Abstract 1682
The introduction of Imatinib has significantly improved the outcome for patients with Ph+ CML. The complete cytogenetic response (CCgR) is a strong and confirmed predictor of improved ...long-term outcome. According to current recommendations, Imatinib (IM) should be continued indefinitely. However, optimal responders can be eligible for investigational trials of treatment discontinuation.
This study (ClinicalTrials.gov NCT 00858806) describes the effects of a policy of intermittent Imatinib (INTERIM) treatment (one month on/one month off) on cytogenetic and molecular responses in a selected population of patients ≥ 65 years old who were receiving treatment with Imatinib for > 2 years and were in stable complete cytogenetic response (CCgR). The primary endpoint of the study was the proportion of patients who maintained CCgR after 1 year of INTERIM. The secondary endpoint was the level of BCR-ABL transcripts during INTERIM
Cytogenetic and molecular responses were monitored by FISH and RT-Q-PCR every 3 months. The definition of CCgR, and of CCgR loss was based on CBA of marrow metaphases which was performed at baseline and in all the patients who became FISH positive (BCR-ABL–positive nuclei > 1%). Major molecular response (MMR), corresponding to a 3-log reduction in BCR-ABL transcript level from the standardized baseline, was defined as BCR-ABL ≤0.1%IS and was indicated as MR3.0. For the purposes of this study, complete molecular response (CMR) was defined as a 4-log reduction in BCR-ABL transcript level (<0.01%IS), with a sensitivity of at least 10,000 ABL copies, and is indicated as MR4.0. In case of loss of CCgR or MMR, Ph+ additional cytogenetic abnormalities (ACA) and BCR-ABL kinase domain (KD) point mutation analysis were also performed.
Seventy-six patients have been enrolled. Six patients (8%) lost CCgR (CBA positive), and 3 other patients became FISH positive while remaining CBA negative. At 12 months, the probability of maintaining CBA negativity was 92% (95% CI 86–98%), while the probability of maintaining FISH negativity was 87% (95% CI 79–94%). None of the factors that were examined by univariate and multivariate analysis were found to be associated with an higher probability of either loosing the CCgR (CBA) or showing a FISH positivity (> 1%), with the exception of the duration of imatinib therapy (HR = 0.23, 95% CI 0.008–0.73, P =.01). Among patients with prior Imatinib treatment longer or shorter than 48 months, the probability of maintaining FISH negativity was 94% (95% CI 88–100%) vs 71% (95% CI 53–89%), respectively, HR = 0.23 (P =.007). All the 6 patients who lost CCgR regained the CCgR with daily Imatinib, at the same dose, defined by FISH negativity after 3 to 9 months (4/6 also CBA negative, 2 patients refused bone marrow aspiration). At baseline, all but one patient (99%) were in MMR (MR3.0, BCR-ABL ≤0.1%IS), and 63 patients (83%) were in MR4.0 (<0.01%IS). After one year of intermittent Imatinib, 18/76 patients (24%) lost MR3.0 and 25/63 (39%) patients lost MR4.0. No patient lost complete hematologic response, progressed to accelerated or blastic phase, developed ACA in Ph+ cells, or developed BCR-ABL mutations. After one year, the remaining 70 patients were allowed to go back to continuous treatment, or to continue the intermittent treatment. During the first six months of follow-up (month 13 to 18), 1 of 70 discontinued Imatinib for atrial fibrillation and 9 of 70 went back to continuous treatment because FISH negativity loss (1 patient) or MMR (MR3.0) loss (8 patients). All the patients continue to be regularly observed and monitored and the first twelve months of follow-up will be presented.
The intermittent use of imatinib in older patients in stable CCgR after continuous imatinib treatment results in the transient loss of the CCgR in a minority (8%) of the patients. However, the disease burden at the molecular level significantly increased. A policy of intermittent treatment may be an alternative both to chronic continuous treatment and to treatment discontinuation, particularly in the elderly. However, a longer follow up is required before drawing final conclusions.
This work was supported in part by EuropeanLeukemiaNet through the European Treatment and Outcome Study (EUTOS) and by Cofin 2009.
Baccarani:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Di Raimondo:celgene: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.
