Ulf Tidefelt

Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry

Acute myeloid leukemia (AML) is most common in the elderly, and most elderly are thought to be unfit for intensive treatment because of the risk of fatal toxicity. The Swedish Acute Leukemia Registry covers 98% of all patients with AML (nonacute promyelocytic leukemia) diagnosed in 1997 to 2005 (n = 2767), with a median follow-up of 5 years, and reports eligibility for intensive therapy, performance status (PS), complete remission rates, and survival. Outcomes were strongly age and PS dependent. Early death rates were always lower with intensive therapy than with palliation only. Long-term survivors were found among elderly given intensive treatment despite poor initial PS. Total survival of elderly AML patients was better in the geographic regions where most of them were given standard intensive therapy. This analysis provides unique real world data from a large, complete, and unselected AML population, both treated and untreated, and gives background to treatment decisions for the elderly. Standard intensive treatment improves early death rates and long-term survival compared with palliation. Most AML patients up to 80 years of age should be considered fit for intensive therapy, and new therapies must be compared with standard induction.

Targeting p53 in Vivo: A First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer

PURPOSE APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246. PATIENTS AND METHODS APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg. RESULTS MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkins lymphoma with a p53 splice site mutation showed a minor response. CONCLUSION We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.

Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry

Our knowledge about acute promyelocytic leukemia (APL) patients is mainly based on data from clinical trials, whereas population-based information is scarce. We studied APL patients diagnosed between 1997 and 2006 in the population-based Swedish Adult Acute Leukemia Registry. Of a total of 3897 acute leukemia cases, 3205 (82%) had non-APL acute myeloid leukemia (AML) and 105 (2.7%) had APL. The incidence of APL was 0.145 per 100 000 inhabitants per year. The median age at the time of diagnosis was 54 years; 62% were female and 38% male. Among younger APL patients, female sex predominated (89% of patients <40 years). Of the 105 APL patients, 30 (29%) died within 30 days (that is, early death (ED)) (median 4 days) and 28 (26%) within 14 days from diagnosis. In all, 41% of the EDs were due to hemorrhage; 35% of ED patients never received all-trans-retinoic acid treatment. ED rates increased with age but more clearly with poor performance status. ED was also associated with high white blood cells, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count. Of non-ED patients, 97% achieved complete remission of which 16% subsequently relapsed. In total, 62% are still alive at 6.4 years median follow-up. We conclude that ED rates remain very high in an unselected APL population.

Use of inflammatory markers for early detection of bacteraemia in patients with febrile neutropenia.

The aim of the study was to evaluate the ability of procalcitonin, C-reactive protein, serum amyloid A, interleukin-6 and interleukin-8 to predict bacteraemia during the 2 first d of fever in neutropenic patients. A total of 94 febrile neutropenic episodes in 60 patients were studied. Plasma samples were analysed at 10-h intervals from the onset of fever. Clinical events were categorized into 4 groups: 1) bacteraemia caused by other agents than coagulase-negative staphylococci (non-CNS bacteraemia) (n=21), 2) coagulase-negative staphylococci bacteraemia (n=15), 3) microbiologically or clinically documented infection without bacteraemia (n=26) and 4) fever of unknown origin (n=32). In non-CNS bacteraemia all markers, except for serum amyloid A, showed significantly higher levels compared to patients with fever of unknown origin (p<0.05). For non-CNS bacteraemia the highest negative predictive value was found for procalcitonin (94%), followed by interleukin-6 (89%), C-reactive protein (88%) and interleukin-8 (87%). Procalcitonin, with a cut-off level of 1.4 ng/ml during 10–20 h after fever onset, showed the highest positive predictive value (67%) for a non-CNS bacteraemia. In conclusion, the value of the analysed markers to predict a non-CNS bacteraemia in neutropenic patients was limited due to low sensitivity and positive predictive value. However, procalcitonin, interleukin-6, C-reactive protein, and interleukin-8 could give useful information for the clinician in excluding a non-CNS bacteraemia.

