bluuebunny/crossref_metadata_2025 huggingface dataset:
Observational Study of Magnetic Resonance Imaging Monitoring in Patients with Aplastic Anemia (AA) and Low or Int-1 Risk of Myelodysplastic Syndromes(MDS) Complicated with Iron Overload
Authors: Du Yali , Han Bing , Long Zhangbiao , Chen Miao , Hou Bo , Feng Feng , Wang Zhao
Published: October 2019

Objective: To observe the clinical characters and magnetic resonance imaging (MRI) T2* change in patients with aplastic anemia (AA) and low or int-1 risk of myelodysplastic syndromes(MDS) complicated with iron overload.

Methods:This is a prospective study. Patients with AA and low and intermediate-1 risk factors of MDS complicated with iron overload were enrolled. Clinical parameters and T2* of liver, heart and pancreas were collected regularly.

Results: Of all the 92 recruited patients (54 males and 38 females), the median age was 47.5 (15~18) year-old, median disease duration was 26 (3~407) months. There were 54 AA patients and 38 MDS patients. SF was related to liver T2* and pancreatic T2*(AA group r=-0.476,-0.509, respectively, P<0.05; MDS group r=-0.401, -0.565, respectively, P<0.05) in both groups, but not related to cardiac T2* in either group. SF level was correlated with transfusion amount in AA patients (r=0.403, P<0.05), but not in MDS patients (r=0.234, P>0.05. Of the 20 patients who received iron-chelation therapy, 3 (15%) had diarrheas, 2 (10%) decreased in hemoglobin, 2 (10%) decreased in platelet, 2 (10%) had increased creatinine, 1 (5%) had allergic dermatitis, but the symptoms relieved after drug withdrawal. 2 patients died of bone marrow failure during the follow-up period. 38 patients finished the half-year evaluation. Those (18 cases) who chelated adequately had significant decrease in SF (3354.9±3287.3 vs 2119.3±1742.0 ng/ml, P=0.044). Meanwhile an increase in hemoglobin level (83.5±30.0 vs 96.7±31.6 g/L, P=0.01) was noticed in those with decreased SF. 26 patients finished one year follow-up, those (15 cases) who chelated adequately had significant decrease in SF (3583.9±3543.8 vs 1693.9±1532.5 ng/ml, P=0.006), increase in cardiac T2* (25.0±13.4 vs 32.3±15.7 ms, P=0.015) and left ventricular ejection fraction (LVEF) (63.6±8.6 vs 67.1±5.2 %, P=0.028) , whereas no such changes were found in those did not chelate adequately. No change was found either in chelated or non-chelated groups in hemoglobin, WBC count, platelet count, SGPT, TBil, creatinine level, liver or pancreas T2* value. For those with decreased SF, even without chelation, increase in hemoglobin level (91.1 ±29.9 vs 108.4±31.4 g/L, P=0.046),cardiac T2* (25.5±13.7 vs 33.1±15.9 ms, P=0.014)) and LVEF level (63.6±8.6 vs 67.2±5.4 %, P=0.027) were also documented.

Conclusion: SF was related to liver T2* and pancreatic T2* in both AA and MDS groups. SF was relevant to transfusion amount in patients with AA but not MDS. Adequate iron chelation can decrease the SF level, and might bring improvement in cardiac T2* and LVEF level. Decrease of SF even without chelation might also benefit patients.

Disclosures

No relevant conflicts of interest to declare.
Galectin-3 and Myocardial Fibrosis By Cardiac Magnetic Resonance in Thalassaemia Major
Authors: Ricchi Paolo , Meloni Antonella , Di Matola Tiziana , Spasiano Anna , Filosa Aldo , Costantini Silvia , Atripaldi Luigi , Esposito Salvatore , Cinque Patrizia , De Franceschi Lucia , Pepe Alessia
Published: October 2019

Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) technique is the only validated non-invasive approach used for detecting macroscopic myocardial fibrosis. Galectin-3 has been shown to participate in tissue fibrogenesis and was already associated with LGE-assessed myocardial replacement fibrosis in a cohort of patients with non-ischemic dilated cardiomyopathy (NICM).

Our aim was to investigate the relationships between galectin-3 circulating level and myocardial fibrosis in patients with thalassemia major (TM) who underwent CMR technique during the Myocardial Iron Overload in Thalassemia (MIOT) project.

All patients underwent also an extensive biohumoral characterization, including Troponin, NT Pro BnP, BNP, VES, PCR assay.

At UOSD Malattie rare del globule Rosso of Cardarelli hospital (Naples, Italia), between January 2015 and March 2016, all patients who underwent contrast-enhanced CMR were progressively enrolled to test Galectin-3.

Eighty-six patients were evaluated (males 43%; age 37, SD 8 years): six (7%) had diabetes mellitus (DM), 64 had anti-HCV antibodies and 28 (32%) were HCV RNA positive. Median galectin-3 value was 14.04ng/mL (5.26 ng/mL), and LGE was detected in 42 (49%) patients. Patients with LGE had higher galectin-3 than those without (14.48 ± 5.98, vs 13.63 ± 5.98), but without a statistically significant difference (p=0.109).

Galectin-3 was significantly associated with age (R=0.34; p=0.001), but not with sex.

