bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Use of 2nd generation Tyrosine Kinase Inhibitors (TKI) after Failure to 2 Prior TKI: Long-Term Follow-up.
Authors: Garg Ravi n Jain , Kantarjian Hagop M , O’Brien Susan , Quintas-Cardama Alfonso , Faderl Stefan , Estrov Zeev , Cortes Jorge 
Published: April 2020

Abstract
The 2nd generation tyrosine kinase inhibitors (TKI), nilotinib and dasatinib, are effective after imatinib failure. These agents are now also being used as 3rd line therapy after failure to 2 prior TKI. Preliminary data suggests responses can be achieved with this strategy, but the long-term benefit is unknown.
To investigate the long-term benefit of using a 2nd generation TKI after having failed imatinib and another TKI.
Patients with CML who were sequentially treated with 3 different TKI’s at M.D. Anderson Cancer Center were reviewed. Response to the 3rd TKI were scored according to standard definitions. Event-free survival (EFS) was considered from the time the 3rd TKI was started to loss of major hematologic response, loss of cytogenetic response, transformation to accelerated (AP) or blast (BP) phase, or death. Failure-free survival (FFS) was considered from start of 3rd TKI to event as defined for EFS, or loss of complete cytogenetic response (CCyR) or discontinuation because of toxicity.
37 patients were treated: 29 with dasatinib after imatinib and nilotinib failure, and 8 with nilotinib after imatinib and dasatinib failure. The median age was 61 years (yrs) (range, 19 to 70). The median time on imatinib was 33 months (mo) and 15 (41%) had transformation before starting 2nd TKI. Median time on 2nd TKI was 7.7 mo. At the start of 3rd TKI, 16 pts (43%) were in chronic phase (CP), 9 (24%) in AP, and 12 (32%) in BP. Best response to 3rd TKI in CP was 1 major molecular response (MMR), 2 CCyR, 1 partial cytogenetic response (PCyR), 5 minor cytogenetic response (mCyR), 2 complete hematologic response (CHR), and 5 no responses (NR); in AP, there was 1 CCyR, 2 PCyR, 1 mCyR, 4 CHR, and 1 NR; in BP, 2 CCyR, 1 PCyR, 1 mCyR, 2 return to CP (RCP), and 6 NR. Four patients discontinued treatment because of toxicity despite an acceptable response. The median CCyR duration was 28 mo; only 2 pts in CP who achieved CCyR (1 had MMR) had a sustained response lasting 20 and 24 mo, respectively. Both received dasatinib after imatinib and nilotinib failure, and had G250E and H396R at start of dasatinib, respectively. The table shows median (in months) OS, EFS and FFS by disease stage.
CP AP BP OVERALL No. 16 9 12 37 OS NR 19.6 4.8 18 EFS NR 4.7 4 8 FFS 20 4.7 2 4
7 pts continue on therapy (all CP): 2 sustained CCyR (1 MMR), 1 PCyR (lost CCyR), 2 mCyR, 2 no cytogenetic response (1 lost mCyR).
Use of 2nd generation TKI after failure to 2 TKI may induce responses in some pts but these are usually not durable except in some pts in CP. New treatment options are needed for these pts.
The Prevalence of 25-Hydroxyvitamin D Deficiency in Post-HSCT Pediatric Patients.
Authors: Duncan Christine , Vrooman Lynda , Bechard Lori , Barry Elly , Lehmann Leslie E. 
