bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of BCR-ABL Kinase Domain Mutations in Chronic Myeloid Leukemia Patients Treated with Tirosin-Kinase Inhibitors
Authors: Manrique Gonzalo , Bittencout Roberta , Pérez Verónica , Sholl Vanesa , Cappetta Monica , Zubillaga Noel , Hassan Rocio , Boschi Susana , Elizondo Victoria , Seuanez Hector , Zalcberg Ilana , Martinez Lem , Escuder M. Rosario Uri arte 
Published: April 2020

Abstract
Background. Point mutations in the kinase domain (KD) of the BCR-ABL are the most frequent mechanism of drug resistance in CML patients treated with kinase inhibitors (TKI). More than 80 mutations with different frequency and clinical significance have been reported. One of them, the T315I confers resistance to all TKIs available. The detection of mutations in KD allows early identification of high-risk patients and therefore guides clinical therapy decisions.
Aim. To assess the mutation status of a group of CML pts resistant to TKI from Uruguay (n=35) and Brazil (n=30).
Methods. KD mutation screening was performed by RT-PCR and direct sequencing according to Branford et al. (2002). Additionally, we developed a rapid, specific, sensitive and low cost allele specific (AS)-RT-PCR assay to identify T315I, using Branford’s KD amplification primers in combination with an allele specific primer for the T315I point mutation detection. BCR-ABL transcript levels were also measured by RQ-PCR according to international recommendations.
Results and Discussion. RT-PCR and direct sequencing analyses performed in all pts showed the presence of T315l mutation in 3/65 cases. Other 11 showed the alternative mutations Y253H (n=2), E450A, G250E (n=2), E459K (n=2), E450G, F317L (n=2) and E255K; and the remaining 55 showed no mutations in the ABL KD. All 65 samples together with cDNA from 15 non-resistant CML pts and 10 cDNA from non-CML were analyzed by AS-RT-PCR assay for T315l mutation in order to validate the method. T315l was identified in the 3 samples in which the mutation was previously detected by direct sequencing and in 1 pt that had been classified as KD mutation negative. This result was then confirmed by direct sequencing of the AS-PCR product. T315 was neither detected in samples positive for other mutations nor in samples of non-resistant CML and non-CML patients, supporting the specificity of the method. Assessment of the sensitivity of the AS-RT-PCR was performed on serial dilutions experiments using RNA from T315 positive pt into RNA from CML-T315l negative pt, showing that the T315I mutation was detectable to a level of 0.01 % by AS-PCR, while through direct sequencing method the sensitivity was 10–20%. The prevalence of mutations in our study was 15/65 (23%).
Conclusions. Our results showed that the AS-RT-PCR described here is a convenient and easy tool to be used in a clinical routine laboratory for rapid screening for BCR-ABL T315. This, together with direct sequencing, constitutes a suitable approach for CML resistance monitoring and therapeutic choice.