Patients with DM, with anti-HCV antibodies and with HCV-RNA positivity, had significant higher level of Galectin 3 with respect to those without (22.5± 11.1 vs 13.4± 4, p=0.009; 14.9 ± 5.4 vs 11.5± 3.7, p=0.001; 16.2 ± 6.5 vs 13± 4.2, p=0.011, respectively).

No correlation was found between Galectin 3 and other tested biochemical variables and iron overload and cardiac parameters.

In conclusion, in our cohort of TM patients there was a great prevalence of myocardial fibrosis. In patients with myocardial fibrosis, the level of galectin-3 was higher and comparable to that found in a previous study performed in patients with NICM, but not significantly different with respect to those without fibrosis. The elevated prevalence of patients with previous exposure to HCV virus and/or DM and/or iron overload may significantly influence Galectin-3 level limiting the ability of the marker to identify patients without fibrosis.

Disclosures

De Franceschi: F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding. Pepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.
Association Between Cardiac Iron Clereance and Hepatic Siderosis
Authors: Pepe Alessia , Pistoia Laura , D'Ascola Domenico , Gamberini Maria Rita , Gagliardotto Francesco , Filosa Aldo , Cirotto Carla , Casini Tommaso , Maggio Aurelio , Riva Ada , Positano Vincenzo , Meloni Antonella
Published: October 2019

Introduction. The aim of this multicenter study was to evaluate in thalassemia major (TM) if the cardiac efficacy of the three iron chelators in monotherapy was influenced by hepatic iron levels over a follow up of 18 months.

Methods. Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we evaluated prospectively the 98 patients those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans and who showed evidence of significant cardiac iron (global heart T2*<20 ms) at the basal MRI. Iron overload (IO) was measured by T2* multiecho technique. We used cardiac R2* (equal to 1000/T2*) because cardiac R2* is linearly proportional to cardiac iron and hepatic T2* values were converted into liver iron concentration (LIC) values.

Results. We identified 3 groups of patients: 47 treated with deferasirox (DFX), 11 treated with deferiprone (DFP) and 40 treated with desferrioxamine (DFO).

Percentage changes in cardiac R2* values correlated with changes in LIC in both DFX (R=0.469; P=0.001) and DFP (R=0.775; P=0.007) groups. All patients in these 2 groups who lowered their LIC by more than 50% improved their cardiac iron (see Figure 1).

Percentage changes in cardiac R2* were linearly associated to the log of final LIC values in both DFX (R=0.437; P=0.002) and DFP groups (R=0.909; P<0.0001).

Percentage changes in cardiac R2* were not predicted by initial cardiac R2* and LIC values.

In each chelation group patients were divided in subgroups according to the severity of baseline hepatic iron overload (no, mild, moderate, and severe IO). The changes in cardiac R2* were comparable among subgroups (P=NS) (Figure 2).

Conclusion. In patients treated with DFX and DFP percentage changes in cardiac R2* over 18 months were associated with final LIC and percentage LIC changes.

In each chelation group percentage changes in cardiac R2* were no influenced by initial LIC or initial cardiac R2*.

Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures

Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..
Average Monthly Cost of Iron Chelator Treatment in Adult Patients with Sickle Cell Disease
Authors: Master Samip , Mansour Richard Preston
Published: October 2019

Introduction:

Iron overload in adult patients with sickle cell disease (SCD) can lead to variety of complications like liver dysfunction/cirrhosis, cardiac enlargement, diabetes mellitus, hypogonadism and arthropathy. These complication can be prevented by iron chelation therapy .We did retrospective analysis to find incidence of iron over load in this population and also did a survey to find the insurance status in this population.

Methods:

We take care of approximately 300 adult patients with SCD at out hematology clinic. We did retrospective analysis to investigate the prevalence of iron overload in this population. We also did survey on 100 adult patients with SCD to find out about the insurance converge for them. Web search was done to find out the average monthly cost of iron chelators.

Results:

On retrospective analysis of 458 adult patients with SCD, we found that 117/458(25.58%) had iron over load. Majority of them, 93/117 were SS type of SCD. Results of survey done on 100 adult patients with SCD showed that 61 had Medicaid, 2 were free care, 25 had Medicare and 12 had private insurance. The average monthly cost of Deferiprone is $ 18762, while that of Deferasirox is $ 13,082.

Conclusions:

Iron over load is a common complication affecting a quarter of the adult patients with SCD. The treatment of iron overload is expensive, as just the iron-chelator therapy costs approximately 160 to 220 K per year. In an attempt to minimize additional iron accumulation in our chronically transfused patient population we encourage the schedule of exchange of 1 unit phlebotomy and 1 unit of red cell infusion every two weeks.

Disclosures

No relevant conflicts of interest to declare.
Successful Management of a Left-Sided Endocarditis Patient Complicated with Hemophagocytic Lymphohistiocytosis---a Rare Case Report and Literature Review
Authors: Zhang Qiguo , Zeng Hui , Xu Peipei , Wang Jing , Yang Ronggong , Xu Jingyan , Zhou Rongfu , Ouyan Jian , Chen Bing
Published: October 2019

Objective: To increase the knowledge and experience of treating left-sided endocarditis patients complicated with hemophagocytic lymphohistiocytosis.

Method: One case with left-sided endocarditis and secondary hemophagocytic lymphohistiocytosis was reported and related PubMed literatures were reviewed.

