bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Presentation, Treatment Response and Survival in Adult Acute Biphenotypic Leukemia: Single Centre Experience.
Authors: Abdulwahab Amal S. , AlJurf Mahmoud D. , Elkum Nasser M. , Almohareb Fahad I. , Owaidah Tarek M. 
Published: October 2019

Abstract
Background: Acute leukemia is classified as lymphoid or myeloid depends on antigen expression. Knowledge about acute biphenotopic leukemia (BAL) is limited; both in terms of clinical and biological presentation and also in regard to treatment outcome. Hereby we are completing the work done by our group which looked at the laboratory features of BAL by reviewing the clinical presentation and response to different chemotherapy protocols used at our institute for treatment of patients with BAL to estimate over all survival.
Methods: Out of 478 adult patients with acute leukemia, we analyzed 15(3.1%) cases classified as BAL according to EGIL score system. Clinical data were collected retrospectively and analyzed. Five different chemotherapy protocols had been used. Six(40%) patients had received VCEPM (Vincristine 1.4mg/m2 x 4 doses, Cyclophosphamide 600mg/ m2 , Etoposide 100mg m2 daily for 5 doses, Prednisone 60mg/m2 for28 days). Four (27%)cases had received 1423 KFSH protocol (Cyclophosphamide 1200mg/m 2 x 1 dose, Daunorubicin 45mg/m2 for 3 doses, Vincristine 1.4mg/m2 once every week x 4 doses, Prednisone 60mg/m2 for 21 days, L-Asparaginase 6000 iu/m 2 every 3 days x 6 doses). Standard ICE protocol was used for induction in 3 cases and in 2 patients modified St Jude protocol (Vincristine 1.5mg/m 2 once every week x 4 doses, Daunomycin 25mg/m2 once every week x 2 doses, Prednisone 40mg/m 2 daily for 25 dose, L-Asparaginase 10000u/m 2 every 3 days for 6 doses, Etoposide 300mg/m 2 every 4 days x 3 doses and Cytarapin 300mg/m 2 every 4 days x 3 doses).
Results: We had 11 males and 4 females with mean WBC count on presentation of 74.7 x 109/L.Chromosomal karyotype was done for all except one, 4(29%) were normal and 8(53%) had complex karyotype Of all patients with BAL leukemia, 4(27%), 8(53%) and 10(67%) had hepatomegaly,splenomegaly and lymphadenopathy respectively. Initial evaluation done on D14 post chemotherapy revealed evidence of residual leukemia (> 5% blasts) in 1 out of 6 patients treated with VCEPM and 7 out of the other 9 patients received different other protocols. Out of the eight patients with residual leukemia, 4 had received salvage chemotherapy with FA (Fludarabine 30mg/ m2, Cytarabine2mg/ m2 x 5doses) and 2 had received MEC (Mitoxantrone 6mg/ m2 , Etopside 80mg/ m2, Cytarabine1mg/ m 2 x 6 doses) and one received modified St Jude while one underwent for SCT. ALL except one had achieved CR. Total of 10(66%) underwent SCT in CR. Although there were 9 (60%) died during the follow up, the OS at two years was (50%).
Conclusion: Adult BAL is an aggressive disease that is associated with complex karyotype with poor response to single lineage treatment. The use of hybrid drugs (VCEPM like) that are effective for lymphoid and myeloid leukemia improve the respond.
Figure Figure
Hypersensitivity and Allergic Reations to L-Asparaginase in Childhood ALL.
Authors: Santo Shelly , Kapelushnik Joseph , Moser Asher M. 
Published: October 2019

Abstract
Asparaginase (ASP) is an effective antileukemic agent. However, hypersensitivity and/or allergic reactions (HA), estimated to occur in 2.5%–45% of patients are major limitations for its clinical use. The risk of developing hypersensitivity and/or an allergic reaction to ASP increases with higher doses, IV (vs. IM), continuous infusions and repeat treatment after prolonged abstinence. We surveyed the rate of HA in pediatric ALL in Israel, and identified additional factors of clinical significance.
Methods: Data was gathered from the medical records of 245 children treated for ALL during the years 2000–2006 from 4 Pediatric Hematology-Oncology wards. All children were enrolled on the Israel National Leukemia Study 1998 or 2003, modified from BFM protocols. In Brief, patient received 8 doses of ASP in the induction and 4 additional doses in each reinduction, starting after a two-month period free of ASP. The uniform treatment used an E coli L-ASP preparation and was replaced with a pegylatedE coli ASP preparation in case of HA. The definition and severity of the HA was defined by the professional opinion of the treating medical team.
