bluuebunny/crossref_metadata_2025_split huggingface dataset:
CXCR4 as a Predictor of Response in Acute Myeloid Leukemia
Authors: Pastore Domenico , Mestice Anna , Giannoccaro Margherita , Liso Arcangelo , Martelli Maria Paola , Carluccio Paola , Albano Francesco , Delia Mario , Rossi Antonella Russo , Leo Manuela , Pannunzio Alessandra , Liso Vincenzo , Falini Brunangelo , Specchia Giorgina 
Published: April 2020

Abstract
The expression of CXCR4 (CD184) has been associated with poor prognosis in Acute Myeloid Leukemia (AML) and it has also been suggested that the CXCL12(SDF-1a)/CXCR4 interaction contributes to the resistance of leukemia cells to chemotherapy-induced apoptosis. Inhibition of CXCR4 was found to enhance chemotherapy-induced apoptosis in a subset of leukemic myeloblasts that carry Flt3 mutations and to overcome chemoresistance associated with stromal activity. NPM variants with a cytoplasmic localization represent the most common mutation detected in myeloid malignancies and are associated with a favourable clinical outcome. A recent study provides biological evidence for a novel role for NPM as a negative regulator of CXCR4 signalling induced by CXCL12: suppression of NPM expression enhanced chemotactic responses to CXCL12, and conversely, over-expression of a cytosolic NPM mutant reduced chemotaxis induced by CXCL12. We investigated whether CD184 expression is a negative predictor factor for response to chemotherapy and if there is clinical evidence that NPM mutations could overcome chemoresistance to induction therapy in this subset of patients. The expression of CD184 was analyzed by flow cytometric methods in a group of 70 cases of adult AML at onset of disease, diagnosed at our Institution since January 2006. The diagnosis was performed according to FAB/WHO criteria; all patients received intensive chemotherapy according to institutional protocols. There were 34 males and 36 females and median age was 46 years (range 18–65). AML cells were gated based upon their CD45 expression and samples were considered positive if CD184 was expressed by more than 20% of blasts. CD184 was positive in 45 and negative in 25 cases. There was no significant difference between the two groups in terms of sex, age, Hb level, WBC and Plt counts, percentage of blasts, and occurrence of the NPM mutation. The CR rate was 45% in CD184+ and 82% in CD184- (p=0.03); among CD184+ cases, the CR rate was significantly higher in NPMc+ cases, (p=0.03). Our results show that CD184 expression is associated with a lower rate of CR after induction therapy and this association is stronger in NPM unmutated cases, suggesting that CD184 expression is a negative predictive factor for response to chemotherapy. Further data are needed to verify if the biological role of the cytosolic NPM mutant as a negative regulator of CXCR4 signalling induced by CXCL12 could have a clinical role contributing to overcome the resistance of leukemic cells to induction chemotherapy.
Sequential Cytarabine and Alpha-Particle Immunotherapy with Bismuth-213 (213Bi)-Labeled-HuM195 (Lintuzumab) for Acute Myeloid Leukemia (AML)
Authors: Rosenblat Todd , McDevitt Michael R. , Mulford Deborah A. , Pandit-Taskar Neeta , Weiss Mark A. , Heaney Mark L. , Chanel Suzanne , Morgenstern Alfred , Larson Steven M. , Scheinberg David A. , Jurcic Joseph G. 
