bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective Survey of Children Treated for Relapsed Acute Lymphoblastic Leukemia (Complete Remission (CR) Rates): A Report from the Therapeutic Advances in Childhood Leukemia (TACL) Consortium.
Authors: Ko Richard H. , Ji Lingyun , Sposto Richard , Barnette Phillip , Bostrom Bruce , Hutchinson Raymond , Raetz Elizabeth , Seibel Nita , Twist Clare , Eckroth Elena , Gaynon Paul , Loh Mignon 
Published: November 2019

Abstract
Introduction: Event-free survival (EFS) for children with ALL is approximately 80%. Despite substantial success in achieving second and subsequent remissions, survival of patients with relapsed ALL (rALL) remains dismal. We propose that progress depends on identification of novel drug combinations with more activity in rALL than those commonly employed. The literature suggests a 40% CR rate for second and subsequent relapse (Br. J Haematol2005;131:579). However, CR rates depend on the number of prior therapeutic attempts and duration of any prior response, complicating identification of promising regimens. Limited patient numbers and a large number of potential candidate regimens discourage randomized trials. We surveyed local experience with rALL to establish a robust benchmark for evaluation of novel drug combinations.
Methods: The TACL Consortium (www.tacl.us) was formed to develop novel drug combinations for patients with rALL. We initiated a review of all patients with rALL treated between 1995 and 2004 at eight TACL institutions. Detailed data on therapy, response, and duration of response were collected on all patients.
Results: Of 313 rALL patients, 62% were males, 27% were older than 10 years at diagnosis, 26% had initial white blood counts (WBC) at diagnosis >=50,000/uL, and 46% were high-risk by NCI risk criteria. Re-induction attempts ranged between 1 and 9 and most commonly employed combinations of traditional ALL agents. Limiting analyses to patients with marrow involvement, we obtained 86% CR’s for 1st relapse (95% confidence interval 80%–90%), 44% for second relapse (35%–53%), and 30% for third relapse (19%–43%). CR rates declined with the number of prior treatment attempts (see Table, p<0.001). With first relapse, the CR rate trended lower in older patients (<10 y.o., 89%; ≥ 10 y.o., 78%; p=.056). With second relapse, CR rates increased with a longer duration of the prior remission (p<0.005), but this was not true for first relapse. (p=0.33).
Conclusion: Our data support a 40% baseline CR rate for 2nd and subsequent relapse ALL and provide a useful benchmark for comparison with new therapies.
CR Rates by Treatment Attempt and Duration of Any Prior Remission CR Rates (percent) CR status/ duration of previous CR 2nd Attempt 3rd Attempt 4th Attempt CR not achieved with prior attempt 8/8 (100) 3/14 (21) 10/35 (29) CR < 18 months 41/52 (79) 26/ 69 (38) 5/ 22 (23) CR 18–36 months 59/ 66 (89) 14/ 23 (61) 1/ 1(100) CR ≥ 36 months 61/ 68 (90) 7/ 10 (70) 1/ 1(100) CR unknown 16/22 (73) 2/2 (100) 1/ 1(100) Totals 185/216 (86) 52/118 (44) 18/ 60 (30)
Pharmacokinetic and Pharmacodynamic Effects of PEG-Asparaginase in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia: Results from a Single Agent Window Study.