P-Glycoprotein Inhibitor Valspodar (PSC 833) Increases the Intracellular Concentrations of Daunorubicin In Vivo in Patients With P-Glycoprotein–Positive Acute Myeloid Leukemia

PURPOSE The aim of the present study was to evaluate the effect of the cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells in vivo during treatment. PATIENTS AND METHODS Ten patients with acute myeloid leukemia (AML) were included. Leukemic cells from seven of the patients were P-glycoprotein (Pgp)-positive. dnr 100 mg/m(2) was given as a continuous infusion over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography. RESULTS The mean dnr concentrations in leukemic cells 24 hours after the start of infusion (before valspodar) were 18.8 micromol/L in Pgp-negative samples and 13.5 micromol/L in Pgp-positive samples. After 8 hours of valspodar infusion, these values were 25.8 and 24.0 micromol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr concentration against time in the plasma. For the seven patients with Pgp-positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on day 2 (P<.05) when valspodar was given. In the three patients with Pgp-negative leukemia, no significant difference was observed. CONCLUSION These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo.

Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks

Cytogenetically normal acute myeloid leukemia (CN-AML) compose between 40% and 50% of all adult acute myeloid leukemia (AML) cases. In this clinically diverse group, molecular aberrations, such as FLT3-ITD, NPM1, and CEBPA mutations, recently have added to the prognostic accuracy. Aberrant DNA methylation is a hallmark of cancer, including AML. We investigated in total 118 CN-AML samples in a test and a validation cohort for genome-wide promoter DNA methylation with Illumina Methylation Bead arrays and compared them with normal myeloid precursors and global gene expression. IDH and NPM1 mutations were associated with different methylation patterns (P = .0004 and .04, respectively). Genome-wide methylation levels were elevated in IDH-mutated samples (P = .006). We observed a negative impact of DNA methylation on transcription. Genes targeted by Polycomb group (PcG) proteins and genes associated with bivalent histone marks in stem cells showed increased aberrant methylation in AML (P < .0001). Furthermore, high methylation levels of PcG target genes were independently associated with better progression-free survival (odds ratio = 0.47, P = .01) and overall survival (odds ratio = 0.36, P = .001). In summary, genome-wide methylation patterns show preferential methylation of PcG targets with prognostic impact in CN-AML.

Assessment of systemic inflammation markers to differentiate a stable from a deteriorating clinical course in patients with febrile neutropenia

In this study, we evaluated the predictive values of procalcitonin (PCT), C‐reactive protein (CRP), interleukin‐6 (IL‐6) and serum amyloid A (SAA) for determining the clinical course in febrile neutropenic patients. Daily plasma analyses during the fever course were performed in 101 episodes with fever and chemotherapy‐induced neutropenia (neutrophil count <0.5 × 109/L). Procalcitonin (PCT) and IL‐6 values were significantly higher in febrile episodes in patients who developed complications. Procalcitonin with a cut‐off value of ≤0.4 ng/mL or IL‐6 ≤50 pg/mL 3 d after fever onset indicated daily high negative predictive values (NPVs) (91–100%) for episodes with complications. No marker could predict deterioration; however, daily low plasma concentrations of PCT or IL‐6 during the first 8 d of fever were found to be a good predictor of no subsequent complications in neutropenic patients and therefore to be a helpful tool for limiting anti‐microbial therapy.

Large-volume apheresis for the harvest of peripheral blood progenitor cells for autologous transplantation

