bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Outcome of Relapsed or Refractory Pediatric B-Cell Non-Hodgkin Lymphoma in Japan
Authors: Osumi Tomoo , Mori Tetsuya , Fujita Naoto , Saito Akiko M. , Nakazawa Atsuko , Tsurusawa Masahito , Kobayashi Ryoji 
Published: November 2019

Abstract
Introduction
Relapsed or refractory pediatric B-cell non-Hodgkin lymphoma (B-NHL) has been reported to be extremely difficult to cure. We previously conducted a retrospective study of pediatric relapsed or refractory B-NHL in Japan between 1996 and 2004 and found that the four-year overall survival rate was only 20.5% (Fujita N. e al. PBC. 2008). Rituximab, a chimeric anti-CD20 monoclonal antibody, is expected to be effective in improving the prognosis of pediatric relapsed or refractory B-NHL and was approved for use in 2003 in Japan. Here, we retrospectively assessed the treatment and prognosis of pediatric relapsed or refractory pediatric B-NHL in the rituximab era in Japan.
Methods
We collected relapsed pediatric B-NHL cases from patients enrolled in our current study, JPLSG B-NHL03 study, which was the first nationwide multicenter trial for newly diagnosed pediatric B-NHL. We collected information on treatment and outcome after induction failure or relapse.
Results
In 33 patients enrolled this study, the median age at diagnosis was 9.7 years and male predominance was observed. Nine cases were pathologically subclassified initially as diffuse large B-cell lymphoma, 11 as Burkitt lymphoma, 11 as Burkitt Leukemia and two as others. According to initial Murphy staging, most cases were in the advanced stage. The most common site of relapse was abdomen (8 cases), followed by bone marrow (8 cases) and central nervous system (7 cases). Twenty-three cases relapsed in one site while 10 did so in multiple sites. Among them, 20 relapsed within six months after initial diagnosis.
Among them, 28 patients received some rituximab combined treatment as salvage therapy. R-ICE (rituximab, ifosfamide, carboplatin and etoposide) regimen was the most popular and used in 22 patients as first-line salvage therapy. As a result, 22 patients (66.7%) achieved complete remission (CR) by some salvage therapy. 23 received hematopoietic stem cell transplantation (HSCT). Their 5-year overall survival rate was 48.5%, which was far more superior to both our previous study (Figure 1) and another on relapsed or refractory B-NHL in childhood.
In risk factor analysis for survival, rituximab combined treatment and HSCT did not influence the outcome, but achievement of CR after salvage treatment resulted in significantly better survival (68.2% vs 9.1%, p=0.001). These results suggest that the advent of rituximab induced an improvement of CR rate for relapsed paediatric B-NHL, which resulted in an improvement of the survival rate.
Conclusion
In conclusion, the prognosis of the pediatric relapsed or refractory B-NHL in a Japanese cohort remained poor but is showing improvement in the rituximab era.

Disclosures
No relevant conflicts of interest to declare.
R-EPOCH Is Superior to R-CHOP As a First-Line Regimen in De Novo DLBCL Patients with High Ki-67 Expression
Authors: Huang Jia-Jia , Jiang Wenqi , Li Zhi-Ming 
Published: November 2019

Abstract
Diffuse large B-cell lymphoma (DLBCL) patients with high Ki-67 expression receive limited benefits from R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy. This study aims to compare the R-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and R-CHOP regimens as first-line therapy in DLBCL patients with high Ki-67 expression. Data from 44 untreated DLBCL patients with high Ki-67 expression receiving R-EPOCH therapy were matched with those from 132 untreated DLBCL patients with high Ki-67 expression receiving R-CHOP therapy based on the International Prognostic Index (IPI: age, Ann Arbor stage, performance status, LDH level, number of extranodal sites), gender, and Ki-67 expression. In the R-EPOCH group, 42/44 patients were eligible for response evaluation. A total of 35 patients (83.3%) achieved complete remission (CR); 6 patients (14.3%) achieved partial remission (PR); and one patient (2.4%) exhibited progressive disease (PD) after 2 cycles of therapy. Patients in the R-EPOCH group presented better survival outcomes than those in the R-CHOP group (3-year overall survival [OS]: 89.9% vs. 70.2%, p=0.041; 3-year progression-free survival [PFS]: 86.6% vs. 59.7%, p=0.024). The survival superiority of the R-EPOCH over the R-CHOP regimen persisted when considering only patients of low-to-intermediate IPI risk, but it was not observed in those of high IPI risk. Our data suggest that R-EPOCH is superior to R-CHOP as a first-line regimen in DLBCL patients with high Ki-67 expression, especially in those of low-to-intermediate IPI risk.