Authors: Appel Inge M. , Kazemier Karin M. , Veerman Anjo J.P. , van Wering Elisabeth , Den Boer Monique L. , Pieters Rob 
Published: November 2019

Abstract
L-Asparaginase is an effective drug for treatment of children with acute lymphoblastic leukemia. The effectiveness is generally thought to result from a rapid depletion of asparagine in serum and cells. Several studies have shown that in vitro resistance to this drug is an independent prognostic factor in ALL. We investigated the clinical response of one in vivo dose of 1000 IU/m2 PEG-Asparaginase and its pharmacokinetic and pharmacodynamic effects in children with newly diagnosed ALL before the start of combination chemotherapy. 57 children (36M / 21F) were enrolled in the study: 2 pro B-ALL, 38 common/ pre B-ALL and 17 T-ALL. Genotyping of precursor B-ALL revealed 11 hyperdiploid, 8 TELAML1 positive, 2 BCRABL positive, no MLL rearrangement, 8 normal, 11 others. The clinical response to PEG-Asparaginase on day 0 (5 days after the PEG-Asparaginase infusion) was defined as good when the number of leukemic cells of peripheral blood was < 1 × 109/L, as intermediate when leukemic cells were 1-10 × 109/L, and as poor when leukemic cells were > 10 × 109/L. The in vivo window response was significantly related to immunophenotype and genotype: 26/38 common / pre B-ALL cases, especially those with hyperdiploidy and TELAML1 rearrangement, demonstrated a good clinical response compared to 8/17 T-ALL (p=0.01). Both BCRABL positive ALL cases showed a poor response (p=0.04). A poor in vivo clinical window response was related to in vitro resistance to L-Asparaginase (p=0.02) and both in vitro as well as in vivo response were prognostic factors for long-term event-free survival (Hazard ratio 6.4; p=0.004, and Hazard ratio 3.7; p=0.01, respectively). The L-Asparaginase activity in the serum was >100 IU/L for at least 15 days. The asparagine levels remained below the detection limit of 0.2 mM for at least 26 days with a concomitant rise in serum aspartate and glutamate. These findings confirm that PEG-Asparaginase will yield its pharmacodynamic effects for 2-4 weeks. After administration of one in vivo dose of 1000 IU/m2 PEG-Asparaginase no changes in apoptotic parameters or changes in intracellular levels of twenty amino acids in leukemic cells could be measured, in contradiction to the changes found after in vitro exposure. This may be explained by the rapid removal of apoptotic cells from the circulation in vivo. Otherwise it is possible that in vivo mesenchymal cells from the bone marrow supply leukemic blasts with asparagine in response to treatment with L-Asparaginase.
Conclusion: The clinical response to one dose of 1000 IU/m2 PEG-Asparaginase intravenously is related to phenotype and genotype and predicts outcome. These results suggest that children with ALL with a poor clinical response to PEG-Asparaginase might benefit from a more intensive antileukemic therapy.
Different FLT3 Inhibitors Display Limited, Non-Overlapping Profiles of Specific FLT3-ITD Resistance Mutations in a Cell-Based Screen.
Authors: von Bubnoff Nikolas , Saenger Jana , Peschel Christian , Duyster Justus 
Published: November 2019

Abstract
Mutations causing resistance to therapeutic kinase inhibition can be identified in target kinases in various malignant diseases, such as Bcr-Abl in CML, FLT3-ITD in AML, cKit in GIST, EGFR in NSCLC, and FIP1L1-PDGFRalpha in HES/CEL. Thus, mutations in target kinases constitute a general mechanism of resistance to therapeutic kinase inhibiton. It has been shown that sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. We therefore intended to determine, whether different FLT3 inhibitors would produce distinct profiles of secondary, FLT3 resistance mutations. Using a cell-based screening approach, we generated FLT3-ITD expressing cell lines resistant to the FLT3 inhibitors su5614 and PKC412. The frequency of resistant clones per million cells in the presence of inhibitor at 10 times the IC50 was 0.17 for su5614 (1,5?M) and 0 with PKC412 (100nM). When FLT3-ITD transformed cells were mutagenized with ENU (ethylnitrosourea) prior to addition of inhibitors, the frequency of resistant clones increased to 2.33 with su5614, and to 0.34 with PKC412. When we analyzed FLT3-ITD TK1 and TK2 for mutations that may confer inhibitor resistance, we found mutations in 127 out of 179 cell clones (71%) with su5614. Nine different exchanges affecting six positions in TK2 were identified, within or shortly behind the FLT3-ITD A-loop, with exchanges of D835 predominating. We did not detect exchanges affecting TK1. With PKC412, four out of 26 resistant clones (15%) contained mutations. In contrast to su5614, no mutations of TK2 were identified. However, three different amino acid exchanges emerging with PKC412 exclusively affected N676, which is located in TK1 of the FLT3-ITD split kinase domain. This is in line with the observation of a FLT3-ITD N676K exchange identified in a single AML patient with clinical resistance to PKC412 (Heidel et al, 2006). When expressed in cell lines, the identified TK2 A-loop mutations shifted dose-response curves to higher concentrations of su5614, but did not affect response to PKC412, su11248 or sorafenib. However, Y842D caused a strong resistance towards sorafenib, but not to su11248 or PKC412. Recent results also demonstrate a differential response of TK1 N676 exchanges towards different FLT3 inhibitors. We are currently analyzing su11248- and sorafenib- resistant FLT3-ITD clones for specific resistance mutations. Our results demonstrate that cell-based resistance screening is a useful and valid tool for prediction of resistance mutations to kinase inhibitors. In contrast to Bcr-Abl kinase inhibitors such as imatinib, nilotinib and dasatinib, which display highly overlapping resistance profiles, FLT3 kinase inhibitors may generate distinct, non-overlapping profiles. This opens the possibility of using combined FLT3 inhibitor therapy in AML to prevent resistance due to FLT3-ITD kinase domain mutations.
Overexpression of APC Reduces Stem Cell Capacity and Leukemogenic Potential of PLZF/RAR-Positive Leukemic Stem Cells.
Authors: Seshire Anita , Beissert Tim , Oancea Claudia , Hoelzer Dieter , Ruthardt Martin , Puccetti Elena 
Published: November 2019

Abstract
Acute myeloid leukemia (AML)-associated fusion proteins (AAFP), such as PML/RAR, PLZF/RAR or AML1/ETO have leukemogenic potential in vivo which is related to their capacity to induce a differentiation block and aberrant self renewal in early hematopoietic progenitors. The potential of the AAFP to induce the leukemic phenotype is strictly related to their capacity to oligomerize and to form high molecular weight complexes (HMW). Furthermore we recently showed that the deregulation of the Wnt-signaling seems to be a key event for the leukemogenesis by the above mentioned AAFP because it is indispensable for the aberrant self renewal of leukemic stem cells (LSC). A „tandem affinity purification” (TAP) screen of KG1 cells expressing PLZF/RAR, PML/RAR or AML-1/ETO for elucidating the composition of the related HMW revealed the „adenomatous polyposis coli” protein (APC) as an interaction partner of PLZF/RAR. APC is a key inhibitory regulator of the Wnt-signaling and is frequently inactivated by mutations in colon carcinomas. Therefore the role of the interaction between APC and PLZF/RAR for the leukemogenesis was further investigated. Here we report that i.) only PLZF/RAR strongly interacted with APC as confirmed by co-immunoprecipitation experiments; ii.) the overexpression of APC reverted the aberrant activation of the Wnt-signaling by PLZF/RAR as revealed by a reduction of the TCF/LEF mediated transcriptional activity; iii.) the overexpression of APC also reduced the self renewal potential of PLZF/RAR-positive HSC as revealed by a reduced replating efficiency of these cells in semi solid medium, as well as by a reduction of the colony number in colony forming units spleen (CFU-S) assays; iv.) APC was able to revert the leukemogenic potential of PLZF/RAR-positive LSC as revealed by the retroviral overexpression of APC in bone marrow isolated from mice with PLZF/RAR-induced AML which were inoculated into secondary recipients. In fact until now the presence of APC significantly increased the survival of these secondary recipients with respect to mock-infected controls. Taken together these data strongly suggest that the direct interaction with PLZF/RAR is an important mechanism for the functional inactivation of APC which contributes to the aberrant activation of the Wnt-signaling in PLZF/RAR-positive cells. Furthermore our data provide further evidence that the aberrantly activated Wnt-signaling pathway represents a valid target for molecular therapy approaches.
The Structure of the GM-CSF Receptor Ternary Complex Reveals a New Mode of Cytokine Receptor Activation.
Authors: Lopez Angel , Hercus Timothy , Hansen Guido , Woodcock Joanna , McClure Barbara , Stomski Frank , McKinstry William , Parker Michael Parker 
Published: November 2019

Abstract
Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pleiotropic cytokine that controls the production and function of blood cells, is deregulated in multiple diseases such as asthma, arthritis and leukaemia yet offers therapeutic value in Crohn’s disease and as an adjuvant in anti-cancer therapy. Its receptors are heterodimers consisting of a ligand-specific alpha subunit and a beta subunit which is critical for signalling and is shared with the interleukin (IL)-3 and IL-5 receptors. The latter have also been implicated in pathologies such as acute myeloid leukaemia and allergic inflammation respectively. Despite the clear involvement of this family of receptors in human diseases their three dimensional structures in complex with the cognate ligand is not known and the mechanism by which they signal has remained an enigma. In particular it has baffled scientists that the membrane proximal domains of the beta subunit are 120A apart, too big a distance to allow transphosphorylation of the receptors by their associated JAK-2 kinases and receptor activation. We report here the structure of the human GM-CSF/GM-CSF receptor ternary complex and its assembly into hexamers (comprising 2 molecules of GM-CSF, alpha subunits and beta subunits each) and into unexpected dodecamers or higher order complexes. The dodecamer arrangement allows the interaction of two hexamers through a distinct site 4 which is composed of both alpha and beta subunits. Importantly, mutagenesis of the GM-CSF receptor at the dodecamer interface revealed that whilst site 4 is not involved in high or low affinity binding of ligand it is critical for receptor activation and signalling. This novel form of receptor assembly likely applies also to the IL-3 and IL-5 receptors, providing a structural basis for understanding cytokine receptor activation and for the development of novel therapeutics.
