bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Factors Associated To Achievement Of Complete Or Partial Response In MDS Patients Treated With Azacitidine Outside Clinical Trials
Authors: Breccia Massimo , Voso Maria Teresa , Maurillo Luca , Niscola Pasquale , Autore Francesco , Aloe Spiriti Maria Antonietta , Buccisano Francesco , Tatarelli Caterina , Tendas Andrea , Fenu Susanna , Latagliata Roberto , Alimena Giuliana 
Published: October 2019

Abstract
Azacitidine is able to induce responses and to prolong survival (OS) in intermediate/high risk MDS subgroups or in CMML: in the AZA001 trial, median OS was significantly longer for azacitidine patients compared with the combined conventional care regimen (CCR) group. We retrospectively assessed prognostic factors associated to the achievement of these responses in a large series of MDS patients treated outside clinical trials. Overall, we recruited for this study, 166 primary or secondary MDS and 21 CMML diagnosed and treated with azacitidine in 6 different hematologic units. Patients were recruited consecutively, without any criteria of exclusion. All patients received azacitidine with a schedule of 5+2+2 or of 7 consecutive days every 28 days until progression or unacceptable toxicity. Clinical parameters (age, sex, WHO classification, IPSS) and baseline cytogenetic evaluation were retrospectively collected. Of 166 MDS patients recruited, 103 were males and 63 females; median age was 69.5 years (range 49-89). A median of 8 cycles was performed (range 1-60). According to IPSS stratification there were 29 intermediate-1 risk patients, 118 intermediate-2 patients and 15 high–risk patients (7 patients not determined). According to WHO classification, 37 patients were diagnosed as having RAEB-1, 101 patients as RAEB-2, 28 patients as RCMD. Of 21 CMML patients recruited, 19 were males and 2 females; median age was 67.5 years (range 62-89). According to WHO classification, 14 patients were CMML-2. Overall, 41 patients (22%) achieved a CR/PR according to IWG 2009 criteria. Analysis of factors associated to the achievement of best responses revealed that pre-azacitidine WBC higher than 5 x 109/l (p=0.02) neutrophil count higher than 0.5 x 109/l (p=0.03) and platelet count higher than 150 x 109/l (p=0.01) were significantly associated to CR/PR achievement. We did not reveal significant differences, when compared to patients that did not achieve a response, in terms of sex, age, hemoglobin level at baseline, bone marrow blast count, cytogenetic profile, IPSS stratification. In conclusions, from our results, based on a large series of patients treated outside clinical trials, it seems that, independently from cytogenetic or hematological subtype, only clinical parameters at baseline could influence the achievement of a good response with azacitidine.

Disclosures:
No relevant conflicts of interest to declare.
Long-Term Outcome Of Higher-Risk MDS Patients Treated With Azacitidine: Single Centre Experience
Authors: Ricco Alessandra , Sgherza Nicola , Rossi Antonella Russo , Carluccio Paola , Franco Adele , Pasciolla Crescenza , Casieri Paola , Specchia Giorgina 
Published: October 2019

Abstract

Background
The primary goals of treatment for patients with higher-risk MDS are to improve bone marrow function, suppress AML transformation and prolong survival. The international phase 3 trial, AZA-001, established that azacitidine (AZA) significantly prolonged median overall survival and significantly delayed median time to AML transformation as compared with conventional care regimens. AZA was also associated with significant improvements in other clinically relevant outcomes, including reducing the need for transfusion, hospitalization and intravenous antimicrobials, and improving quality of life. Although several clinical trials have examined the safety of AZA, limited data are available about the long-term use of this drug.

Aims
We report a retrospective analysis of the outcome of 16 higher-risk MDS patients (M/F: 7/9) treated at our Institution with AZA, from June 2008 to June 2013, with a median follow-up of 33.5 months (range 24-60) after the start of AZA to determine the characteristics of this subset of long-term survivors.

Patients and Methods
Median age at diagnosis was 68 years (range 51-75) and PS was <2 in 13 cases (81.2%). Diagnosis according to the 2008 WHO Classification was refractory anemia with excess blasts (RAEB)-1 in 7 cases and RAEB-2 in 9 cases. Cytogenetic risk was low in 6 cases (37.5 %; all with normal karyotype) and high in 10 cases (62.5%; all with complex abnormalities). All patients received AZA administered subcutaneously at a dosage of 75 mg/m2 daily for 7 days, repeating the cycle every 28 days; median number of AZA cycles received was 25 (range 19-56).
Results
According to International Working Group 2006 criteria, 4 patients (25%) achieved complete response, 7 patients (44%) achieved partial response, and 5 (31%) stable disease. 13 patients (81%) are still alive and continuing to receive AZA. Two patients (12.5 %) died due to disease progression, one after 27 months and one after 29 months after the start of AZA. One patient died to infection disease (pneumonia). AZA treatment has lasted more than 3 years in 4 (25%) of the 16 patients. Peripheral cytopenias were the most common advent events for treatment.

