bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of GM-CSF on Arsenic Trioxide (As2O3, Trisenox) Therapy in Patients with Myelodysplastic Syndrome (MDS): Preliminary Results of a Phase II Study.
Authors: Mavromatis Blanche H. , Kessler Craig M. , Cheson Bruce D. , Sein Aung , Sharp Stewart A. 
Published: April 2020

Abstract
Background: Arsenic trioxide(As2O3) has proven clinical efficacy in relapsed acute promyelocytic leukemia, and is currently being studied in the upfront setting. At micromolar doses, As2O3 induces apoptosis and cellular differentiation, promotes histone acetylation, and inhibits tumor angiogenesis. In preclinical MDS studies, As2O3 inhibits proliferation of malignant hematopoietic cells, and increases rates of apoptosis in short term cultures. Notably, pre-treatment with GM-CSF increases sensitivity of cells to the effect of As2O3. Single agent clinical activity has also been demonstrated in MDS and multiple myeloma.
Methods: As2O3 was combined with GM-CSF in pts with MDS in a phase II trial. Eligible patients included those with Low/Int-1 and Int-2/High risk disease. Pts received treatment with As2O3 0.25 mg/Kg d1–d5 the first week, then twice a week for 9 weeks, then 2 weeks off. The cycle was repeated if a response was observed. GM-CSF was administered twice a week for the entire cycle. Pt characteristics are summarized in the table below.
Toxicity: Grade 3 and 4 study related AEs included peripheral neuropathic pain (1/7), febrile neutropenia (2/7), infection (4/7), abdominal pain (2/7), thrombocytopenia (2/7), hypoxia (1/7), chills associated with infusion (1/7), VT despite normal electrolytes (1/7), AV block (1/7). Results. 7 pts were enrolled (5M/2F), RA (1), RARS (3) and RAEB (3). A minor hematologic response was seen in one patient with RARS. One patient with RAEB2 showed a reduction of marrow blast count from 15% to &lt; 5% after one cycle. 3 pts completed less than one cycle and response could not be assessed.
Conclusion: The data suggest that As2O3 with GM-CSF is active in MDS, however with significant side effects. The study of As2O3 with the newer approved agents such as 5-azacitidine or lenalidomide should be undertaken, but done sequentially in order to minimize any overlapping toxicities.
Patient Characteristics and Results Patient Age MDS Subtype Cytogenetics IPSS Number of Cycles Response Overall Survival months) Nl: normal, RA: refractory anemia; RARS: refractory anemia with ringed sideroblasts; RAEB1: refractory anemia with excess blasts 1; Int risk: intermediate risk; IPSS: international prognostic scoring system 1 76 RARS Nl Int risk-1 3 Minor HI-E 28+ 2 75 RAEB1 Nl Int risk-2 2 PR 10 3 78 RA Nl Int risk-1 1 SD 7 4 69 RAEB1 Nl Int risk-1 &lt;1 NA NA 5 58 RARS Nl Int risk-1 1 SD 25+ 6 65 RARS 7 del, 20 del Int risk-2 1 SD NA 7 62 RAEB1 Complex: 3q-, abn ch 12, 5q-, -7, 2 ring ch8, trisomy 22 Int risk-2 &lt;1 NA NA
A Retrospective Analysis of 70 Cases of Transient Leukemia (TL) in Neonates with Down Syndrome (DS).
Authors: Muramatsu Hideki , Watanabe Nobuhiro , Matsumoto Kimikazu , Nakamura Tomohiko , Mimaya Junichi , Suzuki Chizuko , Kojima Seiji , Kato Koji 
Published: April 2020