Published: April 2020

Abstract
HuM195, a humanized anti-CD33 monoclonal antibody, targets myeloid leukemia cells and has single-agent activity against acute myeloid leukemia (AML). To enhance the potency of native HuM195 and avoid nonspecific cytotoxicity seen with β-emitting radioimmunoconjugates, the α-emitting radiometal 213Bi was conjugated to HuM195. The feasibility, safety, and antileukemic activity of 213Bi-HuM195 were shown in a phase I trial (Jurcic et al. Blood 2002). Because of the short-range (50–80 μm) and high linear energy transfer (8400 keV) of α particles, radioimmunotherapy with 213Bi is ideally suited for the treatment of residual disease. To determine the effects of 213Bi-HuM195 against cytoreduced disease, we treated 31 patients (median age, 67 years; range, 37–80) with cytarabine 200 mg/m2/day for 5 days followed by 213Bi-HuM195 in a phase I/II trial. Thirteen patients had untreated AML (5 with de novo AML; 8 with secondary AML). Eight patients had AML in untreated first relapse, and ten patients had heavily pretreated relapsed AML (n=7) or primary refractory AML (n=3). Nine patients had poor-risk cytogenetics. During the phase I portion of the study, cohorts of 3–6 patients were treated with 18.5, 27.75, 37, and 46.25 MBq/kg. Prolonged myelosuppression with grade 4 leukopenia &gt; 35 days was the most common dose-limiting toxicity. The maximum tolerated dose (MTD) was 37 MBq/kg. Extramedullary toxicity was primarily limited to ≤ grade 2 events, including infusion-related reactions; however, grade 3/4 liver function abnormalities were seen in four patients (13%). Treatment-related deaths occurred in two of 21 patients (10%) who received the MTD. Significant reductions in marrow blasts were seen at all dose levels, and clinical responses were observed in 6 of the 25 patients (24%) who received doses of at least 37 MBq/kg (2 CR, 2 CRp, 2 PR). The median response duration was 7.7 months (range, 2–12). Pharmacokinetic and biodistribution studies suggested that saturation of all available CD33 sites by 213Bi-HuM195 was possible after cytoreduction with cytarabine. Sequential administration of cytarabine and 213Bi-HuM195 is tolerable and can produce complete remissions in patients with AML.
Impact of CRi on the Outcome of Elderly Patients with Untreated Acute Myeloid Leukemia (AML)
Authors: Etienne Anne , Charbonnier Aude , Prebet Thomas , Coso Diane , D’Incan Evelyne , Doglio Marie-Francoise , Sainty Daniele , Mozziconacci Marie-Joelle , Rey Jerome , Vey Norbert 
Published: April 2020

Abstract
New international recommendations of response for treatment of AML include morphologic complete remission with incomplete blood count recovery (CRi). This response criteria was defined following evaluation of new drugs used for the treatment of AML in first relapse (Sievers et al., JCO2001;19:3244–3254). The objective of our study was to evaluate this criterion in elderly patients with AML who are in first line of treatment. Between 1995 and 2006, 454 patients aged 55 years or older with previously untreated acute non promyelocytic leukemia received a conventional anthracycline and cytarabine induction chemotherapy in our institution. Ages were between 55 and 85 years (median 65 years). Two hundred and fourty-eight patients achieved a complete response (CR) (55%), 37 patients achieved CRi (8%), 104 patients had persisting leukemia (23%), and 49 died during remission induction therapy (13%). Multilineage dysplasia, secondary AML and blasts expressing CD34 were significantly more frequent in patients achieving CRi than CR (58% versus 29%, p=0.001, 33% versus 15%, p=0.007, and 79% versus 54%, p=0.01, respectively). No favorable prognostic karyotype was found in the CRi group but cytogenetic distribution did not differ statistically between the two groups. All patients who reached CR or CRi were scheduled to receive consolidation. Only 24 patients (65%) in CRi actually received this consolidation chemotherapy course and 11 patients (30%) had intensification (intermediate-dose cytarabine and/or autologous stem cell transplantation) whereas for patients achieving CR, 233 (94%) and 214 patients (86%) received consolidation and intensification, respectively (p&lt;0,001 for both). None of the patients in CRi received an allogenic stem cell transplantation whereas 18 (7%) of CR patients had one (p=0,2). Disease-free survival (DFS) and remission duration were significantly different between patients in CRi and CR, with a median of 4 and 12 months, and 5 and 9 months respectively (p&lt;0,001 and 0,03). The median overall survival (OS) was also significantly lower for patients in CRi versus CR, respectively 8 and 23 months (p&lt;0,001). By landmark analysis, there was no difference in OS between patients in CRi and a group of 98 patients with induction failure surviving at least 60 days (p=0,4). We also noted that OS was better, in the group of patients in CRi, for those who finally achieved CR criteria after 1 or more course of post-remission chemotherapy (median 16 months, against 7 months for patients still in CRi, p=0,03). Our results show that the CRi criterion is not equivalent to CR in elderly patients who received intensive chemotherapy as the first line treatment of AML. This should be kept in mind when the results of new agents used in this setting are compared to historical data.