Conclusions
Allogeneic stem cell transplantation remains the only potentially curative treatment for MDS but the vast majority of patients with MDS are ineligible for transplantation because of comorbidities, advanced age, or lack of a suitable donor. Study in a larger series of patients is warranted, but our experience shows that in the absence of intolerable toxicity or disease progression, continued AZA treatment seems to improve the outcome of higher-risk MDS patients who are not eligible for transplantation.

Disclosures:
No relevant conflicts of interest to declare.
High Prevalence Of Aspirin-Resistance In Myeloproliferative Neoplasms
Authors: Demory Jean-Loup , Bruge Judith , Cambier Nathalie , Rose Christian , Charpentier Agnès 
Published: October 2019

Abstract
Aspirin is recommended and widely prescribed to MPN patients without any evaluation of its efficacy. We report on 46 patients followed in our institution for a Myeloproliferative Neoplasm and treated by low-dose aspirin (75 to 160 mg p. day) alone or aside a cytoreductive therapy, mainly hydroxy-urea ; on the occasion of a routine visit we measured the response of their platelets to arachidonic acid in order to assess their sensibility to aspirin. Most patients (25) had ET, 15 had PV, 4 had CML and 2 Myelofibrosis. Response to arachidonic acid was measured on a citrated whole blood sample using an impedance-based semi-automatic aggregometer (Multiplate®) ; TRAP (Thrombin Receptor Activating Peptide) aggregation was performed systematically as a positive control. In 20 patients out of 46 (43,5%) there was persistence of a significant aggregability to arachidonic acid defining the resistance to aspirin according to our reference values : 10/25 ET (38%), 9/15 PV (62%)and 1/4 LMC. These proportions are much higher than those we note in heart or vascular diseases as well as those reported in published series. The observance of aspirin treatment could be considered doubtful only in a minority of patients (5/46) ; as the resistance appeared more frequent in PV we could assume a biais linked to the utilization of whole blood, but most PV patients were well controlled and did not have an elevated hematocrit. In untreated or refractory ET patients, the persistence of an increased platelet count suggests that aspirin dosage was not adequate although there was no statistical significance between daily dose and resistance. We observed an ischemic complication (transient stroke) in a single patient whose platelet count was not controlled despite hydroxy-urea but remained sensible to aspirin.
We conclude that aspirin resistance is frequent in MPN treated with low-dose aspirin and that a monitoring is worth to increase the dose or change for another inhibitor.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Spectrum and Molecular Pathophysiology of Shwachman-Diamond Syndrome
Authors: Shimamura Akiko 
Published: October 2019

Abstract
Shwachman-Diamond Syndrome (SDS) is an inherited marrow failure syndrome associated with exocrine pancreatic dysfunction and leukemia predisposition. SDS patients may also manifest additional non-hematologic abnormalities. Autosomal recessive mutations in the SBDS gene are found in over 90 percent of patients fitting the classical clinical phenotype of SDS. The advent of genetic testing has revealed an unexpectedly broad range of SDS phenotypes. Through the Shwachman-Diamond Syndrome Registry, we found that diagnosis may be obscured by cryptic or non-classical presentations of SDS. The timely diagnosis of SDS carries profound ramifications for medical management and treatment. We are developing assays utilizing massively parallel next generation sequencing to address this challenging diagnostic problem. Clinical applications of next generation sequencing to the diagnostic algorithm for marrow failure or myelodysplastic syndrome and implications for medical treatment will be explored.

