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Sequential phase II Southwest Oncology Group studies (S0112 and S0301) of daunorubicin and cytarabine by continuous infusion, without and with ciclosporin, in older patients with previously untreated acute myeloid leukaemia.

ABSTRACT: Attempts to overcome multi-drug resistance in acute myeloid leukaemia (AML) have been limited by toxicities. To investigate the effect of reducing peak drug levels, we performed sequential phase II studies using continuous infusion daunorubicin and cytarabine without (AD) and then with ciclosporin (ADC) in older patients with AML. Untreated patients (age 56+ years) received daunorubicin (45 mg/m2 per day for 3 d) and cytarabine (200 mg/m2 per day for 7 d), both by continuous infusion, without (S0112, 60 patients) and then with (S0301, 50 patients) the addition of ciclosporin. Complete response (CR) rates were 38% on S0112 and 44% on S0301. Fatal induction toxicities occurred in 17% and 12% respectively, arising primarily from infection and haemorrhage. Median overall and relapse-free survival was 7 and 8 months for AD respectively, and 6 and 14 months for ADC. Patients with phenotypic or functional P-glycoprotein had somewhat higher CR rates with ADC than AD, although confidence intervals overlapped. In these sequential trials, continuous infusion AD produced CR rates comparable to those with bolus daunorubicin. The addition of ciclosporin did not cause undue toxicities, produced a similar CR rate, and possibly improved relapse-free survival. Further correlate analyses did not identify a subpopulation specifically benefitting from the addition of ciclosporin.

SUBMITTER: Chauncey TR

PROVIDER: S-EPMC2967366 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Sequential phase II Southwest Oncology Group studies (S0112 and S0301) of daunorubicin and cytarabine by continuous infusion, without and with ciclosporin, in older patients with previously untreated acute myeloid leukaemia.

Chauncey Thomas R TR Gundacker Holly H Shadman Mazyar M List Alan F AF Dakhil Shaker R SR Erba Harry P HP Slovak Marilyn L ML Chen I-Ming IM Willman Cheryl L CL Kopecky Kenneth J KJ Appelbaum Frederick R FR

British journal of haematology 20091011 1

Attempts to overcome multi-drug resistance in acute myeloid leukaemia (AML) have been limited by toxicities. To investigate the effect of reducing peak drug levels, we performed sequential phase II studies using continuous infusion daunorubicin and cytarabine without (AD) and then with ciclosporin (ADC) in older patients with AML. Untreated patients (age 56+ years) received daunorubicin (45 mg/m2 per day for 3 d) and cytarabine (200 mg/m2 per day for 7 d), both by continuous infusion, without (S ...[more]

PMID: 19821823

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Project description:PurposeEffective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML.Patients and methodsAdults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m2 per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS).ResultsMedian age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months).ConclusionVenetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.

Project description:BackgroundPatients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations.MethodsIn this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. The primary endpoint was overall response to treatment at 24 weeks in all evaluable patients. This study is registered with ClinicalTrials.gov, number NCT01500733, and is fully enrolled.FindingsBetween Dec 22, 2011, and Jan 2, 2014, we enrolled 51 patients; 47 had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months (IQR 12.9-27.0). 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. 32 (97%; 95% CI 86-100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0.4 months. 12 (80%; 95% CI 52-96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Grade 3 or worse treatment-related adverse events were neutropenia in 12 (24%) patients (grade 4 in one [2%] patient), anaemia in seven (14%) patients, and thrombocytopenia in five (10%) patients (grade 4 in one [2%] patient). Grade 3 pneumonia occurred in three (6%) patients, and grade 3 rash in one (2%) patient.InterpretationThe activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings.FundingIntramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute, Danish Cancer Society, Novo Nordisk Foundation, National Institutes of Health Medical Research Scholars Program, and Pharmacyclics Inc.

Dataset Information

Sequential phase II Southwest Oncology Group studies (S0112 and S0301) of daunorubicin and cytarabine by continuous infusion, without and with ciclosporin, in older patients with previously untreated acute myeloid leukaemia.

Publications

Sequential phase II Southwest Oncology Group studies (S0112 and S0301) of daunorubicin and cytarabine by continuous infusion, without and with ciclosporin, in older patients with previously untreated acute myeloid leukaemia.

Similar Datasets

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