Published: April 2020

Abstract
Children undergoing HSCT are at risk for vitamin D deficiency due to lack of sun exposure, the recommended use of sunscreen, dietary insufficiency, and the effects of medications such as glucocorticoids and calcineurin inhibitors. We assessed the prevalence of 25-hydroxyvitamin D (25-OH vitamin D) deficiency in pediatric post-HSCT patients in an outpatient oncology clinic during 4 weeks in May 2008. Patients found to have low 25-OH vitamin D levels were referred for dietary counseling and given supplementation or repletion as needed. 25-OH vitamin D and parathyroid hormone (PTH) levels were measured in 62 (88.6%) of 70 eligible patients. 83.8% of patients had a 25-OH vitamin D level less than the institutional lower limit of normal, 30 ng/mL. 29% of patients were 25-OH vitamin D insufficient with levels 20–29 ng/mL (range of 20–29). 54.8% of patients were 25-OH vitamin D deficient with levels &lt;20 ng/mL (range 5–19). The prevalence of insufficiency and deficiency was similar between male (87.8%; 57.6%) and female patients (57.6%; 55.2%).The mean duration of days following transplant was 532.6 days (median 251.5 days). The mean age at transplant was 3.7 years (median 3.5 years). 47% of patients were female. 75.8% were Caucasian. 90.3% received allogeneic transplants. The underlying diseases were as follows: ALL (27.4%), AML/MDS (24.2%), bone marrow failure (11.3%), nonmalignant hematologic diagnosis (8.1%), solid tumor (8.1%), immunodeficiency (6.5%), lymphoma (6.5%), and other diagnoses (8.1%). 8 patients regularly took either an over-the-counter multivitamin or vitamin D supplement and all 8 patients had 25-OH levels less than 30 ng/mL. There was a negative inverse correlation of (r= −0.3, p=0.029) between PTH and 25-OH vitamin D. There were no significant associations between 25-OH vitamin D level and any of the following: corticosteroid or calcineurin inhibitor use in the preceding year, time from transplant, age at transplant, current age, or graft-versus-host disease. 25-OH vitamin D insufficiency and deficiency are common following pediatric HSCT. We recommend vitamin D screening for all post-HSCT pediatric patients. Further investigation is needed to identify potential risk factors for vitamin D deficiency and the long-term effects of deficiency on bone health and development.
Clinical Significance of Autoantibody Expression in Allogeneic Stem Cell Recipients.
Authors: Moon Joon Ho , Lee Soo Jung , Kim Jong Gwang , Chae Yee Soo , Kim Shi Nae , Kim Yun Jeong , Rok Young , Suh Jang Soo , Lee Kun Soo , Sohn Sang Kyun 
Published: April 2020

Abstract
Some allogeneic stem cell recipients manifest autoimmune disease-like symptoms associated with the occurrence of various autoantibodies. We studied the association of autoantibodies with chronic graft-versus-host disease (cGVHD) and survival in allogeneic stem cell recipients. From Nov. 2001 to Mar. 2008, 121 patients with hematological diseases who had survived at least 3 months after allogeneic stem cell transplantation (SCT) were enrolled in the current study. Forty-seven patients (38.8%) expressed at least one of various autoantibodies after allogeneic SCT. ANA was expressed most commonly in recipients (n=22, 18.2%). Anti-dsDNA antibody was positive in 7 (5.8%), anti-Sm antibody in 6 (5%), rheumatoid factor (RF) in 17 (14.0%), and positive Coombs test in 12 (9.9%). The FANA pattern revealed 11 nucleolar, 6 speckled, and others (n=5). Positive rate of autoantibody was higher in patients with cGVHD (47.8 vs. 27.8%; p=0.025) and in patients with extensive cGVHD (62.5 vs. 27.2%; p&lt;0.001). The expression of autoantibodies had a statistical correlation to specific organ involvement of cGVHD: ANA to sicca syndrome (p=0.010), anti-Sm antibody to hepatic GVHD (p=0.003), and RF to sicca syndrome (p=0.039) and musculoskeletal GVHD (p=0.026). The 5-year survival of autoantibody-positive patients was 63.8% and that of negative patients was 47.9% (p=0.003). The incidence of underlying disease relapse was lower in autoantibody-positive patients (20.2% vs. 39.3%; p=0.011). However, GVHD-specific survival was not related with autoantibody expression. Advanced age group (p=0.005, OR=0.246), unrelated donor (p=0.005, OR=0.218), and the presence of acute GVHD (p=0.029, OR=0.315) were significantly associated with a lower incidence of autoantibody expression. In conclusion, the expression of autoantibodies after allogeneic SCT was related with cGVHD. Patients expressing autoantibodies had a better survival and low incidence of underlying disease relapse.