Results: A 40-year-old Asian female came to hospital with uncontrolled repeated fever that had lasted for more than one month. Prior to this admission, the patient suffered a sub-acute liver failure of unknown cause and received artificial liver support and intravenous hepatic protectants in the local hospital, and the patient responded well. At that time echocardiography revealed congenital heart disease. After admission to our hospital, her lab results showed pancytopenia, coagulation abnormal and significantly elevated levels of total bilirubin, soluble CD25 and serum ferritin. Bone marrow biopsy was negative for hemaphagocytosis. The full body PET-CT was performed and the results demonstrated hepato-splenomegaly and relatively increased standard uptake value (SUV) of the spleen, with no signs of malignancies. Several sets of blood cultures were all positive for methicillin-resistant Staphylococcus epidermidis (MRSE). Two weeks later, cardiac ultrasound images were obtained and showed a completely well-shaped vegetation attached to the aorta valve, which confirmed the diagnosis of definite infectious endocarditis (IE). So the final diagnosis was the MRSE-related left-sited infectious endocarditis and acquired HLH. The Multi-disciplinary team (MDT) discussed this critical case, since the allergic reaction of vancomycin and no therapeutic effect of tecolplanin for 10 days, the patient was treated by high dose daptomycin(10 mg/kg once daily) and chemotherapy according to HLH-2004 protocol, afterwards the patient's condition was improved, cardiothoracic surgery was performed smoothly and the vegetation on the aortic valve was successfully removed. Till now the patient has been in good condition for more than 2 years. There are only 4 case reports pertinent to endocarditis with HLH published in PubMed and these related cases were also reviewed.

Conclusion: This case report is the description of another rare and complicated condition in which the patient concurrently developed left-sided infectious endocarditis and acquired HLH. High dose daptomycin monotherapy was effective for controlling MRSE-related left-sided IE. Early diagnosis and intervention is very important for the successful treatment of HLH. Our case also highlights the importance of the multi-disciplinary team (MDT) model in dealing with similar critical cases in the clinic work.

Disclosures

No relevant conflicts of interest to declare.
Rationale for Investigator-Assigned Prophylaxis Dosing Frequency in the Leopold I Study
Authors: Humphries Thomas J. , Church Nikki , Lalezari Shadan , Poulsen Lone H. , Yoon Mia , Maas Enriquez Monika
Published: October 2019

The LEOPOLD I study (part B) in severe hemophilia A was a multicenter, phase II/III, open-label trial to assess the safety, tolerability, and efficacy of prophylaxis treatment with BAY 81-8973, an unmodified recombinant factor VIII product. Dose and dose frequency of the prophylaxis regimen during the study were at the investigators' discretion. A questionnaire was sent to sites poststudy to determine what elements led to the assignment of patients to a twice-weekly regimen rather than 3 times weekly. Seventeen specific questions were posed, plus 1 labeled as "other," allowing the investigator to insert a rationale not otherwise specified.

Responses to the questionnaire were received for 13 of 17 patients (76%) assigned to twice-weekly prophylaxis. The 2 most frequent responses were "treatment options were discussed with the patients" (67%) and "patient preference" (61%). Additional responses in descending frequency included "prophylaxis regimen was adapted to the patient's physical activity and schedule" (28%) and "already on a twice-weekly regimen before the study," "sedentary lifestyle," "noncompliance with a 3-times-weekly regimen," and "other" (17% each). "Minimal arthropathy," "no target joints," and "patient's age" were included at 11% each.

These results demonstrate that discussions between patient and doctor are appropriately considered paramount to treatment decisions. The other elements mentioned are known parameters thought to contribute to bleeding phenotype in hemophilia.

Disclosures

Humphries: Bayer: Employment. Church:Bayer: Employment. Lalezari:Pfizer: Honoraria; Bayer: Honoraria; TEVA pharmaceuticals: Consultancy. Poulsen:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Investigator for Clinical Trials; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Investigator for Clinical Trials, Mentor, Speakers Bureau; SOBI: Speakers Bureau; Ferring: Speakers Bureau; Pfizer: Consultancy. Yoon:Bayer Inc: Employment. Maas Enriquez:Bayer Pharma AG: Employment.
Type 3 Von Willebrand Disease: A Case Report of a Rare Entity
Authors: Phillips Stephanie , Lazarchick John , Bergmann Shayla
Published: October 2019

Background:

Von Willebrand Factor (VWF) is essential for proper hemostasis. It serves as a carrier protein for factor VIII and also aids in platelet adherence to damaged endothelium. Von Willebrand Disease (VWD) may result from congenital absence of VWF, structural or functional abnormalities or mutations leading to mild decreases in expression of VWF. Type 3 VWD is an autosomal recessive disorder, which accounts for only 1% of patients with VWD and is characterized by a virtual absence of VWF and low levels of Factor VIII.

Objective:

To describe a case of Type 3 VWD including the presentation, diagnosis and clinical course.

Design/Method: Case Report.

A 4 month old female presented with a history of 8 hours of persistent bleeding from an injection site following vaccination administration. At that time, the patient's platelet count and PT/PTT were normal. She had a few intermittent episodes of persistent bleeding with minor abrasions and had labs repeated at the age of 4 months which were significant for a prolonged PTT of 59.5 seconds with normal PT and platelet count. Factor VIII level was <1% and VWF activity was <15%.