Age and Prognosis in Pediatric AML
Authors: Edslev Pernille Wendtland , Abrahamsson Jonas , Clausen Niels , Forestier Erik , Gustafsson Göran , Heldrup Jesper , Hovi Liisa , Jahnukainen Kirsi , Jonmundsson Gudmundur , Palle Josefine , Zeller Bem , Hasle Henrik 
Published: April 2020

Abstract
Introduction. Results from St. Jude and M. D. Anderson, USA, suggested that AML children &lt; 10 years have significantly better outcome than patients aged 10–21 years. Similarly, the Medical Research Council, UK, showed superior survival in children &lt; 10 years due to a lower relapse rate compared to 10 – 15 year olds. We describe the AML outcome by age in the Nordic countries.
Patients. Within the population based NOPHO AML protocols (NOPHO-AML 93 and NOPHO-AML 2004) we treated 403 patients aged 0 – 18 years from 1993 – 2007. Patients with Down syndrome and AML-M3 were excluded. The children were divided into three age groups; 0 –1 year (27%), 2 –9 years (41%) and 10+ years (32%). The oldest age group had a male preponderance. MLL-aberrations were more common among the youngest and t(8;21) among the oldest. FAB-type M5 was seen in 35% of 0–1 year olds versus only in 16% of children aged 10+.
0 – 1 year&#x2028; n= 109 2 –9 years&#x2028; n = 165 10 – 18 years&#x2028; n = 129 Boys/girls 44/67 = 0.67 80/87 = 0.94 80/49 = 1.63 p = 0.01 WBC&gt;100×109/L 18 (17%) 14 (9%) 18 (14%) p = 0.10 Cytogenetics&#x2028; t(8;21) &#x2028; t(9;11) &#x2028; Other MLL 1 (1%)&#x2028; 14 (13%)&#x2028; 21 (19%) 24 (15%)&#x2028; 12 (7%)&#x2028; 16 (10%) 15 (12%)&#x2028; 9 (7%)&#x2028; 9 (7%) p = 0.01&#x2028; p = 0.39&#x2028; p = 0.03 FAB type&#x2028; M4&#x2028; M5 22 (20%)&#x2028; 38 (35%) 32 (19%)&#x2028; 31 (19%) 26 (20%)&#x2028; 21 (16%) p = 0.96&#x2028; p = 0.00 Protocol&#x2028; NOPHO-AML 93&#x2028; NOPHO-AML 04 75 (25%)&#x2028; 34 (32%) 125 (42%)&#x2028; 40 (37%) 96 (32%)&#x2028; 33 (31%) p = 0.4
Results. Almost half of the patients experienced events during follow-up. Types of events, event-free survival (EFS), and overall survival (OS) are shown in the table.
0 – 1 year n= 109 2 –9 years n = 165 10 – 18 years n = 129 Induction death 2 (2%) 4 (2%) 3 (2%) p = 0.9 Resistant disease 2 (2%) 2 (1%) 9 (7%) p = 0.01 Death in CR 6 (6%) 4 (2%) 8 (6%) p = 0.2 Relapse 34 (31%) 64 (39%) 42 (33%) p = 0.4 5-year EFS 57% 54% 48% p = 0.5 5-year OS 68% 68% 64% p = 0.7
Conclusion. Older children are more often male, more frequently have t(8;21) and less often M5-subtype or MLL-aberrations. The OS and EFS are similar among all ages. However, older children more often have resistant disease. The risk of death during induction and relapse is similar.
The Comparison Between Matched Related Donor and Alternative Donor for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acquired Aplastic Anemia: KSBMT2007-02 Study
Authors: Kim Hawk , Koo Hong Hoe , Kook Hoon , Kim Byung Soo , Kim Sung Hyun , Kim Hack-Ki , Kim Hyeoung Joon , Bae Sung Hwa , Sohn Sang Kyun , Shin Ho-Jin , Ahn Hyo Seop , Won Jong-Ho , Yoon Sung-Soo , Lee Young-Ho , Jeong Dae-Chul , Jo Deog-Yeon , Joo Young-Don , Kim Min Kyoung , Hyun Myung Soo , Lee Kyoo Hyung 
Published: April 2020

Abstract
Backgound; Although allogeneic hematopoietic stem cell transplantation (alloSCT) from matched related donor (MRD) is a standard therapy for severe acquired aplastic anemia (AA), alternative donor (AD) alloSCT is increasing and the survival of alloSCT from AD improves nowadays.
Aims: We planned this study to review the recent result of alloSCT survival and to compare AD with MRD.
Methods: A retrospective study comparing MRD and AD for alloSCT in patients with AA was conducted by Korean Society of Blood and Marrow Transplantation (KSBMT2007-02 study).
Results: The patient population was AA, pure red cell aplasia, paroxysmal nocturnal hemoglobinuria, and they underwent alloHSCT from 1997 and 2007. Total 336 patients were enrolled in 24 Korean alloSCT centers. Survival analysis was done in 331 patients because data were not available in 5 patients. Two hundred five adult patients with AA were also analyzed to define the characteristics of adult AA patients. AA was 97.3% and median age at alloSCT was 20.4 (1–62) years old. Median time from diagnosis to alloSCT was 6.2 (0.2–248.4) months. Male was 48.9%. Seventy nine percent patients received bone marrow (BM) as a stem cell source. AD had longer time from diagnosis to alloSCT (p=0.049) and received more peripheral blood (PB) or cord blood (CB) as a stem cell source (16.3% vs. 31.7%, p=0.004). Univeriate analysis showed MSD (p&lt;0.001), age less than 15 years (p=0.010), BM as stem cell source (p=0.036) and disease duration less than 12 months (p=0.007) were significant predictor for better survival. However, multivariate analysis revealed that donor type was not significant factor (p=0.087) whereas age and BM was predictors for better survival. When 205 adult AA patients were analyzed, AD had more graft failure (p=0.005), delayed neutrophil engraftment (p=0.035), more acute graft versus host disease (GvHD; p=0.009). However, there were no different between AD and MRD in terms of platelet engraftment (p=0.618), incidence of SOS (p=0.735) and relapse rate (p=0.360). MRD (p=0.011), age less than 30Y (p=0.001), disease duration less than 12M (p=0.003), no prior immune suppression therapy, (p=0.007) and platelet transfusion less than 90U (p=0.010) significantly affected survival. Only age and platelet transfusion were significant factor for better survival in multivariate analysis.
Summary: In conclusion, our study showed that donor type was not a significant factor for survival. Therefore, AD should be considered earlier when there is no MRD in patients with AA.
The Effect of the CASP8 -6526N Del Promoter Polymorphism on Outcome in T-Cell Depleted Unrelated Donor Haemopoetic Stem Cell Transplants (HSCT)
Authors: Krishnamurthy Suchitra , Shaw Bronwen E. , Byrne J. L , Seedhouse C. , Mayor Neema P , Madrigal A. J , Russell Nigel H. 
Published: April 2020

Abstract
The 6 nucleotide insertion-deletion polymorphism (-6526N del) in the CASP8 promoter has been demonstrated to destroy an Sp1 binding site, resulting in reduced caspase-8 activity and expression and a reduced susceptibility of 652 6N del/del T-lymphocytes to undergo apoptosis in response to anti-FAS and to tumour infiltrating lymphocytes. As the susceptibility of T-lymphocytes to undergo apoptosis could affect outcome following allogeneic HSCT we have investigated the impact of the CASP8-652 6N del polymorphism in both donors and recipients on the outcomes of patients undergoing unrelated donor HSCT.
