PURPOSE Patients with chronic myelogenous leukemia in accelerated phase (CML-AP) that is resistant or intolerant to imatinib have limited therapeutic options. Dasatinib, a potent inhibitor of BCR-ABL ...and SRC-family kinases, has efficacy in patients with CML-AP who have experienced treatment failure with imatinib. We now report follow-up data from the full patient cohort of 174 patients enrolled onto a phase II trial to provide a more complete assessment of the efficacy and safety of dasatinib in this population. PATIENTS AND METHODS Patients with imatinib-resistant (n = 161) or -intolerant (n = 13) CML-AP received dasatinib 70 mg orally twice daily. Results At a median follow-up of 14.1 months (treatment duration, 0.1 to 21.7 months), major and complete hematologic responses were attained by 64% and 45% of patients, respectively, and major and complete cytogenetic responses were achieved in 39% and 32% of patients, respectively. Responses were achieved irrespective of imatinib status (resistant or intolerant), prior stem-cell transplantation, or the presence of prior BCR-ABL mutation. The 12-month progression-free survival and overall survival rates were 66% and 82%, respectively. Dasatinib was generally well tolerated; the most frequent nonhematologic severe treatment-related adverse event was diarrhea (52%; grade 3 to 4, 8%). Cytopenias were common, including grade 3 to 4 neutropenia (76%) and thrombocytopenia (82%). Pleural effusion occurred in 27% of patients (grade 3 to 4, 5%). CONCLUSION Dasatinib is effective in patients with CML-AP after imatinib treatment failure.
Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myelogenous leukemia (CML) and resistance to ...imatinib mesylate treatment remain poorly investigated. Here, we report that CD34(+) progenitors from patients with CML at diagnosis are selectively targeted by the cytokine/alarmin interleukin (IL)-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following imatinib mesylate therapy, whereas IL-33 counteracts in vitro imatinib mesylate-induced growth arrest in CML CD34(+) progenitors via reactivation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the antiproliferative effects of imatinib mesylate on CD34(+) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(+) progenitors from patients with CML by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL-transfected bone marrow progenitors was less efficient in IL-33-deficient mice compared with wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance.
Megakaryocytes are naturally polyploid cells that increase their ploidy by endomitosis. However, very little is known regarding the mechanism by which they escape the tetraploid checkpoint to become ...polyploid. Recently, it has been shown that the tetraploid checkpoint was regulated by the Hippo-p53 pathway in response to a downregulation of Rho activity. We therefore analyzed the role of Hippo-p53 pathway in the regulation of human megakaryocyte polyploidy. Our results revealed that Hippo-p53 signaling pathway proteins are present and are functional in megakaryocytes. Although this pathway responds to the genotoxic stress agent etoposide, it is not activated in tetraploid or polyploid megakaryocytes. Furthermore, Hippo pathway was observed to be uncoupled from Rho activity. Additionally, polyploid megakaryocytes showed increased expression of YAP target genes when compared to diploid and tetraploid megakaryocytes. Although p53 knockdown increased both modal ploidy and proplatelet formation in megakaryocytes, YAP knockdown caused no significant change in ploidy while moderately affecting proplatelet formation. Interestingly, YAP knockdown reduced the mitochondrial mass in polyploid megakaryocytes and decreased expression of PGC1α, an important mitochondrial biogenesis regulator. Thus, the Hippo pathway is functional in megakaryocytes, but is not induced by tetraploidy. Additionally, YAP regulates the mitochondrial mass in polyploid megakaryocytes.
High dose chemotherapy in light chain or light and heavy chain deposition disease.
Conventional chemotherapy for myeloma yield unsatisfactory results in light and/or heavy chain deposition disease ...(H)CDD Because of the well-established dose-response effect of high dose melphalan in multiple myeloma, aiming to dramatically reduce the pathogenic monoclonal immunoglobulin (MIg) level, high dose therapy is a tempting alternative approach.
We treated 11 young patients with L(H)CDD by high dose therapy with the support of autologous blood stem cell transplantation. All had renal symptoms, including four who required dialysis and seven who had various, mainly cardiac, extrarenal manifestations.
No toxic deaths occurred. A decrease in the MIg level was observed in eight patients, with complete disappearance from serum and urine in six cases. Improvement in manifestations related to MIg deposits were observed in six patients, including renal, cardiac, and hepatic responses in 4/11, 4/4, and 2/2 cases, respectively. Histologic regression of MIg deposits was documented in cardiac, hepatic, and skin biopsies. In contrast, examination of the kidney still showed light chain deposits in one patient who had renal transplantation 3years after high dose therapy, at a time when he was in persisting remission.