Results:

A complete Von Willebrand panel was sent to Mayo Medical Labs and showed a Factor VIII level of 2%, VWF antigen 6%, VWF activity of 8, and an absence of VWF multimers. Confirmatory VWF full gene sequence analysis testing was sent to Blood Center of Wisconsin and showed a heterozygous sequence variant, c.2435delC, in the VWF gene consistent with a diagnosis of VWD Type 3. VWF full gene sequence analysis was also sent on both parents. Mother's results showed that she is a carrier of the same VWF gene sequence variant. Father's results were negative. Given the patient only has a heterozygous sequence variant yet still has expression of VWD, gene duplication testing was sent to Blood Center of Wisconsin to look for possible duplication of this area. Results of this testing showed that the patient had two pathogenic variants, one on each allele: heterozygous c.243delC in exon 18 and a deletion involving exon 6 in the VWF gene.

Conclusion:

This case represents the clinical presentation and diagnosis of a patient with Type 3 VWD. While VWD is not uncommon, diagnosis of VWD Type 3 is quite rare. VWD Type 3 is inherited in an autosomal recessive fashion. In the case of our patient, only one parent was identified as a carrier of the same gene sequence mutation. Therefore, the second pathogenic variant resulting in VWD Type 3 was found to be a de novo deletion, further adding to the uniqueness of this case.

Disclosures

No relevant conflicts of interest to declare.
SIRT6 Inhibition As a Novel Approach for Treating Acute Myeloid Leukemia
Authors: Cea Michele , Cagnetta Antonia , Soncini Debora , Minetto Paola , Lovera Davide , Guolo Fabio , Colombo Nicoletta , Ballerini Filippo , Clavio Marino , Miglino Maurizio , Gobbi Marco , Lemoli Roberto M
Published: October 2019

Currently available therapeutics against Acute Myeloid Leukemia (AML) have improved patient outcome. However, resistance develops even to novel therapies and patient overall survival remains low, especially for patients who are not eligible for allogeneic bone marrow transplantation. Therefore, there is an urgent need to overcome the biologic mechanisms underlying drug resistance in AML, to enhance the efficacy of existing treatments and to facilitate the design of novel approaches. Recently, our group has demonstrated that SIRT6, a NAD+-dependent histone deacetylase involved in genome maintenance, is frequently up-regulated in Multiple Myeloma and its targeting induces cancer cell killing (Cea M. et al, Blood 2016). Furthermore, gene expression analyses performed by our groups show that SIRT6 is also up-regulated in AML and confers poor prognosis in a series of 200 primary AML cases from our Hematology Clinic. Thus, these data suggested a role for SIRT6 in AML biology. High SIRT6 expression was typically observed in AML cell lines characterized by constitutive DNA damage and intense replicative stress. Likewise, primary AML cases exhibiting an intermediate-to-high chromosome instability (CIN) gene expression signature were also those with the highest SIRT6 expression, and worst prognosis. Subsequent studies demonstrated that SIRT6 silencing or its chemical inhibition, as observed in Multiple Myeloma exacerbates DNA damage in response to genotoxic agents, sensitizing AML cells to cytarabine (ARA-C) and idarubicin in vitro. Overall, enhancing genotoxic stress while concomitantly blocking DNA double-strand breaks (DSBs) repair response, may represent an innovative strategy to increase chemosensitivity of AML cells. Mechanistic studies revealed that SIRT6 acts as a genome guardian in AML cells by binding DNA damage sites and activating DNA-PKcs and CtIP by deacetylation, which in turn promotes DNA repair. Overall our data suggest that genomic instability is present in all hematologic malignancies including AML. Strategies aimed to shift the balance towards high DNA damage and reduced DNA repair by SIRT6 inhibition can decrease AML growth and may benefit patients with otherwise unfavorable outcomes.

Disclosures

Gobbi: Gilead: Honoraria; Takeda: Consultancy; Janssen: Consultancy, Honoraria; Roche: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.
FOXC1 Expression in Acute Myeloid Leukemia: Potential Predictor of Disease Relapse and/or Refractory Disease
Authors: Swaminathan Mahesh , Jensen Tor W , Ray Tania , Andruska Neal D , Shah Anit , Egner James R. , Ray Partha S.
Published: October 2019

Background:

The mesenchymal transcription factor Forkhead Box C1 (FOXC1), derepressed in hematopoietic stem progenitor cells (HSPCs) in the setting of acute myeloid leukemia (AML), but not in normal HSPCs, was recently demonstrated to play an important role in AML disease onset and progression by blocking myeloid lineage differentiation and enhancing clonogenic potential. Herein we sought to further examine the prognostic value of FOXC1 in AML and whether FOXC1 expression is a potential predictor of disease relapse and/or lack of response to induction chemotherapy in AML.

Methods:

Expression of FOXC1 mRNA in mixed karyotype AML bone marrow samples was examined using publicly available microarray datasets (n=521, n=244). The clinical significance of FOXC1 gene expression as a prognostic biomarker was evaluated using censored overall survival (OS) and event-free survival (EFS) data. Degree of statistical significance in the univariate and multivariate analyses performed was assessed using log-rank test and Cox regression model, respectively.