Disclosures:
No relevant conflicts of interest to declare.
Day 30 Platelet Count As a Prognostic Marker of Survival in Acute Myeloid Leukemia
Authors: Mangaonkar Abhishek , Mohsin Jamal , Mansour Joshua , Mondal Ashis , Kolhe Ravindra B. , Jillella Anand , Kota Vamsi , Puttagunta Haarika 
Published: October 2019

Abstract
Introduction:
Acute myeloid leukemia (AML) affects about 3.5 per 100,000 people per year in the western world. High dose chemotherapy with anthracycline and cytarabine combination has resulted in complete remission rates of around 60% even in elderly patients. Complete remission (CR) is commonly defined as bone marrow blast count of less than 5% with recovery of all three cell lines in the peripheral blood. CR with incomplete count recovery is where there is no evidence of persistent disease but there is an incomplete recovery of blood counts, is also seen frequently and it has been shown to have poor prognosis as compared to patients with normal count recovery. Above normal platelet count is seen in small percentage of patients and the significance of this has not been well described.. We hypothesized that patients with a high platelet count at recovery from induction therapy have an increased survival as compared to those with normal or below normal platelet counts.
Methods:
We did a retrospective chart review of 123 consecutive patients with a diagnosis AML at Georgia Regents University Cancer Center that were admitted for induction treatment between 2005 and 2012. Highest platelet count between days 25 to 35 from the date of initiation of induction chemotherapy was taken for this analysis. Patients were divided into three groups: platelet count <50,000 (n=21); 50,000-400,000 (n=80) & >400,000 (n=22). Stratified survival with Kaplan-Meir curves were calculated for each of the groups.
Results:
Mean follow-up period was 94.122 months and median survival was 33.917 months. Mean survival (in months) for the first group was 23.157; 57.801 for the second group & 187.388 for the third group. Difference between survival curves was statistically significant (p=0.003).
Conclusion:
Patients with complete remission appear to have significant survival advantage as compared to those with incomplete platelet recovery. Review of patients across various large clinical trials from US showed that the patients with CR have 3-5 year survival advantage as compared to those with incomplete platelet recovery. Platelet count at the end of one month after initiation of induction chemotherapy can also be used to predict long-term prognosis. This observation would serve as a valuable addition to the already established prognostic markers such as cytogenetics and molecular studies. Our results need to be validated in a larger set of patients.

Disclosures
Kolhe: Georgia Regents University: LLS grant Other, Research Funding. Jillella:Emory University: Research Funding. Kota:Georgia Regents University: LLS grant Other, Research Funding; Emory University: Advisory board, Ponatinib, Advisory board, Ponatinib Other; Teva: Speakers Bureau.
G17V Rhoa Mutation in Circulating DNA Is a Useful Marker for Diagnosis of AITL and AITL-Related Lymphoma
Authors: Nakamoto-Matsubara Rie , Sakata-Yanagimoto Mamiko , Nguyen Tran , Furuta Junichi , Ito Takayoshi , Komeno Takuya , Ogawa Seishi , Chiba Shigeru 
Published: October 2019

Abstract
[Background] Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma. We and others reported that the G17V RHOA mutation is frequent and highly specific to AITL and AITL-like peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Thus, detection of this mutation serves as a novel diagnostic strategy for AITL and AITL-like PTCL-NOS.
[Aim] Analysis of disease-specific mutations in serum DNA from AITL and PTCL-NOS patients.
[Method] Genomic DNA was collected from tumors and sera from 16 AITL and PTCL-NOS patients and 11 B-cell malignancy patients. Seven out of 16 T-cell lymphoma and all B-cell malignancy patients did not receive prior treatment. Amplicon-based sequencing by Ion Torrent PGM was performed to analyze the G17V RHOA mutation as well as TET2 and DNMT3A mutations in these samples.
[Result] Three out of 7 tumor samples of T-cell lymphoma patients whose serum was preserved prior to treatment were positive for the G17V RHOA mutation. In the serum of these 3 patients, allele frequencies of the G17V RHOA mutation were 0.006 - 0.072 (mean 0.015, SDV 0.026), while 0 (mean 0, SDV 0) in the serum of the remaining 4 T-cell lymphoma patients and all the 11 B-cell malignancy patients whose tumor samples did not show RHOA mutation. Because we set cut off value as 0.002 (0.2%) based on the ROC curve, RHOA mutation was segregated into positive and negative faithfully according to whether the mutation was identified in the tumor samples. Then, we analyzed TET2 and DNMT3A mutations in sera of 5 patients whose tumor samples were positive for TET2 (n=2; a single mutation in each sample) and DNMT3A (n=3; 5 mutations all together), respectively. TET2 and DNMT3A mutations were detected in all the 5 sera, although 2 out of the 5 DNMT3A mutations were undetectable. In the clinical courses, RHOA mutations became undetectable after the treatment in sera of all the 3 patients whose pre-treatment sera were positive, while TET2 mutations were detected even after the treatment in sera of both patients whose pre-treatment sera were positive.
[Conclusion] Biopsy is sometimes difficult in lymphoma patients with progressed diseases. Identification of the disease-specific G17V RHOA mutation in serum may provide a non-invasive method to diagnose AITL and AITL-like PTCL-NOS, although inapplicable to detect minimum residual disease. Stable detection of TET2 mutations regardless of chemotherapy might indicate the presence of the mutations in the 'pre-cancerous cells' which are resistant to the chemotherapy.