Within a median follow-up of 51months, three patients were retreated because of multiple myeloma relapse, of whom one died and one required hemodialysis, and renal function secondarily deteriorated in a patient who had resistant multiple myeloma. Otherwise, no manifestations related to MIg deposits occurred or recurred in any patient.
Present results of this retrospective study argue in favor of a benefit of high dose therapy with stem cell support in young patients with L(H)CDD.
Nilotinib is now recommended for patients with newly diagnosed chronic myeloid leukaemia in chronic phase and leads to important rates of molecular response 4·5 log (MR(4·5)), allowing the prospect ...of therapy cessation. However, most patients do not reach this criterion and nilotinib is taken for lengthy periods, resulting in chronic or late-onset adverse events. Nilotinib combined with interferon might further increase rates of MR(4·5), avoid late side-effects, and allow therapy cessation. In a phase 2 trial we aimed to assess the feasibility, safety, and deep molecular response of the combination of nilotinib (600 mg daily) and peginterferon alfa-2a in newly diagnosed patients with chronic-phase chronic myeloid leukaemia (CML).
In a non-randomised, open-label, phase 2 trial, we enrolled adult patients (age ≥18 years) without any organ failure who had BCR-ABL-positive, chronic-phase CML, at diagnosis. After a priming procedure with 90 μg per week of peginterferon alfa-2a alone for a month, we gave patients peginterferon alfa-2a 45 μg per week combined with nilotinib 600 mg daily until 24 months after interferon initiation. The primary endpoint was the cumulative incidence of MR(4·5) at 12 months after initiation of peginterferon alfa-2a. Data were analysed by a modified intention-to-treat principle. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-019786-28.
Between March 24, 2011, and Sept 27, 2011, we enrolled 42 patients. One patient withdrew consent before receiving any study treatment so was excluded from analysis; 41 patients received treatment with peginterferon alfa-2a and nilotinib. At 12 months, seven (17%) patients had achieved MR(4·5). Haematological and hepatic adverse events were frequent-with grade 3-4 neutropenias occurring in ten (24%) patients, grade 3-4 thrombocytopenias occurring in ten (24%) patients, grade 3-4 cholestatic events occurring in seven (17%) patients, and grade 3-4 elevations in aspartate aminotransferase or alanine aminotransferase occurring in three (7% patients-particularly during the first 3 months. However, 30 (73%) patients remained on interferon therapy at 1 year. Three grade 3-4 cardiac events (7% of patients, all coronary stenoses) occurred at later timepoints.
The combination of peginterferon alfa-2a resulted in good molecular responses in patients. Despite substantial toxic effects, most patients remained on the study drugs for more than a year. This combination should now be tested in a randomised controlled trial.
Novartis Pharma.
The National School Lunch Program (NSLP) provides $14.2 billion annually to serve 4.9 billion lunches. While policies are in place to ensure students consume items from all food groups, food waste ...and poor diet quality remain prevalent. Qualitative photograph estimation is frequently utilized to assess food waste. The Veggie Meter® (VM) is a validated tool that objectively evaluates fruit and vegetable (FV) intake by measuring skin carotenoid levels.
Qualitatively assess tray waste among middle school students utilizing before and after lunch tray photographs while quantitatively comparing their VM scores to FV tray waste.
Researchers photographed 57 student lunch trays at a rural middle school. The VM assessed FV intake in a subsample of 39 students.
Trays were tracked using a non-identifiable ID code. Photographs were matched and independently coded by three coders using the Comstock indirect measurement technique, in which scores (0-5) inversely reflect intake of each food item. Inter-rater agreement was 90%. Means and standard deviations were calculated for individual food items and total lunch tray waste. VM scores range from 0-850, with higher scores indicating higher FV intake. A Pearson's correlation determined the relationship between VM score and individual food item intake on a subsample of participants. Significance was set at p<0.05.
On average, 50% of food on the lunch trays was discarded. Of all tray waste, 75% of the participants discarded uneaten fruits and vegetables. Overall, participants had low VM scores (173.5±61.1; n = 39). There was a significant negative correlation between VM scores and waste of vegetable items (r=-0.37, p=0.035) and fruit items (r=-0.38, p=0.021).