Results:

FOXC1 mRNA expression was a significant predictor of OS on univariate (hazard ratio [HR] 1.592 95% confidence interval [CI] 1.263-2.007, P = 0.0001) and multivariate (HR 1.755 95% CI 1.355-2.273, P < 0.0001) analyses. This effect on OS could be attributed to disease relapse and/or lack of response to induction chemotherapy as FOXC1 mRNA expression also proved to be a significant predictor of EFS on univariate analysis (hazard ratio [HR] 1.539 95% confidence interval [CI] 1.208-1.961, P = 0.0002) and multivariate analysis (HR 1.678 95% CI 1.280-2.201, P = 0.0001), independent of age, FLT3 ITD status, NPM1 status or cytogenetic risk status. Compared to patients who experienced disease remission, FOXC1 expression was significantly elevated in patients experiencing disease relapse following induction chemotherapy (P<0.02), and in patients who were non-responders to induction chemotherapy (P<0.002)

Conclusions:

FOXC1 expression in AML is an independent prognostic predictor of decreased OS and EFS and is significantly associated with disease relapse and/or refractoriness to induction chemotherapy. A risk of relapse/non-response score that incorporates FOXC1 expression status may prove to be of value in identifying patients at the time of initial diagnosis who are likely to fail induction chemotherapy. Further studies are warranted to explore the prognostic and predictive utility of FOXC1 expression in the clinical management of AML.

Figure Figure.

Disclosures

Ray: Onconostic Technologies, Inc.: Employment. Shah:Onconostic Technologies, Inc.: Employment. Ray:Onconostic Technologies, Inc.: Consultancy, Equity Ownership; 3N Diagnostics Ltd.: Consultancy, Equity Ownership.
Massive Parallel Sequencing and Mutations Analysis of Mismatch Repair Genes in Recurrent Childhood Acute Lymphoblastic Leukemia Cases-Identification of Possible Molecular Signature of Poor Clinical Outcome
Authors: Kato Keisuke , Yoshimi Ai , Matsushima Satoru , Kobayashi Chie , Fukuda Kunio , Koike Kazutoshi , Tsuchida Masahiro
Published: October 2019

[Introduction] Mechanism of recurrence is fully characterized and is significant to improve prognosis in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and T lymphoblastic leukemia (T-ALL).. We have analyzed recurrent cases of childhood BCP-ALL and T-ALL. [Procedure] We analyzed clinical samples of 18 cases with BCP-ALL and 3 cases with T-ALL, who had been treated in our institution. We have investigated gene status of IKZF1, CRLF2, CDKN2A/2B, JAKs, IL7RA, and TP53 using RT-PCR and MLPA methods and IGH/TCR on genomic PCR. Whole exome analysis was done using Ion AmpliSeq Exome in seven cases. [Result] We analyzed clinical samples of 21 cases with ALL, who had been treated in our institution. The cases were 18 cases with BCP-ALL and 3 cases with T-ALL. We have investigated gene status of IKZF1, CRLF2, CDKN2A/2B,JAKs,IL7RA, NOTCH (for T-ALL), and TP53. Whole exome analysis was done in two cases, particularly for a case from which we have established cell line. < Result > Eight BCP-ALL cases with P2RY8-CRLF2 chimeric transcript: four cases of which had P2RY8-CRLF2 chimeric transcript only at initial diagnosis; two cases obtained transcript at recurrence. This was confirmed employing LD-PCR genomic analysis. Ten BCP-ALL cases had deletion of IKZF1; two showed deletion at relapse and a case demonstrated deletion at diagnosis only. Two BCP-ALL cases showed mutation of IL7RA. One of T-ALL cases from which we have established cell line showed mutation of MSH2 and more than 200 non-synonymous mutations on whole exome analysis. One T-ALL cases showed mutation of JAK3 at diagnosis. One BCP-ALL case had MLH1 mutation < Discussion > The present study has suggested acquisition of complex genetic change at different point of evolution may work in recurrence of ALL. The present study has indicated P2RY8-CRLF2 works not as simple growth advantage but rather as manifestation of genomic instability. This may be also illustrated by recurrent cases with T-ALL having mutation of MSH2 and BCP-ALL having mutation of MLH1.

Mutation of mismatch repair gene may be driver of gene mutation acquisition and consequently alterations of CREBBP and RAS or IKZF1, TP53, mismatch repair genes, or emergence of P2RY-CRLF2 chimeric transcript may be prognostically relevant in childhood acute lymphoblastic leukemia.

Disclosures

No relevant conflicts of interest to declare.
Biweekly Bendamustine Monotherapy for Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphoma and Mantle Cell Lymphoma: A Rabbit-14 Trial
Authors: Igarashi Tadahiko , Wakita Hisashi , Tsujimura Hideki , Aotsuka Nobuyuki , Masuda Shinichi , Utsu Yoshikazu , Murata Naoya , Irisawa Hiroyuki , Tsukasaki Kunihiro , Itoh Kuniaki
Published: October 2019

[Background]

Bendamustine has demonstrated high response rates in non-Hodgkin lymphomas (NHL). However, standard administration schedule frequently shows delayed hematological recovery resulting in the discontinuation of treatment. Here we designed a novel treatment schedule that could be more tolerable and conducted randomized phase II study (UMIN000008702).

[Methods]

Patients (pts) with relapsed/refractory(R/R) indolent B-cell NHL and mantle cell lymphoma were randomly assigned to standard arm (120mg/m2 on day1 and 2, every 3 weeks) or Benda-14 arm (120 mg/m2 on day1 and 15, every 4 weeks) of bendamustine monotherapy. Each arm was repeated to 6 cycles and the accomplishment rate (AR) of all scheduled treatment was analyzed as primary end point.