Genotyping was performed on 186 donor/recipient pairs who underwent an HSCT from a donor from the Anthony Nolan Trust in one of 25 transplant centres in the United Kingdom between 1997 and 2006. All patients were transplanted for a haematological malignancy and had long term clinical data collated. Diagnoses were CML: 40.3%; MDS: 4.3%, ALL: 16.6%; AML: 23.6 %, lymphoproliferative disorders: 10.4 %, multiple myeloma: 4.8%. The frequency of the 3 genotypes in the Caspase 8 promoter region was as follows: RECIPIENTS: WT/WT=0.26; WT/del=0.49; del/del=0.24 and DONORS: WT/WT=0.33; WT/del=0.40; del/del=0.25. Frequencies in both the donor and recipient populations were in Hardy-Weinberg equilibrium.
Our findings show that the overall survival (OS) in recipients who received a transplant from a donor with a WT/WT genotype was significantly better as compared to donors with WT/del or del/del genotype (52% v 34% at 5 years; p=0.03). The disease free survival (DFS) at 3 years was also significantly better (39% v 18%; p=0.03). In addition, we found a significant reduction in grade II-IV acute GVHD (17% v 30%; p=0.04) and a trend towards lower incidence of chronic GVHD (42% v 63%; p=0.06) and transplant related mortality (TRM) (19% v 35%; p=0.06) in these patients. No significant difference in disease relapse was seen.
The results were particularly striking in the subgroup of recipients where one or two deletions were present (WT/del or del/del genotype). The OS was 62% in those who received a graft from a donor with WT/WT genotype compared to 36% with other donors (p=0.01). This remained significant in multivariate analysis (HR 0.53; CI 0.29, 0.98; p=0.04). This subgroup also had a lower risk of relapse (p=0.02).
In this cohort, the majority (156/186) of recipients had in-vivo T-cell depletion using Alemtuzumab. As Alemtuzumab depletes T-cells in part by apoptosis induced via a caspase 8 dependent pathway, we hypothesize that recipients who receive a transplant from a donor with WT/WT genotype are likely to get more effective T-cell depletion and hence less acute GVHD and reduced TRM resulting in improved survival. The mechanism of interaction between donor and recipient genotypes remains to be explored.
Figure Figure
Mismatching at HLA-DPB1 Is Not Associated with Survival in Patients with Acquired Aplastic Anemia Who Receive Unrelated Bone Marrow Transplantation
Authors: Yagasaki Hiroshi , Kojima Seiji , Kato Shunichi , Kato Koji , Yabe Hiromasa , Sakamaki Hisashi , Kawase Takakazu , Tsuchida Masahiro , Kigasawa Hisato , Morishima Yasuo , Kodera Yoshihisa 
Published: April 2020

Abstract
DNA typing for HLA-A, -B, -C, -DQB1 and -DRB1 determines outcome in patients with severe aplastic anemia (SAA) who receive unrelated bone marrow transplantation (U-BMT). Based on our previous study of 300 subjects, complete matched (10/10) donors are preferable, but 1-allele-mismatched (9/10) donors are also acceptable. Several studies have addressed the additive effects of HLA-DPB1 for patients with hematological malignancies. In recent reports, HLA-DPB1 mismatching decreased the incidence of relapse, but increased the incidence of acute GVHD. However, the impact of matching for HLA-DPB1 remains unknown in SAA patients. To explore the impact of HLA-DPB1 on the outcome, we analyzed outcomes in 169 recipients with SAA who received U-BMT from an HLA complete matched or 1-allele mismatched donor through the Japan Marrow Donor Program. Median patient age was 17 years (range: 1 to 64 years), and 102 males and 67 females were included. Among 169 pairs, 101 were matched for 10/10 alleles and 68 matched for 9/10 alleles. Although the overall survival was comparable between the groups (10/10 matched group; 75.2%, 9/10 matched group; 