bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Overall Survival in Myeloma Patients Treated with Regimens Including Thalidomide/Revlimid/Velcade Vs Melphalan/Prednisone; a Retrospective Analysis.
Authors: Ashley Pandora , Holguin Mark , Song Juhee
Published: October 2019

Abstract 4961

A retrospective study was conducted to ascertain if the use of thalidomide, revlimid and or velcade was associated with improved survival compared to melphalan and prednisone or vincristine, adriamycin and dexamethasone (VAD). To avoid possible confounding issues of treatment with high dose chemotherapy and stem cell rescue, those patients were excluded from this analysis.

From 1997 to 2003, 98 patients diagnosed with myeloma and treated at Scott & White Memorial Hospital using non-transplant containing regimens were identified through the Scott & White Tumor Registry. Patients were divided into two groups based on treatment received. One group was treated with melphalan and prednisone or VAD chemotherapy (59 patients) and the second group was treated with regimens that included thalidomide, revlimid, or velcade (39 patients).

Median survival times were estimated for the entire cohort and each treatment group. Kaplan-Meier estimates of the survival by treatment received were estimated and log-rank test was performed to compare the survival distributions of the two treatment groups. Five year survivals of the 2 groups were compared using the Z test.

Median follow-up time for the entire cohort is 32.6 months (95% CI: 24.4-37.6) Median survivals are 38.7 months (95% CI 32.7-58.5) for the thalidomide/revlimid/velcade group and 24.4 months (95% CI: 14.4-35.7) for the melphalan and prednisone or VAD group. Five year Kaplan-Meier survival estimates are 0.3452 (95% CI: 0.2007-0.4945) for the thalidomide/revlimid/velcade group and 0.1325 (95% CI: 0.0593-0.2354) for the melphalan and prednisone or VAD group. The difference in survival between the two groups is statistically significant with p value of 0.0179.

In this retrospective analysis, treatment with newer agents such as thalidomide, revlimid or velcade is associated with a significant improvement in survival compared to melphalan and prednisone or VAD.

Disclosures

No relevant conflicts of interest to declare.
Continuous Administration of Low-Dose Cyclophosphamide and Prednisone as a Salvage Treatment for Multiple Myeloma.
Authors: Zhou Fan , Guo Lieping , Shi Haotian , Lin Chenhui , Hou Jian
Published: October 2019

Abstract 4962

Objective

To assess the efficacy and tolerability of continuous low-dose cyclophosphamide and prednisone regimen (CP) as a salvage therapy for multiple myeloma (MM).

Method

The CP regimen consisted of oral cyclophosphamide at 50 mg and prednisone at 15 mg daily. A total of 27 consecutive patients received the CP regimen: 19 patients had severe comorbid conditions; 8 were unwilling to continue conventional chemotherapy due to severe infection associated with conventional treatment. All patients had received 1-4 chemotherapeutic regimens prior to the current study.

Result

The overall response rate (complete remission, very good partial response, and partial response) was 66.7%. The median time to response was 2 months. In the patients who responded to the treatment, the median progression-free survival has not been reached. In the non-responding patients, the median progression-free survival was 4 months. In patients with severe comorbid conditions and unwilling to accept conventional chemotherapy because of severe infection, the physical conditions improved significantly.

Conclusion

Continuous low-dose CP regimen is an effective and well-tolerated salvage therapy for MM.

Disclosures

No relevant conflicts of interest to declare.
Modulation of Soluble Interleukin -2-Receptor (sIL2R) in Human Immunodeficiency Virus Myeloma (HIV-M) Patients Treated with Biaxin Pentoxifylline Dexamethasone (BPD).
Authors: McPherson Eugene , Patel Sanjay , Tassy P.
Published: October 2019

Abstract 4965

Soluble interleukin-2-receptor (sIL2R) is a T-cell derived cytokine that induce proliferation of activated T-cells, modulates macrophage function and phenotype and participates in differentiation of B cells. sIL2R levels reflect immune-system activation. and is elevated in HIV-M and may be used to predict esponse to therapy with immunomodulation therapy with BPD.sIL2R has been reported in several malignant diseases with correlation to disease activity. Proinflammatory cytokines IL-6, TNF-alpha, and IL-1b are positively correlated to sIL2R.Plasma cells may produce IL-6 by autocrine mechanism but a paracrine mechanism is involved in IL-6 production in bone marrow stromal cells. Growth of myeloma cells can be induced IL-6. We present a 43 YOF with HIV-M with elevated levels of sIL2R, C-reactive protein (CRP), IgG-kappa,lambda,IgM kappa level with serum free light chain

kappa/lambda ratio. Treatment with biaxin,pentoxifylline, and low dose dexamethasone for 12-24 weeks resulted in normal levels of sIL2R, CRP, IgG,IgM and serum free light chain ratios.

Conclusion

Modulation of sIL2R with BPD in HIV-M patients with elevated proinflammatory cytokines may arrest the disease proliferation by controlling the growth potential IL-6 in both bone marrow plasm cells and peripheral blood mononuclear cells and correlates with the duration of survival.

Disclosures

No relevant conflicts of interest to declare.
Hydroxyurea Effect On Marked Splenomegaly Associated with Primary Myelofibrosis: Response Rates and Correlation with JAK2V617F Allele Burden.
Authors: Siragusa Sergio , Vaidya Rakhee , Tefferi Ayalew
Published: October 2019

Abstract 4971

Background

Marked splenomegaly severely compromises quality of life in primary myelofibrosis (PMF). Preliminary results from the use of small molecule JAK2 inhibitors suggest prominent activity in reducing spleen size. In order to put such salutary effect of investigational drug therapy in context, it is important to determine the value of conventional therapy in this regard.

