bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mixed Phenotype Blast Phase of Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitor Therapy
Authors: Gong Zimu , Bai Shi , Hu Shimin 
Published: October 2019

Abstract
Background
Chronic myeloid leukemia is a myeloproliferative neoplasm that is characterized by BCR-ABL1fusion gene and typically exhibits three distinct stages: chronic phase, accelerated phase and blast phase (BP). With tyrosine kinase inhibitors (TKIs) becoming standard front-line therapy, the progression of CML to BP has been dramatically decreased. In pre-TKI era, the blasts were of myeloid lineage in approximately 70% of patients with CML-BP, lymphoid lineage in approximately 30% of patients, and rarely, mixed phenotype. In the era of TKI era, cases of CML-BP with mixed phenotype are rarely reported to date.
Methods
Cases of CML diagnosed since year 1998 when TKI therapy was implemented in our institution to present were reviewed for blastic transformation. Clinical characteristics and laboratory data were collected. Lineage was assigned based on flow cytometry, cytochemistry or immunohistochemistry according to the 2008 WHO classification.
Results
A total of 430 patients were diagnosed with CML-BP: 278 (64.7%) had myeloid BP, 138 (32.1%) lymphoid BP, and 14 (3.3%) mixed phenotype BP (Table 1). Of these 14 cases of mixed phenotype BP, 10 were of B/myeloid and 4 T/myeloid. Molecular assay showed that 4 patients had p190 subtypeBCR-ABL1transcript and the remaining 10 patients had p210 subtype. There are 8 men and 6 women. The median age at diagnosis of CML-BP was 52 (range 23-70). Five patients presented with CML-BP initially, and the remaining 9 patients developed BP later during treatment with a median interval of 17.4 months from initial diagnosis of CML to blast transformation.
Twelve of the 14 patients received TKIs, 11 patients received multi-agent chemotherapy (including hyper-CVAD regimen), and 7 patients underwent allogeneic stem cell transplantation (allo-SCT). In 12 patients with known treatment response, 11 achieved complete cytogenetic response, and 7 achieved major molecular response. Of the 7 cases treated with allo-SCT, all achieved complete cytogenetic response, and 6 achieved major molecular response. Patients with mixed phenotype BP had a slightly better prognosis than patients with myeloid or lymphoid BP. The overall survival after blastic transformation was 17.8 months (range 0.7-73.2 months) in patients with mixed phenotype BP, comparing to 9.6 month in patients with myeloid BP and 15.9 months in patients with lymphoid BP. However, limited by the small sample size, no statistical significance was reached.
Conclusion
Blastic transformation of CML with mixed phenotype is rare. The prognosis of patients with mixed BP is poor. Aggressive chemotherapy in combination with TKIs might be effective, and allo-SCT may offer a chance of deep response and probably longer overall survival.

Disclosures
No relevant conflicts of interest to declare.
Nilotinib As Second or Third-Line Therapy for Myeloid Chronic Leukemia Chronic-Phase in Mexican Patients
Authors: Ayala Manuel , Domínguez Jacqueline , Chavez Antonieta 
Published: October 2019