Abstract 3412
The phase II explorative study of intermittent Imatinib (IM) treatment (InterIM) in elderly patients with Ph + chronic myeloid Leukemia (CML) who achieved a stable complete cytogenetic ...response (CCgR) after at least 2-years standard IM therapy (any dose between 300 and 800 mg/day) was started in April 2008 and closed for the enrollment in August 2009, since more than 78 patients required by statistics were included into the study. The main objective of the study was to investigate if after 12 months (trial time) the CCgR achieved with standard (daily administration) IM therapy could be maintained with InterIM. For this purpose, the CgR status was assessed by Interphase Fluorescence In Situ Hybridization (I-FISH) on peripheral blood (≥ 200 cells counted) every 3 months. When I-FISH (% Ph + nuclei) increased more then 1%, chromosome banding analysis (CBA) on bone marrow was performed to confirm the loss of CCgR and to check for additional cytogenetic abnormalities (ACA). At the present time, out of the 95 patients who were enrolled, 82 patients were evaluable and out of them 77 (94%), 73 (89%), 71 (87%) and 70 (85%) completed 3, 6, 9 and 12 months of the treatment program, respectively. Therefore, the great majority of patients completed the study core and at the end of 2010 all the patients are expected to complete the trial time (12 mo). During the first 12 months of InterIM, 1% to 11% of the evaluable patients at 3, 6, 9 and 12 months showed an I-FISH >1% Ph+ nuclei (Figure 1).
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Totally, eleven (13%) out of 82 patients treated with InterIM showed an I-FISH >1% and they were checked by CBA on bone marrow (Figure 2). Out of them only 3 cases, that means 4% of the 82 evaluable patients, lost the CCgR and resumed standard IM therapy (daily administration), but none completed 3 months of therapy. All the patients lost the MMR and increased several folds the BCR-ABL transcript levels. Two pts had a low risk Sokal and one a high risk; age was 66, 69, 77 years; time from diagnosis was 29, 91 and 100 months; duration of IM therapy was 29, 83 and 84 months; the IM dose was 400mg in all cases.
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As concern as molecular response, 99% of the patients had a major molecular response (MMR=<0.001-0.1 BCR-ABL/ABLISX 100) at the baseline. The proportion of the patients who maintained the MMR after 3, 6, 9 and 12 months of InterIM was 95%, 92%, 91%, 84%, respectively. Interestingly, we found a weak but significant correlation between the % of BCR-ABL + nuclei and the BCR-ABL transcript levels in the patients who completed the trial time (12 mo) (r=0.27; p=0.001).
In conclusion, the results of the InterIM study core (12 months), clearly show that Intermittent Imatinib (IM) treatment (InterIM) is sufficient to maintain the complete cytogenetic response (CCgR) previously achieved with standard IM therapy in elderly (≥ 65 years) Ph+ CML patients. The risk to loose the CCgR has been very low (4%), while the benefit either in terms of reduction of IM dose and of costs of therapy or in terms of compliance (data not shown) was very high.
This work was supported in part by CML-Leukemia Net and Progetto Regione Lombardia.
No relevant conflicts of interest to declare.
Background: Physical inactivity is often associated with positive energy balance and fat gain.
Objective: We aimed to assess whether energy intake in excess of requirement activates systemic ...inflammation and antioxidant defenses and accelerates muscle atrophy induced by inactivity.
Design: Nineteen healthy male volunteers were studied before and at the end of 5 wk of bed rest. Subjects were allowed to spontaneously adapt to decreased energy requirement (study A, n = 10) or were provided with an activity-matched diet (study B, n = 9). Groups with higher (HEB) or lower (LEB) energy balance were identified according to median values of inactivity-induced changes in fat mass (ΔFM, assessed by bioelectrical impedance analysis).
Results: In pooled subjects (n = 19; median ΔFM: 1.4 kg), bed rest–mediated decreases in fat-free mass (bioelectrical impedance analysis) and vastus lateralis thickness (ultrasound imaging) were significantly greater (P < 0.03) in HEBAB (−3.8 ± 0.4 kg and −0.32 ± 0.04 cm, respectively) than in LEBAB (−2.3 ± 0.5 kg and −0.09 ± 0.04 cm, respectively) subjects. In study A (median ΔFM: 1.8 kg), bed rest–mediated increases in plasma leptin, C-reactive protein, and myeloperoxidase were greater (P < 0.04) in HEBA than in LEBA subjects. Bed rest–mediated changes of glutathione synthesis rate in eythrocytes (l-3,3-2H2cysteine incorporation) were greater (P = 0.03) in HEBA (from 70 ± 19 to 164 ± 29%/d) than in LEBA (from 103 ± 23 to 84 ± 27%/d) subjects.
Conclusions: Positive energy balance during inactivity is associated with greater muscle atrophy and with activation of systemic inflammation and of antioxidant defenses. Optimizing caloric intake may be a useful strategy for mitigating muscle loss during period of chronic inactivity.
Abstract 860
Elderly CML patients treated with Imatinib (IM) in early chronic phase (CP) have similar cytogenetic response and survival compared with younger patients, but they show a lower ...compliance to standard IM therapy (400 mg/day).
The aim of the study is to investigate if CCgR that has been achieved with standard (daily administration) IM therapy can be maintained with the same dose of IM given intermittently (INTERIM).