Abstract
Transient Leukemia (TL) occurs in approximately 10% of infants with Down syndrome(DS). Most of cases achieve spontaneous remission, but there are severe, potentially lethal cases which manifest hepatic fibrosis or cardiopulmonary failure. COG reported the incidence of 17% early death in 48 TL cases in DS, but no other large case series reported till now. We retrospectively analyzed Japanese 70 cases of TL in DS to identify the prognostic factors associated with early death. From 1992 to 2006, 46 boys and 24 girls were treated in 14 Japanese institutes. 16 cases (22.9%) were dead in their early life, and 12cases (17.1%) developed AMKL. One patient died with relapsed AMKL, so the overall survival rate was 75.7%. Univariate analysis showed that mechanical ventilation (p=0.001), pulmonary hypertension (p=0.0105), low birth weight (p=0.0063), early gestational age (p=0.0016), low Apgar score at 1min (p=0.0003), low Apgar score at 5min (p=0.0057), high WBC count (p=0.0006), elevated aspartate aminotransferase(AST) (p=0.0004) and elevated direct bilirubin (p&lt;0.0001) are associated with early death of TL in DS. Multivariate proportional hazard model identified gestational age (p=0.0266; RR 0.708) and elevated direct bilirubin (p=0.0487; RR 1.076) as independent prognostic factors. Prospective clinical study is needed to find the optimal therapeutic approach to save neonates with TL who have these poor prognostic factors.
Leukocyte Alkaline Phosphatase Score in Myelodysplastic Syndrome: A Comparison of Patients with Normal and Abnormal Proportions of Bone Marrow Blasts.
Authors: Lipshitz Jay , Tafel Natalie , Patel Dilip 
Published: April 2020

Abstract
The expression of leukocyte alkaline phosphatase (LAP) in neutrophils has been shown to be reduced in some patients with myelodysplastic syndrome (MDS), but increased in the refractory anemia (RA) subtype. We performed a retrospective study looking at the LAP scores of 14 patients with MDS. Patients were grouped according to bone marrow blast percentage. Those with less than 5% blasts in the marrow (refractory anemia and refractory anemia with ringed sideroblasts) comprised one group (n=7) and those with 5% to 19% blasts (refractory anemia with excess blasts) comprised a second group (n=7). LAP scores in the group with fewer than 5% blasts were significantly higher (range 71 to 116, mean 93.6) than LAP scores in the 5%–19% group (range 2 to 46, mean 26.6) (p&lt;0.0001). Our results suggest that LAP score may correlate with disease severity in MDS. If this finding is confirmed in larger prospective studies then LAP score may be a useful, relatively non-invasive aide in assessing the course and progression of myelodysplastic syndrome.
LAP Scores for Patients 1 through 7 in the Groups “Marrow Blasts &lt;5%” and “Marrow Blasts 5%–19%” 1 2 3 4 5 6 7 The LAP scores of the two groups differed significantly (p&lt;0.0001). The mean for the “Blasts&lt;5%” group was 93.6 (SD=16.9), and the mean of the “Blasts 5%–19%” group was 26.6 (SD=7.1). There was no crossover between groups, in that the lowest LAP score in the &lt;5% group was 25 points higher than the highest LAP score in the 5%–19% group. Blasts &lt; 5% 91 76 88 103 116 71 90 Blasts 5%–19% 16 45 30 42 5 2 46
Automated Neutrophil Morphology and Its Utility in the Assessment of Neutrophil Dysplasia and in the Diagnosis of Myelodysplastic Syndromes.
Authors: Miguel Amparo , Orero Maite , Collado Rosa , Perez Pedro L. , Pacios Alejandro , Carbonell Felix 
Published: April 2020

Abstract
The assessment of neutrophil dysplasia is very useful for the diagnosis of the Myelodysplastic Syndromes (MDS), and the common accepted method for that purpose is the microscopic examination of blood and/or bone marrow smears. But one of the problems in the daily practice, is the lack of reproducibility between the different observers, and technical problems, like the time of the stain, quality of the stain, including quality of the reagents and time of the smear after blood draw. The last advanced hematology instruments, like the Coulter LH750®, provide, together with the report of the WBC differential, automated morphological data about some of the different types of leukocytes: Neutrophils, Lymphocytes, Monocytes and Eosinophils. This Research Data (RPD), gives information about the Mean and Standard deviation of the Cell Volume, Conductivity, and Scatter using a technology called VCS technology. We have collected 53 patients affected of MDS, and 18 affected with Chronic Myelomonocytic Leukemia (CMML) and we compared the leukocyte automated leukocyte morphological data (WRPD) of the patients with the WRPD of 59 normal persons. One of the modifications in the actual WHO classifications is the differentiation between CMML with or without dysplasia and Mylodysplastic Syndromes with or without trilineage dysplasia, that also affect the prognosis. We have checked also these new parameters for this purpose. The results have shown: The Mean Neutrophil Scatter (MNES) and Mean Neutrophil Conductivity (MNEC) was significant lower in the MDS compared with the normal (both p&lt;0.0001) the ROC curve analysis show a Sensitivity of 71.8% with a Specificity of 86.4% and a cut off of &lt; 139.3 for the MNESand a Sensitivity of 70.4% with a Specificity of 76.3% and a cut off of &lt; 150.9 for the MNECdetecting MDS. For the differentiation of MDS and CMML with or without dysplasia the results have shown a significant difference p = 0.02 in the MNESbetween CMML-1 and CMML-2 and MDS with or without trilineage dysplasia. The changes in the Neutrophil Scatter and in the Neutrophil Conductivity (lower values) correlates with the dysplastic feature neutrophil degranulation observed in the microscope.
Conclussion: MNEC and MNES seem to be useful in the detection of neutrophil dysplasia and helpful in the diagnosis of MDS.
Figure Figure
Coexistence of a Heterozygous JAK2(V617F) Mutation and a Secondary BCR-ABL Translocation within the Compartment of Committed Myeloid Progenitors in Chronic Idiopathic Myelofibrosis.
Authors: Bornhaeuser Martin , Mohr Brigitte , Oelschlaegel Uta , Bornhauser Peter , Jacki Swen , Ehninger Gerhard , Thiede Christian 
Published: April 2020