Results: Forty-Eight of the 245 patients (19.6%) developed an HA reaction. 25 of the 48 were defined as severe. A wide range of HA was noticed between the treating centers (6.4%–29.4%). 16/48 of the children with HA were treated on a high-risk protocol (33% vs. 14% of the entire group, p<0.05), including 10/25 (40%) with severe HA. A higher incidence of HA was noticed at the start of the reinduction, with 23 (47.8%) of the patients developing a HA to ASP on the reinduction cycle’s first or second dose. Pegylated ASP had significantly more HA vs. E. coli L-ASP treatments (8/145; 5.5% vs. 37/2610; 1.4%, p <0.01). PEG was also associated with allergies of higher severity, (8/9; 88.9% vs. 43.6%). A careful analysis revealed no differences between the allergenic and non-allergenic groups of children in relation to sex, age, mortality and/or chromosomal abnormality.
Conclusions: The overall HA rate (with the noticed wide variations) and the high incidence at the beginning of the reinduction protocol are within the described literature, We believe that the lack of steroid treatment that precedes ASP in the reinduction contributes to the high rate of HA at this point. The findings regarding the PEG were unexpected. We found a relationship between the higher risk group and the development of HA as well as the severity. We believe that the differences observed between treating wards are due to unclear definitions of reaction and of severity .We have noticed a wide variability in executing the supporting treatment. We recommend a revision of the reinduction protocol to initiate steroids at the beginning of all treatment cycles and to consider the use of a different than E. coli source after a hypersensitivity or allergic reaction.
Asparagine Depletion, Safety and Antibody Production after E Coli Asparaginase Treatment in Children with Newly Diagnosed Acute Lymphoblastic Leukaemia Treated with EORTC 58951 Protocol: A Single Center Report.
Authors: Bertrand Yves , Goutagny Marie Pierre , Poulat Anne Lise , Girard Sandrine , Acquaviva Cecile , Saban Christine Vianey , Vermot-Desroches Claudine , Bourdin Laurence , Alex Cedric , Rougemond Eric , Kebaili Kamila 
Published: October 2019

Abstract
Randomised trials in pediatric ALL show that multiple doses of E Coli Asparaginase (ASP) are associated with better outcome. In the EORTC 58951 protocol, all the patients except those with high risk features (HR or VHR) had 8 IV doses of ASP during induction Ia and were randomized during induction Ib to receive or not ASP (8 IV doses vs 0) and protocol II (8 IV doses vs 4), respectively long arm and short arm. The aim of this study was to report on safety, asparagine (ASN) depletion and antibody production in 28 consecutive patients with newly diagnosed previously untreated ALL.
Methods. Twenty-eight patients included in the EORTC 58951 protocol were analyzed: one had very low risk features, 22 were average risk patients and 6 had HR features. Thirteen patients were randomized in the short ASP arm and 9 in the long ASP arm. ASN levels were assessed on days 35 of Ia, 27of Ib and 22 of IIa. The amino acid assays employed the HPLC method. Serum samples were taken for antibody titers against ASP analyzed by ELISA on days 12 and 35 of Ia, 17 and 27 of Ib (long arm only) and 8 and 22 of IIa, and before the start of maintenance therapy.
Results. Twenty-eight patients aged 1year 3 months to 14 years 6 months (median 6 years) with newly diagnosed ALL (precursor B-cell: 25 ; T-cell: 3) were assessable. All patients achieved CR after induction phase Ia. Four patients had allogeneic bone marrow transplantation in first CR because of VHR features. Two other patients with HR features had intensified chemotherapy. Preliminary data showed that ASN depletion was obtained in all patients at the end of phase Ia, in all the patients “long arm” at the end of Ib and in one patient ” short arm” at the end of Ib All patients had depletion of ASN after protocol IIa We observed very few severe clinical allergic reactions in this series of patients (10%). Two patients were switched to Erwinia asparaginase because of clinical hypersensitivity. Investigation on correlation between the antibody production against ASP, clinical allergic reaction and depletion of ASN are in progress.
Conclusions. Multiple doses of ASP given intravenously were well tolerated in this series of 28 consecutive patients with previously untreated ALL. Preliminary results reveal that the rate of antibodies production was low and depletion of ASN was obtained in near all the patients. Some patients presented with clinical allergic reactions but had low levels of ASN and no appearance of anti ASP antibodies. Other had antibodies without clinical allergy and with depletion of ASN.