Methods

Study population was selected from the Mayo Clinic PMF database and consisted of patients treated with hydroxyurea (HU) as first-line therapy for symptomatic, marked splenomegaly (palpable at >10 cm below the left costal margin) and in whom follow-up information was available to assess response. Palpable spleen size measurements were recorded before and after 3, 6 and 12 months of HU therapy. Spleen response was defined as minimal (< 25% reduction), minor (25-50%), or major (>50%). Standard statistical procedures were used to correlate spleen response with other clinical and laboratory parameters, including cytogenetic and JAK2V617F mutational status.

Results

46 consecutive patients (median age, 62 years; range 38-75; 30 males) met the above stipulated eligibility criteria for study inclusion. Pre-treatment IPSS risk categories were low, intermediate-1 (int-1), int-2 and high in 4, 13, 10 and 19 patients, respectively; 7 patients were transfusion-dependent. Quantitative JAK2V617F and pre-treatment cytogenetic information were available in 25 and 36 patients, respectively; 15 (60%) patients were positive for JAK2V617F and mutant allele burden was > 50% in 6 patients; 17 (47%) patients carried either favorable (n=5) or unfavorable (n=12) cytogenetic abnormalities.

Overall response rate (major and minor) was 35% (16 of 46 patients) and major response rate 17%. Overall response rates were 10%, 67% and 33% in patients with undetectable JAK2V617F or mutant allele burden of < or ≥ 50%, respectively (p=0.04). Overall response rates in patients with normal, favorable and unfavorable karyotype were 32%, 40% and 33%, respectively (p=0.9). Response was not affected by age, sex, HU dose or pretreatment status regarding spleen size, IPSS score or transfusion need.

Conclusions

The current study provides background information on the value of conventional chemotherapy for controlling PMF-associated marked splenomegaly. The study also suggests a positive effect of JAK2V617F on treatment response to HU, a detail that needs to be considered when assessing the corresponding effect from a JAK2 inhibitor therapy.

Disclosures

Off Label Use: Hydroxyurea use in myelofibrosis.
The JAK2V617F Mutation but NOT Platelet Parameters Predict Thrombotic RISK IN Patients with Philadelphia-Negative MYELOPROLIFERATIVE Disorders (MPDs).
Authors: Wijayasinghe Deepti , Hart Stephen , Solkar Saida , McNamara Christopher j
Published: October 2019

Abstract 4984

Venous and arterial thromboses are important disease complications of both essential thrombocytopenia (ET) and polycythaemia vera (PV), the commonest MPDs. Predicting and managing this risk is not straightforward as the absolute platelet count does not necessarily correlate with thrombotic risk.

We retrospectively studied the platelet parameters, median platelet volume and platelet crit, in addition to the absolute platelet count using a Sysmex XE-2100 in patients with MPDs to determine if there was any relationship between these and subsequent thrombotic risk, as well as the JAK2V617F gene status. This has not been done previously.

There were 82 patients (25 PV, 33 ET, 13 chronic idiopathic myelofibrosis, 11 MPD unclassifiable) with a median age of 63 (range 37-94). Thromboses occurred in 32/82 patients (26 venous, 6 arterial) after follow up of 12-108 months. The JAK2V617F mutation was found in 77% of all patients. The median platelet count at diagnosis, prior to any therapy, of those patients who subsequently went on to experience a thrombotic event was not significantly different from those who did not: median platelet count 529 v 563 (p=0.06), median platelet volume 8.6 v 8.3 (p=0.36), platelet crit 0.49 v 0.5 (p=0.079).

Thrombosis was more likely to occur in those patients with a JAK2V617F mutation; thrombosis occurred in 43 % of JAK2V617F cases compared with 26% of cases without the mutation. The median platelet count in the JAK2V617F unmutated group was higher than in the group with the mutation (620 v 530 p=0.04); other platelet parameters in the two groups did not show any difference based on the presence of the mutation (median platelet volume 8.2 v 8.6 (p= 0.29), median platelet crit 0.52 v 0.5 (p=0.06)).

We conclude that platelet parameters, as assessed by a modern automated haematology analyser, do not predict for thrombotic risk in patients with newly diagnoses MPDs. Other factors such as platelet dysfunction, inherited thrombophilia and underlying vascular disease risk factors may be important. Our findings support the notion proposed by others that the presence of the JAK2V617F is a thrombotic risk factor.

Disclosures

No relevant conflicts of interest to declare.
Clinical Results in Patients with Primary and Secondary Myelofibrosis Treated with Monthly Cycles of Oral Melphalan.
Authors: Carmosino Ida , Latagliata Roberto , Breccia Massimo , Cannella Laura , Vozella Federico , Volpicelli Paola , Santopietro Michelina , Spadea Antonio , Petti Maria Concetta , Alimena Giuliana
Published: October 2019