Considering the vast NSLP funding, the issue of food waste should be considered. This study revealed high tray waste, with the highest amount documented in FV items. Further, students' food waste was correlated with low FV intake. This highlights the need for programming that addresses food waste and FV consumption in rural middle school students.
NIFA
Abstract ▪3770▪This icon denotes a clinically relevant abstract
Second generation tyrosine kinase inhibitors such as dasatinib (Sprycel®, Bristol-Myers Squibb) induce significantly higher levels of ...cytogenetic and molecular responses than imatinib when given as frontline therapy for chronic phase chronic myelogenous leukemia (CP-CML) (DASISION trial, Kantarjian et al., NEJM 2010). Dasatinib is associated with the occurrence of pleural effusions (PE). The cumulative incidence of all grades PE in DASISION trial was reported to be 10% by 12 months and 14% by 24 months.
To analyse efficacy of dasatinib first line and to test risk factors associated with the occurrence of PE. (EudraCT 2008–006854–17).
Newly diagnosed CP-CML patients (pts) were assigned to dasatinib 100 mg/d. Dasatinib Cmin levels were assessed 24+/−2h after intake by tandem mass spectrometry after 2 weeks of therapy and every 3 months during 12 months thereafter. Pts with high Cmin values (Cmin ≥ 3 nM) at day 15 were randomized between dasatinib dose reduction or not. As the trial is still recruiting, the effect of randomization (treatment adaptation) was not analysed. For the purpose of this study, patients with at least 12 months follow-up were analysed for efficacy and all enrolled patients were analysed for safety. Molecular assessments were expressed as BCR-ABL/ABL (IS) in %.
Efficacy. In March 2012, 125 pts out of 191 pts enrolled in the trial had at least 12 months follow-up. Sokal scores were high for 18%, intermediate for 36% and low for 46% of pts. The median age was 52 (18–89) years. The rates of complete cytogenetic responses (CCyR) at 3, 6, and 12 months were 74%, 87%, and 97% respectively on evaluable samples, and 60%, 82%, and 95% when results were analysed according to the intention-to-treat principle taking into account missing values. The cumulative incidences of major molecular response (MMR) by 3, 6, 9 and 12 months were 21%, 46%, 56%, and 62% respectively. Of note 11 pts (9%) did not have a BCR-ABL (IS) ≤10% at 3 months. None of these patients reached a MMR by 12 months compared to a 68% (95% CI: 60–77) cumulative incidence of MMR in the other 114 pts. At 12 months, molecular response 4.5 (MR4.5) rate was 25%, including 80% of the pts with undetectable BCR-ABL transcript (sensitivity 4 to 5 log). Safety. 12 pts out of 191 (6.3%) presented a PE corresponding to a cumulative incidence of 9% by 24 months. 95 pts had at least one high Cmin value during the pharmacokinetic follow-up and 10 pts developed PE as compared to 2 out of the 96 remaining pts (p= 0.018). Cumulative incidence of PE by 24 months was 13.4% in high Cmin group as compared to 4.8% in low Cmin group (p=0.04). We next analysed whether the measurement of dasatinib Cmin at day 15 could predict the risk to develop a PE. Fifty pts (26%) had a high Cmin value at day 15 (group A) and 141 had a low Cmin (group B). The cumulative incidence of PE by 24 months was 17.4% in group A compared to 6.9% in group B (p=0.021) (fig 1). We next search for clinical factors influencing Cmin value at day15 of dasatinib 100 mg/d. Median Cmin values were significantly higher in patients aged 50 and over as compared to younger patients (2.5 nM versus 1.6 nM, p=0.0032). As expected, age 50 and over was also associated with an increased risk of pleural effusion.
Current data demonstrate efficacy of dasatinib 100 mg/d similar or even better to that reported in other frontline trials such as the DASISION trial. We provide evidences suggesting that a high Cmin (>3nM) at day 15 and/or age 50 and over identify patients treated with dasatinib 100 mg/d with a high risk of PE. The benefit of dasatinib dose reduction is randomly tested for this group of patients in the OPTIM-Dasatinib trial and may be a major issue in elderly patients. Display omitted
Rousselot:BMS, Novartis: Research Funding. Nicolini:BMS, Novartis: Consultancy, Research Funding. Coiteux:Novartis, BMS: Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Roy:Novartis, BMS: Speakers Bureau. Dartigeas:Roche: Consultancy. Guilhot:ARIAD: Honoraria. Mahon:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy.
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