The Vast Majority of CML-CP Patients Treated with Dasatinib (70 mg BID) Who Progress after Long-Term Follow-up (24 mo) Remain in Chronic-Phase
Authors: Cortes Jorge , Mauro Michael , O’Brien Susan , Borthakur Gautam , Wierda William , Matloub Yousif , Sinha Ritwik , Liu David , Kantarjian Hagop 
Published: April 2020

Abstract
Patients with Chronic Myeloid Leukemia (CML) who develop resistance to imatinib have poor clinical outcomes. The disease stage at the time of imatinib failure is an important prognostic factor for this outcome. Specifically, although patients with advanced-stage CML, particularly those in blast-crisis at the time of imatinib failure, had a high rate of cytogenetic response to second-line tyrosine kinase inhibitors (TKIs), these responses were not durable in most instances. In contrast, patients who remained in chronic-phase (CML-CP) at the time of imatinib failure substantially benefited from second-line TKIs, achieving PFS and OS that appear favorable compared to historical data of patients treated with non-TKI therapeutic modalities. Because the prognosis for those in chronic-phase is significantly better than patients who have progressed to accelerated- or blast-phase, it is important to examine the clinical status of patients at the time of TKI failure. This study examined the clinical status of patients in the START-C trial (CA180-013) at the time of disease progression after imatinib and dasatinib therapy. Progression was defined as: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), increasing WBC count, development of accelerated- or blast- phase CML, or death due to any cause. Of 387 participants, 322 (83%) were progression-free at the 2-year follow-up. Of the 65 patients with any criteria for progression as defined above, 46 subjects had progressive disease (loss of MCyR = 14, loss of CHR = 14, increasing WBC counts = 8, development of accelerated-phase CML = 10). The remaining 19 patients died. Thus, only 10 out of 65 (15%) progression events were due to the development of advanced disease and 36 patients (55%) remained in chronic-phase despite a loss or lack of therapeutic response to imatinib and subsequent dasatinib. In summary, 2.6% (10/387) of all patients analyzed transitioned to accelerated-phase CML after first- and second-line therapy. Importantly, development of blast-crisis CML was also not observed in our study population. In a 5-year follow-up of the IRIS trial comparing imatinib to interferon as first-line therapy, a projected 17% of subjects relapsed and 7% developed advanced-phase disease after imatinib. Despite the fact that patients analyzed in our study sequentially failed both imatinib and dasatinib, most remained in chronic-phase after dasatinib failure and are expected to benefit from additional therapeutic options.
Vitamin B12 Deficiency in Patients with Chronic Myeloid Leukemia
Authors: Siddique Muhammad K , Sarwar Hafiz M. Y. 
Published: April 2020

Abstract
High vitamin B12 (cobalamin) levels have been documented in patients with untreated chronic myeloid leukemia. However, the literature about vitamin B12 deficiency in patients with chronic myeloid leukemia who are receiving imatinib is scarce. The objective of this study was to investigate the prevalence of vitamin B12 deficiency in patients with chronic myeloid leukemia. We retrospectively reviewed the medical records of 195 patients with chronic myeloid leukemia seen in the outpatient clinic of our institution between 2006 and 2007. The median age of patients was 35 (range 9 – 77); 118 (60%) patients were males and 77 (40%) were females. All patients included in the study were receiving imatinib. Macrocytic anemia at any given time during the course of treatment was documented in 61 (31%) out of 195 patients. Serum vitamin B12 and folate levels were measured in all patients with macrocytic anemia using chemiluminescent enzyme immunoassay. Among these 61 patients, 33 (54%) had low vitamin B12 levels (&lt; 200 pg/ml), 12 (20%) had indeterminate levels (200 – 300 pg/ml) and 16 (26%) patients had levels &gt; 300 pg/ml. Folate levels were within normal range (3 – 17 ng/ml) in all but two patients and both of these patients had folate levels &lt; 3 ng/ml and vitamin B12 levels &gt; 300 pg/ml. Among 195 study patients, 33 (17%) had macrocytic anemia with low vitamin B12 levels and 12 (6%) had macrocytic anemia with indeterminate vitamin B12 levels. We conclude that vitamin B12 deficiency is prevalent in our patients with chronic myeloid leukemia who are taking imatinib. This is of significance because our patient population is non-vegetarian. Serum vitamin B12 should be measured as a part of work up for anemia in patients with chronic myeloid leukemia. Correction of vitamin B12 deficiency in these patients could improve their tolerance to imatinib, which potentially is a myelosuppressive drug. In our study, measurements of serum methylmalonic acid (MMA) and homocysteine levels in patients with indeterminate vitamin B12 levels were not performed; although these measurements could have confirmed the diagnosis of vitamin B12 deficiency in this subgroup. We suggest that a similar study be conducted in a different patient population elsewhere.