Abstract
Background.- Nilotinib has 30-fold higher potency and increased selectivity against Bcr-Abl.Fast and deep responses can be achieved with nilotinib after failure to imatinib. In this study, we report the response rates and long-term results of using nilotinib after failure to imatinib or beyond. At the Specialty Hospital CMN "La Raza" nilotinibexperience launching this late 2006, has developed institutional experience.
Objective.- To evaluate the cytogenetic and molecular response to treatment with nilotinib in the second line treatment of patients with CML-CP and its correlation with early molecular-response.
Methods- During the experience with nilotinib as second-line therapy or beyond on CML-CP, 110 CML patients have been treated; established dose of nilotinib for all phase was 400 mg BID. Dose adjustments due toxicity were performed in accordance to previous publications, hematological and no hematological toxicity were scored in conformance to CTCAE v3. Patients were evaluated for hematologic, cytogenetic and molecular responses. Of all patients with CP-CML diagnosed treated with nilotinib, sixty-nine patients were included in the analysis, we selected those who had undergone a molecular evaluation at 3 months. In this study by BCR-ABL mutation status was analyzed. Twenty-seven percent (30 of 110) of the imatinib-resistant patients had BCR-ABL mutation(s) at baseline. One imatinib-resistant patients had the T315I mutation at baseline. The data from 69 patients with CP-CML were analyzed. Distribution of Sokal risk groups were as follows low-16/intermediate-14/high-57/NA-13%.
Results.- Overall, 57 of the 69 patients (83%) of them had a transcript of ≤ 10% at 3 months. Forty-five out of 69 patients (65%) with transcript of ≤10% at 3 months achieved MMR at 12 months, while only 2 of 12 patients (17%) with ratio >10% had MMR, and 83% did not reach the MMR. The EFS by level of transcripts ≤10% at 3 months in 57 patients with 2 events was 96% while in >10% in 12 patients with 4 events was 67%, with an average estimate of time of EFS of 62 vs 43 months respectively. The EFS by MMR at 12 months in 32 patients without events was 100%, while without MMR in 37 patients with 6 events was 84% P=0.022. Nilotinib induced complete cytogenetic responses in 60 percent and 48% molecular responses in the 110 patients treated, 58% of which were major molecular responses, and deep molecular response 42%. To date, 96 of the treated patients remain alive (87%) and continue on treatment.
Conclusions.- Nilotinib (Tasigna) is efficacy and well-tolerated treatment for patients with CML as second-line or beyond in our patients, The 48-month follow-up results show that nilotinib therapy continued to be effective, is comparable to diverse results of other international reports in developed countries.

Disclosures
No relevant conflicts of interest to declare.
Managing BCR-ABL 1 Negative Myeloproliferative Neoplasms in an Emerging Economic Environment
Authors: Benneh Amma A. , Asare Eugenia Vicky Naa Kwarley , Olayemi Edeghonghon 
Published: October 2019

Abstract
Background:
Myeloproliferative neoplasms (MPN) are a group of diseases characterized by clonal disorders of the pluripotent stem cell. The annual incidence of all subtypes of MPN is 6-10/100,000 population. MPN without Philadelphia chromosome or BCR-ABL1 fusion gene such as Polycythaemia Vera(PV), Essential Thrombocythaemia (ET) and Myelofibrosis (MF) are known as BCR-ABL1 negative MPN. Diagnosis and management of these conditions in a limited resource environment can be challenging. Some successes have however been chalked when diagnostic and therapeutic difficulties have been overcome.
Methodology: A retrospective patient chart review of patients who attended Hematology clinic at the Department of Hematology, Korle-Bu Teaching Hospital was conducted between January 2005 and December 2015.This review included all adult patients diagnosed with PV, ET and MF over the period. Diagnosis of MPN was made mainly by film comment, bone marrow aspirate, trephine biopsy and JAK 2 mutation analysis if patient could afford. Patients records were analyzed for demographic characteristics, clinical signs, hematological parameters, treatment options and outcomes.
Results:
The annual incidence of MPN over the period under study was 2.4 per year. The median age was 46 (range 24 - 75) years. There was male predominance of 1.9: 1. Splenomegaly was the commonest organomegaly seen. Polycythaemia Vera was the commonest (10; 38.5%) BCR-ABL1 negative MPN to be diagnosed at the hospital within the period. Treatment options available for patients with PV was venesection and hydroxycarbamide. For ET and MF it was hydroxycarbamide and supportive treatment. The longest survivor within the period of study has lived with Polycythaemia Vera for the past 10 years.
Conclusion:
The diagnosis and management of BCR-ABL1 negative MPN in emerging economic environments can be challenging as resources are limited. Certain conditions such as Hyperreactive malarial splenomegaly (HMS) can also mimic MPN and as such a high index of suspicion coupled with appropriate diagnostic facilities are required for early diagnosis and prompt management. Despite these odds, the disease is controlled reasonably well in our environment giving the patients more years of quality life than they would have had without any intervention.