Abstract 4985

Prolonged continuous oral Melphalan treatment was successfully employed in patients with Idiopathic Myelofibrosis (IM); however, a high incidence of evolution into blastic phase (BP) was observed. In order to reduce the incidence of BP and other side effects, a different Melphalan schedule with intermittent monthly cycles was tested at our Institution. From 1/2003 to 2/2009, 24 patients (16 males and 8 females, median age 66.2 years, range 41.7 – 76.2) were enrolled into the study; 19/24 had primary IM while in 5 there was a previous history of Polycythemia Vera/Essential Thrombocythemia. Six patients (25%) had been pretreated with Hydroxyurea. A symptomatic splenomegaly was present in all patients, with median spleen enlargement below costal margin of 12 cm (range 7 – 22). Median WBC level was 11.6 × 109/l (range 3.6 – 63.6), with 11/24 patients having WBC > 12.0 × 109/l; in addition, 3 patients had PLT level > 500 × 109/l, 11 patients Hb level < 10 g/dl and 3 patients had transfusional requirement. Melphalan was administered orally at the dose of 8 mg/day for 5 consecutive days every month. Twelve patients (50%) had a reduction of spleen enlargement > 75%, 2 patients > 50% and 1 patient > 25%, with a global response rate of 15/24 patients (62.5%): the remaining 9 patients had no variation in spleen volume. Elevated WBC values reduced to normal in all but one patient, elevated PLT values reduced to normal in 2 out of 3 patients, transfusional requirement disappeared in 1 out of 3 patients. Median number of cycles to best response was 10 (range 2 – 30). As concerns hematological toxicity, 4 patients had Hb decrease < 8 g/dl, with 3/4 requiring transient transfusional support, and 1 patient had PLT decrease to < 50 × 109/l. One patient resistant to treatment died from broncopneumonia and 1 patient with normal PLT values died from cerebral hemorrhage; two patients had a grade 3 – 4 gastro-intestinal hemorrhage. Interestingly, only 2/24 patients (8.3%) had a BP evolution after 8 and 16 months from start of Melphalan, respectively. After a median number of treatment cycles of 18 (range 2 – 68), 12 patients are still in therapy and 12 discontinued Melphalan due to toxicity (4), resistance (3), relapse (3) or evolution to BP (2). In conclusion, the intermittent cyclic schedule of oral Melphalan seems capable to maintain a good response rate with reduction of symptomatic spleen enlargement in more than 50% of patients without excessive toxicity and with a lower rate of BP evolution, as compared to continuous Melphalan administration.

Disclosures

No relevant conflicts of interest to declare.
A Case of Massive Intracerebral Haemorrage in Advanced Myelofibrosis Due to Atypical Metaplasia.
Authors: Caramella Marianna , Gabutti Cristina , Del Curto Cecilia , Campidelli Cristina , Nador Guido , Pungolino Ester , Morra Enrica
Published: October 2019

Abstract 4988

BACKGROUND

Primary myelofibrosis is a chronic myeloproliferative disease characterized by connective tissue deposition in the bone marrow and extramedullary hematopoiesis commonly involving the liver and the spleen.

CASE REPORT

We report the case of a 60 year old patient with advanced Post Thrombocitemia Myelofibrosis extensively localized in almost all organs. He was referred to our Center in April 2008; clinical, radiological and haematological features suggested an evolution into Myelofibrosis. Molecular analysis for V617F JAK2 mutation was negative. Hemogram showed leukocytosis, mild anemia and normal platelet count. After few months of treatment with Danazol and Thioguanine, he was admitted for hemodynamic failure; echocardiography and chest X-ray were normal; abdomen CT scan confirmed important splenomegaly and didn't show any deep thrombosis. During hospitalization he developed massive intracerebral haemorrhage, cause of death. Post mortem histopatological examination documented osteomyelosclerosis and wide localization of extramedullary hematopoiesis. Morphological examination of the specimens showed an extensive dissemination of megakaryocytes, erythroid and myeloid precursors immunoreactive with factorVIII, hemoglobin, and myeloperoxidase respectively. We documented intravascular involvement of spleen, liver, lymph nodes, lungs, adrenal glands, myocardium, and central nervous system. Noteworthy fibrosis associated with haematopoietic cells were broadly distributed into retroperitoneal tissue.

CONCLUSIONS

Despite the massive myeloid metaplasia shown by the autopsy, general conditions of the patient until hospitalisation were good. Physical and radiological examination didn't reveal vascular and organ involvement. Although myeloid metaplasia is a possibility in advanced myelofibrosis, the assessment of cerebral and myocardial localization is difficult to find and standard radiological exams are not useful. In the subset of patients with Myelofibrosis and unexplained organ failure it could be interesting to look for an intravascular metaplasia throughout a multi-step approach: i) CD34+ peripheral cells count, since a very high count of these cells could suggest an extensive metaplasia; ii) high resolution pulmonary CT scan; iii) perfusional myocardial and/or pulmonary scintigraphy.

Disclosures

No relevant conflicts of interest to declare.
The Analysis of JAK2 and MPL Mutation as Well as JAK2 SNPs in MPN Patients by MassARRAY Assay.
Authors: Zhang Su-Jiang , Qiu Hongxia , Li Jianyong
Published: October 2019

Abstract 4989

Introduction

Recent studies have shown that JAK2 V617F, MPL W515L/K and JAK2 exon 12 mutations underlie the major molecular pathogenesis of myeloproliferative disorders (MPN).

Methods

To ascertain the real prevalence of these mutations and the influence of genetic susceptibility in Chinese MPN patients, we applied Allele-Specific Polymerase Chain Reaction (AS-PCR), directly sequencing and MassARRAY assay into our study.

Results

The positive rate of JAK2 V617F in polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) was 82.0%, 36.6% and 51.1% individually. We also found one ET patient, two PMF patients harboring MPL W515L mutation, and three PV patients harboring JAK2 exon 12 mutations. All of these patients were confirmed as JAK2 V617F negative. Moreover, clinical data demonstrated that PV patients with JAK2 exon 12 mutations had higher hemoglobin and lower age as well as WBC than PV patients with JAK2 V617F. In addition, through analysis of 4 polymorphic loci of JAK2 gene, no significant difference of distribution frequency was found among PV, ET and PMF patients. Distribution frequency of haplotype was not found to have significant difference among PV, ET and PMF patients either.

Conclusion

We conclude that JAK2 V617F is major molecular pathogenesis in Chinese MPN patients. MPL W515L mutation and JAK2 exon 12 mutations can also be found in JAK2 V617F negative MPN patients.