Abstract
Myeloproliferative disorders such as polycythemia vera (PV), essential thrombocytosis (ET) and chronic idiopathic myelofibrosis (CIMF) are clonal hematopoietic diseases with clinical similarities including the risk of transformation into acute myelogeneous leukemia. By definition, these diseases have been separated from Philadelphia chromosome positive (Ph+) CML requiring negativity for the BCR-ABL transcript in PCR studies of bone marrow or peripheral blood. Several groups independently discovered a gain of function mutation of the Janus kinase 2 (JAK2) gene in Ph-negative myeloproliferative diseases. This mutation has been associated with the proliferation of clonogenic progenitors independently of exogenous cytokine stimulation. A sixty-six year old male patient presented with moderate splenomegaly (3 cm under the costal marigin), mild anemia (11.3 g/dl), elevated lactate deyhdrogenase, an increased count of circulating CD34+ cells and a dry bone marrow aspirate. Marrow histology confirmed a prefibrotic stage of chronic idiopathic myelofibrosis (CIMF). Metaphase cytogenetics as well as BCR-ABL FISH were performed on samples from bone marrow, blood and sorted CD34+, CD3+, CD19+ and CD14+ cells from a steady-state back-up leukapheresis. The JAK2(V617F) mutation was confirmed by an allele-specific PCR assay. A screen for BCR-ABL was performed by FISH and PCR in sorted cells as well as in individual colonies (CFU-GM and CFU-E).
Four Philadelphia-chromosome positive metaphases could be detected out of 86 derived from the autologous leukapheresis product harvested and cryopreserved as back-up shortly after diagnosis. The BCR-ABL translocation could be detected by fluorescence in-situ hybridisation (FISH) in 2/16 (12.5%) isolated granulocyte/macrophage colonies only whereas all erythroid colonies were negative. The JAK2 mutation was detectable in all clones and was enriched in CD34+ selected cells. The patient experienced progressive splenomegaly despite the achievement of a molecular response measured by quantitative BCR-ABL PCR after treatment with imatinib mesylate.
Our in-vitro investigations suggest that the secondary BCR-ABL translocation within the myeloid compartment was of minor pathophysiological relevance in this patient with CIMF harbouring a heterozygous JAK2 mutation.
Familial Essential Thrombocythemia in a Child with Elevated Thrombopoietin Concentrations and Skeletal Anomalies.
Authors: Robins Edwin B. , Biguzzi Sergio 
Published: April 2020