Disclosures
No relevant conflicts of interest to declare.
Fc Gamma Rll (CD32b) Expression Affects Anti-CD20 Monoclonal Antibody Cellular Responses and Is Down Regulated in Rituximab Resistant Pre-Clinical Models
Authors: Mavis Cory , Stewart Kayle , Gu Juan J , Wallace Paul K. , Hernandez-Ilizaliturri Francisco J. 
Published: November 2019

Abstract
Rituximab's primary mechanisms-of-action include: antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CMC), induction of apoptosis and anti-proliferation. The acquirement of phenotypic changes in cancer cells or host immune cells over time may affect rituximab responsiveness and underscores the complexity of the potential mechanisms-of-resistance to anti-CD20 monoclonal antibodies (mAbs). Laboratory studies had demonstrated the importance of FcγRIIa and FcγRIII activating receptors in the biological activity of rituximab and other monoclonal antibodies (mAbs) in cancer medicine. Recently, investigators had focused their efforts in the study of FcγRIIb function expressed primarily on normal and malignant B-cells and its role in inflammatory conditions or hematological malignancies. FcγRIIb is an inhibitory low affinity Fcg receptor capable to induce potent inhibitory (apoptotic) signals via immune receptor tyrosine-based inhibition motif (ITIM). Previously, we generated several rituximab-resistance lymphoma cell lines (RRCL) and demonstrated a global down-regulation of CD20. On the other hand, forced expression of CD20 in RRCL did not restore rituximab sensitivity suggesting the existence of additional mechanisms of resistance to mAbs targeting CD20 (Tsai et al Clin Cancer Res. 2012;18:1039-50). To this end, we evaluated the expression and significance of FcγRIIb (CD32b) in RRCL. FcγRIIb gene and protein expression levels were determined in a panel of rituximab sensitive (RSCL) or RRCL by quantitative polymerase chain reaction (qPCR) and western blotting respectively. Subsequently, we silenced FcγRIIb in RSCL using siRNA interference and evaluated changes in the capacity of several mAbs targeting CD20 (rituximab, ofatumumab, and obinotuzumab) of inducing CMC or ADCC in vitro. RRCL were found to have almost a complete loss in FcgRIIb mRNA and protein levels when compared to RSCL. In addition, silencing of FcγRIIb in RSCL decreased the capacity of rituximab (P=0.04 [ADCC] and P=0.15 [CMC]), ofatumumab (P=0.02 [ADCC] and P =0.10 [CMC]), and obinituzumab (P=0.02 [ADCC] and P<0.01 [CMC]) in inducing effective ADCC and CMC when compared to scramble transfected cells. Together our data suggests that the chronic exposure of lymphoma cells to rituximab results in the decreased expression of FcγRIIb. In addition, FcγRIIb low affinity inhibitory receptors appear to contribute to rituximab anti-tumor activity in vitro. Additional in vivo experiments are ongoing to further define the role of FcγRII in the anti-tumor activity of mAbs targeting CD20 and how it is down regulated in the context of acquired resistance to rituximab-based therapies. (Research, in part, supported by The Eugene and Connie Corasanti Lymphoma Research Fund)