Disclosures
Asare: Intramural University of Ghana Research fund: Research Funding; Vanderbilt University Medical Center Gift Funds: Research Funding. Olayemi:Intramural University of Ghana Research fund: Research Funding; Vanderbilt University Medical Center Gift Funds: Research Funding.
Extra Medullary Hematopoiesis in Patients with Polycythemia Vera Rare and Unusual Presentations
Authors: Yassin Mohamed A. , Mohamed Shehab , Nashwan Abdulqadir 
Published: October 2019

Abstract
Extramedullary Hematopoisis refers to the presence of hemopoietic elements in locations other than the bone marrow medullary space, it may be seen in many conditions, including chronic hemolytic anemias like thalassemia Intermedia or major. The common sites of involvement are the liver, spleen and the lymph nodes. Less common sites include the central nervous system, adrenal gland, kidney, perirenal soft tissues, breast, peritoneum and gastrointestinal tract the paraspinal region is a relatively uncommon location for these hemopoietic deposits. There are a few case reports of EMH occurring in the spineMost cases have been reported in connection with thalassemia, although it has also been described in patients with sickle cell anemia,myelodysplastic syndrome and myelofibrosis. To the best of our knowledge, there are very few documented case reports in the literature of patients with polycythemia vera and Extra medullary Hemayopoiesis.The reported cases are limited in this regard only 11 cases were reported from 1979 till 2015, Paraprasesis is the most common presenting symptom, Age between 30 to 75 year with Male to female 6:1,Thoracic region is most affected site Most cases treated by surgery ,radiotherapy or both Poorer outcome compared to MF cases
Overall the mortality in EMH with polycythemia vera is higher than MF and thalassemia, some of them due to fatal location of cord compression (cervical)
No definite guidelines have as yet been formulated for the treatment of such patients with EMH. Excision and decompression, radiotherapy, hypertransfusion and hydroxyurea alone or in combination have been proposed as well as lack of consensus about what is complete remission is it clinical or clinical and radiological and what is partial response is it any reduction of the mass lesion or any degree of clinical improvement in conclusion there is necessity to establish consus for treatment and definition of CR ,PR or No response in EMH with polycythemia vera.

Disclosures
No relevant conflicts of interest to declare.
Application of Next Generation Sequencing for Prognostic Stratification in Myelodysplastic Syndromes
Authors: Xu Yuanyuan , Li Yan , Hou Guangyuan , Chen Chongjian , Yu Li 
Published: October 2019

Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by a deregulation of blood cell formation with cytopenia in varying degrees and frequently develop into acute myeloid leukemia (AML). Next generation sequencing (NGS) has significantly contributed to diagnosis and prognostication in patients with MDS. To explore the role of acquired mutations in MDS biology and clinical features, we performed mutational profiling of 111 genes in 125 patients with MDS based on target-sequencing. The results showed that 89% of patients had one or more carcinogenic mutations. Mutation frequencies of several genes, including ASXL1 (16.8%), RUNX1 (14.4%) and TET2 (12%), were above 10% in MDS patients. According to univariate analysis in 108 patients with survival data, mutations of GATA1/2, TP53 and DNMT3A were identified as adverse prognostic factors for overall survival (OS), while RUNX1, KRAS/NRAS, SRSF2 and TET2 mutations were determined as unfavorable factors for progression free survival (PFS). By multivariate COX regression analysis, mutations of KRAS/NRAS, GATA1/2 and DNMT3A were independent risk factors for OS, whereas IDH1/2 gene mutations were favorable factors for PFS. By evaluation of the clinical benefit of hypomethylating agents (HMAs), it showed that for patients harboring mutations associated DNA methylation or not and receiving HMAs treatment or not, the order of the outcome from good to bad was geneWT with non-HMAs, geneWT with HMAs, genemutwith HMAs and genemutwith non-HMAs. Therefore, target-sequencing of mutational spectrum is a feasible and highly promising prediction method for prognostic evaluation in patients with MDS, which would contribute to personalized therapeutic decisions.