Disclosures

No relevant conflicts of interest to declare.
The Decrease of JAK2 V617F Allele Burden in Leukemia Transformation of An Elderly Patient with Myelofibrosis.
Authors: Zhang Su-Jiang , Li Jianyong , Xu Wei
Published: October 2019

Abstract 4990

Recently there were two different model about clone genesis of acute myeloid leukemia (AML) transformed from pre-existing JAK2 V617F positive myeloproliferative neoplasm (MPN). One model showed the leukemia cells were come from JAK2 V617F negative clone, however, the other indicated that the leukemia cells were still developed from JAK2 V617F positive clone. Here, we report a elderly AML patient who was developed from pre-existing myelofibrosis (MF) with homozygous JAK2 V617F mutation. In leuekmic transformation phase, heterozygous JAK2 V617F mutation was identified, supported the idea that the leukemia cells may be come from JAK2 V617F negative clone. Moreover, no other cytogenetic and molecular genetic abnormalities were further found. After one course of CAG regimen, complete remission was achieved. Further follow-up is still in progress.

Disclosures

No relevant conflicts of interest to declare.
FCγRIIa Polymorphism Is Not Associated with Overall Response in Diffuse Large B-Cell Lymphoma Treated with Rituximab.
Authors: Levy Debora , Oliveira-Souza, Pamela , Bellesso Marcelo , Maciel Felipe Vieira Rodrigues , Pereira Juliana , Bydlowski Sergio Paulo
Published: October 2019

Abstract 4994

Background

Low-affinity receptor for the Fc region of immunoglobulin G (IgG) (FcγR) is constitutively expressed on resting human neutrophils. These receptor, termed FcγRIIa display biallelic polymorphism which have functional consequences with respect to binding and/or ingestion of targets opsonized by human IgG subclass antibodies. Rituximab is a chimeric monoclonal antibody directed against CD20, an antigen found in most B-cell malignancies. Multiple mechanisms have been proposed for the activity of Rituximab, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and a direct proapoptotic effect. F(ab')2 Rituximab homodimers were shown to be effective in inducing apoptosis of B-cell lymphoma cell lines in vitro. Recently, it have been established that ADCC is important as predominant mechanism of lymphoma cell clearance and that Fcγ receptors (FcγRs) are critical for the in vivo actions of Rituximab in non-Hodgkin lymphoma (NHL). A genomic polymorphism at amino acid 131 of FcγRIIA has been described whereby the presence of Histidine (H) rather than Arginine is associated with responses to the CD20-directed immunoglobulin G1 (IgG1) Rituximab among patients with indolent lymphoma. FcγRIIA genotype have been associated with a better clinical and molecular response in follicular lymphoma patients treated as first line therapy with Rituximab alone and in patients with diffuse large B-cell lymphoma (DLBCL) treated with the concomitant administration of Rituximab and CHOP (R-CHOP).

Methods

Here we analyzed the role of specific polymorphism of activating FcγRIIA in 42 patients with DLBCL treated with R-CHOP concerning prediction complete response (CR) using a polymerase chain reaction-restriction fragment length polymorphism method.

Results

The median age of the patients was 48 years (15 to 82). Out of the 42 patients 18 (42.8%) were stage III-IV and 17 (40.4%) had more than 2 factors of the International Prognostic Index. Thirty-seven (87.6%) had CR, 1 (2.3%) had partial remission (PR) and 4 (10.1%) had refractory disease (RD). Four ( 10.8%) of the patients that acquired CR relapsed. Deaths occurred in 3 (7.1%) patients with follow up of 2 years. Eight (19%) patients showed polymorphism HH, 21 (50%) HR and 13 (31%) RR. The univariate analysis did not show correlation between FcγRIIa H/H or R allele polymorphism and CR (p > 0.05).

Conclusion

Contrary to recent report we showed that FcγRIIa polymorphism is not associated to overall response in patients with DLBCL treated with Rituximab.

Disclosures

No relevant conflicts of interest to declare.
Plasmablastic Lymphoma – A Single Institution Experience.
Authors: Mohamed Zainab , Novitzky Nicolas , McDonald Andrew
Published: October 2019

Abstract 5003

Introduction

Plasmablastic lymphoma (PL) is a rare subtype of B-cell Non Hodgkin lymphoma that often involves the oral cavity of HIV-positive individuals but according to the WHO classification may occur in other sites.

Patients and Methods

A retrospective review of the charts of 25 HIV+ patients with PL who were seen from 2004 until 2008 was undertaken. Prognostic factors for outcome were determined by non parametric statistics. Survival was determined by the Kaplan and Meier method.

Results

Data from 12 male and 13 female patients with a median age of 35 years (30-57) were reviewed. Patients were mostly Ann Arbor stage 1 (44%) or stage 4 (40%). 92% of patients had extranodal involvement. The commonest extranodal site was the oral cavity, nasopharynx or maxillary sinus (32%), followed by bone (28%). Overall 76% presented with malignant lesions outside the oral cavity. At presentation median ECOG performance status and IPI was 1. Median LDH was 708 IU (310-17010). Median CD4 count was 63 ×106 /l (23-368). HIV infection was detected in 32% of patients at the time of lymphoma diagnosis; 20% had been on antiretroviral (ARV) therapy in excess of 6 months prior to presentation and 52% had been treated or continued treatment for tuberculosis (TB). Patients not yet on ARV were commenced on this treatment together with chemotherapy. All received anthracycline-containing (CHOP) chemotherapy and 19 had 4 or more cycles, while 5 were lost to follow up. 14 patients (56%) received radiotherapy either as palliation (6 patients) or involved field radiotherapy after achieving CR (8 patients). At median overall survival of 267 (27-1246) days 48% have achieved CR and 10 patients (40%) survive disease free for longer than 1 year. More favourable outcome was associated with any radiotherapy (p=0.01) and involved field radiotherapy (p=0.016).