Abstract
We describe a 2-year-old child with an incidental finding of persistent elevated platelet count. The platelet count at the time of referral was 900 × 109/L. His physical examination revealed bony abnormalities of the right upper extremity, and hand. (Photo1) X-Ray of the hand revealed amputation of the fingers of the right hand with rudimentary metacarpal bones, and evidence of shorter radius and ulna of the of the left forearm when compared to the right. The physical examination was otherwise normal with the exception of moderate splenomegaly. Further workup revealed normal iron stores, and no inflammatory process which could explain the thrombocytosis. Chromosomal breakage and rearrangements studies were normal and confirmed a normal male karyotype. A bone marrow aspirate and biopsy revealed megakaryocytic hyperplasia with many binucleated and trinucleated megakaryocytes. (Photo 2) The erythroid and myeloid series were well represented and of normal morphology. Flow cytometry for ALL specific and CMLspecific markers were normal. The platelet count reached 2,800 × 109/L, and serum thrombopoietin level was obtained, which returned 2119.8 pg/ml. The patient was placed on hydroxyurea and aspirin 81mg/day, and reduction in the platelet count occurred. After six months of hydroxyurea therapy the platelet count rose again to pretreatment levels. Hydroxyurea was discontinued and anagrelide started with moderate platelet reduction. Family members were also evaluated. The siblings all had normal platelet counts but the mother had an elevated platelet count 900 × 10 9/L. The bone marrow aspirate of the childs mother was also consistent with ET. The JAK2 kinase mutation was not found in the mother or the child. The childs mother was also found to have an elevated thrombopoietin level of 475.6 pg/ml and was started on hydroxyurea.
No connection has been made between our patients congenital anomalies and the thrombocytosis. To our knowledge there have been no other reports of such features in either adult or pediatric patients with ET. Because this childs mother was also subsequently diagnosed with ET, familial ET is a more likely diagnosis. The diagnosis of familial ET is further supported by the elevated TPO concentration in our patient. Sporadic cases of familial ET with elevated thrombopoietin concentrations have been reported. Although ET has been reported in patients as young a 6 weeks, our case is different than other reported pediatric cases of ET because of not only the elevated TPO but the associated skeletal anomalies of our patient. To date neither the child or the mother has suffered any thrombohemorrhagic events, which have been reported to occur at rates varying from 20% to 40%. The mother and child are being followed prospectfully with serial blood counts, serum TPO concentrations.
Figure Figure Figure Figure
A Phase II Study of Oral Interferon-Alpha (IFN-a) for Patients with Essential Thrombocythemia or Polycythemia Vera.
Authors: Quintas-Cardama Alfonso , Giles Francis , Cortes Jorge , Kantarjian Hagop , Verstovsek Srdan 
Published: April 2020

Abstract
Recombinant human IFN-α has been the mainstay of therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders for many years. However, the response rates of IFN-α therapy have been frequently challenged by high dropout rates due to side effects and inconvenient subcutaneous dosing schedules. Accordingly, we design a phase II study to evaluate the efficacy and safety of natural human IFN-α administered by the oral mucosal route in patients (pts) with essential thrombocythemia (ET) or polycythemia vera (PV). Pts were eligible if they had failed (inability to normalize platelet count in ET, or to reduce the frequency of phlebotomy or splenomegaly by 50% in PV, after 6 months of therapy with hydroxyurea (HU) and anagrelide (AG)), were intolerant to HU and AG, or refused to receive standard cytoreductive therapy. HU or AG therapy had to be stopped at least 3 weeks prior to start of oral IFN-α. Prior exposure to IFN-α was not allowed. Oral IFN-α was administered at 150 IU three times daily as a lozenge. A total of 14 pts (8 PV, 6 ET) have been treated. Median age was 57 (range, 32 to 79), time from diagnosis to oral IFN-α therapy 2 months (range, 0 to 32), Hb 14.2 gm/dL (range, 11.2 to 15.4), WBC 9.75 ×109/L, (range, 5.6 to 17.3), platelets 812 ×109/L (range, 360 to 1389). Five patients were previously treated with HU, four with AG, and 3 with imatinib mesylate. Six pts with PV had received phlebotomies and 2 presented with marked splenomegaly. The JAK2 V617F mutation was detected in 10 of 11 evaluated pts and 2 of 14 pts (14%) had abnormal cytogenetics. All 14 pts are evaluable for response and toxicity. No responses have been observed among any of the 14 pts treated. Ten (71%) pts discontinued oral IFN-α therapy due to lack of response (n=9) or disease progression (n=1, elevation of platelets), and 4 are currently on therapy. Duration of therapy varied: 2.5 months = 2 pts, 3 months = 6 pts, 4 months = 4 pts, 6 months = 2 pts. Therapy with oral IFN-α was very well tolerated: grade 1 headache was noted in 2 pts, and grade 1 paresthesia in 1 pt. We conclude that oral IFN-α is very well tolerated but has no activity in the treatment of pts with ET or PV at the dose and schedule employed in this study.
WP1066 Inhibits Growth of Human Cells Carrying the JAK2 V617F Mutation.
Authors: Manshouri Taghi , Estrov Zeev , Quintas-Cardama Alfonso , Cortes Jorge , Giles Francis , Harris David , Priebe Waldemar , Kantarjian Hagop , Verstovsek Srdan 
Published: April 2020

