mg/m2/day × 5 and cytarabine 2 gm/m2/day × 5. Second induction with the same regimen was permissible if marrow blasts over 5% persisted on day 21 or thereafter. Consolidation courses were administered for up to 3 cycles, with clofarabine at a dose of 25 mg/m2/day × 4 days and cytarabine 2 gm/m2/day × 4 days. The primary objectives of this trial are to estimate rates of CR (complete remission) and EFS (event free survival). A stopping rule would be imposed if there was reasonable evidence that the CR rate was inferior to that obtained with standard induction 7+3, 70% (Fernandez et al. NEJM 2009; 361:1249–59). Absent early stopping, 50 patients will be treated. Twenty-five patients with non-APL AML, RAEB2, CMML2, or myelofibrosis with >10% blasts have been treated thus far; their median age is 52, range 22–63. Eleven patients had antecedent hematologic disorders(AHD). Four patients had poor risk cytogenetics, four patients had normal cytogenetics with Flt3+, and 5 patients had good risk cytogenetics. The most significant grade 3/4 toxicity occurring in 2 patients, was a constellation of pulmonary infiltrates, hypoxia, and diffuse alveolar hemorrhage that responded to steroids. This incidence is not dissimilar to the pulmonary toxicity described with single-agent high-dose cytarabine (Andersson et al. Cancer 1990; 65:1079–84). Pulmonary toxicity has not occurred in 8 subsequent patients given steroid premedication. The other grade 3 adverse events (AEs) included pneumonia (8), viral respiratory infection (6), abscess (4), bacteremia (13), and one additional grade 4 AE was septic shock. There has been no treatment related mortality. Fifteen of 17 currently evaluable patients have achieved CR, all but one with a single course, and 1 additional patient attained CRp (complete remission with incomplete platelet recovery). Using a model that accounts for cytogenetics, age, AHD, and organ function, the observed CR rate of 88% (95% CI 64%to 95%) exceeds the expected rate of 61% had the same patients received other high-dose cytarabine containing regimens but without clofarabine. Given the recent shortage of daunorubicin and the lack of assurance that an idarubicin dose (18mg/m2) that would be the nominal equivalent of 90mg/m2 daunorubicin is safe (Garcia-Manero et al. Haematologica 2002; 87:804–7), GCLAC may be a suitable alternative induction regimen for newly diagnosed AML and advanced myelodysplastic syndrome or myeloproliferative neoplasm. Disclosures: Becker: Sanofi-Oncology: Research Funding. Off Label Use: Clofarabine is FDA approved for treatment of relapsed pediatric acute lymphoblastic leukemia.

Antifungal prophylaxis with Amphotericin B deoxycholate emulsified in lipids for acute myeloid leukemia patients treated in low economy countries

2015 ◽  
Vol 57 (2) ◽  
pp. 474-476
Author(s):  
Bishesh Sharma Poudyal ◽  
Bishal Gyawali ◽  
Binaya Sapkota ◽  
Sampurna Tuladhar ◽  
Gentle Sunder Shrestha ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Amphotericin B ◽  
Myeloid Leukemia ◽  
Antifungal Prophylaxis ◽  
Amphotericin B Deoxycholate ◽  
Acute Myeloid

scholarly journals Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jorge E. Cortes ◽  
Tara L. Lin ◽  
Geoffrey L. Uy ◽  
Robert J. Ryan ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Link Type ◽  
Secondary Acute Myeloid Leukemia ◽  
The Mean ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality‐adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up. Methods Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. Results The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. Conclusions This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 (https://clinicaltrials.gov/ct2/show/NCT01696084) and is complete.

Safety and activity of venetoclax in combination with high-dose cytarabine in children with relapsed or refractory acute myeloid leukemia.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10004-10004 ◽  
Author(s):  
Seth E Karol ◽  
Thomas Alexander ◽  
Soumyasri Das Gupta ◽  
Stanley B. Pounds ◽  
Kristin Canavera ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Phase 1 ◽  
High Dose ◽  
Phase 2 ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

10004 Background: Venetoclax is an orally available BCL-2 antagonist with demonstrated activity in adults with newly diagnosed or relapsed acute myeloid leukemia (AML). Here, we describe the first use of venetoclax 1) in combination with high-dose cytarabine and idarubicin 2) in patients 2-22 years old with relapsed AML. Methods: Patients with relapsed AML or AML refractory to at least two courses of induction therapy were enrolled in this Phase 1 study with a rolling-six design. All patients received venetoclax (240 or 360 mg/m2) on days 1-28 and low-dose (LD: 100 mg/m2 every 12 hours x 20 doses) or high-dose (HD: 1000 mg/m2 every 12 hours x 8 doses) cytarabine beginning on day 8 (Table). Patients who had previously received < 270 mg/m2 of doxorubicin equivalents also received idarubicin 12 mg/m2 on day 8 in dose level 4; other patients were enrolled on the expansion cohort at dose level 3. Non-hematologic CTCAE grade 3 or higher toxicities were intensity limiting (ILT), excluding those anticipated with HD cytarabine. Results: Among 18 evaluable patients, a single ILT (prolonged hematological suppression beyond day 50) was observed (Table). Toxicities were consistent with the underlying cytotoxic chemotherapy, with 14 patients experiencing a total of 40 grade 3 toxicities including 6 documented infections and 23 episodes of febrile neutropenia. There was 1 grade 4 fungal sepsis. The recommended phase 2 dose of venetoclax was 360 mg/m2 (max 600 mg) when combined with HD cytarabine or HD cytarabine/idarubicin. Of the 12 patients with > 50% reduction in blasts following the 7-day venetoclax window therapy, end-of-cycle marrow responses included 7 CR/CRi and 3 PR. Minimal residual disease negative remissions occurred in 4 patients. BH3 profiling of samples and a phase 2 expansion of both dose levels 3 and 4 to further characterize the promising activity of these combinations are underway. Conclusions: Venetoclax combined with cytarabine or cytarabine/idarubicin is active and well tolerated in pediatric patients with relapsed/ refractory AML. Clinical trial information: NCT03194932. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document