[Results]

A total of 46 pts were enrolled into the study. Baseline characteristics were: median age 64 years (range 46-78); 48% male; 76% follicular lymphoma; 33% ECOG PS ≥1; 50% having one previous regimen. 65% stage III/IV. 24% bone marrow positive. 33% with bulky mass (>6cm). Using random allocation, twenty two and 24 pts were assigned to standard and Benda-14 arm and the AR of 6 cycles in each arm was 41 and 38%, respectively. The median number of cycles was 4.5 in both arms. Eleven (50%) in standard and 10 (42%) in Benda-14 arm withdrew from protocol due to mainly prolonged hematological toxicities. Three withdrew due to disease progression. Two withdrew due to adverse events (AE). Grade 4 non-hematological AE was observed in one. Overall response rate (ORR) in the standard arm was 77% (95% confidence interval [CI], 59 to 95), including a 50% complete response (CR) compared with 83% (95% CI, 68-99), including a 46% CR in Benda-14 arm.　After a median follow-up time of 16 months, the median event-free survival (EFS) in the standard arm and Benda-14 arm was 14.6 months (95% CI, 8-26) and 15 months (95% CI, 11 - not reached), respectively. There was no significant difference between two arms in AR and in EFS (p=0.431). The overall survival (OS) in both arms was the same of 89% at 15 months.

[Conclusions]

Although this study did not confirm the superiority of Benda-14 to complete 6 cycles of treatment, Benda-14 arm appears to be equally tolerable and active as the present standard therapy. Benda-14 could be a study arm of next trial that determines better practical strategy for this disease population.

Disclosures

Igarashi: Zenyaku-Kogyo Inc.: Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.
Phase II Study of Epigenetic Therapy with Hydralazine and Valproate in Cutaneous T-Cell Lymphoma
Authors: Espinoza Ramiro , Aguilar Rodríguez Manuel , Zapata Nidia P. , Torres Jorge Carlos , Nolasco Diana Berenice , Alarcon Barrios Silvia Eugenia , Cervera Eduardo , Candelaria Myrna , Lozano Valentin , Sosa Alejandro , Espinoza Javier , Vieyra Magnolia , Gutierrez Jorge , Sosa Luis Mario , González Reynaldo , Oñate Luis , Labardini Juan
Published: October 2019

Objectives: To evaluate the therapeutic response to treatment with transcriptional therapy that combines hydralazine / valproate(Transkrip) in cancer patients with cutaneous T-cell lymphoma

Determine toxicity, duration of response and time to progression of epigenetic therapy with hydralazine / valproate in patients with T-cell lymphomas

Material and methods

an open-label, phase II, prospective and longitudinal in the National Cancer Institute of Mexico was carried out, recruiting patients diagnosed with Cutaneous T based on WHO classification 2008, newly diagnosed untreated, demographic data were analyzed and vital and somatometry signs, assessment of efficacy was established according to the therapeutic response in lymphomas measured at each visit at the affected sites for each patient, using the m-SWAT system sorted in complete response (CR), partial response (PR ), stable disease (SD) and progression (PE) and is considered response to patients with complete or partial response, these data were collected in the form of case report at baseline in the first consultation, during treatment and at the end the study at each visit to the doctor. Statistical analysis was performed with SPSS version 13.0 software.

results

16 patients were selected with diagnosis of cutaneous T-cell lymphoma, one patients discontinued the study at baseline and 4 patients had disease progression during the first months of the study, a total of 10 patients who completed 18 months of study continuing the compassionate use treatment.

The median age of patients was 45.8 years analyzed (18-83 years) of which 8 are women (53%) and 7 men (47%) with an ECOG 1 in 93.3% of patients, with an average weight of 72.5 ± 15.99 kg, height 1.6 ± 0.1 m, body mass index 28.3 ± 5.7 kg / m2, 46.7% of overweight patients, systolic blood pressure an average of 116.2 ± 14.3 mmHg and diastolic 75.1 ± 11.04 mmHg with respiratory rate 19.43 ± 1.74 resp / min and 77.8 ± 12.3 cardiac beats / min. Of the 10 patients who completed the study, 100% had complete or partial response itching to 6 month continuing unchanged at month 18, the dream as an adverse event occurred in 33% of patients, this being more frequent, adverse events attributed to the drug were known, expected and mild. From 6 months of treatment, the percentage of partial response and complete response of m-SWAT and pruritus were greater than 90% of patients.

conclusions:

Hydralazine/Valproate (Transkrip) is a medication that offers patients with cutaneous T-cell lymphoma, both first-line and refractory, a therapeutic alternative with high efficiency and good safety profile.

Disclosures

No relevant conflicts of interest to declare.
Dual SYK/JAK Inhibition Overcomes Ibrutinib Resistance in Chronic Lymphocytic Leukemia
Authors: Wang Yue Lynn , Lu Pin , Coffey Greg P , Pandey Anjali , Guo Ailin
Published: October 2019

Ibrutinib (a BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases. We demonstrated that cerdulatinib delivered potent tumor inhibition in 60 primary CLL patient samples, especially in those with poor prognostic indicators. Importantly, cerdulatinib, but not ibrutinib, is able to overcome the support of microenvironment and induces CLL cell death at clinically achievable concentrations. Further, cerdulatinib blocked proliferation of ibrutinib-sensitive and ibrutinib-resistant primary CLL cells and of BTKC481S-transfected cells. These anti-tumor effects are correlated with the inhibition of BCR and JAK-STAT signaling and downstream inhibition of the functions of AKT, ERK and NFκB. Collectively, our results show that simultaneous targeting of BCR and JAK-STAT pathways is a more effective strategy relative to single BTK inhibition.