Prognostic Factors in Chronic Myelomonocytic Leukemia: A Retrospective Analysis of 41 Patients
Authors: Chen Bobin , Xu Xiaoping , Ma Yan , Wang Xiaoqin , Lin Guowei 
Published: April 2020

Abstract
Purpose To investigate clinical characteristic and prognostic factors for chronic myelomonocytic leukemia (CMML).
Methods Retrospective cohort study was used in the study. Information for CMML patients was collected, including symptoms, CBC, results of bone marrow aspire and pathology, cytogenetic. All patients were followed up regularly. Analysis of survival and prognostic factors was performed by Kaplan-Merier cure, log rank test and Cox regression model.
Results Forty-one cases were diagnosed as CMML, including 27 male and 14 female patients. Median WBC was 13.7× 109/L. Five patients had leukocytopenia(1.92- 3.46×109/L). Median monocyte count in the peripheral blood was 2.13×109/L, but lower monocyte count (&lt;1×109/L) occurred in 8 patients. All patients presented with bone marrow dysplasia, and most showed hyperplasia, except 3 cases. Abnormal chromosome was detected in 34% cases. Median survival time was 20 months, and there were no difference of survival duration between CMML-1 and CMML-2. Univariate analysis showed that age (&gt; 60 yrs), neutrophil count (&lt;2.0′109/L), lymphocyte count (&lt;1.0′109/L), mature monocyte count (35′109/L) and anemia (Hb&lt; 60g/L) were associated with poor prognosis for CMML. There was no statistical significance in LDH, gender, abnormal chromosome for survival time. Only lymphocyte count and neutrophil count in peripheral blood were independent prognostic factor for CMML after Multivariate analysis.
Conclusion CMML mainly occur in elderly patients. Although most patients have leukocytosis and monocytosis at diagnosis, few case shows leucopenia and monocytopenia. Median survival time for CMML is 20 months. Age, neutrophil, lymphocyte and monocyte count, severe anemia are related to CMML prognosis. Neutropenia and lymphopenia in peripheral blood are independent prognostic factor for CMML.
09:00–09:05Escalated Dasatinib Dose up to 60 Mg O.D. in Elderly Patients with Chronic Myeloid Leukemia in Late Chronic Phase Resistant to or Intolerant of Imatinib-12 Months Follow-up
Authors: Iuliano Francesco , Russo Antonio , Caroleo Maria Cristina , Conforti Filomena , Serra Anna 
Published: April 2020

Abstract
Background: Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multitargeted kinase inhibitor of BCR-ABL, SRC, and other kinases that is approximately 300 times more potent than Imatinib in vitro. Dasatinib has been shown to be effective and safe in pts with CML resistant or intolerant to Imatinib, As might be expected, older patients experienced more adverse events, both hematologic and non-hematologic with the standard dosage of 100 mg once daily. Data regarding tolerability in elderly pts are scanty The aim of this study is to test if escalated dasatinib dose up to 60 mg once daily is as effective as standard dose of 100 mg QD with a better toxicity profile in elderly patients with chronic myeloid leukemia in late chronic phase resistant to or intolerant of Imatinib.
Patients and Methods: As of July 2007, 4 eligible patients have been enrolled and treated :4F ; median age 77 y [range 73–82]; 1 imatinib-resistant, 3 imatinib-intolerant). Dasatinib was given at 20 mg once daily (QD) starting dose with dose escalation to 40 mg QD or 60 mg QD in pts tolerant or lacking response. Complete blood counts were obtained weekly for the first 12 weeks; bone marrow cytology and cytogenetics every 1 months, and molecular monitoring of BCR-ABL transcript levels by real-time qPCR every 12 weeks. The primary endpoint was toxicity. Median time from diagnosis of CML was 62 months (range 36 – 88). Prior therapy included interferon-alpha in 1/4. 50 percent of pts had 400 mg of prior imatinib. 25% had 600 mg. 100 % of pts received imatinib for &gt;3 yrs. Best response to prior imatinib therapy was a CHR in 100, and partial (PCyR) cytogenetic responses in 75 % of pts. No BCR-ABL baseline mutations were found.
