Improved overall survival with Gemtuzumab Ozogamicin (GO) compared with best supportive care (BSC) in elderly patients with untreated acute myeloid leukemia (AML) not considered fit for intensive chemotherapy: final results from the randomized phase III study (AML-19) of the EORTC and gimema leukemia groups

peer reviewe

Inclusion of Older Patients with Cancer in Randomized Controlled Trials with Patient-Reported Outcomes:a Systematic Review

Objectives: Inclusion of patient-reported outcomes (PROs) in cancer randomised controlled trials (RCTs) may be particularly important for older patients. The objectives of this systematic review were to quantify the frequency with which older patients are included in RCTs with PROs and to evaluate the quality of PRO reporting in those trials. Methods: All RCTs with PRO endpoints, published between January 2004 and February 2019, which included a patient sample with a mean/median age ≥70 years, were considered for this systematic review. The following cancer malignancies were considered: breast, colorectal, lung, prostate, gynaecological and bladder cancer. Quality of PRO reporting was evaluated using the International Society for Quality of Life Research-PRO standards. Studies meeting at least two-thirds of these criteria were considered to have high-quality PRO reporting. Results: Of 649 RCTs identified with a PRO endpoint, only 72 (11.1%) included older patients. Of these, 35 trials (48.6%) were conducted in patients with metastatic/advanced disease. PROs were primary endpoints in 20 RCTs (27.8%). Overall survival was the most frequently reported clinical outcome in studies of patients with metastatic/advanced cancer (n=28, 80%). One-third of the RCTs (n=24, 33.3%) were considered to have high-quality PRO reporting. Overall, the largest prevalence of RCTs with high-quality PRO reporting was observed in prostate and colorectal cancers. Conclusions: Our review indicates not only that PRO-RCT-based studies in oncology rarely include older patients but also that completeness of PRO reporting of many of them is often suboptimal

Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: A GIMEMA, ERIC and UK CLL FORUM study

We performed an observational study on the efficacy of bendamustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del (17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion. (Registered at clinicaltrials.gov identifier: 02491398)

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL 6560 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and \u3b3-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade 653, 18.2%) and 27.3% (grade 653, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107

Survival improvement over time of 960 s-AML patients included in 13 EORTC-GIMEMA-HOVON trials

We report the outcomes of secondary acute myeloid leukemia (s-AML) patients included in one of 13 European Organisation for Research and Treatment of Cancer (EORTC) collaborative AML trials using intensive remission-induction chemotherapy. Among 8858 patients treated between May 1986 and January 2008, 960 were identified as having s-AML, either after MDS (cohort A; n = 508), occurring after primary solid tumors or hematologic malignancies other than MDS (cohort B; n = 361), or after non-malignant conditions or with a history of toxic exposure (cohort C; n = 91). Median age was 64 years, 60 years and 61 years in cohort A, B and C, respectively. Among patients ≤60 years and classified in the cohorts A or B (n = 367), the 5-year overall survival (OS) rate was 28%. There was a systematic improvement in the 5-year OS rate over three time periods (p 60 years of age (n = 502), the OS was dismal, and there was no improvement over time

Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups

The most effective post-remission treatment to maintain complete remission (CR) in adults aged between 46 and 60 years with acute myeloid leukaemia (AML) is uncertain. Previously untreated patients with AML in CR after induction chemotherapy with daunorubicin and cytarabine were randomized between two intensive courses of consolidation therapy containing high-dose cytarabine, combined with amsacrine or daunorubicin and a standard consolidation and maintenance therapy containing standard dose cytarabine and daunorubicin. One hundred fifty-eight CR patients were assigned to the intensive group and 157 patients to the standard group. After a median follow-up of 7.5 years, the 4-year survival rate was 32 % in the intensive group versus 34 % in the standard group (P = 0.29). In the intensive group, the 4-year relapse incidence was lower than in the standard group: 55 and 75 %, respectively (P = 0.0003), whereas treatment-related mortality incidence was higher: 22 versus 3 % (P < 0.0001). Two intensive consolidation courses containing high-dose cytarabine as post-remission treatment in patients with AML aged between 46 and 60 years old did not translate in better long-term outcome despite a 20 % lower relapse incidence. Better supportive care and prevention of treatment-related complications may improve the overall survival after intensified post-remission therapy in this age group

WITH: a system to write clinical trials using XML and RDBMS.

The paper illustrates the system WITH (Write on Internet clinical Trials in Haematology) which supports the writing of a clinical trial (CT) document. The requirements of this system have been defined analysing the writing process of a CT and then modelling the content of its sections together with their logical and temporal relationships. The system WITH allows: a) editing the document text; b) re-using the text; and c) facilitating the cooperation and the collaborative writing. It is based on XML mark-up language, and on a RDBMS. This choice guarantees: a) process standardisation; b) process management; c) efficient delivery of information-based tasks; and d) explicit focus on process design

Obesity and autologous stem cell transplantation in acute myeloid leukemia

In the bone marrow transplant setting, several authors hypothesized that severely overweight patients are at increased risk of transplant-related toxicity, but different definitions of obesity, different body weight groupings and heterogeneous samples of patients were analyzed. To overcome these limitations, we retrospectively considered a homogeneous group of 54 patients (median age 36.5 years), with a diagnosis of de novo acute myeloid leukemia (AML), autografted in first complete remission (CR) with the Bu-Cy2 conditioning regimen, dosed on actual body weight. Patients were classified into three groups (obese, non-obese, underweight) using body mass index (BMI = kg/m2); for each group we analyzed transplant-related toxicity and mortality, overall survival and disease-free survival (OS/DFS). In spite of the relatively small number of patients, in our results high BMI appears a predictive factor for an increase of treatment-related toxicity and mortality. Moreover, 30 (55%) patients are currently alive in continuous CR, and after a median follow-up of 76.5 months (range 14-137) statistically significant differences in OS and DFS were detected between obese and non-obese groups (P = 0.012 and 0.021, respectively). Our study suggests that obesity may represent an independent risk factor for autograft in AML and further investigations are warranted