Fungal and Bacterial Infections in Acute Myeloid Leukemia Patients Treated with Induction Regimens Including Fludarabine: A Retrospective Analysis of 224 Cases.
Authors: Malagola Michele , Peli Annalisa , Damiani Daniela , Candoni Anna , Tiribelli Mario , Martinelli Giovanni , Piccaluga Pier Paolo , Paolini Stefania , Lauria Francesco , Bocchia Monica , Gobbi Marco , Pierri Ivana , Zaccaria Alfonso , Zuffa Eliana , Mazza Patrizio , Priccolo Giancarla , Gugliotta Luigi , Bonini Alessandro , Visani Giuseppe , Cristina Skert , Cesare Bergonzi , Aldo Roccaro , Carla Fili , Fanin Renato , Baccarani Michele , Russo Domenico 
Published: October 2019

Abstract
Infections are the major cause of morbidity and mortality of acute myeloid leukemia (AML). Invasive Fungal Infections (IFIs) occur in at least 10 to 20% of the patients submitted to induction and consolidation treatments, are responsible for death during induction in up to the 5% of the cases and may cause a delay in consolidation and intensification therapy. Among the risk factors for IFIs it has been included the use of Fludarabine (Fluda), which can induce severe and prolonged immunosuppression. In this study we retrospectively analyzed the infections occurred in 224 newly diagnosed AML patients, aged at least 65 years, consecutively treated with an induction regimen including Fluda, Ara-C and idarubicine with or without etoposide (FLAI/FLAIE). During induction phase, 181/224 (81%) patients experienced a fever of undetermined origin (FUO), the incidence of Gram negative and positive sepsis was 16% (37/224) and 29% (65/224) respectively and 7/224 (3%) patients developed a possible/probable IFI. In 6/224 patients (3%) a proven IFI was found (4 aspergillosis and 2 candidiasis). We then collected the data of the incidence of infections during the first consolidation course (FLAI: n=70; high-dose Ara-C [HD-AC]: n=65; idarubicine and HD-AC: n=89). The overall incidence of FUO was 34% (76/224), the number of Gram negative and positive sepsis was 52/224 (23%) and 49/224 (22%), respectively and 2/224 (1%) patients developed a proven IFI (3 aspergillosis and 1 candidiasis). We subsequently evaluated the incidence of infections in the three different consolidation groups. No significant differences were observed in terms of FUO, Gram positive and negative bacteraemia/sepsis and possible, probable and proven IFIs, during consolidation with Fluda-based regimen and with HD-AC-based regimens. Interestingly, the overall incidence of IFIs during consolidation with FLAI was significantly lower than during consolidation with HD-AC-based treatment program (0% vs 9%; p=0.02). These data, even though retrospectively collected, suggest that Fluda-based chemotherapy is not followed by increased incidence of infections, in particular IFIs, in comparison with conventional non-Fluda based regimens commonly used for AML induction. In our series, Fluda-based consolidation chemotherapy caused a significantly lower incidence of IFIs compared to HD-AC-based consolidation. This may be related to the lower duration of neutropoenia in patients treated with FLAI with respect to those treated with HD-AC/HD-AC + idarubicine.
Prognostic Index for Older Adult Patients with Newly Diagnosed Acute Myeloid Leukemia: The Edouard Herriot Hospital Experience.
Authors: Plesa Claudiu , Le Quoc-Hung , Chelghoum Youcef , Elhamri Mohamed , Tigaud Isabelle , Anglaret Bruno , Ducastelle Sophie , Perrin Marie-Claire , Nicolini Frank , Belhabri Amine , Troncy Jacques , Thiebaut Anne , Revesz Daniela , Wattel Eric , Dumontet Charles , Michallet Mauricette , Thomas Xavier 
Published: October 2019

Abstract
The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of complete responses and long-term overall survival. Therefore, a clinically usefull prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies in this patient population. Overall, 243 of the 432 patients (56%, 95% CI: 51–60%) achieved CR (229 of them after the first induction course and 14 after salvage therapy). The median disease-free survival (DFS) and the median overall survival (OS) of the entire cohort were 8.4 months (95% CI: 7.2–10.1 months) and 8.3 months (95% CI: 7.2–10 months) respectively. A prognostic score is presented based on the multivariate analysis of 432 newly diagnosed non-M3 AML patients aged more than 60 years, selected on the base of their initial performance status and the absence of severe co-morbidity factors, for entering onto five successive clinical trials combining an anthracycline and cytarabine. Four clinically relevant parameters are included in this index: cytogenetics at diagnosis, history of previous hematologic disorder, hematologic features at diagnosis, and LDH level at diagnosis. Using this stratification system, three risk groups were defined: a favorable-risk group A (OS of 39% at 2 years and 21% at 5 years), an intermediate-risk group B (OS of 19% at 2 years and 8% at 5 years), and a poor-risk group (OS of 5% at 2 years and 0% at 5 years). The prognostic index estimates the outcome of elderly AML patients usually selected for intensive chemotherapy trials using four easily determined parameters and might identify patients who are really candidates for this treatment strategy from those for whom investigational therapy or palliation may be most appropriate.