Results: The analyses with a median follow-up of 12 months (7–12) months show hematologic toxicity (grade 3 thrombocytopenia and leukopenia) at 60 mg OD in 2 out 4 pts. Dose interruptions occurred in 1/4 pts at 60 mg One pts was intolerant to dasatinib and switched to HU Patients received an average daily dose of 40 mg/day (range 20–60 mg). Non-hematologic toxicity consisted mainly of grade 1 diarrhea, headache 2 patients experienced grade II muscolo-skeletal toxicity and fatigue at 60 mg/day.) 100% pts had a CHR, and 50% a PCyR.
Conclusions: Dasatinib demonstrated substantial hematologic activity in elderly patients with late CP-CML. Despite the maximum dose reached was 60 mg QD only the 75% of pts were able to continued the treatment. because of toxicity. The novel TKIs therapies constitute an important therapeutic challenge in this particularly subset of patients when compared with younger patients
Hepatitis B Virus Reactivation and Severe Hepatitis during Chemotherapy with Fludarabine In a Patient with Leukemia
Authors: Türkkan Emine , Pekün Fügen , Atay Didem Y. 
Published: April 2020

Abstract
It is generally accepted that seroconversion of hepatitis B virus (HBV) surface antigen (HBsAg) to an antibody to HBsAg (HBsAb) indicates clearance of HBV. The reverse seroconversion to hepatitis B virus infection has been sporadically described in hematological patients receiving cytotoxic therapy and can be associated with the development of acute hepatitis. Here we report a 14-year-old male patient who developed HBV reactivation after intensive chemotherapy containing fludarabine for second bone marrow relaps of acute lymphoblastic leukemia. Fludarabine is a chemotherapatic agent that used for the treatment of relapsed acute leukemia in pediatric patients. He was HBsAg(−)/anti-HBs(+) and with normal ALT levels before intensive chemotherapy (fludarabine, dexamethasone, GCSF, alexan)for treatment of second bone marrow relaps. 6 weeks after completing two cyclus of chemotherapy with fludarabine, the patient developed transaminitis and evidence of active HBV infection (the patient had test results positive for HBsAg, negative for HBsAb, and positive for HBV DNA). the serum levels of aminotransferases were increased progressiveley. Lamivudine was administered immediately after confirming the HBV reactivation, which considerably improved jaundice, aminotransferase levels and serum HBV DNA titers after one month. The patient was able to resume the chemotherapy under continuis lamivudine treatment. This case indicates the need for physicians to be aware of fludarabine-related HBV reactivation, closely monitor and detect reactivation early, even in an HBsAg-negative patient.
Pre-Transplant Hyperferritinemia Is Associated with Low Incidence of Chronic Gvhd, High Relapse Rate and Impaired Survival in Patients with Hematological Malignancies after Allogeneic HSCT
Authors: Hagglund Hans Gustaf , Lorenz Fryderyk , Remberger Mats , Wahlin Bjorn , Wahlin Anders 
Published: April 2020

Abstract
Background: Iron overload is common after allogeneic hematopoietic stem cell transplantation and may cause liver damage. High pre-transplantation serum ferritin levels have been reported to be associated with impaired survival post transplantation in patients with acute myeloid leukemia or myelodysplastic syndrome.
Design and Methods: We performed a retrospective study of 309 adult patients with haematological malignancies who underwent allogeneic hematopoietic stem cell transplantation after myeloablative (51%) or non-myeloablative conditioning (49%). The aim was to determine the incidence of hyperferritinemia and iron overload and the effects of these conditions on graft versus host disease, relapse and survival in patients with blood disorders who receive allogeneic stem cell grafts.