The study population is represented by elderly patients (≥ 65 years old) with Ph+ CML and with stable CCgR after at least 2 years of standard IM therapy (daily administration). IM is given at the same dose that was given at the time of enrollment by the following intermittent schedule: 1 week on / 1 week off for the 1st month; 2 weeks on / 2 weeks off for the 2nd and 3rd month; 1 month on / 1 month off from the 4th month thereafter. In cases of loss of CCgR INTERIM was stopped and standard therapy (daily administration) was resumed. After 12 months, the patients who are in continuous CCgR are advised to continue the intermittent study schedule and to be followed indefinitely. The CgR status was evaluated at baseline (by conventional cytogenetics on bone marrow and FISH on peripheral-blood) and every 3 months during the study (only by FISH on peripheral-blood). If FISH (% of Ph+ cells) increased more than 1% in two consecutive examinations, evaluation of marrow cells metaphases was performed to confirm the loss of CCgR and to check for additional cytogenetic abnormalities. Quantitative molecular assessment of BCR-ABL transcript by RQ-PCR on peripheral blood was due at baseline and every 3 months during the study and mutational analysis of ABL was performed in case of loss of CCgR.
One-hundred and fourteen patients have been considered eligible, but 17 (15%) refused to enter into the protocol. Out of 97 enrolled patients, 87 started INTERIM, 5 patients (5%) went off the study for major protocol violation before the 3rd month and, at present, 82 patients are ongoing. Of these 82 patients, 52, 30 and 11 completed the 3rd, 6th and 9th month, respectively. The preliminary results of the first 6 months are here reported. The distribution of patients according to FISH results is shown in Fig. 1. Only 1/68 pts (at 6th month) showed an increased >1% in Ph+ cells by FISH but he maintained a CCgR when checked by conventional cytogenetic. As showed in Fig. 2, 96 to 87% of patients maintained a major molecular response MMR (≤0,1) according to International Scale (IS).
This study is trying to test the minimum effective dose of Imatinib to maintain the CCgR in elderly CML patients with stable CCgR. The preliminary results at 6 months do not show negative trends both for cytogenetic and molecular response. Therefore, the study is ongoing and all patients are expected to complete the trial time (12 months).
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No relevant conflicts of interest to declare.
Abstract Several algorithms for early prediction of poor-mobilizing patients after chemotherapy and granulocyte colony-stimulating factor administration have been proposed. They generally define ...peripheral blood cut-off levels of CD34+ cells at a fixed day after starting chemotherapy, mostly with cyclophosphamide. To define an algorithm for early addition of plerixafor regardless of the chemotherapy regimen used, we retrospectively analyzed 280 chemomobilization attempts in 236 patients treated at our institution between 2002 and 2012. In multivariate analysis, CD34+ absolute count and CD34+ percentage upon total leukocyte count at day 1 (defined as the first day in which leukocytes reached a value > 1 × 109 /L) were the only factors able to predict a total harvest ≥ 2 × 106 CD34+/kg. In patients with day 1 CD34+ lower than 20/μL, the CD34+ percentage was a more reliable predictor of stem cell harvest in the following days than CD34+ absolute count. Upon definition of the best CD34+ cut-off value for identification of poor-mobilizing patients, an algorithm was set up to guide plerixafor administration. It was prospectively validated in 20 patients in 2013 with encouraging results in terms of low incidences of both mobilization failure and plerixafor use. Large prospective trials that define the most cost-effective strategy for just-in-time rescue plerixafor are warranted.
The mechanism by which dobutamine increases the contraction of chronically dysfunctional myocardium and its effects on metabolism are still unknown. The aim of this study was to assess regional ...myocardial metabolism at rest and during an intracoronary dobutamine infusion in patients with hibernating myocardium. Eleven asymptomatic patients with single proximal stenosis of the left anterior descending coronary artery and persistent left ventricular dysfunction at rest (undergoing percutaneous transluminal coronary angioplasty PTCA) were studied prospectively. Regional left ventricular function was assessed by two-dimensional (2D) echocardiography and regional perfusion by thallium-201 single-proton-emission computed tomography. Great cardiac vein and aortic blood samples were obtained for measurements of lactate and plasma free fatty acid (FFA) concentrations. Inotropic challenge, obtained by using intracoronary dobutamine infusion, increases regional left ventricular function. However, the arteriovenous AV lactate difference was 0.206 ± 0.070 mmol/L at rest, and it decreased to 0.018 ± 0.069 mmol/L (
p < 0.05 vs baseline) and 0.066 ± 0.068 mmol/L (
p < 0.05 vs baseline) at 4 and 10 minutes of dobutamine infusion, respectively. Thus the hibernating myocardium does not produce lactate at rest. However, when regional contraction is stimulated, dobutamine-induced inotropic challenge may cause a perfusion-contraction mismatch with an activation of anaerobic glycolysis.