Disclosures
No relevant conflicts of interest to declare.
Sustained Remissions after Discontinuation of Ibrutinib in Relapsed/Refractory CLL: A Basis for Reducing Drug Toxicity and Treatment Costs?
Authors: Houranieh Jenna , Fleischman Roger A 
Published: October 2019

Abstract
In contrast to traditional chemotherapy, patients responding to biological or targeted therapies often are treated indefinitely until progression or toxicity. This therapeutic model, however, increases treatment costs, may induce greater toxicity and theoretically could select for earlier emergence of drug resistance. Moreover, little data is available regarding the outcomes of patients who discontinue targeted therapies after achieving remission. In this regard, we report two patients with relapsed/refractory CLL who chose to stop therapy unrelated to toxicity or disease status after the induction of remission by the BTK inhibitor ibrutinib. Patient A started ibrutinib for progressive CLL at an absolute lymphocyte count (ALC) of 137,000mm3 and recurrent hemolytic anemia. After 5 months, the hemolysis had resolved (Hgb 15.6 g/dl) while the ALC had declined to 9200mm3. Treatment was then interrupted due to patient preference. One month after drug discontinuation, the ALC was in the normal range at 1400mm3 and remained within or near the normal range for a total of 12 months. Two months later, the ALC was again markedly elevated at 68,000mm3and anemia recurred. The patient then agreed to restart ibrutinib. Thus far, after 5 months of re-treatment, he has had prompt resolution of the anemia and achieved a partial remission with a slowly decreasing lymphocytosis. Patient B was started on ibrutinib for a rising ALC (26,000mm3) and severe hemolytic anemia. After 9 months of treatment, the hemoglobin was 13 g/dl and the ALC was in the normal range at 3300mm3. Due to unrelated medical problems, ibrutinib therapy was stopped. Currently, 6 months since drug discontinuation, the ALC remains in the normal range and no other signs of CLL are present. These clinical observations suggest that interruption of ibrutinib may be feasible in at least some CLL patients who achieve remission. Even if flow cytometry were performed at monthly intervals to detect early recurrence and ensure prompt re-institution of therapy, the cost savings would still be considerable. Of course, clinical trials will be necessary to confirm equivalent long-term efficacy and overall survival for intermittent versus continuous ibrutinib therapy in CLL.

Disclosures
No relevant conflicts of interest to declare.
12-Month Full Donor Chimerism Is Associated with Low-Grade Acute Graft Versus Host Disease (aGVHD) and Predicts Superior Outcomes in Reduced Intensity (RIC) Alemtuzumab-Based Transplants for MDS and AML
Authors: Kanellopoulos Alex George , Paneesha Shankaranarayana , Xenou Evgenia , Qureshi Iman , Eden Dewi Tomos , Sutton David John , Pryor Rebecca , Cain Lorna , Arbuthnot Carolina , Lovell Richard , Borg Anton , Randall Katie , Holder Kathy , Suhr Julie , Baker Lynda , Ryan Lynn , Kaparou Maria , Kishore Bhuvan , Nikolousis Emmanouil 
Published: October 2019

Abstract
Introduction
Reduced intensity (RIC) Alemtuzumab conditioned allogeneic stem cell transplants have enabled a successful graft versus leukaemia effect while GvHD rates were low. The impact of chimerism on outcome has scarcely been studied in RIC, Alemtuzumab-based transplants.
Patient characteristics
Retrospective analysis of 50 patients with high risk MDS (n=14) and AML (n=36) undergoing RIC-Alemtuzumab transplant in our center since 2006. Median age was 62 years (range 51-72) and there were 33 male and 17 female recipients. All donors were fully (10/10) matched in HLA-loci. 11 patients had a sibling donor while 39 had a matched unrelated donor. 29 patients were conditioned with fludarabine, melphalan and alemtuzumab while 21 patients received fludarabine, busulphan and alemtuzumab.
Results
The median follow-up of patients was 18.2 months (range 15-90). Median overall survival was 27.4 months and median progression free survival 33 months. At 3 months post-HSCT 72% (n=36) and 18% (n=9) of patients were full and mixed chimeras respectively. At 12 months post-HSCT n=19 and n=10 of patients were full and mixed donor respectively. 14 patients (28%) developed grade 1-2 GvHD while only 1 (2%) grade 3-4 GvHD. Patients who attained 12-month full donor chimerism in whole blood (WB), had a mean PFS of 85 months as compared to 81.5 months for mixed chimeras (p= 0.04). In 3-months, those who were full donor in WB had a mean PFS 95 months compared to 33 for mixed chimeras in WB (p= 0.016). 3, 12 -month T-cell chimerism did not influence OS and PFS. The presence of grade I-II GVHD was significantly associated with 12-month full donor chimerism in both WB and T-cells (p<0.05).
Conclusion
In our series of AML/MDS patients who received RIC Campath-based allografts, full donor chimerism is a surrogate marker for progression free and overall survival. All grade I/II aGVHD patients achieved full donor chimerism in whole blood.