64.5%, p=0.633), the incidence of acute GVHD (II–IV) was significantly higher in the 9/10 matched group (15.3%) than in 10/10 matched group (32.2%) (p=0.012). Therefore the impact of HLA-DPB1 matching was analyzed independently in each group. In the 10/10 matched group, 30 of 101 pairs (30%) were matched for HLA-DPB1, whereas 71 pairs (70%) were mismatched for HLA-DPB1. In the 9/10 matched group, 21 of 68 pairs (30%) were matched for HLA-DPB1, whereas 47 pairs (70%) were mismatched for HLA-DPB1. In the 10/10 matched transplants, the survival rate was comparable between the HLA-DPB1 matched group (74.4%) and the HLA-DPB1 mismatched group (75.7%) (p=0.894). The incidence of acute GVHD (II-IV) was lower in the HLA-DPB1 matched group (8.0%) than in the HLA-DPB1 mismatched group (18.1%), but this difference was not significant (p=0.193). In 9/10 matched transplants, the survival rate was comparable between the HLA-DPB1 matched group (71.4%) and the HLA-DPB1 mismatched group (61.7%) (p=0.826). The incidence of acute GVHD (II-IV) was also lower in the HLADPB1 matched group (21.0%) than in the HLA-DPB1 mismatched group (37.2%), but this difference was not significant (p=0.169). The incidence of chronic GVHD and rejection rate were not associated with HLA-DPB1 matching. In conclusion, HLA-DPB1 matching is not essential for U-BMT recipients with SAA when 10/10 or 9/10 allele-matched donors are available.
A Higher Prevalence of HIT Antibodies in Patients May Be Due to Contaminated Heparin
Authors: Bansal Vinod , Cunanan Josephine , Adiguzel Cafer , Litinas Evangelos , Nelson Kelly , Fareed Jawed 
Published: April 2020

Abstract
During the period of November 2007-January 2008, an increased prevalence of adverse reactions to heparin in hemodialysis patients was noted. These adverse events were attributed to the presence of purposeful contaminant, namely oversulfated chondroitin sulfate (OSCS). The OSCS exhibited a molecular profile similar to heparin (14–16 KDA) and was a weaker anticoagulant (30–40 USP U/mg), however when mixed with heparin it produced super-additive anticoagulant effects. Similar to heparin, the OSCS also produced HIT antibody mediated aggregation of platelets and serotonin release. The contaminated heparin was reportedly used in dialysis globally during the period March 2007–May 2008. Since dialysis patients have been exposed to contaminated heparin, the OSCS may have triggered the generation of anti-heparin platelet factor 4 antibodies (HIT abs). Earlier analysis of dialysis patients plasma obtained in 2006 and 2007, consistently showed a very low prevalence of HIT abs in these patients (5 %). To test the hypothesis that maintenance hemodialysis patients exposed to potentially contaminated heparin may have a greater prevalence of HIT abs, blood from 80 patients on maintenance hemodialysis for the past several weeks, was drawn in June 2008. Plasma samples were analyzed for the presence of HIT abs using a commercially available ELISA kit from GTI (Brookfield, WI). While there was no change in the platelet count, the prevalence of HIT abs in these patients was markedly higher 15/78 (19.2%). Subtyping of the antibody also showed a higher prevalence of IgG subtype in contrast to the previously determined abs which were mainly IgA and IgM. The OSCS was also found to strongly complex with platelet factor 4 and initiate heparin induced platelet aggregation responses. These observations suggest that OSCS contaminant in recalled heparin is capable of triggering a differential immunogenic response in comparison to contaminant free heparin. Regardless of the increased generation of HIT abs no reports on any adverse events and/or thrombocytopenia were apparent from the site where the blood samples were drawn.