Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine

Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery &lt; 9 and 17% ADL index &lt; 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age &gt; 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.</p

Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine

Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery &lt; 9 and 17% ADL index &lt; 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age &gt; 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.</p

Ibrutinib added to 10-day decitabine for older patients with AML and higher risk MDS

The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index ≥3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5 months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1 mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53 had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85

Increasing abdominal pressure with and without PEEP: effects on intra-peritoneal, intra-organ and intra-vascular pressures

Intra-organ and intra-vascular pressures can be used to estimate intra-abdominal pressure. The aim of this prospective, interventional study was to assess the effect of PEEP on the accuracy of pressure estimation at different measurement sites in a model of increased abdominal pressure

Increasing abdominal pressure with and without PEEP: effects on intra-peritoneal, intra-organ and intra-vascular pressures

Intra-organ and intra-vascular pressures can be used to estimate intra-abdominal pressure. The aim of this prospective, interventional study was to assess the effect of PEEP on the accuracy of pressure estimation at different measurement sites in a model of increased abdominal pressure

Adjunctive volasertib in patients with acute myeloid leukemia not eligible for standard induction therapy: a randomized, phase 3 trial

In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1–10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized ≥5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95–2.89]; P = 0.071). At final analysis (≥574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8–1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections