bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Glucocorticoid-Induced TNF-Related Protein (GITR) Ligand in the Interaction of Acute Myeloid Leukemia with NK Cells.
Authors: Krusch Matthias , Baltz Katrin M. , Baessler Tina , Kanz Lothar , Salih Helmut R. 
Published: April 2020

Abstract
NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance and eradication of hematological malignancies. The activity of NK cells is governed by a balance of activating and inhibitory surface receptors. Glucocorticoid-induced TNF-related protein (GITR) and its ligand (GITRL) are members of the TNF/TNF receptor (TNFR) superfamily, which mediates multiple cellular functions including proliferation, differentiation, and cell death. Recently we reported that NK cells express GITR while cancer cells express GITRL and GITR-GITRL interaction down regulates NK cell-mediated anti-tumor immunity (Baltz et al., FASEB J 2007). Here we demonstrate that GITRL is expressed on 6 of 7 investigated acute myeloid leukemia (AML) cell lines and on primary AML cells in 30 of 52 (59%) patients, while no GITRL expression was detected on CD34+ cells of healthy donors (n=5). GITRL expression was not restricted to a specific French-American-British (FAB) subtype, but was significantly (p&lt;0.05, one-way ANOVA) associated with monocytic (FAB M4, M5) differentiation. In addition, no association with a particular cytogenetic abnormality or with expression of MHC class I was observed. Reverse signaling via GITRL led to phosphorylation of ERK and JNK resulting in significantly (p&lt;0.05, Mann-Whitney U-test) enhanced production of IL-10 and TNF by patient AML cells (n=10). In line, specific inhibitors for JNK and ERK1/2 blocked the cytokine release by AML cells demonstrating that activation of MAP kinases is responsible for the production of the immunoregulatory cytokines following GITRL stimulation. Importantly, blocking GITR-GITRL interaction in cocultures of AML and NK cells significantly (both &lt;0.05 Mann-Whitney U-test) increased cellular cytotoxicity about 70% and IFN-γ production about 60%, and this was due to restored NK cell NF-κB activity. Thus, GITRL substantially influences immunoediting by AML cells and enables the escape of AML cells from NK cell-mediated immune surveillance. The correlation found between GITRL expression and NK cell susceptibility may provide useful information for NK cell-based immunotherapy.
Interplay of CXCR4 and FLT3-ITD in the Regulation of Stem Cell Migration and Proliferation.
Authors: Jacobi Angela , Ryser Martin F. , Koch Sina , Lehmann Romy , Bornhaeuser Martin , Brenner Sebastian 
Published: April 2020

Abstract
Activating mutations of the FLT3-receptor tyrosine kinase such as the short internal tandem duplication (ITD) represent the single most common genetic aberration in patients with acute myeloid leukemia (AML). FLT3-ITD mutations are present in about 25% of AML patients and are associated with high blast counts and a higher rate of relapse after conventional chemotherapy. CXCR4 and its ligand SDF-1 are of central importance for stem cell homing to the bone marrow. In FLT3-ITD positive AML, CXCR4 expression on stem cells is negatively correlated to overall survival. Using retroviral vector transduction we achieved overexpression of the human FLT-ITD transgene, the FLT3-wt or the GFP control gene in greater than 70% of cord blood hematopoietic progenitors (HP). In contrast to previously published data in murine cell lines, we found that FLT3-ITD positive human cells display strongly reduced migration towards the CXCR4 ligand SDF-1. Analysis of SOCS3 (suppressor of cytokine signaling 3) expression revealed strongly increased mRNA expression in FLT3-ITD overexpressing CD34+HP and FLT3-ITD positive AML blasts. Since SOCS3 is a known antagonist of CXCR4 signaling, increased SOCS3 levels might cause the observed inhibition of SDF-1 dependent migration. For individually tested CD34+HP from 6 cord blood donors, co-cultivation of FLT3-ITD overexpressing HP on the irradiated mouse stromal cell line M210-B4 or on primary mesenchymal stromal cells resulted in an increased formation of early cobble stones and a dramatic proliferation advantage for suspended cells compared to naïve, FLT3-wt or GFP-transduced HP. Addition of the CXCR4 chemokine inhibitor AMD3100 to the co-culture decreased the cobble stone formation and growth advantage of FLT3-ITD transduced cord blood HP. Similar results were obtained using FLT3-ITD positive AML cells from 3 patients. Using CFSE to track cell proliferation and PI/Annexin staining to analyze apoptosis, we demonstrate that the addition of AMD3100 had no effect on apoptosis but decreased the proliferation rate of FLT3-ITD positive blast cells. Using primary AML blasts and FLT3-ITD transgene overexpressing cord blood HP, we demonstrate that the robust FLT3-ITD mediated proliferation advantage can be partly inhibited by the CXCR4 antagonist AMD3100.
The Hypoxic Microenvironment in Acute Myelogenous Leukemia: Critical Role of CXCR4 in the Induction of HIF-1α.
Authors: Andreeff Michael , Dietrich Martin , Corn Paul , Konoplev Sergej , Konopleva Marina , Samudio Ismael 
Published: April 2020

Abstract
The bone marrow microenvironment provides functional and structural support for both normal and leukemic hematopoietic stem cells. Importantly, the marrow microenvironment is known to be hypoxic. Given the many critical functions of HIF-1α, we investigated HIF-1α levels in leukemic cell lines and primary AML blasts. Surprisingly, HIF-1α expression was non-detectable in AML cells grown in suspension cultures under normoxic (21% O2) or hypoxic (1% O2) conditions. Normoxic co-cultures with bone marrow-derived mesenchymal stromal (MSC) or MS5 cells likewise did not induce HIF-1α, but hypoxic co-culture conditions induced HIF-1α protein without changes in HIF-1α mRNA levels, suggesting post-transcriptional regulation. Functionality of HIF-1α was confirmed by concomitant increase in the levels of glucose transporter glut-1, the HIF-1α downstream target. Inhibition of stroma-leukemia cell interactions with the small molecule CXCR4 inhibitor AMD3465 (Genzyme/Anormed) at 100 nM completely abrogated the induction of HIF-1α in HL-60 and MOLM13 AML cells. While SDF-1 was unable to induced HIF-1α under normoxic conditions, it did so under both physical (1% O2) and chemical (COCl2) hypoxic conditions, in two different cell lines. Inhibition of P13K (with LY294002) or MEK/ERK signaling (with CI-1040) abrogated HIF-1α induction under hypoxic conditions. Immunohistochemical staining of bone marrow samples from primary AML confirmed the presence of HIF-1α in leukemic cells localized adjacent to bone-lining stromal elements. Results suggest that
the bone marrow microenvironment of AML is hypoxic in vivo; in leukemia cells HIF-1α induction under low oxygen tension depends on the presence of stromal cells; HIF-1α induction is dependent on SDF-1/CXCR4 and is mediated by activation of P13K and MAPK signaling.
Altogether these findings suggest that SDF-1α/CXCR4 interactions contribute to the survival of leukemic cells via specific induction of HIF-1α signaling by the bone marrow microenvironment. Disruption of these interactions via CXCR4 inhibition strategies may suppress multiple pro-survival HIF-1α targets in leukemic cells.
Gentuzumab-Ozogamicin (GO) Plus Idarubicin (I) and Cytarabine (C) as Induction Treatment for Elderly Patients with Poor-Risk Cytogenetics Acute Myeloid Leukemia (AML).
Authors: Harousseau Jean-Luc , Recher Christian F.R. , Vey Norbert , Witz Francis , Lioure Bruno B.L. , Tournilhac Olivier , Himberlin Chantal , Bouscary Didier , Ifrah Norbert N.I. 
Published: April 2020

Abstract
Introduction. The prognosis of AML in patients over 60 years of age remains very poor. As in younger patients karyotype is a major prognostic factor. Elderly patients with poor risk cytogenetics have a dismal outcome and complete remission (CR) rates with conventional chemotherapy are usually &lt; 45% (and &lt; 25% if complex abnormalities). GO has been used in combination with chemotherapy in relapsed or newly diagnosed AML, but with reduced doses in order to decrease hepatic toxicity.
Methods. In this multicentric open-label Phase II study we have evaluated the combination of I (8 mg/m2/D × D1-5) + C (100 mg/m2/D × D1-7) with GO (6 mg/m2 on D3) in AML patients aged 60–75 years with poor risk cytogenetics and fit enough to undergo cytotoxic chemotherapy. Other inclusion criteria were: CD33+ AML, PS 2, de novo or secondary AML (excluding M3 and Ph1 + AML), no cardiac, renal or hepatic dysfunction.
Results. 44 pts aged 60–74 (median 68) were treated in 13 GOELAMS centers. Karyotype results were: chromosome (chr) 5 abnormalities 22, chr 7 abnormalities 26, chr 5+7 abnormalities 14, complex abnormalities 26. In 13 cases (30%) AML was secondary (chemoinduced 9, prior myeloproliferative or myelodysplastic syndrome 4). Median duration of hospitalisation was 31 D (4–51). In CR patients median duration of neutropenia was 19 D (14–28) and median duration of thrombocytopenia was 15D (5–29). Bacterial or fungal infections were documented in 71% of cases. 7 patients had severe bleeding including 3 deaths, (2 cerebral hemorrhage, 1 intestinal bleeding). Grade 2 hepatic dysfunction was seen in 30% of patients including 3 (7%) pts with veino-occlusive disease (one death). There were 17 (38%) CR (16 CR, 1 CRp), 6 (14%) toxic deaths and 21 (48%) failures. The CR rates was 41% (7/17) for patients aged 70–75 and 37% (10/27) for patients &lt; 70 years. While CR rate was 50% (6/12) in patients with isolated chr 5 or 7 abnormalities, it was 35% (9/26) in patients with complex abnormalities.
Conclusion. In this population of elderly but relatively fit patients with poor risk cytogenetics AML the addition of GO 6 mg/m2 to conventional chemotherapy did not appear to increase the CR rate mostly because of leukemic resistance. The incidence of aplasia-related toxicities and of hepatic complications does not encourage to use higher doses of GO.
Post-Consolidation Immunotherapy with Histamine Dihydrochloride and Interleukin-2 in AML: Long Term Follow-Up of Leukemia-Free Survival and Overall Survival.
Authors: Brune Mats L. , Rowe Jacob M. , Szer Jeff , Hogge Donna E. , Catalano John , Wallhult Elisabeth , Nilsson Bo I. , Simonsson Bengt , Spearing Ruth , Allard Stephane , Stadtmauer Edward A. , Hellstrand Kristoffer 
Published: April 2020

Abstract
PURPOSE. To assess the long-term outcome of AML patients (pts) in complete remission (CR) after a phase III study which compared the effect of post-consolidation immunotherapy with interleukin-2 (IL-2) and histamine dihydrochloride (HDC) on leukemia-free survival (LFS) and overall survival (OS).
PATIENTS & METHODS. A multi-national, randomized, open-label, phase III study which recruited 261 AML pts in first remission (CR1) and 59 in subsequent remission (CR&gt;1) was conducted between June 1998 and October 2000. Pts were enrolled after after termination of consolidation therapy, stratified by country and CR status, and randomized to either treatment or no treatment (standard of care, control). Forty-one % of pts were &gt;60 yrs (median 57), and 54% were males. Study arms were balanced for known prognostic factors. Two patient populations were studied, i.e. all pts randomized (ITT population; n=320) and pts in CR1. The treatment was self-administered at home and included ten 3-week courses of low-dose IL-2 (aldesleukin, Chiron Corp) 18 000 U/kg sc bid, plus HDC (EpiCept) 0.5 mg sc bid. Cycles 1–3 comprised 3 wks of treatment and 3 wks of rest, whereas in cycles 4–10 the rest periods were 6 wks. As reported previously (Blood2006; 108:88), the trial met the primary endpoint of prolonged leukemia-free survival (LFS) for all pts randomized (p=0.008 in favor of the treatment arm) at a median of 46 months of follow-up. The present long-term assessment of efficacy was conducted in August 2006, 30 months after the lock of the original data base.
RESULTS. Follow-up forms were retrieved from 86% (n=107; 59 HDC/IL-2 recipients, 48 no treatment,) of the 124 pts pts who were alive at original study cut-off. In the long-term analysis, median LFS in the ITT population was 11 and 8.8 months in HDC/IL-2 and no treatment groups, respectively. In the CR1 population, median LFS was 15 and 9.7 months in HDC/IL-2 and no treatment groups, respectively. The benefit of treatment both for the ITT population (p=0.017) and in CR1 pts (p=0.026) was demonstrated by log-rank testing. Kaplan-Meier (KM) estimates for LFS at 60 months revealed a trend in favor of the treatment group in the ITT population (29.6 vs 20.6%; p=0.065) and a significant difference in the CR1 population (34.4 vs 21.7%, p=0.024). The median OS of CR 1 pts were 44 months (HDC/IL-2) and 28 months (no treatment), but the difference did not attain statistical significance (log rank test: p=0.22; KM estimate at 60 months: p=0.07).
CONCLUSION. Post-consolidation immunotherapy with HDC/IL-2 results in significant long-term improvement of LFS.
Comprehensive Risk Factor Analysis in 939 Adults with Acute Myeloid Leukemia Receiving Risk Stratified Post-Remission Therapy: Results of the Prospective Randomized AML96 Trial of the German Study Initiative Leukemia (DSIL).
Authors: Ehninger Gerhard , Bornhaeuser Martin , Thiede Christian , Aulitzky Walter E. , Bodenstein Heinrich , Dorken Bernd , Einsele Hermann , Gramatzki Martin , Hanel Mathias , Helm Gisela , Ho Anthony D. , Jakob Andreas , Krumpelmann Ulrich , Leimer Lothar , Link Hartmut , Mahlmann Stefan , Neubauer Andreas , Pfluger Karl-Heinz , Sandmann Mathias , Schafer-Eckart Kerstin , Schmitz Norbert , Schuler Ulrich S. , Soucek Silke , Stuhlmann Reingard , Tischler Hans-Joachim , Wagner Thomas , Wandt Hannes , Illmer Thomas , Schaich Markus A. 
Published: April 2020

Abstract
In a up-front randomized study, 939 adult patients up to the age of 60 years received a double induction therapy. One course of MAV (mitoxantrone 10 mg/m2 days 4–8, cytarabine 100 mg/m2 continuous infusion days 1–8, etoposide 100 m g/m2 days 4–8) was followed by one cycle of MAMAC (cytarabine 1 g/m2, every 12h days 1–5; amsacrine 100 mg/m2 days 1–5). Patients with intermediate risk cytogenetic (IRCG) and a HLA matched sibling received an allogeneic transplantation, those with poor risk cytogenetic (PRCG) were intended to be transplanted from a sibling or unrelated donor. All AML patients without an available donor received the randomly assigned first postremission therapy (PRT) mitoxantrone combined with intermediate-dose cytarabine (I-MAC; total dose 12 g/m2) or high-dose cytarabine (H-MAC; total dose 36 g/m2). As second PRT, patients with t(8;21) received an additional cycle of chemotherapy. An autologous transplantation was scheduled for IRCG and PRCG without an allogeneic donor. The CR rate was 88% for patients with t(8;21), with IRCG 71%, and 50% with PRCG. The 5-year-survival was 21% (95% CI: 16–27%) in the PRCG, 40% (95% CI: 36–45%) in the IRCG and 74% (95% CI: 60–88%) in the t(8;21) group. No difference was observed between the I-MAC and the H-MAC group. In a multivariate analysis, a significant (p&lt;.01 for each parameter) better overall survival was observed in patients under the age of 37 years, blast count &lt;10% at day 15, high myeloperoxidase positivity, low CD34 expression, WBC &lt;15*10^9/L, thrombocytes &gt;50*10^9/L, and IRCG compared to PRCG. The relapse incidence was higher in patients without an allogeneic donor, a Flt3 mutant/wildtype ratio &gt; 0.8 or PRCG. A risk score build out of the sum of the individual hazard ratios (SHR) was able to discriminate two groups for the IRCG with a marked difference in the 5-year-survival (low SHR: 55% [95% CI: 48–62%]; high SHR: 33% [95% CI: 28–38%]) was well as for the PRCG group (low SHR: 44% [95% CI: 32–56%]; high SHR: 13% [95% CI: 7–18%]). The risk score identified in this large patient cohort may allow individual tailoring of therapeutic interventions in future AML trials.
FLAG-IM (Fludarabine, Ara-C, G-CSF, Idarubicin, Mylotarg) Is an Effective Salvage Regimen Producing High Rates of Remission (CR+CRi) in Relapsed/Refractory AML.
Authors: Goyal Sagun D. , Uy Geoffrey L. , Augustin Kristan M. , Hladnik Lindsay , Abboud Camille N. , Cashen Amanda F. , Westervelt Peter , DiPersio John F. , Vij Ravi 
Published: April 2020

Abstract
Despite advances in post-remission therapy, the outcome of patients (pts) with relapsed or refractory AML remains poor. In particular, pts who relapse with an initial remission duration of &lt; 1 year, fail a previous salvage regimen, or relapse after allogeneic transplant have dismal outcomes with CR rates ranging from 0–20%. Between April 2004 and June 2007, we treated 41 pts with a novel salvage regimen, FLAG-IM, for relapsed or refractory AML. Treatment consisted of fludarabine 25mg/m2/d on d1-5, cytarabine 2000 mg/m2/d on d1-5, idarubicin 12mg/m2/d on d1-5, and gemtuzumab ozogamicin (Mylotarg) 9 mg/m2 on d8 with G-CSF 5 mcg/kg on d1 until neutrophil recovery. CD33 expression in ≥ 30% of the blast population by flow cytometry was required for treatment. Pt population consisted of 20:21(M:F) with median age of 47 years (range 16–68), and included pts with secondary AML (n=6, 15%), intermediate risk (22, 54%) and poor risk (16, 39%) cytogenetics. Treatment indication included primary refractory disease in 7 (17%), 1st relapse, 1st salvage with initial remission duration of &lt; 1 yr in 16 (39%), and 2nd or higher salvage regimen in 14 (34%). 17 (41%) received FLAG-IM for relapse post-allogeneic transplant. Of the 41 pts treated, 38 are evaluable for response. By IWG criteria, a CR was achieved in 12/38 (32%) and CRi in 10/38 (26%) for an overall response rate of 58%. Eight (21%) had persistent disease while 8 (21%) died with aplasia. With a median follow up of 397 days (range 23–1136), the median overall survival (OS) for the entire cohort was 147 days with 1 yr KM estimate of OS is 28.7% (95%CI, 13.4–43.9). Median event-free survival was 108 days with 1 yr KM estimate of 18.9% (95%CI, 6.1–31.6). For pts who achieved a CR or CRi, neutrophil recovery (ANC&gt;500/mm3) occurred at a median of 28 days (range 21–50). The principal nonhematologic toxicity was grade 3-4 hepatotoxicity which occurred in 13 (32%) pts which was generally transient but fulfilled criteria for VOD in 3 (7%) pts. Of the 16 pts (39%) who underwent subsequent allogeneic transplant post FLAG-IM, median OS was 1089 days vs 94 days for no transplant, p=0.0002, with 1 yr KM estimate of 52.4% (95%CI 26.4–78.2). We conclude that FLAG-IM is an effective salvage regimen for AML with high rates of remission observed in a historically refractory patient population. The high response rates have allowed subsequent allogeneic transplantation in a significant fraction of patients resulting in long term survivors.
A Phase II Study of Bortezomib (Velcade®), Cylophosphamide (Cytoxan®), Thalidomide (Thalomid®) and Dexamethasone as First-Line Therapy for Multiple Myeloma.
Authors: Jagannath Sundar , Bensinger Bill , Vescio Robert , Camacho Elber , Wolf Jeffrey , Irwin David , Capo Gerardo , McKinley Marti , Vesole David H. , Mazumder Amitabha , Crowley John , Esseltine Dixie , Durie Brian 
Published: April 2020

Abstract
Background: A phase II trial evaluating the response rate with sequential administration of Bortezomib, cyclophosphamide, and dexamethasone (3 cycles) followed by Bortezomib, Thalidomide, and dexamethasone (3 cycles). The primary endpoints are overall response, achievement of ≥ very good partial response (VGPR), as well as assessment of safety and tolerability. This report provides results for 25 of 43 planned eligible pts.
Methods: Pts with newly diagnosed, untreated symptomatic myeloma were eligible. Treatment consisted of three 21-day cycles of Bortezomib 1.3mg/m2 days 1, 4, 8, and 11, Cyclophosphamide 300mg/m2 IV days 1 and 8 and dexamethasone 40mg po or IV days 1, 2, 4, 5, 8, 9, 11, 12; followed by three 21-day cycles of Bortezomib 1.0 mg/m2 days 1, 4, 8, and 11; Thalidomide 100 mg po daily and dexamethasone as before. Pts received thrombosis prophylaxis with ASA cycles 4–6. Upon completion of the 6 courses, pts proceeded to stem cell harvest and/or maintenance therapy. Responses were assessed by International Response Criteria.
Results: As of August 2007, 25 pts have been enrolled: median age 60 years; 65% male; 75% Stage III (D/S); IgG 66%, IgA 16%; 17% light chain only. All pts fully evaluable for response thus far (13/13 [100%]) have achieved at least PR. Of these, 7/13 (54%) have achieved ≥VGPR (with nCR/CR in 31%). The median time to PR was 2 cycles or 42 days. Maximum response occurred by cycle 4 for 12/13 (92%)pts. Overall, both components of the sequential regimen were very well tolerated. One pt had a ruptured colonic diverticulum related to dexamethasone, but recovered well and achieved nCR on trial. There have been 24 therapy attributed toxicity events ≥Grade 2 of which 11 have required drug/schedule adjustments: 3 each for cyclophosphamide (neutropenia), dexamethasone (hyperglycemia, pneumonia, perforated viscus) and Thalidomide (neuro related) plus 2 for Bortezomib (neuropathy). No deep vein thromboses (DVT) have occurred in the study. 3 pts have already proceeded to successful stem cell harvest with transplant planned.
Conclusion: The addition of cyclophosphamide and Thalidomide to Bortezomib/dexamethasone combination has improved the depth of response with ≥VGPR (54%) and CR/nCR (31%) compared to our previous 2-drug experience which produced ≥VGPR (38%). This very well tolerated new regimen is potentially an important step forward with further results and confirmation available by December 2007.