The Influence of Cytochrome P450 3A Gene Polymorphisms on Tacrolimus Concentrations in Hematopoetic Stem Cell Transplantation Patients.
Authors: Ogasawara Masahiro , Kosugi Mizuha , Matsuoka Satomi , Asamuma Shinsuke , Noguchi Shinsuke , Fujii Sirou , Wada Akinori , Ota Shuichi , Nakata Masanobu , Imai Kiyotoshi , Kobayashi Naoki , Kiyama Yoshio , Kasai Masaharu 
Published: April 2020

Abstract
Objective: Tacrolimus is a commonly used immunosuppressive drug in hematopoetic stem cell transplantation (SCT). It is characterized by a relatively narrow therapeutic range and a large individual variation in concentrations. It is metabolized mainly by cytochrome P450 (CYP) 3A which has genetic polymorphisms influencing enzymatic activities; CYP3AP1*1 and *3 genotypes representexpressor and non-expressor, respectively. The objective of this study is to investigate whether the tacrolimusconcentration per dose and renal toxicity by tacrolimus is associated with CYP3AP1 gene polymorphisms.
Methods: 105 Japanese SCT patients (55 AML, 19 ALL, 11 CML, 6 MDS, 4 NHL, 1 HL, 2 ATL, 2 MM, 4 AA, 1 MF), receiving tacrolimus were studied. DNA was extracted from peripheral blood samples. CYP3AP1 genotype was analyzed by PCR-restriction fragment length polymorphism using specific primers and a restriction enzyme, AciI. Blood tacrolimus concentrations were measured twice a week by a commercially available EISA kit.
Results: The frequency of the CYP3AP1 *1/*1, *1/*3 and *3/*3 genotype was 8, 31, and 61% of 105 patients, respectively, and the genotype distribution was not different significantly from that of 121 Japanese healthy volunteers (3, 39, and 58%, respectively). The frequency of CYP3AP1 genotypes of white Americans is reported to be 2, 12 and 86%, respectively, indicating the ethnic difference of distribution. The dose-adjusted concentrations of tacrolimus 5 to 7 days following SCT were significantly higher in CYP3AP1 *3/*3 patients than in CYP3AP1 *1/*1 and *1/*3 patients (665.0±148.0 ng/ml per mg/kg vs. 409.0±116.2 ng/ml per mg/kg, P&lt;0.001). The dose needed to achieve the target concentration (10 to 15 ng/ml) between 40 to 60 days following SCT, when the blood concentrations of tacrolimus tended to be stable in most patients, is significantly lower in CYP3AP1 *3/*3 patients than in CYP3AP1 *1/*1 and *1/*3 patients (0.008±0.005 mg/kg vs.0.018±0.005 mg/kg, P&lt;0.001). Above grade two adverse events related to tacrolimus were observed only in CYP3AP1 *3/*3 patients (3 patients in grade 4 and 6 patient in grade2), suggesting the contribution of a higher concentration to renal toxicity by tacrolimus.
Conclusion: The tacrolimus concentration per dose in SCT patients is influenced by the CYP3AP1 gene polymorphism. This is the first report showing the relationship between CYP3AP1 gene polymorphism and the tacrolimus concentration in SCT patients to the best of our knowledge. Information of CYP3AP1 genotype may be helpful to determine the initial tacrolimus dose adequate for each patient.
The FcγRllla Polymorphism Correlates with Chronic Graft-Versus-Host Disease and Treatment Related Mortality.
