Population-based registries may provide data complementary to that from basic science and clinical intervention studies, all of which are essential for establishing recommendations for the management of patients in the real world. The same quality criteria apply for the evidence-based label, and both high representation and good data quality are crucial in registry studies. Registries with high coverage of the target population reduce the impact of selection on outcome and the subsequent problem with extrapolating data to nonstudied populations. Thus, data useful for clinical decision in situations not well covered by clinical studies can be provided. The potential clinical impact of data from population-based studies is exemplified with analyses from the Swedish Acute Leukemia Registry containing more than 3300 acute myeloid leukemia (AML) patients diagnosed between 1997 and 2006 with a median follow-up of 6.2 years on (1) the role of intensive combination chemotherapy for older patients with AML, (2) the impact of allogeneic stem cell transplantation on survival of younger patients with AML, and (3) the continuing problem with early deaths in acute promyelocytic leukemia. We also present the first Web-based dynamic graph showing the complex interaction between age, performance status, the proportion of patients given intensive treatment, early death rate, complete remission rate, use of allogeneic transplants, and overall survival in AML (non-AML).

Mutations in the TP53 tumor suppressor gene occur at different frequencies in a variety of human malignancies.1 TP53 encodes a DNA-binding transcription factor that induces cell growth arrest, senescence and cell death by apoptosis upon cellular stress, including oncogenic stress and DNA damage. In hematological malignancies TP53 mutations are common in relapsed/refractory disease and confers a dismal prognosis.2 PRIMA-1 and the analog APR-246 (PRIMA-1MET) can restore wild-type conformation of mutant p53 and induce apoptosis in tumor cells of various origin.3, 4, 5 APR-246 is the first compound targeting mutant p53 to enter into a clinical trial. In the first in-man study APR-246 was given daily as a 2 h intravenous infusion for 4 consecutive days. The maximum tolerable dose using this schedule was defined as 60 mg/kg daily and the most common adverse effects were neurological.3 This is an extension of the first in-man study aiming at optimizing the dose regimen to obtain better antitumor response with less toxicity. The primary objective was to evaluate safety and tolerability of APR-246 with the new dosing schedule. Secondary objectives were to determine the pharmacokinetic (PK) profile and assess antitumor effects of APR-246. Main inclusion criteria were: relapsed/refractory non-M3 acute myeloid leukemia (AML) or chronic lymphatic leukemia (CLL) with deletion of 17p not eligible for other therapies, age 18 years, ECOG performance status 0–2 and life expectancy of at least 2 months. Main exclusion criteria were hepatic transferase 5 upper limit of normal (ULN), creatinine 1.5 ULN, severe cardiac or respiratory disease. The trial was conducted in accordance to the Declaration of Helsinki and ICH-GCP guidelines and was registered at ClinicalTrials.gov, identifier NCT00900614. The dosing schedule was designed to maximize drug exposure without increasing peak concentrations. Four daily infusions were given using a boosting infusion of 50 mg/kg during 45 min followed by a 85 mg/kg as a 5 h and 15 min infusion, in total 135 mg/kg, with an option to repeat the treatment in 21 day cycles. Interim analyses were scheduled at completion of every three patients or whenever necessary at any occasion. Dose limiting toxicity (DLT) was defined as study drug–related Common Terminology Criteria for Adverse Events (CTCAE) grade 1 for ataxia/incoordination, tremor and confusion; CTCAE grade 2 for somnolence, depressed level of consciousness and seizures; and other CTCAE grade 2, 3 or 4. Dose de-escalation was made twice by decision from the study board due to toxicity. After treating three patients on the starting dose of 135 mg/kg, there was a dose reduction to 105 mg/kg (45 mg/kg bolus+60 mg/kg infusion). This schedule was given to five patients when a second de-escalation was made to 67.5 mg/kg (25 mg/kg+42.5 mg/kg). Efficacy was assessed by blood and bone marrow sampling at baseline, on day 4 and on day 21 for AML, and by lymph node evaluation manually; and with computed tomography (CT) scans at baseline and on day 21 for CLL. Predefined response criteria for AML was a reduction of blast cell count of 25% in peripheral blood and/or bone marrow, and for CLL a reduction of lymphocytes in peripheral blood of 25% and/or a 25% reduction of tumor size assessed by CT scan or palpation of peripheral lymph nodules and/or disappearance of B symptoms. A Mini Mental Test was performed before and after infusion at day 1 and day 4. Safety visits twice weekly were made until day 21. PK samples were collected at baseline, 45 and 90 min after start and 2 h after completed infusion. PK calculations were performed by non-compartmental analysis. Plasma concentrations of APR-246 were determined using a validated LC-MS/MS method.3 Eleven patients were screened and ten were included at four centers, eight with AML and two with CLL. One patient failed screening due to an ongoing systemic infection and was not included. All patients had relapsed or refractory disease with a median of two previous lines of therapy (range 1–3). Three out of eight patients analyzed (exon 2–11) had TP53 mutations. Patient demographics are summarized in Table 1. Using the 6 h infusion administration, the PK of APR-246 was characterized by a low clearance (151±35 ml/h per kg) and a large distribution volume (824±219 ml/kg; mean±s.d., n=10) indicating a distribution of APR-246 throughout the whole body. APR-246 concentrations declined in plasma with a t1/2 of about 3.8±0.8 h. At steady state (day 4), no accumulation of APR-246 was observed with the adopted 6 h infusion schedule or after repeated cycles. Plasma clearance and distribution volume were similar at day 1 and day 4, suggesting time-independent kinetics, and in line with the PK parameters previously obtained in the range of doses 2–90 mg/kg after a 2 h infusion. This suggests dose-independent kinetics also up to a daily dose of 135 mg/kg per day given as a 6 h infusion. In total, 41 adverse events (AE) were considered to have probable or possible relationship to study treatment. There was a relation between the dose and the number of AE:s probably associated with study medication: 16, 11 and 1 AE:s were reported at dose levels 135, 105 and 67.5 mg/kg, respectively (Table 2). The most commonly reported AE were vomiting, constipation and dizziness, followed by nausea, electrocardiogram QT-prolongation, cough and fatigue. Two AE:s were classified as dose limiting at 135 mg/kg; dizziness, reported for the second included patient, and tremor, reported for the third included patient. Based on this, the dose for the following patients was decreased to 105 mg/kg. The only two severe adverse events (SAE) judged as probably related to the study medication occurred at this dose level, both in the same patient (03-102) and on the same day; electrocardiogram QT-prolongation and dyskinesia. Patient 03-102 was discontinued from the study due...