Results: For overall survival and for relapse-free survival, only high pretransplantation ferritin (&gt;400ug/l) and advanced stage of disease were significant in multivariable analysis. High pretransplantation ferritin and advanced stage of disease were also significant for relapse risk at 3 years, but ferritin was not significant for non-relapse mortality. In multivariate analysis, ferritin, age, type of donor, and previous transplantation were significant factors for cGVHD at one year.
Conclusions: Hyperferritinemia was associated with lower risk of cGVHD and increased risk of relapse and death, but not with increased non-relapse mortality. The lower rate of cGVHD among patients with high ferritin levels can be explained by an immunosuppressive effect of ferritin, reducing graft versus host disease and graft versus leukaemia effect, resulting in increased risk of relapse and impaired chance of survival. Therefore, these conditions might be best explained by an immunosuppressive effect of ferritin and not by a direct toxic effect.
Neurological Complications Following Allogeneic Haematopoietic Stem Cell Transplantation
Authors: Tan Yamin , Huang He , Luo Yi , Shi Jimin , Cai Zhen , Lin Maofang 
Published: April 2020

Abstract
Allogeneic hematopoietic stem-cell transplantation (Allo-SCT) has become the standard of care for a number of malignant and non-malignant disorders. Neurological complications associated with these procedures remain frequent. These complications result from a variety of causes. Known risk factors include the underlying disorder, therapies used for immunosuppression, especially the use of cyclosporine A or FK506, and toxicities from radiation or chemotherapy, but other risk factors might also be of importance. We retrospectively analyzed neurological complications of 152 patients (range 10–49 years old) who underwent Allo-SCT in our transplantation center between August 2005 and July 2008. In all, there were 95 (62.5%) cases of unrelated donor transplantation, 54 (35.5%) cases of sibling donor transplantation, and 3 (2.0%) cases of haploidentical transplantation. Post-SCT neurological complications were seen in 16(10.5%) patients. They were seen in 4 cases after related donor SCT and in 12 cases after unrelated donor SCT. Neurological symptoms occurred between day −4 day and +512 day after transplantation. The complications included 4 cases with relapsed leukemia of central nervous system (2 in ALL, 1 in CML, 1 in AML), 3 cases with encephalorrhagia, 3 cases with epilepsy, 2 cases with demyelinating disease, 2 cases with encephalitis, 1 cases with multiple myositis,1 cases with peripheral neuritis. Seven cases died of neurological complication, including 4 with relapsed leukemia of central nervous system and 3 with encephalorrhagia. Other patients were cured. High dose gamma globulin conbined with Methylprednisolone were used in demyelinating disease. Antiepileptic agents were used in epilepsy. Cyanocobalamin was used in peripheral neuritis. In conclusion, neurological complications commonly occurred in Allo-SCT, and encephalorrhagia might be the main indication that needs intensive care. Moreover, central nervous system leukemia and demyelinating disease, multiple myositis should have clinical interests.
The Relationship of JAM2 Polymorphisms and Graft-Versus-Host-Disease (GVHD) after Allogeneic Stem Cell Transplantation
Authors: Park Eunkyung , Park Sung-Hyo , Lim Kyu-Hyoung , Song Ji Ae , Kim Inho , Yoon Sung-Soo , Park Seonyang 
Published: April 2020

Abstract
Introduction: The junctional adhesion molecule 2 (JAM2) gene plays a key role in tight junction formation in epithelial and endothelial cell. We studied JAM2 polymorphism in GVHD and non-GVHD patients after allogeneic stem cell transplantation.
Methods: We tested 3 sites of JAM2 gene - rs2276220 (G/A), rs963103 (T/C), rs974680 (G/A) - and studied the possible link between the JAM2 polymorphism and the risk of GVHD. We studied 251 patients who had treated with allogeneic stem cell transplantation. The three-SNP block study was performed with rs2276220-rs963103-rs974680 haplotypes. The JAM2 gene was screened for polymorphisms by SNaPShot method. We used SAS version 8.1 (SAS Institute Inc., Cary, NC, USA) for statistic analysis. The odds ratio and p-value was adjusted with multiple logistic regression analysis about age, gender, stem cell source, disease status at the time of transplantation, and conditioning regimen.