Disclosures
No relevant conflicts of interest to declare.
The Efficacy and Tolerability of Generic of Imatinib in a Very Specific Group of Chronic Myeloid Leukemia (CML)
Authors: Conchon Monika 
Published: November 2019

Abstract
Introduction:
Most of the patients with CML started to receive a generic formulation of imatinib (IM) in May 2013, available in the Public Health in Brazil.
The lack of information about the tolerability and efficacy of generics was a concern to patients and doctors who have been treating with Glivec, the original IM from Novartis since 2002.
Objectives:
To evaluate the efficacy and tolerability of generic of IM in CML chronic phase (CP) patients who had achieved a stable major molecular response (MMR) with Glivec before May 2013.
Methods:
The absolute level of BCR-ABL transcript from peripheral blood was serially measured every 3 to 6 months by RT-qPCR. Only level variation > 0,1% expressed on the International Scale and adverse events were noted.
Results:
Forty CML-CP patients in MMR defined as BCR-ABL (IS) £ 0,1% in at least to consecutive times, who started the generic IM in May 2013 were evaluated. All of them received 400 mg of generic IM during 24 months.
Of 40 patients, 24 (60%) had no variation on sequential analysis and 13 (32,5%) had one or two variation of BCR-ABL/BCR between 0,1% to 1,16%, but re-achieved MMR.
Two patients, due to compliance issue, lost MMR. One re-achieved MMR with generic imatinib, the other one with nilotinib.
One patient presented hepatic toxicity grade 3, and was switched to dasatinib, without lack of MMR.
Overall, MMR was maintained in all but one patient (98%).
Conclusion:
In this specific MMR group, the use of generic IM was found to be safe and highly effective in maintaining MMR.

Disclosures
No relevant conflicts of interest to declare.
Clinical Relevance of Failure to Achieve Early Molecular Response in Chronic Myeloid Leukemia in Chronic Phase
Authors: Lee Ji Yun , Lim Sung Hee , Kim Hae Su , Yoo Kwai Han , Song Haa-Na , Cho Jinhyun , Park Silvia , Kim Seok Jin , Kim Won Seog , Kim Kihyun , Jang Jun Ho , Jung Chul Won 
Published: November 2019

Abstract

Purpose
The early molecular response (EMR, ≤ 10% BCR-ABL1 at 3 months) of tyrosine kinase inhibitor (TKI) treatment for patients with chronic myeloid leukemia (CML) in chronic phase (CP) has been reported to have strong correlation with long-term outcome. We aim to investigate the prognostic interaction of the EMR and major molecular response (MMR).
Methods
We retrospectively reviewed data for a total of 165 patients with newly diagnosed CML-CP who received TKIs (imatinib, nilotinib, or dasatinib) as first-line treatment between January 2003 and April 2013. Of the total 128 patients who were regularly monitored by peripheral blood molecular analysis, 85 had a BCR-ABL1 assessment at 3 months and were finally included in the analysis.
Results
The median age of all patients was 49 years and 87.1% received imatinib as first line treatment. High risk group by Sokal and EUTOS were 29.4% and 14.1%, respectively. Patients with EMR (n = 56, 65.9%) had a tendency to have low risk disease and to be treated with 2nd generation of TKIs. With a median follow-up duration of 53.6 months (range, 5.4-131.3), the 5-year OS, 5-year FFS, and 5-year EFS were 92.5%, 74.8%, and 68.0%, respectively. Median time to achieve MMR was 11.1 months (95%CI, 8.4 - 13.8). The outcomes at 5 year comparing patients whose BCR-ABL1 transcript levels ≤ 10% vs >10% at 3 months were as follows: OS, 92.2% (95% CI 84.9-99.1) vs 92.8% (95% CI 83.7-102.3), p = 0.819; FFS, 84.7% (95% CI, 75.6-94.4) vs 57.4% (95% CI, 39.0-75.0), p < 0.001; and EFS, 73.6% (95% CI 62.5-85.5) vs 57.8% (95% CI 40.0-76.0), p = 0.050. Six (10.7%) of 56 patients with BCR-ABL1 transcript levels ≤ 10% at 3 months failed to achieved an MMR and 18 (62.1%) of 29 patients with > 10% at 3 months achieved an MMR. Based on these heterogeneous clinical outcomes, we further explored subgroup analysis according to the achievement of MMR for refined discrimination of survival outcomes. There was no significant difference of clinical outcomes between ≤ 10% vs > 10% at 3 months among the patients who achieved MMR (OS, p = 0.376; FFS, p = 0.793; and EFS, p = 0.266). In patients who did not achieved MMR, only FFS was significantly difference between ≤ 10% vs > 10% at 3 months (OS, p = 0.489; FFS, p = 0.014; and EFS, p = 0.199).
Conclusion
Patients who failed to achieve EMR but finally reached MMR have excellent prognosis that whether we have to change TKI for EMR failure is to be addressed by ongoing prospective clinical trials.