Authors: Takami Akiyoshi , Espinoza J. Luis , Ishiyama Ken , Ohyachi Satomi , Kato Yuki , Kawamura Yoshimi , Kondo Yukio , Yasue Shizuka , Ohtake Shigeki , Nakao Shinji 
Published: April 2020

Abstract
The FcγRllla (FCGR3A) 158V/V allotype displays a higher antibody-dependent cellular cytotoxicity compared to the FCGR3A-158V/F or 158F/F allotype, leading to susceptibility to rheumatoid arthritis, better clinical response to rituximab in NHL, and lower risk of periodontitis. We tested the hypothesis that FCGR3A polymorphism influences the development of GVHD and GVL, and TRM. The FCGR3A-158V/F genotype was determined in 49 recipient and donor pairs who underwent HLA-matched SCT in our institute. Subjects with the recipient FCGR3A-158V/V allotype and the donor FCGRA-158V/V allotype were almost one-third and twice as likely to develop chronic GVHD respectively (Table 1). The recipients with the FCGR3A-158V/V allotype had a 60% increase in probability of 3-year TRM. Multivariate analysis showed that the recipient FCGR3A-158V/V allotype and the donor FCGRA-158V/V allotype were independent risk factors for chronic GVHD (HR = 0.8 and 1.2, respectively), as well as the unrelated donor BMT (HR = 1.6) and the related donor PBSCT (HR = 2.4). The recipient FCGR3A-158V/V was an independent predictor for 3-year TRM (HR = 4.0) with the high risk disease (HR = 3.0) and the cord blood transplantation (HR = 5.0). We conclude that the recipient and donor FCGR3A polymorphism is associated with the development of chronic GVHD and TRM after HLA-matched SCT. These findings could therefore be useful in selecting the donor and creating therapeutic strategies for improving the final outcome of allogeneic SCT. Besides, these raise the question of whether the genetic risk factor in a recipient might also be involved in the mechanisms of chronic GVHD.
Table 1
FCGR3A allotype 2–4 acute GVHD(HR) Chronic GVHD (HR) 3 YR TRM (HR) *P&lt;0.05 Recipient FCGR3A-158V/V 46% (1.2) 17%* (0.8*) 72%* (4.0*) Recipient FCGR3A-158V/F or 158F/F 39% 57% 44% Donor FCGR3A-158V/V 46% (1.1) 67%* (1.2*) 43% (0.5) Donor FCGR3A-158V/F or 158F/F 38% 30% 50%
Anti Von Willebrand Factor Aptamer ARC 1779 for Refractory Thrombotic Thrombocytopenic Purpura.
Authors: Firbas Chri sta , Jilma Bernd , Wagner Patricia G , Hutabarat Renta , Schaub Robert G , Gilbert James C. , Knoebl Paul 
Published: April 2020

Abstract
Background: The investigational anti von Willebrand Factor (vWF) aptamer ARC1779 effectively inhibits vWF activity in blood samples of controls and of patients suffering from thrombotic thrombocytopenic purpura (TTP) (Jilma et al, Blood2007;110:279a, Gilbert et al. Circulation2007;116:2678–2686).
Methods: A 39 year old comatose male patient with acute (TTP) was treated with daily plasma exchange. Further, the patient received rituximab (375mg/m2 first treatment on day 8, and weekly thereafter for 8 weeks) and was splenectomized on day 18. Due to the refractory nature of his TTP, the patient received a concomitant intravenous infusion of ARC1779 at a rate of 2 μg/kg/min beginning on day 30.
Results: ARC1779 increased the platelet count slightly from 7 to a maximum of 30/nL; during this period septicaemia and DIC may have blunted the rise in platelet counts. However, platelet counts dropped to 5/nL by 16h after cessation of infusion (day 34). The infusion of ARC1779 was re-started on day 37, and platelet counts increased from 9 to 45/nL. (Figure) Due to a temporary lack of drug, the dose of ARC1779 was stopped at 78h, and platelet counts fell to 12/nL by 12 h after interruption of the infusion. (circle in the Figure) When ARC1779 was re-started, platelet counts increased to a maximum of 97/nL and the patient’s neurologic status improved to near normal under therapy with ARC1779 over the next week.