Disclosures
No relevant conflicts of interest to declare.
The Prognostic Value of Molecular Bone Marrow Involvement in Aggressive Lymphoma
Authors: Goldschmidt Neta , Darawshy Fares , Slyusarevsky Elena , Pogrebijski Galina , Ben Yehuda Dina , Gatt Moshe E. 
Published: October 2019

Abstract
Introduction: Morphological bone marrow (BM) involvement in diffuse Large B-cell lymphoma (DLBCL) and primary T-cell lymphoma (PTCL) has prognostic and therapeutic implications. The prognostic role of molecular BM involvement (B and T cell gene rearrangement (GR) studies), in patients with no evidence for involvement is uncertain.
Objective: To evaluate the prognostic role of molecular BM involvement in patients with DLBCL and PTCL, and its significance in the rituximab era.
Methods: This is a retrospective study of 416 patients with DLBCL (358) or PTCL (58) treated 1995-2010. All patients underwent BM biopsy for morphology and GR studies on BM aspirates at diagnosis and/or at end of treatment (EOT). Most patients were treated with CHOP or R-CHOP based protocols after diagnosis. Medical records were reviewed for details of initial disease characteristics, type and response to treatment, relapse if occurred and the date of death or last follow-up. Patients were classified into one of three groups according to BM results: morphology positive (MorphPos); morphology negative/GR positive (MorphNeg/GRpos); morphology negative/GR negative (MorphNeg/GRneg).
Main outcome measures: Overall survival (OS) and progression free survival (PFS) among the groups of patients at diagnosis and at EOT.
Results: At diagnosis there were 89 MorphPos, 49 MorphNeg/GRpos and 278 MorphNeg/GRneg patients. GRpos patients had lower complete remission rate (73.9%) than GRneg patients (84.8%; p=0.087). The median OS differed significantly among groups: MorphPos patients 66.4 months (95%CI: 50.7-82); MorphNeg/GRpos patients 89 months (95%CI: 66-111); and MorphNeg/GRneg patients 125 months (95%CI: 113-136), p<0.001. MorphNeg status improved PFS (p<0.001), however GRneg status did not (p=0.09). The hazard ratio for GRpos at diagnosis in MorphNeg patients was 1.52 (95% CI: 0.97-2.4; p=0.068). Among the subgroup of DLBCL patients, the median OS was significantly different: MorphPos patients 75.6 months (95%CI: 57.7-94.1); MorphNeg/GRpos patients 95.5 months (95%CI: 66.9-124.1); and MorphNeg/GRneg patients 129.6 months (95%CI: 118.2-141.1), p=0.036. 73% of DLBCL patients received rituximab. Rituximab improved OS (p<0.001) in all DLBCL patients, yet did not overcome the GR-positivity negative effect on OS. For PTCL patients, BM morphology and/or GR status did not affect survival. 72 patients were tested at the EOT, 5 were MorphPos and 17 GRpos. EOT MorphPos patients had marginally worse OS (p=0.07). EOT GR status in MorphNeg patients did not affect survival (p=0.5)
Conclusions: BM GR positivity at diagnosis, independent of BM morphological involvement, predicts worse OS in DLBCL even in the rituximab era, but not in PTCL. EOT morphologic but not molecular involvement, had marginally negative effect on survival.

Disclosures
No relevant conflicts of interest to declare.
Cooperation Between the CD20 Receptor and hIFN-Alpha Receptor in Overriding the Blocked CD20 Cell-Signaling in Rituximab-Resistant B-NHL By the Fusion Protein Anti-CD20-hIFN-Alpha
Authors: Vega Gabriel G , Franco-Cea Luz A , Huerta-Yepez Sara , Mayani Hector , Martinez-Maza Otoniel , Bonavida Benjamin , Vega Mario I. 
Published: October 2019