Disclosures
Jang: Alexion Pharmaceuticals: Research Funding.
Leukocytosis Can Predict Thrombotic Events in Myelofibrosis
Authors: Vassalli Laura Coutinho , Malafaia Emilia Carolina , Chauffaille Maria L. , Kerbauy Daniella 
Published: November 2019

Abstract
Thrombotic events are the main complication of Philadelphia-negative chronic myeloproliferative neoplasms (MPN). In polycythemia vera (PV) and essential thrombocythemia (ET), risk factors for thrombosis are well established, such as age greater than 60 years and previous thrombosis. However, the role of JAK2 V617F mutation and leukocytosis at diagnosis as risk factor for thrombosis is still controversial. Our aim was to identify factors related to the risk for thrombotic events in the studied population.This study is a retrospective non-interventional cohort. All of the analyses were performed using the database of 142 patients with MPN regularly followed at the Hematology Division (at UNIFESP-SP) from 1992 to 2014. Diagnosis was established according to WHO criteria. We analyzed the JAK2 V617F mutation, hemoglobin (g/dL), hematocrit (%), white blood cells (x109/L) and platelets (x109/L) at the diagnosis and DIPSS-Plus risk score (International Working Group for Myelofibrosis Research and Treatment, 2009). These variables were associated with thrombotic event at any time.Of the 142 patients, 54 had diagnosis of PMF, 28 of PV, 33 of ET and 27 of post-essential thrombocythaemic myelofibrosis (post ET MF) or post-polycythaemic myelofibrosis (post-PV MF). This last group was included in myelofibrosis group for statistical purposes.
Thrombotic events were more frequent in PV patients (39.2%), followed by ET (33.3%), and PMF (20.9%).
From those which JAK2 mutation was obtained, it was positive in 92.4% of PV patients, 62% of PMF and 50% of ET. In none of the three groups, the presence of JAK2 V617F mutation was related to increased risk of thrombosis.
In myelofibrosis, leukocytosis was higher among thrombotic patients (median of 13.7 in thrombotic group versus 9.7x 109/L; p 0.0379). None of the other parameters, hemoglobin, hematocrit, platelets and DIPSS-Plus were statistically significant. In ET, the hemoglobin level at diagnosis was significantly higher in the presence of thrombosis (mean of 14.57 in thrombotic group against 13.03 g/dL in the non-thrombotic one, p 0.0428). The other parameters, hematocrit, white blood cells and platelets were not relevant. The median WBC in the thrombotic group was 9.4 and in the non-thrombotic one 9.3 x109/L. Finally, in polycythemia vera, none of the variables were related to thrombosis. Among the studied population, leukocytosis was increased in patients with thrombotic event in MF. Thus, monitoring leukocyte count in MF is essential to predict thrombosis risk and should be further studied in order to define therapeutic goals in these patients.