Modified Topotecan Combination with Cyclophosphamide and Ara-C (CAT) for Patients with Refractory/Relapsed Leukemia.
Authors: Wu Sui-jing , Du Xin , Lin Wei , Huang Zi-lun , Zhou Xiao-li , Weng Jian-yu , Zhong Li-ye , Lu Ze-sheng 
Published: October 2019

Abstract
The prognosis of patients with leukemia has improved significantly. With combination chemotherapy, 60%–80% of adult patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia(ALL) achieve complete remission(CR). But most patients eventually relapse and do not response to current induction regimens based on cytarabine and anthracyclines any more. This emphasize the need to discover new agents for the treatment of leukemia to improve long-term prognosis. Topotecan is a semisynthetic analogue of the alkaloid camptothecin which acts as a specific inhibitor of topoisomerase I,by stabilization of the topoisomerase I DNA complex which leads to cell death.It also appears to be active against leukemias which have acquired the multi-drug resistant phenotype.[ Ulukan et al. Drug, 2000; Weihrauch et al. Leuk Lymphoma, 2004].It also could go through blood brain barrier[Kollmannsberger et al. Oncology, 1999].Here we observe the effect and side-effects of cyclophosphamide, cytanthetic analogue of rabine and topotecan (Modified CAT) combination regimen for treatment of refractory or relapsed leukemia. The study population comprise 26 patients with relapsed/refractory leukemia,including 12 with AML, 9 with ALL, 2 with myeloid blast phase of CML, 3 with lymphoma. Median age was 35 years.Patients received cyclophosphamide 300mg/m2 every 12 hours for 6 doses on day1 to 3.On day 2, topotecan was given at a dose of 1.5mg/m2/day for 5 days on days 2 to 6, and cytarabine 1.0 g/m2 /day for 5 days on days 2 to 6.The regimen (cytarabine reduced to 0.5g/m2 /day) could be repeated one or two cycles after remission. The total response rate of one course was 57%, eleven patients (42%) achived complete remission(CR). Responses occurred in 7of 12 AML (57%), including 5 CR(41%); in 6 of 9 patients with ALL (67%), including 5 CR(56%); and in 1 of 2 myeloid blast phase of CML(CR 50%). The median overall survival time after treatment was 2+ months, and the median overall survival time after CR was 4+ months. Severe myelosuppression was universal (100% Grade 4 neutropenia and thrombocytopenia), the median time to recovery of neutrophils to ≥0.5×109/L was 18 days,and the median time to platelet recovery to ≥ 20×109/L was 26 days.Infection developed in 96% cases, the most frequent events were oral mucositis(77%, 20/26), sepedogenesis(46%, 12/26),anusitis(38%,10/26),pneumonia(31%, 8/26), two patients died of infection complications(8%). Non-hematologic toxicity was seen frequently in gastrointestinal but it was mild. Nausea and/or vomiting occurred in 13 patients(50%)with gradeI-II in all of them.Two patients(8%) had diarrhea and grade 1–2 in them. In summary, Modified CAT regimen is well tolerated and has significant anti-leukemia activity as salvage therapy for relapsed/refractory leukemia.
The Ontogeny of Definitive Hematopoiesis in the Zebrafish.
Authors: Traver David , Bertrand Julien Y. , Kim Albert D. , Stachura David L. , Cisson Jennifer L. 