Conclusions: ARC1779 was well-tolerated, and caused a reproducible rise in platelet counts, which alleviated severe thrombocytopenia, in an otherwise refractory TTP case. This effect was reproducible under serial “re-challenge”. Together with the observed improvement in neurologic function, the data provide clinical proof-of-concept and suggest that ARC1779 treatment might improve the organ dysfunction which typically occurs in acute TTP. These data provide a rational basis for ongoing and planned phase II trials of ARC1779.
Figure Figure
Relative Impact of Psychosocial Factors, Comorbidities, and Disease Risk on the Utilization of Resources and Overall Outcome in Patients Undergoing Hematopoietic Stem Cell Transplantation
Authors: Speckhart Dawn S , Holland H. Kent , Solomon Scott R. , Morris Lawrence E. , Bashey Asad , Kerns Leslie , Berry Tina , Manion Karen 
Published: April 2020

Abstract
Several studies have begun to examine the relationship between psychosocial variables and outcome in hematopoietic stem cell transplantation (HSCT). Previous studies have also looked at the relationship between the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and overall survival in HSCT which demonstrated a negative relationship between HCT-CI and overall survival. In this study, data was collected on 128 patients undergoing HSCT. Based on the patient’s TERS score, each patient was stratified into one of two groups (low/moderate risk (n=96) vs. high risk (n=32)) based on their predicted psychosocial risk for problems during transplant. Patients were also stratified into two categories on the HCT-CI (low (n= 102) vs. high (n=26)) based on the number of comorbid features present pre-transplant. Patients were also grouped into disease risk categories as classified by the CIBMTR criteria. Only the TERS was found to be a significant predictor of utilization of resources (length of hospitalization) between low/moderate risk (26 days) versus high risk (40 days) patients (p&lt;.02). The HCT-CI (p=.014) and CIBMTR disease risk status (p=.02) were found to be significantly correlated with overall survival. Alone, the TERS showed a similar trend but did not appear to have a significant impact on overall survival. Those patients who scored lowest on all three measures (TERS, HCT-CI and CIBMTR disease risk) had the best overall survival rate, nearing 75% survival at 2 years post HSCT. One would conclude that although psychosocial factors impact the utilization of resources, well equipped transplant centers can provide a relatively safe method for high risk psychosocial patients to undergo HSCT. These results reinforce the impact of the HCT-CI and disease risk on transplant outcome previously found at other large transplant centers.
Acute Lymphoblastic Leukemia Blast Cells Stimulate the Autocrine Production of CCL2 and IL-8 in Bone Marrow Stromal Cells
Authors: de Vasconcellos Jaira Ferreira , Zanchin Nilson Ivo Tonin , Cardoso Angelo A. , Brandalise Silvia Regina , Yunes José Andrés 
Published: April 2020

Abstract
The interactions of Acute Lymphoblastic Leukemia (ALL) blasts with bone marrow (BM) stromal cells have a positive impact on leukemia cell survival and resistance to chemotherapy. ALL stimulates BM stromal cells, which reciprocally promotes leukemia cell survival. To identify molecules critically involved in leukemia–microenvironment crosstalk, we performed gene expression profiling analyses of primary BM endothelial cells (BMEC) and BM mesenchymal stem cells (BMMSC) following stimulation by primary ALL cells. Leukemia stimulation of BM stromal cells upregulates the expression of several inflammatory chemokines, including CCL2 and IL-8/CXCL8. Secretion of these molecules was confirmed by ELISA assays of in vitro co-culture experiments and in BM plasma samples from pediatric ALL patients. Most primary ALL samples were found to express mRNA for CCR2 and CXCR1/CXCR2, which are the cognate receptors for CCL2 and IL-8, respectively. Primary ALL cells expressing at least one myeloid marker (CD13, CD15 or CD33) exhibited increased mRNA expression