Disclosures
No relevant conflicts of interest to declare.
Patient-Reported Outcomes in Myelofibrosis Patients Help to Identify Patients' Needs
Authors: Ionova Tatyana , Nikitina Tatyana , Lomaia Elza , Myasnikov Alexandr , Pospelova Tatyana , Evseev Andrey , Gritsenko Taras , Lyamkina Anna , Machulaytene Elena , Usacheva Elena , Rodionova Anna , Kurbatova Kira 
Published: November 2019

Abstract
Myelofibrosis (MF) is the most symptomatic of the myeloproliferative neoplasms and is associated with the greatest symptom burden and poorest prognosis. Patient-reported outcomes is an effective way to identify patients' needs and risks/benefits of MF treatment. We aimed to study quality of life (QoL) and symptom burden in MF patients in a real-world setting.
44 MF patients - 27 primary MF, 8 post-essential thrombocytopenia, 9 post-polycythemia vera - were enrolled in the multicenter real-world QoL study. Mean age - 60.8±13.3; male/female - 14/30. All the patients received the best available treatment (BAT, n=28) or novel treatment modality ruxolitinib (n=16) for at least 6 months (range 6-160 mths). A high proportion of patients (80%) had intermediate to high prognostic risk scores according to International Prognostic Scoring System. All the patients completed the QoL questionnaire SF-36, symptom assessment questionnaire CSP-MF and Patient Global Impression of Change (PGIC) tool. Integral QoL Index (IQoLI) in MF patients was calculated on the basis of SF-36 and QoL impairment grade was assessed in comparing with QoL population norms (PN). Comparison t-test for independent samples or Mann-Whitney test was applied.
The heterogeneity of MF patients population in terms of QoL impairment was shown: 55% of patients had mild QoL impairment (IQoLI≤25% from PN), 7% - moderate (IQoLI≤25-50% from PN), 38% - severe or critical QoL impairment (IQoLI≤50% from PN). Patients receiving BAT exhibited more pronounced QoL impairment as compared to patients receiving ruxolitinib (p<0.05); they had worse physical functioning, general health, vitality, social functioning, and mental health (p<0.05). All the patients experienced multiple symptoms; the most severe symptoms were fatigue, inactivity and pain in bones/muscles. The symptoms were more expressed in patients on BAT as compared to patients on ruxolitinib (p<0.005). Patient's impression of health changes was better in patients treated with ruxolitinib: the mean PGIC score was higher in patients on BAT on ruxolitinib - 4.4 vs 2.3 (p=0.001).
Quality of life and perceived change in health condition are better and symptom severity is less in MF patients on ruxolitinib therapy than those on BAT. Results of this real-world study demonstrate benefits of ruxolitinib therapy from patient perspective. Patient-reported outcomes are of help to better identify the needs of MF patients.

Disclosures
No relevant conflicts of interest to declare.
The Expression of the Co-Inhibitory Molecule PD-1 and Its Ligand PD-L1 in Patients with MDS
Authors: Geng Suxia , Weng Jianyu , Huang Xin , Wu Ping , Deng Chengxin , Lai Peilong , Du Xin 
Published: November 2019