Results: The minor allele C of rs963103 (T/C) was dominant in patients with acute GVHD (Odds ratio (OR) 2.918, 95% confidence interval (CI) 1.178~7.233; p=0.0207). This phenomenon was distinct in gut GVHD (OR 1.684, 1.019~2.784; p=0.0419). The minor allele A of rs2276220 (G/A) was dominant in patients with infection after allogeneic stem cell transplantation (OR 6.058, 1.266~28.979; p=0.0241). The overall survival (OS) was associated with rs2276220 (hazard ratio (HR) 0.887, 95% CI 0.633~1.242; p=0.0346) and rs974680 (HR 0.969, 0.763~1.23; p=0.0193). The progression-free survival (PFS) was associated with rs2276220 (HR 0.761, 0.544~1.064; p=0.0095) and rs974680 (HR 0.551, 0.274~1.108; p=0.0382). In three-SNP block study which was performed with rs2276220- rs963103-rs974680 haplotypes, ATA (HR 0.844, 0.645~1.105; p=0.0016) and GTA (HR 5.568, 1.686~18.384; p=0.0048) was associated with OS. ATA (HR 0.796, 0.559~1.133; p=0.0039) and GTG (HR 1.339, 0.834~2.149; p=0.0353) was associated with PFS.
Conclusions: The JAM2 gene polymorphism rs963103 was associated with acute GVHD especially with gut GVHD after allogeneic stem cell transplantation; with higher risk in carriers of the C allele. The JAM2 gene polymorphism rs2276220 was associated with infection, OS, and PFS after allogeneic stem cell transplantation; with higher risk in carriers of the A allele.
Obesity Is Associated with An Increased Risk of Infectious Diseases after Unrelated Bone Marrow Transplantation
Authors: Fuji Shigeo , Kim Sung-Won , Yoshimura Ken-ichi , Akiyama Hideki , Okamoto Shin-ichiro , Sao Hiroshi , Takita Junko , Kobayashi Naoki , Mori Shin-ichiro 
Published: April 2020

Abstract
(Background) Both obesity and malnutrition have been considered to be risk factors for complications after bone marrow transplantation (BMT). To elucidate the impact of pre-transplant body mass index (BMI) on the clinical outcome, we performed a retrospective cohort study with registration data from the Japan Marrow Donor Program (JMDP).
(Results) From January 1998 to December 2005, 3935 patients received unrelated BMT through JMDP, and 3827 patients for whom pre-transplant height and weight data were available were included. Patients were stratified according to pre-transplant BMI values (low BMI: BMI&lt;18, n=295; normal BMI: 18≤BMI&lt;25, n=2906; overweight: 25≤BMI&lt;30, n=565; obese: 30≤BMI, n=61). In a univariate analysis, pre-transplant BMI was associated with a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD, P=0.03). Other factors which was associated with higher incidence of grade II-IV acute GVHD was HLA allele disparity, GVHD prophylaxis with CSP compared with TAC and donor age (≥40). Multivariate analysis showed that pre-transplant BMI tended to be associated with an increased risk of grade II-IV acute GVHD (P=0.07). Obesity was associated with an increased risk of infectious diseases compared with normal BMI [odds ratio (OR) 1.9; 95% confidence interval (CI) 1.1–3.2; P=0.02]. Progression-free survival was 54%, 52%, 56% and 47% in low BMI, normal BMI, overweight and obese, respectively in 1 year after BMT, and there was a trend that 1-year non-relapse mortality was higher in obese group (low BMI 29%, standard BMI 31%, overweight 32%, obesity 39%).
(Conclusions) This study shows the correlation between pre-transplant BMI and posttransplant complications. Although BMI strongly depends on multiple factors, the effect of obesity on clinical outcome, as suggested here, should be evaluated in a prospective study.