Abstract
Myeloproliferative disorders (MPDs) are characterized by proliferation of one or more myeloid cell lineages in bone marrow and peripheral blood, with relatively preserved differentiation. Recent discovery of a dominant gain-of-function mutation in the Janus kinase 2 (JAK2) gene in patients with MPDs, involving the substitution of valine for phenylalanine at position 617 of the JAK2 protein (JAK2 V617F), represents the first acquired somatic mutation in hematopoietic stem cells described in these disorders. This discovery has opened new avenues for the development of targeted therapies for MPDs. WP1066 is a small molecule, a member of a novel class of anticancer agents whose development was based upon the backbone of AG490, a tyrphostin with activity against JAK2 V617F-expressing cell lines but limited in vivo activity. We investigated the inhibitory activity of the WP1066 against the JAK2 V617F-mutant expressing erythroid leukemia HEL cell line and peripheral blood mononuclear cells from patients with polycythemia vera (PV). WP1066 significantly inhibited the phosphorylation of JAK2 and downstream signal transduction proteins STAT3, STAT5, and ERK1/2 in a dose- and time-dependent manner. It induced a time- and dose-dependent antiproliferative and pro-apoptotic effects (activation of caspase 3, release of cytochrome c, and cleavage of PARP) in the JAK2 V617F-bearing HEL cell line in the low micromolar range. Pretreatment of cells with pan-caspase inhibitor Z-VAD abolished WP1066-induced apoptosis. The expression of apoptosis related proteins bcl-2, bax, and XIAP, however, was not changed. More important, WP1066 was effective in inhibiting cell growth in clonogenic assays of mononuclear cells harboring the JAK2 V617F mutation obtained from peripheral blood of patients with PV. We conclude that WP1066 is active both in vitro and ex vivo against cells carrying the JAK2 V617F mutation and represents a solid candidate for the treatment of JAK2 V617V-expressing MPDs.
MK-0457 Is a Novel Aurora Kinase and Janus Kinase 2 (JAK2) Inhibitor with Activity in Transformed JAK2-Positive Myeloproliferative Disease (MPD).
Authors: Giles Francis , Bergstrom Donald A. , Garcia-Manero Guillermo , Kornblau Steven , Andreeff Michael , Kantarjian Hagop , Jones Dan , Freedman Steven J. , Verstovsek Srdan 
Published: April 2020

Abstract
MK-0457 (VX-680) was developed as a small-molecule inhibitor of Aurora kinases A, B, and C (Ki,app = 0.66–18 nM). Recent screening for additional kinase activity shows that MK-0457 inhibits JAK-2 with an IC50 of 123 nM for wildtype JAK2 and 295 nM for the JAK2 V617F activating mutation. Based on these in vitro findings, eleven patients with documented JAK2-mutated myeloproliferative disorders (MPDs), including 2 patients with prior MPD progressing to AML, were treated with MK-0457 at either 20, 24 or 28 mg/m2/hr administered by a continuous 5-day intravenous infusion every 3 weeks. The age range was 37– 83 (median 64); 5 (45%) patients were male and performance status was 0 or 1 in 10 (91%) patients. Five (45%) patients were previously splenectomized and 2 (33%) of the non-splenectomized patients had splenomegaly present at baseline. Two (18%) patients had diploid cytogenetics, eight (73%) were pseudodiploid with varying abnormalities and one (9%) had a -17 abnormality. One patient with hepatosplenomegaly at enrollment experienced complete resolution of hepatomegaly and &gt;50% reduction in splenomegaly with a single cycle of therapy. Of the 10 (91%) patients starting therapy with a normal or increased absolute neutrophil count (ANC), all experienced grade 3 or 4 neutropenia during the study period. Transient reductions in platelet counts of patients with normal or elevated baseline platelets were also seen. Six of 7 (86%) patients with serial JAK2 testing had gradual, yet steady reductions in percentage of PCR product with the V617F mutation. MK-0457 is worthy of further exploration at lower doses (20mg/m2/hr) which are more suitable for chronic administration in patients with less aggressive disease, in contrast to patients with AML transformation of JAK2-mutated MPD in which higher, more myelosuppressive doses may be warranted.