Disclosures
Paneesha: Abvie: Honoraria. Kishore:celgene: Other: travel grant.
Haploidentical Stem Cell Transplantation for Rare Pediatric Diseases at Peking University People's Hospital
Authors: Chen Yao , Chen Huan , Xu Lan-Ping , Chen Yu-Hong , Wang Jing-Zhi , Wang Feng-Rong , Zhang Xiao-Hui , Liu Kai-Yan , Huang Xiao-Jun 
Published: October 2019

Abstract
Background:Rare diseases requiring hematopoietic stem cell transplantation (SCT) present a challenge for BMT centers. The patients present at a low frequency, and there are often no established conditioning regimens for these disorders, especially for children without HLA matched sibling donors. We report the conditioning regimen using haploidentical related donors, and outcomes for the following rare disorders transplanted at our center from January 2013 through December 2015. During the past three years we had patients presented with the following: Fanconi anemia (FA), dyskeratosis congenital (DC), adrenal leukodystrophy (ALD) and Wiskott-Aldrich syndrome (WAS).
Methods:We treated these children with rare disorders that required SCT at our center, and are reporting the transplant outcomes for these rare diseases.
Results: All children were transplanted with haploidentical related donors using G-CSF mobilized bone marrow and peripheral blood stem cell. Conditioning regimens and treatment plans were mainly following Beijing protocol and varied with type of disease. Patient characteristics and outcomes are presented in Table 1. No graft failure occurred and three of 5 patients (60%) are alive and well with no evidence of disease.
Conclusions: Our program has treated a variety of rare disorders with an event-free-survival rate of 60%. Our data suggests haploidentical SCT for rare pediatric diseases seems to be challenging and promising.

Disclosures
No relevant conflicts of interest to declare.
Potent Anti-Platelet Metabolite, 12-HETrE, Inhibits Platelet Activation and Thrombosis In Vivo Via Activation of the IP Receptor
Authors: Tourdot Benjamin , Isingizwe Zitha , Yeung Jennifer , Adili Reheman , Holinstat Michael 
Published: October 2019

Abstract
Platelet activation is a critical component of clot formation. Under pathophysiological conditions platelet-mediated clot formation can lead to an occlusive thrombotic event resulting in myocardial infarction and stroke. Regulation of platelet reactivity relies on an understanding of the complex intra-platelet signaling that takes place following activation of various receptors on the platelet surface. Our lab recently identified a novel oxidized metabolite known as 12-HETrE that is formed from 12-lipoxygenase (12-LOX) oxidation of the ω-6 fatty acid DGLA in the platelet. Since DGLA constitutes one of the predominant fatty acids contained in the phospholipids on the platelet membrane and is also a rich source of dietary fatty acid intake through a variety of plant oils, we had originally sought to determine if this metabolite contained inherent regulatory properties on the human platelet. We successfully showed not only that 12-HETrE potently regulates hemostasis and thrombosis in vivo, but additionally identified that the metabolite signals inhibition of platelet activity through a GαS-linked GPCR resulting in formation of cAMP and activation of PKA and VASP. In the current study, we identified for the first time the receptor activated by 12-HETrE in the human platelet. To identify which GPCR is activated by 12-HETrE, we utilized both pharmacologic as well as genetic approaches. Our ex vivo pharmacological data suggested 12-HETrE predominantly signals through the IP receptor in the human platelet. This finding was confirmed using an IP receptor knockout mouse as well as human cell lines expressing or absent IP receptor on their surface. Finally, these findings were confirmed in vivo with wild type or IP knockout mice and assessing the ability of 12-HETrE to inhibit laser-induced thrombosis. Hence, these findings show for the first time that 12-HETrE does in fact regulate inhibition of platelets through the IP receptor. Since 12-HETrE has already been shown to inhibit thrombosis without a significant increase in bleeding diathesis, the current study has elucidated a new target for IP receptor activation and an inhibition of platelet activity and occlusive thrombus formation and should be evaluated for its potential as a new class of anti-thrombotic therapeutics.

Disclosures
No relevant conflicts of interest to declare.