In acute myeloid leukemia (AML) FLT3 internal tandem duplication (ITD) and nucleophosmin 1 (NPM1) mutations provide prognostic information with clinical relevance through choice of treatment, but the effect of age and sex on these molecular markers has not been evaluated. The Swedish AML Registry contains data on FLT3-ITD and NPM1 mutations dating to 2007, and 1570 adult patients younger than 75 years, excluding acute promyelocytic leukemia, had molecular results reported. Females more often had FLT3ITD and/or NPM1mut (FLT3ITD: female, 29%; male, 22% [P = .0015]; NPM1mut: female, 36%; male, 27% [P = .0001]), and more males were double negative (female, 53%; male, 64%; P < .0001). Patients with FLT3ITD were younger than those without (59 vs 62 years; P = .023), in contrast to patients with NPM1mut (62 vs 60 years; P = .059). Interestingly, their prognostic effect had a strong dependence on age: FLT3ITD indicated poor survival in younger patients (<60 years; P = .00003), but had no effect in older patients (60-74 years; P = .5), whereas NPM1mut indicated better survival in older patients (P = .00002), but not in younger patients (P = .95). In FLT3ITD/NPM1mut patients, the survival was less dependent on age than in the other molecular subsets. These findings are likely to have clinical relevance for risk grouping, study design, and choice of therapy.

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative in patients with hematologic malignancies but carries a significant risk of graft-versus-host disease (GVHD). There are no standard treatments for steroid-refractory (SR) gastrointestinal (GI) acute GVHD (aGVHD). This multicenter, international, retrospective medical record review aimed to evaluate the off-label use of vedolizumab, a gut-selective immunomodulator, for treating SR GI aGVHD. Data were collected from patients' medical records; criteria for extraction included no more than 1 allo-HCT and at least 1 dose of vedolizumab as treatment for SR GI aGVHD (ie, stage 1 to 4 GI aGVHD following ≥1 previous treatment regimen(s) containing ≥1 mg/kg methylprednisolone or equivalent). Descriptive analyses of response rate, overall survival (OS), and serious adverse effects (SAEs) were performed. Twenty-nine patients were identified from 7 sites who had received 1 to 10 doses of vedolizumab 300 mg i.v. (median 3 doses) as treatment for SR GI aGVHD. The overall response rate at 6 to 10 weeks after vedolizumab initiation was 64%, and OS at 6 months was 54%. There were 29 SAEs, including 12 infections; 3 SAEs were considered possibly related to vedolizumab, 2 of which were infections. Thirteen SAEs were fatal, 1 of which was possibly vedolizumab-related. There were 8 nonserious infections and 1 serious infection with confirmed GI origin in 8 patients; there was no apparent pattern in the timing of these infections relative to the initiation of vedolizumab treatment. Further data on the efficacy and safety of vedolizumab in this setting from prospective trials are needed.

BACKGROUND: Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in acute leukemia, but outcome is hampered by toxicity. Population‐based data avoid patient selection and may therefore substitute for lack of randomized trials.METHODS: We evaluated alloSCT rates within the Swedish Acute Leukemia Registry, including 3899 adult patients diagnosed from 1997 through 2006 with a coverage of 98% and a median follow‐up of 6.2 years.RESULTS: AlloSCT rates and survival decreased rapidly with age >55 years. The 8‐year overall survival (OS) was 65% in patients <30 years and 38% in patients <60 years and was similar for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Among 1073 patients <60 years, alloSCT was performed in 42% and 49% of patients with AML and ALL, respectively. Two‐thirds of the alloSCTs were performed in first complete remission, and half used unrelated donors, the same in AML and ALL. Regional differences in management and outcome were found: 60% of AML patients <40 years received alloSCT in all parts of Sweden, but two‐thirds of AML patients 40‐59 years had alloSCT in one region compared with one‐third in other regions (P<.001), with improved 8‐year OS among all AML patients in this age cohort (51% vs 30%; P = .005).CONCLUSIONS: More Swedish AML patients received alloSCT, and long‐term survival was better than in recently published large international studies, despite our lack of selection bias. There was no correlation between alloSCT rate and survival in ALL. In adult AML patients <60 years of age, a high alloSCT rate was associated with better long‐term survival, but there was no such correlation in ALL. Cancer 2011;. © 2011 American Cancer Society.