Conclusions

In South Africa PL is associated with late HIV infection and frequently presents outside the oropharynx. The management is complicated by comorbidities, mainly TB infection. However, PL is responsive to chemotherapy and particularly involved field radiotherapy, which in some patients is associated with improved response and long term survival.

Disclosures

No relevant conflicts of interest to declare.
Clinical Outcome and Survival of EBV-Positive Diffuse Large B-Cell Lymphoma.
Authors: Beltran Brady , Quinones Pilar , Morales Domingo , Capellino Alex , Miranda Roberto , Bueso-Ramos Carlos E. , Sotomayor Eduardo M. , Castillo Jorge
Published: October 2019

Abstract 5005

Background

EBV-positive diffuse large B-cell lymphoma (DLBCL) is a new entity included provisionally in the most recent WHO Classification of lymphoid neoplasms. It usually affects elderly patients and has a poor survival. The goal of this study was to evaluate clinical characteristics and survival of EBV-positive DLBCL.

Methods

Between January 2002 and June 2008, twenty patients with EBV-positive DLBCL were deemed eligible for the study. Of those, eighteen cases were evaluable. All cases were positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or Pax-5 expression by immunohistochemistry (IHC). Clinical data were reviewed retrospectively and patient's biopsies were analyzed for the expression of bcl-6, CD10, CD30 and MUM-1 by IHC. The survival estimates were calculated using the Kaplan-Meier method and the log-rank test was used to compare the survival curves.

Results

The mean age was 72.7 years (range 34-95 years). B symptoms occurred in 6 patients (33%). Four patients (22%) presented with stage I, 4 (22%) with stage II, 5 (28%) with stage III and five (28%) with stage IV. The IPI risk score was low in 6 patients (33%), low intermediate in 2 (11%), high intermediate in 6 (33%) and high in 4 (22%). Extranodal disease occurred in 10 patients (55%); the most common extranodal sites were gastrointestinal tract (n=5), lung (n=3), suprarenal gland (n=1), bone (n=1), skin (n=1), tonsils (n=1) and bone marrow (n=1). Of 13 evaluated cases, eleven cases (83%) were of non-germinal center and 2 cases (17%) were of germinal center subtype. According to the Oyama score, 3 cases (17%) had 0 risk factors, 11 patients (61%) had 1 risk factor and 4 (22%) had 2 risk factors with median survival of 41, 11 and 1.5 months, respectively. Eight patients (44%) did not receive chemotherapy because they had a poor performance status. Ten patients (56%) received chemotherapy, eight received CHOP and two received R-CHOP. Overall response was 70% with a complete response in 7 cases and progressive disease in 3. No patients exhibited a partial response. Median survival for the entire group was 10 months; the median survival for the treated group was 17 months while for the untreated group was 2.5 months. The 2 patients treated with R-CHOP obtained a complete response.

Conclusions

EBV-positive DLBCL is an aggressive entity with frequent extranodal disease and a poor prognosis. The latter appears to be due to high IPI scores, non-germinal center immunophenotype and/or the presence of EBV. Although, EBV-positive DLBCL seems to respond well to R-CHOP, the survival remains dismal. Prospective studies are needed to validate EBV's prognostic, predictive and therapeutic value in DLBCL in the post-rituximab era.

Disclosures

No relevant conflicts of interest to declare.
Alcohol Drinking, Smoking, Past History of Gastroduodenal Ulcer, Height, and Risk of API2-MALT1 Fusion Positive and Negative Gastric MALT Lymphoma Among Japanese.
Authors: Kawase Takakazu , Matsuo Keitaro , Nakamura Tsuneya , Kanda Junya , Ito Hidemi , Hosono Satoyo , Watanabe Miki , Yatabe Yasushi , Morishima Yasuo , Tajima Kazuo , Seto Masao , Nakamura Shigeo , Tanaka Hideo
Published: October 2019

Abstract 5010

Extranodal marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue (MALT Lymphoma) is low-grade extranodal lymphoma, and it comprises 7-8% of all B cell lymphomas, and up to 50% of primary gastric lymphoma. It is known that a preexisting chronic inflammation such as Helicobactoer pylori (H. pylori) gastritis can influence its development, however, some MALT lymphomas with no evidence of such inflammation are found. Protracted remissions may be induced by H. pylori eradication therapy, but cases with t(11;18)(q21;q21) appear to be resistant to the therapy. t(11;18)(q21;q21) has been observed in 25-50% of the cases and API2 at 11q21 and MALT1 at 18q21 are fused as a result of this translocation. Thus, API2-MALT1 fusion positive and negative MALT lymphoma may have different etiology, although histological features of both MALT lymphomas have not been clearly delineated. To clarify differences of epidemiological features between API2-MALT1 fusion positive and negative gastric MALT lymphoma, we conducted a case-control study of 61 newly and histologically diagnosed gastric MALT lymphoma cases (14 of API2-MALT1 fusion positive cases and 47 of negative cases) and 610 age and sex frequency-matched non-cancer controls. API2-MALT1 fusion was evaluated by a multiplex reverse transcription-polymerase chain reaction using formalin-fixed, paraffinembedded sections. We evaluated the association with alcohol intake (never drinkers, occasional drinkers, and frequent but moderate (<50 g/day of alcohol) and frequent and heavy drinkers (≥50 g/day of alcohol)), smoking (<5, 5-19, 20-39, ≥40 pack-years), past history of gastroduodenal ulcer, height, and risk of API2-MALT1 fusion positive and negative gastric MALT lymphoma. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using multinomial logistic models adjusted for potential confounders. A significant association was observed between past history of gastroduodenal ulcer and the risk only among fusion negative cases, with ORs of subjects with past history of gastroduodenal ulcer of 2.86 (95% CI, 1.31-6.14; p = 0.008) compared to subjects without past history of gastroduodenal ulcer. No clear associations were observed between alcohol intake, smoking, height and the risk irrespective of positivity of API2-MALT1 fusion. These findings suggest that past history of gastroduodenal ulcer, which may be due to H.pylori infection, does not associated with the carcinogenic mechanism of API2-MALT1 fusion positive gastric MALT lymphoma, and fusion positive and negative tumors have different etiology. Further investigations using large data sets are needed.