The t(6;9) Associated DEK/CAN Fusion Protein Does Not Block Differentiation of Early Hematopoietic Stem Cells but Increases Their Stem Cell Capacity.
Authors: Oancea Claudia , Puccetti Elena , Henschler Reinhard , Ruthardt Martin , Bug Gesine 
Published: November 2019

Abstract
Leukemia-specific translocations such as t(15;17), t(11;17), or t(8;21) lead to the expression of aberrant fusion proteins (FP) such as PML/RAR, PLZF/RAR and AML-1/ETO. These FP induce and maintain the leukemic phenotype by blocking terminal differentiation of early hematopoietic progenitors and by interfering with the biology of the leukemic counterpart of the hematopoietic stem cells. The t(6;9) with its DEK/CAN FP is of particular interest because it is more frequent in young patients and associated with a poor prognosis. The t(6;9)-DEK/CAN fusion occurs with an incidence of 1–5% in adult patients with AML and in most of the cases t(6;9)-positive AML is classified as FAB-M2 or M4. In contrast to other FP the overexpression of DEK/CAN does not block VitD3-induced differentiation in U937 cells. These findings called in question the leukemogenic potential of DEK/CAN. To further disclose the role of DEK/CAN in leukemogenesis we investigated its effect on the biology of early hematopoietic stem cells (HSC) in comparison to PML/RAR. Therefore we retrovirally transduced Sca1+/linmurine HSC (SL cells) with DEK/CAN and PML/RAR and performed both differentiation and stem cells assays (morphology, surface marker expression, replating efficiency, colony forming unit - spleen - CFU-S). Here we show that i.) DEK/CAN in contrast to PML/RAR was apparently unable to block terminal differentiation of SL cells as revealed by morphology and the expression of differentiation-specific surface markers; ii.) DEK/CAN slightly increased the replating efficiency of SL cells, but did not reach the level of PML/RAR with a reduced number of either colony forming units as plating rounds with respect to PML/RAR; iii.) the increased replating efficiency was related to an increased stem cell capacity as revealed by the fact that in contrast to mock infected control cells DEK/CAN-positive cells gave origin to a positive CFU-S assay even after one or two plating rounds in semi-solid medium similar to PML/RAR. Apparently DEK/CAN seems to share with other FP the capacity to increase the self renewal of HSC, but not that to block terminal differentiation. These findings strongly suggest that the effect of DEK/CAN is limited to a very small subset of cells within the stem cell compartment which might represent the origin of a DEK/CAN-positive leukemia. Actually the capacity of DEK/CAN to give origin to leukemia in vivo is under investigation.
Elevated FoxM1 Expression Promotes Cell Cycle Progression by Induction of KIS Expression and Contributes to the Development of Leukemia Cells.
Authors: Keiji Okinaka , Nakamura Satoki , Hirano Isao , Ono Takaaki , Fujisawa Shinya , Shigeno Kazuyuki , Shinjo Kaori , Ohnishi Kazunori 
Published: November 2019

Abstract
[Background] FoxM1, a member of the Fox transcription factor family, plays an important cell cycle regulator of both the transition from G1 to S phase and progression to mitosis. FoxM1 expression was also found to be up-regulated in some solid tumors (basal cell carcinomas, hepatocellular carcinoma, and primary breast cancer). These results suggested that FoxM1 plays a role in the oncogenesis of malignancies. However, it is unknown whether FoxM1 expression contributes to the development or progression of leukemia cells. Therefore, we investigated how FoxM1 regulated the cell cycle of leukemia cells and the expression analysis of the FoxM1 gene in patients with acute leukemias.