of CCR2 (p = 0.02). Leukemia cells from most patients express CCL2 and IL-8 chemokines (ELISA test) but at lower levels than that of BMEC and BMMSC. In vitro functional studies revealed that the proliferation, survival and migration of primary ALL cells co-cultured with BM stromal cells were not affected by addition of CCL2, IL-8 or of neutralizing antibodies to these chemokines. On the other hand, both chemokines were found to enhance BMEC and BMMSC survival in serum-free medium and to increase their proliferation in serum-starved conditions. Interestingly, CCL2 and IL-8 affected endothelial morphogenesis as shown in Matrigel assays. Since CCL2 and IL-8 have suppressive effects in normal hematopoiesis but do not seem to affect primary ALL cells, it is possible that these chemokines may contribute to the establishment of survival/proliferative selective advantage for ALL cells in the leukemic BM microenvironment. In addition, CCL2 and IL-8 seems indirectly to contribute to ALL cell survival by stimulating the supporting BM stromal cells. Finally, preliminary results showed that standard risk pediatric ALL patients with BM plasma levels below 577pg/ml have better survival rates than those with higher CCL2 levels (p = 0.08). In conclusion, this work suggests a significant role for the chemokines CCL2 and IL-8 in the leukemia/microenvironment crosstalk in human ALL, and suggests that these molecules may represent valuable targets for therapeutic intervention in this cancer. Supported by: CNPq, FAPESP.
The Histone Acetyl-Transferase MOZ Cooperates with the Histone Methyl-Transferase MLL to Regulate HOX Gene Expression in Human Hematopoietic Stem Cells
Authors: Paggetti Jérôme , Aucagne Romain , Jacquel Arnaud , Largeot Anne , Lagrange Brice , Solary Eric , Bastie Jean-Noël , Delva Laurent 
Published: April 2020

Abstract
MOZ (MOnocytic leukaemia Zinc finger protein) (also called MYST3 or KAT6A) is a member of the MYST family of HATs which likely acetylate H4K16. The MLL (MixedLineageLeukemia) gene is a frequent target for recurrent chromosomal translocations found in AML and ALL. MLL (KMT2A) is a methyl-transferase targeting H3K4. It was shown that MOZ/CBP leukemia, as observed in MLL-rearranged leukemias, harbors abnormal levels of homeobox (HOX) genes expression. HOX transcription factors have a crucial function in hematopoiesis regulation. In addition, HOXA5, HOXA7, and HOXA9 are often considered to be pivotal HOX genes for MLL transformation, constituting downstream targets of MLL. In our study, we characterize an in vivo cooperation between MOZ and MLL. MOZ co-localizes and interacts with MLL in vivo. We also demonstrate that WDR5, an adaptor protein essential for trimethylation of H3K4, belonging to the MLL complex, co-localizes and interacts with MOZ. Moreover, by in vitro pull-down assays, we show that MOZ can interact with the lysine 4 of histone H3 methylated by MLL, as WDR5. Hence, MLL, WDR5 and MOZ cooperate together on the same targets corresponding to the trimethylated H3K4. MOZ may couple histone acetylation to histone methylation throughout its recruitment on lysine methylated by MLL. Furthermore, ChIP experiments in HSCs indicate that MLL and MOZ are both recruited to HOXA5, HOXA7, and HOXA9 genes promoters in correlation with the presence of H3K9K14ac, H4K16ac, H3K4me2 and H3K4me3, specific epigenetic marks of transcription activation. Remarkably, knockdown of MLL or MOZ inhibits MOZ or MLL recruitment and their specific epigenetic marks from HOX genes promoters, respectively. These alterations are associated with abnormalities in hematopoietic differentiation of HSCs. Our data suggest that the histone methyl-transferase MLL and the MYST family histone acetyl-transferase MOZ functionally cooperate to modulate HOX genes expression through specific epigenetic modifications in HSCs. In conclusion, we provide an example of a mechanism involving a direct cross-talk between two histone modifying enzymes, facilitating the rapid remodeling of chromatin in order to favor the commitment of human HSCs via HOX genes regulation.