Disclosures

No relevant conflicts of interest to declare.
The Utility of Positron Emission Tomography (PET) with 18Fluorodeoxyglucose (18F-FDG) Compared to Standard Procedures in Detecting Bone Marrow Infiltration in Diffuse Large B-Cell Lymphoma in Developing Countries.
Authors: Bellesso Marcelo , Costa Renata Oliveira , Xavier Flavia Dias , Meneguetti José Claudio , Maciel Felipe Vieira Rodrigues , Steinbaun Daniel Salas , Hallack-Neto Abrahao Elias , Chamone Dalton Alencar Fisher , Pereira Juliana
Published: October 2019

Abstract 5015

Background

Computed tomography (CT) scanning and bone marrow biopsy (BMB) are the most used methods for initial staging in Diffuse Large B-cell Lymphoma (DLBCL) in developing countries. In the United States and Europe, 18-FDG PET has demonstrated to be an essential imaging modality for initial staging, early response and final therapeutic assessment in DLBCL patients. Afterward BM biopsy (BMB) is the gold standard to detect BM infiltration in lymphoma. However the ability of the FDG-PET to assess bone marrow (BM) positivity in DLBCL has been investigated and remains a controversial issue in the literature. For that reason we retrospectively compared the BM infiltration by bilateral BMB with FDG-PET at diagnosis in DLBCL patients.

Methods

We evaluated retrospectively 38 patients with DLBCL reporting the number of true-positive, false-positive, true-negative, and false-negative BM positivity by FDG-PET having the bilateral BMB as a reference standard.

Results

Out of 38, BM(+) was detected in 4 (10.5%) patients by BMB and in 14 (36.8%) patients by FDG-PET. The sensitivity and specificity of FDG-PET to recognize BM infiltration were respectively 100% and 71%. Negative and positive predictive values of the FDG-PET to identify BM(+) were respectively 100% and 28.5%. In negative-BMB patients, a positive FDG-PET BM was found in iliac 1 (10%), vertebra 5 (50%), sternum 2 (20%), scapula 1 (10%) and femur 1 (10%). The 18FDG mean maximum standardized uptake value (SUVmax) was 6.85 ± 3.9 in negative-BMB group and 9.77 ± 3.2 in positive-BMB group, p=0,208.

Conclusion

These results suggest that FDG-PET has a good sensitivity in detecting bone marrow infiltration in this type of aggressive lymphoma when compared to bilateral BMB to our knowledge the standard procedure to evaluate BM infiltration in lymphoma staging. Even though this study has several limitations such as one single center experience, a small number of patients and the lack of FDG-PET BM(+) confirmation by guided biopsy in previously negative-BMB patients, the majority of publications have been made in developed countries, and moreover we believe many issues still remain to be answered such as data regarding the FDG-PET cost-effectiveness out of clinical trails, specially in developing countries, in order to elucidate whether these results will be translated into a real benefit in overall survival for these patients.

Disclosures

No relevant conflicts of interest to declare.
Relapsed Marginal Zone B-Cell Lymphoma: Clinical Features and Treatment Outcome.
Authors: Oh Sung Yong , Kim Won Seog , Kim Seok Jin , Kim Jin Seok , Kim Sung Hyun , Lee Dae Ho , Won Jong Ho , Hwang In Gyu , Kim Min Kyoung , Lee Soon Il , Kim Jong Gwang , Yang Deok-Hwan , Kang Hye Jin , Choi Chul Won , Park Jinny , Choi Young Jin , Kim Hyo Jung , Kwon Jung Hye , Suh Cheolwon , Kim Hyo-Jin
Published: October 2019

Abstract 5017

Background

Marginal zone B-cell lymphoma (MZL) has an indolent clinical course and long survival. During its long survival duration, MZL has tendency to relapse frequently. But the natural history and an optimal treatment modality for relapsed MZL has yet to be well established. So we performed a retrospective analysis of identifying the clinical features and outcomes of relapsed MZL.

Methods

From 1994 to 2008, a total of 92 patients with relapsed MZL were analyzed retrospectively.

Results

The median age of our subjects was 53.5 years (range: 23-82 years). This study involved 51 males (55.4%) and 41 females (44.6%). The most common primary sites of involvement were orbit and ocular adnexa (28.3%) followed by lymph node and lymphatic organs (23.9%), and multiple MALT sites (13.0%). The median time to relapse from initial diagnosis was 25.5 months (range: 1.6- 137 months). Of the 53 patients with stage I or II at diagnosis, 42 patients (79.2%) had been shown the loco-regional recurrence. Among these loco-regional relapsed patients, 27 patients were achieved CR (54.1%) or PR (18.9%). The other 11 patients (20.8%) had advanced stage at recurrence.

Adding to 39 patients initially advanced stage III or IV, totally 50 patients were advanced stage at relapse. Of these patients with advanced stage at relapse, 44 patients had been treated. The overall response rate was 54.5% (24 patients), with 18 CRs and 6 PRs.

The median time to progression (TTP) was 34.1 months (95% CI: 11.3-56.9 months) and the estimated 5-year OS was 84.3%.

Conclusion

Loco-regional recurrence was more dominant than distant metastases in stage I or II MZL regardless of treatment modality. Even though patients had relapsed MZL after initial treatment, most of them were well controlled with salvage treatment and could achieve prolong survival.