[Methods] The cells used in this study were human acute leukemia cell lines, U937 and YRK2 cells. Primary acute myeloblastic (25 AML (4 M1, 11 M2, 6 M4, 4 M5)) cells were obtained from the peripheral blood. Human normal mononuclear cells (MNCs) were isolated from peripheral blood (PB) of healthy volunteers after obtaining informed consents. For analysis of proliferation and mitotic regulatory proteins (p27, p21, Skp2, Cdc25B, Cyclin D1, Survivin, Aurora kinase B, and KIS) in leukemia cells, MTT assays and western blot were performed in all cell lines, which untransfected or transfected with siRNA FoxM1, respectively. For cell cycle analysis, flow cytometory analysis was performed in leukemia cells untransfected or transfected with siRNAFoxM1 by PI staining. For analysis of FoxM1 mRNA, quantitative RT-PCR was performed in all cell lines and clinical samples.
[Results] In all leukemia cell lines, the expression of FoxM1B mRNA were significantly higher than normal MNCs. When transfected with the siRNA FoxM1 in leukemia cells, suppression of FoxM1 caused a mean 71% (range 62 to 80%) reduction in S phase cells and a mean 4.4-fold (range 3.2 to 5.6-fold) increase in G2/M phase cells compared to controls. MTT assay demonstrated that the proliferation of the siRNA FoxM1 transfected cells was inhibited compared to the untransfected cells. Moreover, FoxM1 knockdown by siRNA in leukemia cells reduced protein and mRNA expression of Aurora kinase B, Survivin, Cyclin D1, Skp2 and Cdc25B, while increased protein expression of p21and p27. In the clinical samples obtained from patients with acute leukemias, the FoxM1B gene was overexpressed in 22/25 (88%). The relative folds of FoxM1B gene expression were for AML: 2.83 compared to normal MNCs.
[Conclusions] In this study, we report in the first time that FoxM1 is overexpressed in myeloid leukemia cells. These results demonstrated that expression of FoxM1 is an essential transcription factor for growth of leukemia cells, and regulate expression of the mitotic regulators. Moreover, we showed that FoxM1 induced the expression of KIS protein. Therefore, FoxM1 might be one of moleculer targets of therapy for acute leukemias.
A Phase I Trial of AT9283, a Multitargeted Kinase Inhibitor, in Patients with Refractory Hematological Malignancies.
Authors: Ravandi Farhad , Foran James , Verstovsek Srdan , Cortes Jorge , Wierda William , Boone Patricia , Borthakur Gautam , Sweeney Trish , Kantarjian Hagop 
Published: November 2019

Abstract
AT9283 is a small molecule inhibitor of aurora kinases A and B, JAK2, and JAK3 (IC50 <5nM in each case). AT9283 was administered as a 72-hour continuous intravenous infusion to patients with refractory hematological malignancies at 6 different dose levels: 3, 6, 12, 24 and 48 mg/m2 daily x 3. Inclusion/exclusion criteria, and definitions of DLT and MTD were standard. A 3+3 dose escalation phase I design was implemented. To date, 20 patients have been treated: 3 at 3, 3 at 6, 7 at 12, 3 at 24 and 4 at 48 mg/m2/daily x 3. Seven were females; median age was 58 years (range 22 to 86); 19 patients had previously treated acute myeloid leukemia (AML); 15 were in second or subsequent salvage; abnormal cytogenetics were present in 15. Two patients had undergone prior matched unrelated allografts. The median number of prior chemotherapy regimens was 2 (range 1 to 5). Pharmacokinetic data is available for patients treated at early dose levels only. Median systemic clearance varied up to two-fold between patients with some suggestion of a non-linear increase in exposure at higher dose levels. At the completion of the infusion, the plasma concentration of AT9283 decreased rapidly exhibiting a multiphasic elimination and a terminal half-life of 6 to 13 hours. At doses of 3 to 48 mg/m2/D x 3, no MTD has been defined; 2 patients treated at 12 mg/m2/D x 3 developed tumor lysis syndrome which resolved spontaneously in one case and required hemodialysis in the second. This dose level was expanded to treat 6 patients. Patients received a median of two cycles of treatment (range 1 to 3). So far, 6 of 20 patients (30%) exhibited evidence of anti-leukemia activity, with significant reductions in bone marrow blasts (≥ 50%) observed at all dose levels: In summary, AT9283 shows good early results and continues to accrue patients to define the DLT and MTD with the 72-hour infusion schedule. In vitro studies suggest that prolonging the duration of infusion will increase the drug’s biological effect. This will be explored following the identification of the MTD for a 72-hour infusion.