Disclosures

Coffey: Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Pandey:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding.
Targeting ß-Catenin Signaling in DLBCL with ICG-001 and PAM-1 Suppresses Cell Proliferation and Induces Apoptosis
Authors: Fachel Angela A. , Muley Ashlesha Shrikant , Meydan Cem , Agirre Xabier , Cerchietti Leandro , Melnick Ari , Richards Kristy L.
Published: October 2019

Introduction: DLBCL is a fast-growing, aggressive form of NHL and ~30% of the patients are not cured with the current treatment regimens. Recently Wnt/ ß-catenin signaling has been identified as a new target pathway for lymphoma. To specifically target B-catenin we picked two drugs that act downstream of the Wnt/B-catenin pathway. ICG-001 inhibits TCF/β-catenin mediated transcription by competing specifically with β-catenin for CREB binding protein (CBP), but not for p300. PAM-1 is a p21-activated kinase 4 (PAK4) allosteric modulator acting as a nucleo-cytoplasmic shuttling protein. PAK4 interacts with and phosphorylates β-catenin on Ser675, promoting TCF/B-catenin transcriptional activity and stabilizing β-catenin through inhibition of its degradation. We conducted a pre-clinical study with ICG-001 and PAM-1 ß-catenin inhibitors on 16 ABC and GCB DLBCL cell lines and provided a molecular rationale for Wnt/ß-catenin directed therapy.

Material & Methods: RNAseq data from DLBCL cell lines, patient and normal B-cell samples were used to profile transcript abundance of the Wnt pathway in DLBCL. Western blotting was used to measure ß-catenin expression in 16 ABC and GCB DLBCL cell lines. Pharmacological inhibition of ß-catenin-signaling was tested using ICG-001 and PAM-1 compounds. A metabolically active cellular assay (CellTiter Glo) and flow cytometry with annexin V staining were used to determine cell viability and apoptosis. To address the specificity of the drug response, DLBCL cells were transduced with a ß-catenin/TCF pathway reporter, knocked down for ß-catenin, and canonical Wnt target expression was assessed using quantitative real-time (qRT-PCR) and Western blot.

Results: ß-catenin is expressed on all DLBCL cell lines at different levels that do not correlate with the ABC/GCB classification. The ß-catenin inhibitors ICG-001 and PAM-1 significantly reduced viability in all ABC and GCB DLBCL cell lines, regardless of DLBCL subtype. The EC50 after 48h of treatment ranged from 1.4 μM to 6.3 μM for ICG001 and from 80 nM to 870 nM for PAM-1. Both compounds suppressed cell proliferation, induced apoptosis, and reduced Wnt/ß-catenin transcriptional activity.

Conclusions: Our data indicate that targeting ß-catenin pathway with ICG-001 and PAM-1 could be therapeutically beneficial to DLBCL patients.

Disclosures

Melnick: Janssen: Research Funding.
Copy Number Variations in Cytochromes and Glutathione-Transferases As Early Predictors of the Efficacy of Tyrosine Kinase Inhibitors in CML
Authors: Lavrov Alexander V , Ustaeva Oksana A , Adilgereeva Elmira P , Smirnikhina Svetlana A , Chelysheva Ekaterina , Shukhov Oleg , Shatokhin Yuriy V , Mordanov Sergey V , Turkina Anna G , Kutsev Sergey
Published: October 2019

Chronic myeloid leukemia (CML) is characterized by the presence of the chimeric tyrosine kinase BCR-ABL in all leukemic cells. This non-specific enzyme promotes uncontrolled cell proliferation and genome instability. Tyrosine kinase inhibitors (TKI) help most of the people to achieve long standing remission, however up to 20% of patients develop slow response or even primary resistance to the therapy. In this work we focused on copy number variation (CNV) in glutathione transferases (GSTs) and cytochromes (CYPs) as possible predictors of the response rate to TKI. Thirty one CML patient with optimal response and 16 with therapy failure were enrolled in the study. Patient were grouped according to ELN2013 recommendations: BCR-ABL<1% and/or Ph+ 0% for optimal response and BCR-ABL>10% and/or Ph+ >35% at 6 months of TKI therapy for the failures. We found that these two groups of patients had differed frequencies of wild type and mutated genes: CYP1A2, CYP2A6, CYP2C19, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5, GSTM1, GSTP1, GSTT1 (p< 0.0013). Validation in the additional group of 15 CML patients showed that the test allows to predict failures and responders (p=0.02) with high accuracy: positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%.

Disclosures

Chelysheva: Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Shukhov:BMS: Honoraria; Novartis Pharma: Honoraria. Turkina:BMS: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria. Kutsev:Novartis: Speakers Bureau; Pfizer: Speakers Bureau.
Experience with Pegylated Interferon α-2a in 30 Patients Diagnosed with Hematologic Neoplasms
Authors: Bahcecioglu Adile Begum , Etgul Sezgin , Aslan Tuncay , Aydın Muruvvet Seda , Malkan Umit Yavuz , Okay Mufide , Ozdemir Evren , Ciftciler Rafiye , Goker Hakan , Buyukasik Yahya
Published: October 2019

Introduction:

Interferon (IFN-α) is frequently used in various hematologic neoplastic disorders either at failure of first-line treatment or as first-line therapy in selected patients. IFN-α has shown significant activity in treatment, but the therapy is handicapped by high dropout rates due to side effects and cumbersome dosing schedules. Pegylated (peg) IFN- α is formulated by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side chain of IFN- α. This modification prolongs serum half-life and patient exposure to medicine, decreases renal excretion, thus allowing for weekly administration, acceptable toxicity, tolerability and activity profiles.