Disclosures

No relevant conflicts of interest to declare.
Increased Ratios of Internal Organ Volume to Body Mass in Chuvash Polycythemia and HIF-2α Repression of p21Cip Expression through C-MYC.
Authors: Yoon Donghoon , Okhotin David , Kim Bumjun , Okhotina Yulia , Okhotin Daniel J , Miasnikova Galina Y , Sergueeva Adelina I , Polyakova Lydia A , Maslow Alexei , Lee Yonggu , Semenza Gregg L , Prchal Josef T. , Gordeuk Victor R.
Published: October 2019

Abstract 5039

Chuvash polycythemia, the first hereditary disease associated with dysregulated oxygen sensing, is characterized by homozygous germ-line loss-of-function mutation of VHL (598C>T) resulting in elevated hypoxia inducible factor (HIF)-1 and HIF-2 levels, increased red cell mass and propensity to thrombosis. Organ size is determined by the size and number of cells, and its molecular mechanisms are not fully elucidated. Previous work from several groups demonstrated that cell proliferation is regulated in opposite directions by HIF-1α and HIF-2α. HIF-1α inhibits cell proliferation by displacing C-MYC from the promoter of the cyclin-dependent kinase inhibitor, p21Cip, and inducing its expression, while HIF-2α promotes MYC activity and cell proliferation. We determined the volumes of the liver, spleen, and kidneys and the diameter of the head of the pancreas by computerized tomography in 30 individuals with Chuvash polycythemia and 30 age- and sex-matched Chuvash controls and calculated the ratio of organ volume (or diameter) to body mass. The subjects with Chuvash polycythemia had larger ratios of the liver (P<0.01), spleen (P<0.01), kidneys (P<0.05) and head of the pancreas (P=0.05) than Chuvash controls. To test if HIF contributes to this phenotype, we examined Hif1a+/− mice and wild type littermates. We found that Hif1a+/− mice had larger median ratios of liver to body mass (factor of 1.5, P<0.005) and pancreas to body mass (factor of 1.3, P<0.05) than wild type mice. A hepatocyte size analysis revealed that there was no significant difference between Hif1a+/− and wild type mice. To identify how HIF contributes this phenotype, we performed gene expression profiles in the livers of Hif1a+/− and wild type littermates. The profiling results and subsequent individual confirmation showed that compared to wild type mice, Hif1a+/− mice had 2-fold higher HIF-2α mRNA levels (P<0.05) and 9.5-fold lower hepatic p21Cip mRNA levels (P<0.05). Our results showed that relative to body mass, liver, spleen, kidney and pancreas volumes are increased in Chuvash polycythemia. At least in the liver, this phenotype may result from increased HIF-2α and decreased p21Cip1 levels, leading to increased hepatocyte proliferation.

Disclosures

No relevant conflicts of interest to declare.
EVI1 Is Activated During the Generation of Induced Pluripotent Stem (iPS) Cells.
Authors: Laricchia-Robbio Leopoldo , Montserrat Nuria , Giorgetti Alessandra , Belmonte Juan Carlos Izpisúa
Published: October 2019

Abstract 5048

EVI1 gene was first identified as a common site of retroviral integration in murine leukemia models. This gene is part of a complex genomic locus, MDS1-EVI1, that has been described as a target for retroviral integration that may lead to the emergence of a non-malignant dominant hematopoietic stem cell (HSC) clone in mice, in primates, and in humans. These studies suggested that one of the genes encoded by this locus could affect the self-renewal potential of HSC. Recent studies in mice revealed that indeed EVI1 plays an essential role in cell proliferation and it also enhances the self-renewal ability of HSC. The intense attention focused on the MDS1-EVI1 locus as retrovirus integration site prompted us to investigate whether EVI1 might have a role in somatic cell re-programming generated with retroviruses. Recent developments in stem cell research have enabled the re-programming of somatic cells to a pluripotent state using exogenous factors. Induced pluripotent stem (iPS) cells have the potential to differentiate into any cells types and that might be used in the future for clinical therapy. In order to elucidate the molecular events allowing the conversion of adult somatic into pluripotent stem cell, we evaluated EVI1 expression during this process. We found that EVI1 is activated in the early stages of re-programming and then it is silenced once the cells has been fully re-programmed. EVI1 seems to facilitate the initiation of cell re-programming by up-regulating a subset of genes previously described as potent stimulators of stem cells expansion.

Disclosures

No relevant conflicts of interest to declare.
The Effects of Site-Directed Mutation of SHIP Gene On the Regulating Mechanisms of PI3K/Akt Signal Pathway in Human Leukemia Cell Line K562.
Authors: Luo Jianmin , Yang Lin , Liu Xiaojun , Wen Shupeng , Zhang Jingyu
Published: October 2019

Abstract 5050

Introduction

SHIP is an SH2 domain containing inositol-5-phosphatasse that appears to be a negative regulator of hematopoiesis. Our previous researching works have first reported that SHIP gene was genetically altered in leukemia patients and proved that mutation of SHIP gene was closely correlated with the increased phosphorylation of Akt and poor prognosis of AML patients; SHIP gene is a key regulative gene in the PI3K/Akt pathway, and transfection with wild type SHIP gene into K562 cell line can inhibit the proliferation of K562. Up to now, however, there are no any reports about what changes of the PI3K/Akt signal transduction regulation will happened if SHIP has site mutation in leukemia cells. The objectives of our study is to investigate the effects of site-directed mutation of SHIP on the expression level of the protein related to the PI3K/Akt signal pathway in leukemia cells, and to study the effects of site-directed mutation of SHIP on the key PIP3 activity related to the PI3K/Akt signal pathway in leukemia cells.