Published: October 2019

Abstract
Shifting sites of blood cell production during development is common across widely divergent phyla. In zebrafish, like other vertebrates, hematopoietic development has been roughly divided into two waves, termed primitive and definitive. Primitive hematopoiesis is characterized by the generation of embryonic erythrocytes in the intermediate cell mass and a distinct population of macrophages that arises from cephalic mesoderm. The generation of definitive, or multilineage, hematopoietic precursors during embryogenesis remains less well understood. Here we show, using a combination of gene expression analyses, prospective isolation approaches, hematopoietic progenitor cultures, transplantation, and in vivo lineage tracing experiments, that definitive hematopoiesis initiates through committed erythromyeloid progenitors (EMPs) in the posterior blood island (PBI) that arise independently of hematopoietic stem cells (HSCs). EMPs isolated by coexpression of fluorescent transgenes driven by the lmo2 and gata1 promoters exhibit an immature, blastic morphology and express only erythroid and myeloid genes. Transplanted EMPs home to the PBI, show limited proliferative potential, and do not seed subsequent hematopoietic sites such as the thymus or pronephros. In vivo fate mapping studies similarly demonstrate that EMPs possess only transient proliferative potential, with differentiated progeny remaining largely within caudal hematopoietic tissue. By contrast, fate mapping studies of CD41:eGFP+ cells residing in the aorta/gonads/mesonephros (AGM) region demonstrate robust colonization of the pronephros and thymus. Using timelapse microscopy, we show that these sites of adult hematopoiesis are seeded by CD41+ cells that migrate along the pronephric ducts from the AGM. These studies provide phenotypic and functional analyses of the first hematopoietic stem and progenitor cells in the zebrafish embryo and demonstrate that definitive hematopoiesis proceeds through two distinct waves during embryonic development.
Efficacy and Tolerability of Lenalidomide/Dexamethasone in Intensively Pretreated Myeloma Patients: Experiences from the German Named Patient Program.
Authors: Klein Ulrike , Blau Igor W. , Engelhardt Monika , Simon Jan P. , Goldschmidt Hartmut , Einsele Hermann , Knop Stefan 
Published: October 2019

Abstract
Lenalidomide (Len), an immunomodulatory drug, in combination with dexamethasone (Dex) is a new treatment option for patients (pts) with relapsed or refractory multiple myeloma (MM). Reimbursement and drug laws in Germany allow treatment before marketing authorization of a given drug, if no alternatives are available for life-threatening diseases. AIM: To evaluate efficacy and tolerability of MM pts treated with Len/Dex in the German named patient (pt) program.
PATIENT AND METHODS: A comprehensive, previously tested, questionnaire was used to document data from consecutive pt series in five large and specialized university treatment centres. Response was assessed using the EBMT criteria.
RESULTS: 55 pts were documented so far (median age, 63 yrs; 92% stage III Durie & Salmon). Pts were heavily pretreated: 30% had up to 2 previous therapy lines, 35% had three, 13% four and 21% more than four; the median no. was 3 (interquartile range, IQR 2–4). Pts had received a median of 16 (IQR 10–22) previous courses of chemotherapy. Forty-nine patients (89%) had previously received a stem cell transplant (SCT): 41 an autologous and an additional eight allogeneic SCT. That correlates with a 2-fold higher proportion of pts with prior SCT compared to the Len registration trial. Furthermore, the proportion of pts treated with the new drugs thalidomide or bortezomib was even 7–10-fold higher than in the registration trial. Best response could be assessed in 49 pts.: 4% CR, 32% PR, 19% MR, thereby showing an overall reponse rate of 55%. Four patients (8%) progressed during therapy and two (4%) died before response evaluation. The table shows response in different subgroups according to previous therapies. Response (CR/PR/MR) ranged from 88% (7/8) with only 1 previous treatment line shown in the table to 52% (16/31) with 2–3 and 43% (6/14) with 4–5. The most common adverse event III°/IV° was infection occurring in 21/55 (38%) patients. Thrombo-embolic events were observed in three patients (5%). Haematological toxicity grade IV° was seen in 11/46 (24%) patients, most common in course 1 of therapy. Five patients (9%) died during treatment, four due to infection (one in neutropenia) and one patient due to cerebral bleeding. 70% of patients were alive at last follow-up.
CONCLUSION: In this pt cohort Len/Dex induced considerable antineoplastic activity despite extensive pretreatment. Toxicity was moderate and as expected for this risk-cohort. Nevertheless pts with more than 3 prior treatment lines should receive close clinical monitoring in order to prevent life-threatening infection.
Response in different subgroups Over all response Prev. alloSCT Prev. ASCT Prev. thalidomide Prev. bortezomib 3 prev. treatment lines>> n 49 8 40 30 39 19 CR/PR/MR 55% 50% 53% 50% 54% 42%