Abstract
Programmed death receptor 1 (PD-1) is an important immunosuppressive molecule and expresses on activated T cells, B cells and myeloid cells. PD-L1, a primary ligand PD-1, is mainly expressed on T cells and primary B cell surfaces and plays a role in the differentiation and apoptosis of these cells, induces a coinhibitory signal in activated T cells, promotes T cells apoptosis, incompetence and functional exhaustion. The expression of PD-1 is high in patients with hematologic malignancies and a high expression of PD-L1 is found on hematologic malignancies cells.
To further know the characteristics of PD-1 and PD-L1 in patients with MDS, we detected theexpression of PD-1 and PD-L1 in peripheral blood (PB) and bone marrow (BM) samples from 25 RAEB and 10 RARS patients using Real-time PCR. The PD1 and PD-L1 expression levels of 13 PB and 8 BM samples from normal individuals were as controls. The PD-1 levels of PB samples from 25 RAEB patients [42.40(4.5-173.96)%] were significantly higher than that from normal controls [32.32(19.45-41.38)%, P=0.026]. While the level of PD-1 in 10 RARS patients was comparable to that of normal controls and RAEB patients (P=0.401 and P=0.352). Compared to normal controls [23.72(3.23-39.2)%], the median PD-1 level of BM from 10 RAEB patients[36.81(12.14-151.52)%] showed an increasing tendency, but the difference was not statistically significant (P=0.062). PD-L1 expression levels of PB samples from RARS patients were significantly lower than that of normal controls (P=0.009). There were no significant difference between RAEB patients and normal controls about the PD-L1 expression level in PB and BM samples (P=0.248 and P=0.181) and between RAEB and RARS patients about PD-L1 expression level in PB samples (P=0.243). PD-1 level in BM samples from 11 RAEB patients with remission was (31.32±15.75)% and it was lower significantly than that before treatment [(59.94±47.44)%, P=0.034]. After progression or transformation, the expression level of PD1 (54.72±37.27)% increased again and was higher than that in remission (P=0.028).There were also no significant difference on PD-L1 expression among before treatment, bone marrow remission and progression or transformation (P>0.05). In 8 RAEB patients transformed to AML after treatment, PD-1 level has a decreasing tendency(P =0.05)and the change of PD-L1 has no significant difference (P>0.05).
In conclusion, PD1 mRNA level increased significantly in patients with RAEB and the changes of PD-1 was associated with the evolution of the disease after treatment with demethylating agents. The level of PD1 may be used as an indicator to determine the efficacy, but the changes of PD-L1 was not found regularity.

Disclosures
No relevant conflicts of interest to declare.
A Case Report on Coexisting JAK2 V617F and Calr exon 9 Mutation in Essential Thrombocythemia
Authors: Rashid Munazza , Ahmed Rifat Zubair , Ahmed Shariq , Nadeem Muhammad , Ahmed Nuzhat , Shamsi Tahir 
Published: November 2019

Abstract
Myeloproliferative Neoplasms (MPNs) are a heterogeneous group of clonal disorders derived from multipotent hematopoietic myeloid progenitors. Classic "BCR-ABL1-negative" MPNs is an operational sub-category of MPNs that includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These three disorders are characterized by stem cell-derived clonal myeloproliferation. The most common mutation in the MPNs PV, ET and PMF is JAK2 V617F.
JAK2 V617F can be detected in about 95% of patients with PV while remaining 5% of PV patients carry a somatic mutation of JAK2 exon 12. Approximately one third of patients with ET or PMF do not carryany mutation in JAK2 or MPL. In December 2013 mutations were described in calreticulin (CALR) gene in 67-71% and 56-88% of JAK2 V617F and MPL negative patients with ET and PMF, respectively. Since this discovery, CALR mutations have not only been recommended to be included in the diagnostic algorithm for MPNs, but also CALR exon 9 mutations have been recognised to have clinical utility as mutated patients have a better outcome than JAK2 V617F positive patients.CALR mutations have also been reported to be mutually exclusive with JAK2 V617F or MPL mutations. According to our knowledge so farthere have been only six reports published,which described patients harbouring concurrent JAK2 V617F and CALR exon 9 mutations; seven ET, three PMF, one PV and one MPN-U.
In the present study we are reporting ET patient with coexisting JAK2 V617F and CALR exon 9 mutations from our center. In July 2011, 55-years-old female patient was referred to our hospital with a history of gradual elevation of platelet counts accompanied with pain in right hypochondriac region and feet. Bone Marrow aspirate consisted of 'Stag-horn' appearance Megakarocytes. Multiple platelets aggregates and islands were seen throughout the aspirate smear. ARMS-PCR for JAK2 V617F mutation was positive whereas bidirectional Sanger sequencing for CALR exon 9 exhibited c.1214_1225del12 (p.E405_D408del) mutation pattern.

Disclosures
No relevant conflicts of interest to declare.