Abstract
Introduction: The standard treatment of B-NHL consists of rituximab in combination with CHOP (RCHOP) and results in a significant clinical response. Rituximab inhibits cell-proliferation and inhibits cell survival/anti-apoptic signaling pathways. A subset of patients does not initially respond and a subset of responding patients develops resistance to RCHOP. The genetic engineering of a fusion protein, α-CD20-hIFN-α, was found to be active in the rituximab-resistant B-NHL cell lines.
Objective: To investigate the underlying mechanism by which α-CD20-hIFN-α signals in the resistant lines.
Hypothesis: We hypothesized that the treatment with the α-CD20-hIFN-α may result in the cooperation of both α-CD20 and hIFN-α and their interactions with corresponding receptors that will result in overriding α-CD20 blocked cell signaling.
Methods: Rituximab-resistant cell lines, R-2F7 and R-Ramos, were used as models. Cell signaling was determined by western. Sensitivity to drug-induced apoptosis was done by activation of caspase 3 by flow cytometry.
Results: Treatment of the R lines with α-CD20-hIFN-α resulted in the inhibition of cell growth and sensitization to doxorubicin-induced apoptosis. Treatment with single agents alone or combination was not effective. Treatment with the α-CD20-hIFN-α resulted in the inhibition of the NFκB and the p38 MAPK pathways. In addition, the hIFN-mediated signaling pathway, namely, PKC-d, was also inhibited by the α-CD20-hIFN-α.The role of PKC-d in drug sensitization was corroborated by the use of the specific inhibitor, Rotterin, which reversed the drug sensitization by α-CD20-hIFN-α and doxorubicin
Conclusion: The ability of the α-CD20-hIFN-α to inhibit cell survival and anti-apoptotic pathways, that was not achieved with single agents or combination, suggested that there may be a crosslinking of the CD20 and hIFN-α receptors by α-CD20-hIFN-α and results in triggering the cells via both receptors and inhibiting intracellular survival pathways and sensitization to drug apoptosis.
Clinical Implication: The findings also suggest the potential therapeutic application of the combination of α-CD20-hIFN-α and drugs for the treatment of patients resistant to RCHOP.

Disclosures
No relevant conflicts of interest to declare.
Management and Outcomes of Plasmablastic Lymphoma: A Single-Center Experience
Authors: Gupta Arjun , Naina Harris V. 
Published: October 2019

Abstract
Background: Plasmablastic lymphoma (PBL) is a rare aggressive B-cell neoplasm characteristically occurring in patients with HIV infection. Given their rarity, most of the existing literature is from case reports or heterogenous pooled data. Optimal therapy is not clearly defined and outcomes are traditionally poor with median survival in the order of months. We describe the epidemiology, management and outcomes of this rare malignancy at a single center.
Methods: We identified patients with PBL diagnosed between 2000-2015 at Parkland Memorial Hospital. Patients were followed till June 2015. Structured forms were used to interview patients and to abstract relevant (demographics, diagnostics, pathology, therapy and outcomes) clinical data. Logistic regression was used to assess variables for association with the odds of treatment failure. Log-rank test was used to assess differences in survival by treatment regimen. Statistical analysis was performed using SAS software version 9.0 (SAS Institute).
Results: Twenty-nine patients with PBL were diagnosed in the study period. Median age at presentation was 42 years; 24 (83%) were male. Twenty-sex (90%) occurred in patients with HIV infection; median CD4+ count at diagnosis was 93/mm3; median viral load was 97,823 copies/mL. Only 5 patients (17%) were actively taking antiretroviral therapy at the time of diagnosis. Three patients were immunocompetent. The most common primary site of disease was the gastrointestinal tract (13 patients) followed by oral/maxillofacial sites (10 patients). Twenty patients (69%) presented with adanced stage disease (stage III or IV disease). EBV was detected in all 26 cases where it was tested; HHV-8 was negative in all patients. CD20 positivity was seen in only 4 patients (14%). MYC rearrangements were described in 70% patients. EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide and hydroxydaunorubicin), was the most common treatment regimen used in 16 patients (56%). Radiation therapy was administered in 28% of patients. Overall survival across the cohort was 9.9 months. Twenty patients (69%) died during the follow-up period; their median survival was 2.6 months. Nine patients were alive after a median follow-up of 47.8 months. Those who were treated with EPOCH demonstrated a better median overall survival compared to those who were not (26.3 months vs 1.2 months, p value 0.01).
Conclusions: PBL is a rare AIDS-related lymphoma most commonly affecting the oral cavity and gastrointestinal tract. It mostly occurs in HIV patients not on HAART. Patients usually present with advanced stage disease. OS continues to be poor but EPOCH regimens can improve survival compared to non-EPOCH regimens, and should be further explored in this setting.

Disclosures
No relevant conflicts of interest to declare.