Methods

Based on the results of our previous studies, the absence of endogenous SHIP in K562 cells provided a useful systerm to study the role of SHIP in growth and apoptosis. The recombined lentivirus plasmids wtSHIP or muSHIPP28L were transfected stably into human leukemia cells K562. The cell proliferation, cell life cycle and cell apoptosis of K562 transfected with wid-type SHIP or muSHIPP28L were determined by MTT, fluorescent staining and flow cytometry. The expression level and difference of total Akt□Ap-Akt473 and p-Akt308 were reconfirmed by SDS-PAGE western blot. PI(3,4,5)P3 and PI(3,4)P2 was assayed by High pressure liquid chromatography.

Results

The decreased ability of proliferation and DNA synthesis, cell colony fomation ability and enhanced apoptosis rate were observed in K562 cells transfected with wild-type SHIP (Group A), but the same changes had not been observed in K562 cells transfected with muSHIPP28L (Group B) or empty vector (Group C). Wild-type SHIP can down-regulate phosphorylations of Akt308 and Akt473, but muSHIPP28L can't. High pressure liquid chromatography results showed that the PI3,4,5-P3 level was obviously decreased in Group A,no changes above indicate in Group B and Group C. The PI3,4P2 level in Group A was significantly higher than Group B and Group C.

Conclusions

The results confirmed SHIP as a negative regulator for cell proliferation in leukemia cells, and implied that it may function through its normal structure.

Disclosures

No relevant conflicts of interest to declare.
Prevalence of FACTOR IX-R338L (FACTOR IX PADUA) IN A COHORT of PATIENTS with Venous Thromboembolism and Mild Elevation of FACTOR IX LEVELS.
Authors: de Moraes Mazetto Bruna , Orsi Fernanda A. , Siqueira Lúcia Helena , de Paula Erich Vinicius , Mello Tayana B , Annichino-Bizzacchi Joyce Maria
Published: October 2019

Abstract 5057

Introduction

Elevated plasma levels of blood coagulation factor IX (FIX) have been associated with increased risk of venous thromboembolism (VTE) in humans. However, the molecular mechanisms underlying elevated FIX have not been elucidated. Recently, a mutation in the FIX gene resulting in a FIX molecule with Arginine Leucine substitution at position 338 (FIX-R338L or Factor IX Padua) has been associated with very high levels of FIX (776%) in a patient with spontaneous VTE. Recombinant expression of FIX-R338L confirmed the gain-of-function mutation.

Objective

Here we evaluated the levels of FIX and the prevalence of Factor IX Padua in a cohort of patients with VTE followed at our center. The prevalence of FIX Padua was evaluated by using a PCR-RFLP strategy by which PCR with specific primers was followed by digestion with the enzyme TaqI.

Results

The prevalence of FIX Padua was evaluated in a population of 192 patients with spontaneous VTE (69 males and 123 females; median age 36-yo). A population of 192 healthy individuals matched for age, sex and ethnicity was used as a control group for the determination of FIX levels. Median FIX levels was 128.0% (61.0-207.0%) in patients with VTE. Twenty-nine patients presented FIX levels above the 90th percentile (160.2%). Factor IX Padua was not identified in any patients or controls, even in those with elevated FIX levels.

Conclusion

in the present study FIX Padua was not identified in any of our patients, indicating that this mutation is not associated with mild elevations of FIX levels frequently observed in patients with VTE.

Disclosures

No relevant conflicts of interest to declare.
Heparin-Induced Thrombocytopenia: Comparison Between the Standard Gel-Particle Assay (PaGIA) and the Functional Flow Cytometric Assay.
Authors: Tomer Aaron
Published: October 2019

Abstract 5060

Background

Heparin-induced thrombocytopenia and thrombosis (HIT) is an immune-mediated complication that may develop in patients sensitized to heparin. Approximately 5% of patients treated with full dose heparin develop clinical HIT, with about half develop thrombosis that may be associated with severe morbidity and death. However, antibodies may be detected in up to 30% of patients. Thus, current antibody-detection methods carry certain limitations, which pose a serious clinical dilemma in the diagnosis and treatment of HIT.

Objectives

To compare the gel-particle immuno-assay (PaGIA) for the detection of antibodies against heparin-PF4 complex, with the functional flow cytometric assay (FCA) which determines the capacity of the patient's serum to activate platelets in the presence of heparin, similar in concept to the gold-standard, the radioactive Serotonin-release assay.

Methods

Sequential samples from patients clinically suspected for HIT were tested by both PaGIA and the FCA (Tomer 1997, 1999).

Results

118 samples were tested. Positive: 9 (7.6%) patients tested positive by PaGIA, compared to 19 (16.1%) by the FCA. 7,out of the 9 (77.8%) PaGIA -positive samples were also positive by the FCA (relative sensitivity). Negative: 97 out of 109 gel-negative samples (89.0%) were also negative by the FCA (relative specificity). Thrombosis occurred in 3 of the 9 PaGIA-positive (33%) patients, and in 7 of the 19 FCA-positive (36.8%) patients. Of the 12 PaGIA -negative but FCA-positive patients, 4 (33%) had thrombosis. Death rate was also higher among FCA-positive (n=3) compared to PaGIA-positive (n=1) patients. Of the two PaGIA -positive but FCA-negative patients, one had APLA syndrome (APS) with chronic thrombocytopenia, and one had sepsis with cardiogenic shock and multiorgan failure.

ROC-Plot: Overall, the FCA showed significantly higher correlation with the clinical presentation of HIT (4Ts score), compared to the PaGIA (AUC 0.86 vs. 0.62, p<0.001)

Conclusion

The functional FCA demonstrates superior sensitivity and specificity compared to the antibody- detection PaGIA gel-particle assay. The feasible functional FCA (results in 1.5 hr) might be useful for initial diagnosis of HIT, and particularly for confirmation of HIT in patients with confounding presentation, including negative antibody-detection assay.

Disclosures

No relevant conflicts of interest to declare.