The
PTPN11 gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase functioning as a signaling transducer. Germ-line
PTPN11 mutations cause Noonan syndrome (NS), a ...developmental disorder characterized by an increased risk of malignancies. Recently, a novel class of activating mutations in
PTPN11 has been documented as a somatic event in a heterogeneous group of leukemias. Because of the relatively higher prevalence of certain solid tumors in children with NS and the positive modulatory function of SHP-2 in RAS signaling, a wider role for activating
PTPN11 mutations in cancer has been hypothesized. Here, we screened a number of solid tumors, including those documented in NS or in which deregulated RAS signaling occurs at significant frequency, for
PTPN11 mutations. No disease-associated mutation was identified in rhabdomyosarcoma (
n = 13), neuroblastoma (
n = 32), melanoma (
n = 50), thyroid (
n = 85), and colon (
n = 48) tumors; a novel missense change, promoting an increased basal phosphatase activity of SHP-2, was observed in one glioma specimen. Our data document that deregulated SHP-2 function does not represent a major molecular event in pediatric and adult tumors, further supporting our previous evidence indicating that the oncogenic role of
PTPN11 mutations is cell-context specific.
Objectives. An epidemiological study, addressed to identify the pathogens isolated from blood, and their antibiotic susceptibility patterns, was conducted. Methods. 12 laboratories, homogeneously ...distributed in a Northern area of Italy, were required to collected all consecutive non-duplicated strains isolated from blood during February 2008 to February 2009 and sent them to the reference laboratory. Results. A total of 1092 microorganisms were collected, including 653 gram-positive, 385 gram-negative and 54 fungi. Escherichia coli 234, Staphylococcus epidermidis 205, S. aureus 142, S. hominis 87, Enterococcus faecalis 47, S. haemolyticus 33, Klebsiella pneumoniae 33, Pseudomonas aeruginosa 32, Candida albicans 28, Enterobacter cloacae 21 were the prevalent microrganisms found. Samples were collected mainly from medicine (255 strains), intensive care units (154), surgery (99), infectious diseases (93), paediatrics (62) and nephrology (62). Antibiotic resistance (in %) in staphylococci was 65.7 (methicillin), 33.5 (gentamicin), 61.8 (azithromycin), 59.6 (erythromycin), 45.2 (ciprofloxacin) 14.8 (chloramphenicol), 2.0 (teicoplanin), and 24.1 (trimethoprim-sulfamethoxazole) no vancomycin-resistant strain was found. Enterococci showed resistance to vancomycin (10.8), ampicillin (34.4), gentamycin (42.9), ciprofloxacin (42.2) teicoplanin (7.6), erythromycin (54.7) and chloramphenicol (17.5). Enterobacteriaceae exhibited resistance to ciprofloxacin(27.0), ampicillin (74.1), ceftazidime (15.8), cefoxitin (14.7), cefepime (13.3), ceftriaxone (15.0), both imipenem and amikacin (0.95), piperacillin-tazobactam (5.1) and trimethoprim-sulfamethoxazole (32.7). Non fermenting gram negative strains were found resistant to ciprofloxacin (27.3), ceftazidime (9.5), cefepime (14.6), ceftriaxone (81.6), both imipenem and amikacin (18.6), trimethoprim-sulfamethoxazole (65.2), and piperacillin-tazobactam (7.5). Conclusions.These data show a prevalent incidence of gram-positive (59.7 %) in comparison to gram-negative (35.3%) bacteria isolated from blood.A high percentage of methicillin-resistant staphylococci as well as ceftazidime-resistance among Enterobacteriaceae is also observed suggesting that this phenomenon requires periodically surveillance.
Gestational diabetes (GD) results from insufficient endogenous insulin supply. No information is available on features of islet cells in human GD. Herein, we describe several properties of islets ...from a woman with GD. Immunohistochemical stainings and EM analyses were performed on pancreatic samples. Islet isolation was achieved by enzymatic dissociation and density gradient centrifugation. Ex vivo insulin secretion was studied in response to fuel secretagogues. Control islets were obtained from matched non-pregnant, non-diabetic women. Total insulin positive area was lower in GD, mainly due to the presence of smaller islets. β-cell apoptosis and the presence of Ki67 positive islet cells were similar in GD and controls, whereas the amount of insulin positive cells in or close to the ducts was decreased in GD. Ex vivo insulin secretion did not differ between GD and non-pregnant, non-diabetic islets. These findings suggest that in this case of human GD there might mainly be a defect of β-cell amount, not due to increased apoptosis, but possibly to insufficient regeneration.
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