BACKGROUND: The mobilization and harvest of a sufficient number of peripheral blood stem and progenitor cells for autologous transplantation is an important aspect of treatment in patients with certain hematologic and solid tumor disease. The level of CD34+ cells in peripheral blood is often used as a predictor of successful harvest. STUDY DESIGN AND METHODS: A total of 129 apheresis procedures in 38 patients have been investigated retrospectively to evaluate the possibility to predict the outcome by other measures, such as total treated blood volume (TBV) during the apheresis. RESULTS: No significant correlation was observed between the level of CD34+ cells per kg of body weight in collected apheresis components and the TBV in all 129 apheresis procedures. However, analysis of results from 22 apheresis procedures with TBV > 16 L (large‐volume apheresis) and with < 10 × 10(3) CD34+ cells per mL in the peripheral blood found a correlation between TBV and the number of CD34+ cells per kg of body weight in the collected component (R2 = 0.585, p = 0.005). In patients who underwent large‐volume apheresis (> 16 L) and who had < 10 × 10(3) CD34+ cells per mL in their peripheral blood, the number of CD34+ cells in the apheresis component was not correlated with that in the peripheral blood prior to harvest (R2 = 0.262, p = 0.1569). In the patients who underwent apheresis procedures with TBV < 16 L and who had > 20 × 10(3) CD34+ cells per mL in their peripheral blood, there was a correlation between the number of CD34+ cells in the component and the number of CD34+ cells in the peripheral blood (R2 = 0.800, p = 0.0000). However, there was not a correlation in this group between the number of CD34+ cells in the component and the TBV. There were no significant differences in the content of CD34+/CD33+ and CD34+/ HLA‐DR+ cells in the collected component in the two groups. CONCLUSION: TBV appears to be critical for the collection of a sufficient number of progenitor cells in patients with < 10 × 10(3) CD34+ cells per mL in peripheral blood.

Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study

Summary.  Cladribine has single‐drug activity in acute myeloid leukaemia (AML), and may enhance the formation of the active metabolite (ara‐CTP) of cytosine arabinoside (ara‐C). To evaluate the feasibility of adding intermittent cladribine to intermediate‐dose ara‐C (1 g/m2/2 h) b.i.d. for 4 d with idarubicin (CCI), we performed a 2:1 randomized phase II trial in AML patients aged over 60 years. Primary endpoints were time to recovery from cytopenia and need for supportive care following the first course. Sixty‐three patients (median 71 years, range 60–84 years) were included, constituting 72% of all eligible patients. Toxicity was limited, with no differences between the treatment arms. The early toxic death rate was 11%. The median time to recovery from neutropenia and thrombocytopenia was 22 and 17 d from the start of course no. 1, respectively, and the requirement for platelet and red cell transfusions was four and eight units respectively. Patients had a median of 8 d with fever over 38°C, and 17 d with intravenous antibiotic treatment. The overall complete remission (CR) rate was 62%, with 51% CR from one course of CCI in comparison with 35% for the two‐drug therapy (P = 0·014). The median survival with a 2‐year follow‐up was 14 months, and the 2‐year survival was over 30%, with no differences between the treatment arms. Considering the median age and our population‐based approach, the overall results are encouraging.

Pharmacokinetics of Daunorubicin and Doxorubicin in Plasma and Leukemic Cells from Patients with Acute Nonlymphoblastic Leukemia

The pharmacokinetics of daunorubicin and doxorubicin were studied in plasma and leukemic cells from 16 patients with acute nonlymphoblastic leukemia during 19 courses of treatment with the unconjugated or DNA-conjugated drugs. Daunorubicin and doxorubicin are high-clearance drugs with very high apparent volumes of distribution, indicating a pronounced tissue affinity. Both clearance and distribution volume decreased when the drugs were administered as DNA-conjugates indicating a reduction in the tissue affinity. This was more pronounced in the case of doxorubicin and may explain the reduced cardiotoxicity of the DNA-complexes. Daunorubicin reached higher intracellular peak concentrations than doxorubicin, but the latter drug was retained much longer. The cell/plasma concentration ratio was higher for daunorubicin than for its reduced metabolite daunorubicinol. No doxorubicinol was found intracellularly. The observed differences in cellular pharmacokinetics between daunorubicin and doxorubicin may explain the difference between the clinical activity spectras of these two drugs. DNA-conjugation did not markedly modify the uptake of daunorubicin in the leukemic cells, whereas the mean intracellular accumulation of doxorubicin was 60% higher when the drug was administered as a DNA-conjugate. This may enhance the selectivity of doxorubicin in the treatment of acute leukemia.