The results of peg-IFN in polycythemia vera (PV) and essential thrombocythemia (ET) in phase 2 studies are encouraging, with molecular responses in some patients. There is at least one phase 3 study of hydroxyurea versus peg-IFN as first-line cytoreductive therapy for PV. In spite of ongoing international efforts to evaluate peg-IFN in PV, there is limited experience on peg-IFN use in other hematologic neoplasms.

Method: <>All patients who were put on peg-IFN in our center were found in our institutional electronic database. The patients had been recorded prospectively. All patients who had been treated with peg-IFN had been approved by national health authority and all patients had given informed written consent. Responses were evaluated by ELN (chronic myeloid leukemia), IWG-MRT (PV and ET), EUMNET (myelofibrosis), Nordic proposal criteria (hypereosinophilic syndrome), modified consensus criteria (systemic mastocytosis) (Am. J. Hematol 2009;84:790), Cheson criteria (lymphomatoid granulomatosis) and PET response criteria (Erdheim Chester disease) standardized criteria. Adverse effects were classified according to Common Terminology Criteria for Adverse Events (CTCAE4.0). Categorical and continuous data were expressed as ratio (%) and median (range). Statistical analyses were done by SPSS v17 (Chicago, IL).

Results:

There were 30 patients with 8 different hematologic neoplasms: 12 PV, 6 ET, 2 chronic myeloid leukemia (CML), 3 systemic mastocytosis (SM), 4 Erdheim-Chester disease (ECD), 1 primary myelofibrosis (PM), 1 hypereosinophilic syndrome (HES), and 1 lymphomatoid granulomatosis (LG). Detailed descriptive data, toxicity and treatment results are presented in table 1. Responses were observed in all disease categories. Toxicities were frequent in PV/Et, including significant autoimmune disorders (nephritic syndrome, autoimmune hepatitis)

Conclusion:

Peg-IFN is effective in many hematologic neoplastic disorders. Unfortunately, toxicity is a major concern in this treatment.

Disclosures

No relevant conflicts of interest to declare.
Extramedullary Hematopoiesis in Patients with Primary Myelofibrosis Rare and Serious Complications
Authors: Yassin Mohamed A. , Nashwan Abdulqadir , Mohamed Shehab
Published: October 2019

Extra Medullary Hematopoiesis 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, polycythemia vera ,myelodysplastic syndrome and myelofibrosis. To the best of our knowledge, there are very few documented case reports in the literature of patients with myelofibrosis who developed cord compressive symptoms due to EMH in the spine from 1958 till 2016 only 15 cases were reported, In reported cases male to female ratio 7:1 with age range between 30 and 75 year old Paraprasesis are the most common presenting symptoms Thoracic region is the most affected site The degree of anemia and bone marrow fibrosis does not correlate with the occurrence of EMH since it was reported in cases with early fibrosis or mild anemia. Correlation between molecular markers like JAK2 and CALR, MPL is not described

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 consensus for treatment and definition of CR, PR or No response in EMH with MF.

Disclosures

No relevant conflicts of interest to declare.
Not All Polyps Are Created Equal: Multiple Myeloma in the Gut
Authors: Akella Divya , Aparna Fnu , Pekez Marijeta , Nathan Nirmala S. , Ramberan Hemchand , Thakur Kshitij
Published: October 2019

Background: Multiple myeloma is a neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin usually restricted to the bone marrow. Recent literature confirms increased extramedullary involvement of skin, liver and lymph nodes but gastrointestinal multiple myelomas remain rare.

Case: We report a case of 57-year-old female with a past medical history of progressive multiple myeloma IgA lambda on elotuzumab, lenalidomide and dexamethasone therapy, who presented with generalized weakness and black stools for approximately one week. Initial laboratory work demonstrated a hemoglobin of 6.7 grams per deciliter and heme positive stools consistent with anemia secondary to presumed gastrointestinal blood losses. Esophagogastroduodenoscopy (EGD) was unremarkable. Colonoscopy revealed 6 colonic polyps scattered throughout the distal transverse, cecal and descending colon which were excised and sent for pathology. Pathology of the polyps showed plasma cell myeloma with anaplastic features. Immunohistochemistry demonstrated cells that were positive for CD-138 and negative for keratin staining, confirming plasma cell origin. Furthermore analysis was positive for lambda light chain, but negative for kappa light chain. The patient was managed with packed red cell transfusion with no further evidence of recurrent bleeding.

Conclusion: Gastrointestinal multiple myeloma are rare, but as our case demonstrates, they must be considered in the differential diagnosis of patients with gastrointestinal bleeding, particularly those with multiple myeloma. The endoscopic appearance of multiple myeloma polyps may be similar to other more common conditions, making pathological and immunohistochemical analysis of biopsies essential for making a correct diagnosis.

Disclosures

No relevant conflicts of interest to declare.